Journal of Healthy

Giant Osteoclast Formation and Long-Term Oral Bisphosphonate Therapy

2009-01-31T01:35:00.000-08:00

Robert S. Weinstein, M.D., Paula K. Roberson, Ph.D., and Stavros C. Manolagas, M.D., Ph.D.

ABSTRACT

Background Bisphosphonates decrease bone resorption and arecommonly used to treat or prevent osteoporosis. However, theeffect of bisphosphonates on their target cells remains enigmatic,since in patients benefiting from therapy, little change, ifany, has been observed in the number of osteoclasts, which arethe cells responsible for bone resorption.

Methods We examined 51 bone-biopsy specimens obtained aftera 3-year, double-blind, randomized, placebo-controlled, dose-rangingtrial of oral alendronate to prevent bone resorption among healthypostmenopausal women 40 through 59 years of age. The patientswere assigned to one of five groups: those receiving placebofor 3 years; alendronate at a dose of 1, 5, or 10 mg per dayfor 3 years; or alendronate at a dose of 20 mg per day for 2years, followed by placebo for 1 year. Formalin-fixed, undecalcifiedplanar sections were assessed by bone histomorphometric methods.

Results The number of osteoclasts was increased by a factorof 2.6 in patients receiving 10 mg of alendronate per day for3 years as compared with the placebo group (P<0.01).> the number of osteoclasts increased as the cumulative dose ofthe drug increased (r=0.50, P<0.001).> of these osteoclasts were giant cells with pyknotic nuclei thatwere adjacent to superficial resorption cavities. Furthermore,giant, hypernucleated, detached osteoclasts with 20 to 40 nucleiwere found after alendronate treatment had been discontinuedfor 1 year. Of these large cells, 20 to 37% were apoptotic,according to both their morphologic features and positive findingsfrom in situ end labeling.

Conclusions Long-term alendronate treatment is associated withan increase in the number of osteoclasts, which include distinctivegiant, hypernucleated, detached osteoclasts that are undergoingprotracted apoptosis.

Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke

2009-01-31T00:00:00.001-08:00

Ralph L. Sacco, M.D., Hans-Christoph Diener, M.D., Ph.D., Salim Yusuf, M.B., B.S., D.Phil., Daniel Cotton, M.S., Stephanie Ôunpuu, Ph.D., William A. Lawton, B.A., Yuko Palesch, Ph.D., Reneé H. Martin, Ph.D., Gregory W. Albers, M.D., Philip Bath, F.R.C.P., Natan Bornstein, M.D., Bernard P.L. Chan, M.D., Sien-Tsong Chen, M.D., Luis Cunha, M.D., Ph.D., Björn Dahlöf, M.D., Ph.D., Jacques De Keyser, M.D., Ph.D., Geoffrey A. Donnan, M.D., Conrado Estol, M.D., Ph.D., Philip Gorelick, M.D., Vivian Gu, M.D., Karin Hermansson, D.M.Sc., Lutz Hilbrich, M.D., Markku Kaste, M.D., Ph.D., Chuanzhen Lu, M.D., Thomas Machnig, M.D., Prem Pais, M.D., Robin Roberts, M.Tech., Veronika Skvortsova, M.D., Philip Teal, M.D., Danilo Toni, M.D., Cam VanderMaelen, Ph.D., Thor Voigt, M.D., Michael Weber, M.D., Byung-Woo Yoon, M.D., Ph.D., for the PRoFESS Study Group

ABSTRACT

Background Recurrent stroke is a frequent, disabling event afterischemic stroke. This study compared the efficacy and safetyof two antiplatelet regimens — aspirin plus extended-releasedipyridamole (ASA–ERDP) versus clopidogrel.

Methods In this double-blind, 2-by-2 factorial trial, we randomlyassigned patients to receive 25 mg of aspirin plus 200 mg ofextended-release dipyridamole twice daily or to receive 75 mgof clopidogrel daily. The primary outcome was first recurrenceof stroke. The secondary outcome was a composite of stroke,myocardial infarction, or death from vascular causes. Sequentialstatistical testing of noninferiority (margin of 1.075), followedby superiority testing, was planned.

Results A total of 20,332 patients were followed for a meanof 2.5 years. Recurrent stroke occurred in 916 patients (9.0%)receiving ASA–ERDP and in 898 patients (8.8%) receivingclopidogrel (hazard ratio, 1.01; 95% confidence interval [CI],0.92 to 1.11). The secondary outcome occurred in 1333 patients(13.1%) in each group (hazard ratio for ASA–ERDP, 0.99;95% CI, 0.92 to 1.07). There were more major hemorrhagic eventsamong ASA–ERDP recipients (419 [4.1%]) than among clopidogrelrecipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to1.32), including intracranial hemorrhage (hazard ratio, 1.42;95% CI, 1.11 to 1.83). The net risk of recurrent stroke or majorhemorrhagic event was similar in the two groups (1194 ASA–ERDPrecipients [11.7%], vs. 1156 clopidogrel recipients [11.4%];hazard ratio, 1.03; 95% CI, 0.95 to 1.11).

Conclusions The trial did not meet the predefined criteria fornoninferiority but showed similar rates of recurrent strokewith ASA–ERDP and with clopidogrel. There is no evidencethat either of the two treatments was superior to the otherin the prevention of recurrent stroke. (ClinicalTrials.gov number,NCT00153062 [ClinicalTrials.gov] .)

Telmisartan to Prevent Recurrent Stroke and Cardiovascular Events

2009-01-30T23:58:00.001-08:00

Salim Yusuf, M.B., B.S., D.Phil., Hans-Christoph Diener, M.D., Ph.D., Ralph L. Sacco, M.D., Daniel Cotton, M.S., Stephanie Ôunpuu, Ph.D., William A. Lawton, B.A., Yuko Palesch, Ph.D., Reneé H. Martin, Ph.D., Gregory W. Albers, M.D., Philip Bath, F.R.C.P., Natan Bornstein, M.D., Bernard P.L. Chan, M.D., Sien-Tsong Chen, M.D., Luis Cunha, M.D., Ph.D., Björn Dahlöf, M.D., Ph.D., Jacques De Keyser, M.D., Ph.D., Geoffrey A. Donnan, M.D., Conrado Estol, M.D., Ph.D., Philip Gorelick, M.D., Vivian Gu, M.D., Karin Hermansson, D.M.Sc., Lutz Hilbrich, M.D., Markku Kaste, M.D., Ph.D., Chuanzhen Lu, M.D., Thomas Machnig, M.D., Prem Pais, M.D., Robin Roberts, M.Tech., Veronika Skvortsova, M.D., Philip Teal, M.D., Danilo Toni, M.D., Cam VanderMaelen, Ph.D., Thor Voigt, M.D., Michael Weber, M.D., Byung-Woo Yoon, M.D., Ph.D., for the PRoFESS Study Group

ABSTRACT

Background Prolonged lowering of blood pressure after a strokereduces the risk of recurrent stroke. In addition, inhibitionof the renin–angiotensin system in high-risk patientsreduces the rate of subsequent cardiovascular events, includingstroke. However, the effect of lowering of blood pressure witha renin–angiotensin system inhibitor soon after a strokehas not been clearly established. We evaluated the effects oftherapy with an angiotensin-receptor blocker, telmisartan, initiatedearly after a stroke.

Methods In a multicenter trial involving 20,332 patients whorecently had an ischemic stroke, we randomly assigned 10,146to receive telmisartan (80 mg daily) and 10,186 to receive placebo.The primary outcome was recurrent stroke. Secondary outcomeswere major cardiovascular events (death from cardiovascularcauses, recurrent stroke, myocardial infarction, or new or worseningheart failure) and new-onset diabetes.

Results The median interval from stroke to randomization was15 days. During a mean follow-up of 2.5 years, the mean bloodpressure was 3.8/2.0 mm Hg lower in the telmisartan group thanin the placebo group. A total of 880 patients (8.7%) in thetelmisartan group and 934 patients (9.2%) in the placebo grouphad a subsequent stroke (hazard ratio in the telmisartan group,0.95; 95% confidence interval [CI], 0.86 to 1.04; P=0.23). Majorcardiovascular events occurred in 1367 patients (13.5%) in thetelmisartan group and 1463 patients (14.4%) in the placebo group(hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P=0.11). New-onsetdiabetes occurred in 1.7% of the telmisartan group and 2.1%of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04;P=0.10).

Conclusions Therapy with telmisartan initiated soon after anischemic stroke and continued for 2.5 years did not significantlylower the rate of recurrent stroke, major cardiovascular events,or diabetes. (ClinicalTrials.gov number, NCT00153062 [ClinicalTrials.gov] .)

Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke

2009-01-30T23:57:00.000-08:00

Werner Hacke, M.D., Markku Kaste, M.D., Erich Bluhmki, Ph.D., Miroslav Brozman, M.D., Antoni Dávalos, M.D., Donata Guidetti, M.D., Vincent Larrue, M.D., Kennedy R. Lees, M.D., Zakaria Medeghri, M.D., Thomas Machnig, M.D., Dietmar Schneider, M.D., Rüdiger von Kummer, M.D., Nils Wahlgren, M.D., Danilo Toni, M.D., for the ECASS Investigators

ABSTRACT

Background Intravenous thrombolysis with alteplase is the onlyapproved treatment for acute ischemic stroke, but its efficacyand safety when administered more than 3 hours after the onsetof symptoms have not been established. We tested the efficacyand safety of alteplase administered between 3 and 4.5 hoursafter the onset of a stroke.

Methods After exclusion of patients with a brain hemorrhageor major infarction, as detected on a computed tomographic scan,we randomly assigned patients with acute ischemic stroke ina 1:1 double-blind fashion to receive treatment with intravenousalteplase (0.9 mg per kilogram of body weight) or placebo. Theprimary end point was disability at 90 days, dichotomized asa favorable outcome (a score of 0 or 1 on the modified Rankinscale, which has a range of 0 to 6, with 0 indicating no symptomsat all and 6 indicating death) or an unfavorable outcome (ascore of 2 to 6 on the modified Rankin scale). The secondaryend point was a global outcome analysis of four neurologic anddisability scores combined. Safety end points included death,symptomatic intracranial hemorrhage, and other serious adverseevents.

Results We enrolled a total of 821 patients in the study andrandomly assigned 418 to the alteplase group and 403 to theplacebo group. The median time for the administration of alteplasewas 3 hours 59 minutes. More patients had a favorable outcomewith alteplase than with placebo (52.4% vs. 45.2%; odds ratio,1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). Inthe global analysis, the outcome was also improved with alteplaseas compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to1.65; P<0.05).> higher with alteplase than with placebo (for any intracranialhemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranialhemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differsignificantly between the alteplase and placebo groups (7.7%and 8.4%, respectively; P=0.68). There was no significant differencein the rate of other serious adverse events.

Conclusions As compared with placebo, intravenous alteplaseadministered between 3 and 4.5 hours after the onset of symptomssignificantly improved clinical outcomes in patients with acuteischemic stroke; alteplase was more frequently associated withsymptomatic intracranial hemorrhage. (ClinicalTrials.gov number,NCT00153036 [ClinicalTrials.gov] .)

Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein

2009-01-30T23:56:00.000-08:00

Paul M Ridker, M.D., Eleanor Danielson, M.I.A., Francisco A.H. Fonseca, M.D., Jacques Genest, M.D., Antonio M. Gotto, Jr., M.D., John J.P. Kastelein, M.D., Wolfgang Koenig, M.D., Peter Libby, M.D., Alberto J. Lorenzatti, M.D., Jean G. MacFadyen, B.A., Børge G. Nordestgaard, M.D., James Shepherd, M.D., James T. Willerson, M.D., Robert J. Glynn, Sc.D., for the JUPITER Study Group

ABSTRACT

Background Increased levels of the inflammatory biomarker high-sensitivityC-reactive protein predict cardiovascular events. Since statinslower levels of high-sensitivity C-reactive protein as wellas cholesterol, we hypothesized that people with elevated high-sensitivityC-reactive protein levels but without hyperlipidemia might benefitfrom statin treatment.

Methods We randomly assigned 17,802 apparently healthy men andwomen with low-density lipoprotein (LDL) cholesterol levelsof less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivityC-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin,20 mg daily, or placebo and followed them for the occurrenceof the combined primary end point of myocardial infarction,stroke, arterial revascularization, hospitalization for unstableangina, or death from cardiovascular causes.

Results The trial was stopped after a median follow-up of 1.9years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levelsby 50% and high-sensitivity C-reactive protein levels by 37%.The rates of the primary end point were 0.77 and 1.36 per 100person-years of follow-up in the rosuvastatin and placebo groups,respectively (hazard ratio for rosuvastatin, 0.56; 95% confidenceinterval [CI], 0.46 to 0.69; P<0.00001),> rates of 0.17 and 0.37 for myocardial infarction (hazard ratio,0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke(hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and0.77 for revascularization or unstable angina (hazard ratio,0.53; 95% CI, 0.40 to 0.70; P<0.00001),> the combined end point of myocardial infarction, stroke, ordeath from cardiovascular causes (hazard ratio, 0.53; 95% CI,0.40 to 0.69; P<0.00001),> any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02).Consistent effects were observed in all subgroups evaluated.The rosuvastatin group did not have a significant increase inmyopathy or cancer but did have a higher incidence of physician-reporteddiabetes.

Conclusions In this trial of apparently healthy persons withouthyperlipidemia but with elevated high-sensitivity C-reactiveprotein levels, rosuvastatin significantly reduced the incidenceof major cardiovascular events. (ClinicalTrials.gov number,NCT00239681 [ClinicalTrials.gov] .)

Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson's Disease

2009-01-30T19:50:00.000-08:00

Renzo Zanettini, M.D., Angelo Antonini, M.D., Gemma Gatto, M.D., Rosa Gentile, M.D., Silvana Tesei, M.D., and Gianni Pezzoli, M.D.

ABSTRACT

Background Ergot-derived dopamine receptor agonists, often usedin the treatment of Parkinson's disease, have been associatedwith an increased risk of valvular heart disease.

Methods We performed an echocardiographic prevalence study in155 patients taking dopamine agonists for Parkinson's disease(pergolide, 64 patients; cabergoline, 49; and non–ergot-deriveddopamine agonists, 42) and 90 control subjects. Valve regurgitationwas assessed according to American Society of Echocardiographyrecommendations. The mitral-valve tenting area was also measuredand used as a quantitative index for leaflet stiffening andapical displacement of leaflet coaptation.

Results Clinically important regurgitation (moderate to severe,grade 3 to 4) in any valve was found with significantly greaterfrequency in patients taking pergolide (23.4%) or cabergoline(28.6%) but not in patients taking non–ergot-derived dopamineagonists (0%), as compared with control subjects (5.6%). Therelative risk for moderate or severe valve regurgitation inthe pergolide group was 6.3 for mitral regurgitation (P=0.008),4.2 for aortic regurgitation (P=0.01), and 5.6 for tricuspidregurgitation (P=0.16); corresponding relative risks in thecabergoline group were 4.6 (P=0.09), 7.3 (P<0.001),> (P=0.12). The mean mitral tenting area was significantly greaterin ergot-treated patients and showed a linear relationship withthe severity of mitral regurgitation. Patients treated withergot derivatives who had grade 3 to 4 regurgitation of anyvalve had received a significantly higher mean cumulative doseof pergolide or cabergoline than had patients with lower grades.

Conclusions The frequency of clinically important valve regurgitationwas significantly increased in patients taking pergolide orcabergoline, but not in patients taking non–ergot-deriveddopamine agonists, as compared with control subjects. Thesefindings should be considered in evaluating the risk–benefitratio of treatment with ergot derivatives.

Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation

2009-01-30T19:42:00.000-08:00

René Schade, M.D., Frank Andersohn, M.D., Samy Suissa, Ph.D., Wilhelm Haverkamp, M.D., Ph.D., and Edeltraut Garbe, M.D., Ph.D

ABSTRACT

Background Case reports and echocardiographic studies suggestthat the ergot-derived dopamine agonists pergolide and cabergoline,used in the treatment of Parkinson's disease and the restlesslegs syndrome, may increase the risk of cardiac-valve regurgitation.

Methods We used data from the United Kingdom General PracticeResearch Database to identify a population-based cohort comprising11,417 subjects 40 to 80 years of age who were prescribed antiparkinsoniandrugs between 1988 and 2005. We conducted a nested case–controlanalysis within this cohort in which each patient with newlydiagnosed cardiac-valve regurgitation was matched with up to25 control subjects from the cohort, according to age, sex,and year of entry into the cohort. Incidence-rate ratios forcardiac-valve regurgitation with the use of different dopamineagonists were estimated by conditional logistic-regression analysis.

Results Of 31 case patients with newly diagnosed cardiac-valveregurgitation, 6 were currently exposed to pergolide, 6 werecurrently exposed to cabergoline, and 19 had not been exposedto any dopamine agonist within the previous year. The rate ofcardiac-valve regurgitation was increased with current use ofpergolide (incidence-rate ratio, 7.1; 95% confidence interval[CI], 2.3 to 22.3) and cabergoline (incidence-rate ratio, 4.9;95% CI, 1.5 to 15.6), but not with current use of other dopamineagonists.

Conclusions In this study, use of the dopamine agonists pergolideand cabergoline was associated with an increased risk of newlydiagnosed cardiac-valve regurgitation.

Stimulatory Autoantibodies to the PDGF Receptor in Systemic Sclerosis

2009-01-30T19:41:00.000-08:00

Silvia Svegliati Baroni, Ph.D., Mariarosaria Santillo, Ph.D., Federica Bevilacqua, M.D., Michele Luchetti, M.D., Tatiana Spadoni, B.Sc., Matteo Mancini, B.Sc., Paolo Fraticelli, M.D., Paola Sambo, M.D., Ada Funaro, Ph.D., Andrius Kazlauskas, Ph.D., Enrico V. Avvedimento, M.D., Ph.D., and Armando Gabrielli, M.D.

ABSTRACT

Background Systemic sclerosis (scleroderma) is characterizedby immunologic abnormalities, injury of endothelial cells, andtissue fibrosis. Abnormal oxidative stress has been documentedin scleroderma and linked to fibroblast activation. Since platelet-derivedgrowth factor (PDGF) stimulates the production of reactive oxygenspecies (ROS) and since IgG from patients with scleroderma reactswith human fibroblasts, we tested the hypothesis that patientswith scleroderma have serum autoantibodies that stimulate thePDGF receptor (PDGFR), activating collagen-gene expression.

Methods We analyzed serum from 46 patients with sclerodermaand 75 controls, including patients with other autoimmune diseases,for stimulatory autoantibodies to PDGFR by measuring the productionof ROS produced by the incubation of purified IgG with mouse-embryofibroblasts carrying inactive copies of PDGFR or chains orthe same cells expressing PDGFR or . Generation of ROS wasassayed with and without specific PDGFR inhibitors. Antibodieswere characterized by immunoprecipitation, immunoblotting, andabsorption experiments.

Results Stimulatory antibodies to the PDGFR were found in allthe patients with scleroderma. The antibodies recognized nativePDGFR, inducing tyrosine phosphorylation and ROS accumulation.Autoantibody activity was abolished by preincubation with cellsexpressing the PDGFR chain or with recombinant PDGFR or byPDGFR tyrosine kinase inhibitors. Stimulatory PDGFR antibodiesselectively induced the Ha-Ras-ERK1/2 and ROS cascades and stimulatedtype I collagen–gene expression and myofibroblast phenotypeconversion in normal human primary fibroblasts.

Conclusions Stimulatory autoantibodies against PDGFR appearto be a specific hallmark of scleroderma. Their biologic activityon fibroblasts strongly suggests that they have a causal rolein the pathogenesis of the disease.

Prophylaxis versus Episodic Treatment to Prevent Joint Disease in Boys with Severe Hemophilia

2009-01-30T19:40:00.000-08:00

Marilyn J. Manco-Johnson, M.D., Thomas C. Abshire, M.D., Amy D. Shapiro, M.D., Brenda Riske, M.S., M.B.A., M.P.A., Michele R. Hacker, Sc.D., Ray Kilcoyne, M.D., J. David Ingram, M.D., Michael L. Manco-Johnson, M.D., Sharon Funk, B.Sc., P.T., Linda Jacobson, B.S., Leonard A. Valentino, M.D., W. Keith Hoots, M.D., George R. Buchanan, M.D., Donna DiMichele, M.D., Michael Recht, M.D., Ph.D., Deborah Brown, M.D., Cindy Leissinger, M.D., Shirley Bleak, M.S.N., Alan Cohen, M.D., Prasad Mathew, M.D., Alison Matsunaga, M.D., Desiree Medeiros, M.D., Diane Nugent, M.D., Gregory A. Thomas, M.D., Alexis A. Thompson, M.D., Kevin McRedmond, M.D., J. Michael Soucie, Ph.D., Harlan Austin, Ph.D., and Bruce L. Evatt, M.D.

ABSTRACT

Background Effective ways to prevent arthropathy in severe hemophiliaare unknown.

Methods We randomly assigned young boys with severe hemophiliaA to regular infusions of recombinant factor VIII (prophylaxis)or to an enhanced episodic infusion schedule of at least threedoses totaling a minimum of 80 IU of factor VIII per kilogramof body weight at the time of a joint hemorrhage. The primaryoutcome was the incidence of bone or cartilage damage as detectedin index joints (ankles, knees, and elbows) by radiography ormagnetic resonance imaging (MRI).

Results Sixty-five boys younger than 30 months of age were randomlyassigned to prophylaxis (32 boys) or enhanced episodic therapy(33 boys). When the boys reached 6 years of age, 93% of thosein the prophylaxis group and 55% of those in the episodic-therapygroup were considered to have normal index-joint structure onMRI (P=0.006). The relative risk of MRI-detected joint damagewith episodic therapy as compared with prophylaxis was 6.1 (95%confidence interval, 1.5 to 24.4). The mean annual numbers ofjoint and total hemorrhages were higher at study exit in theepisodic-therapy group than in the prophylaxis group (P<0.001for both comparisons). High titers of inhibitors of factor VIIIdeveloped in two boys who received prophylaxis; three boys inthe episodic-therapy group had a life-threatening hemorrhage.Hospitalizations and infections associated with central-catheterplacement did not differ significantly between the two groups.

Conclusions Prophylaxis with recombinant factor VIII can preventjoint damage and decrease the frequency of joint and other hemorrhagesin young boys with severe hemophilia A. (ClinicalTrials.govnumber, NCT00207597 [ClinicalTrials.gov] .)

Surgical versus Nonsurgical Therapy for Lumbar Spinal Stenosis

2009-01-30T19:36:00.000-08:00

James N. Weinstein, D.O., M.S., Tor D. Tosteson, Sc.D., Jon D. Lurie, M.D., M.S., Anna N.A. Tosteson, Sc.D., Emily Blood, M.S., Brett Hanscom, M.S., Harry Herkowitz, M.D., Frank Cammisa, M.D., Todd Albert, M.D., Scott D. Boden, M.D., Alan Hilibrand, M.D., Harley Goldberg, D.O., Sigurd Berven, M.D., Howard An, M.D., for the SPORT Investigators

ABSTRACT

Background Surgery for spinal stenosis is widely performed,but its effectiveness as compared with nonsurgical treatmenthas not been shown in controlled trials.

Methods Surgical candidates with a history of at least 12 weeksof symptoms and spinal stenosis without spondylolisthesis (asconfirmed on imaging) were enrolled in either a randomized cohortor an observational cohort at 13 U.S. spine clinics. Treatmentwas decompressive surgery or usual nonsurgical care. The primaryoutcomes were measures of bodily pain and physical functionon the Medical Outcomes Study 36-item Short-Form General HealthSurvey (SF-36) and the modified Oswestry Disability Index at6 weeks, 3 months, 6 months, and 1 and 2 years.

Results A total of 289 patients were enrolled in the randomizedcohort, and 365 patients were enrolled in the observationalcohort. At 2 years, 67% of patients who were randomly assignedto surgery had undergone surgery, whereas 43% of those who wererandomly assigned to receive nonsurgical care had also undergonesurgery. Despite the high level of nonadherence, the intention-to-treatanalysis of the randomized cohort showed a significant treatmenteffect favoring surgery on the SF-36 scale for bodily pain,with a mean difference in change from baseline of 7.8 (95% confidenceinterval, 1.5 to 14.1); however, there was no significant differencein scores on physical function or on the Oswestry DisabilityIndex. The as-treated analysis, which combined both cohortsand was adjusted for potential confounders, showed a significantadvantage for surgery by 3 months for all primary outcomes;these changes remained significant at 2 years.

Conclusions In the combined as-treated analysis, patients whounderwent surgery showed significantly more improvement in allprimary outcomes than did patients who were treated nonsurgically.(ClinicalTrials.gov number, NCT00000411 [ClinicalTrials.gov] .)

Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer

2009-01-29T22:56:00.000-08:00

Anna Bill-Axelson, M.D., Lars Holmberg, M.D., Ph.D., Mirja Ruutu, M.D., Ph.D., Michael Häggman, M.D., Ph.D., Swen-Olof Andersson, M.D., Ph.D., Stefan Bratell, M.D., Ph.D., Anders Spångberg, M.D., Ph.D., Christer Busch, M.D., Ph.D., Stig Nordling, M.D., Ph.D., Hans Garmo, Ph.D., Juni Palmgren, Ph.D., Hans-Olov Adami, M.D., Ph.D., Bo Johan Norlén, M.D., Ph.D., Jan-Erik Johansson, M.D., Ph.D., for the Scandinavian Prostate Cancer Group Study No. 4

ABSTRACT

Background In 2002, we reported the initial results of a trialcomparing radical prostatectomy with watchful waiting in themanagement of early prostate cancer. After three more yearsof follow-up, we report estimated 10-year results.

Methods From October 1989 through February 1999, 695 men withearly prostate cancer (mean age, 64.7 years) were randomly assignedto radical prostatectomy (347 men) or watchful waiting (348men). The follow-up was complete through 2003, with blindedevaluation of the causes of death. The primary end point wasdeath due to prostate cancer; the secondary end points weredeath from any cause, metastasis, and local progression.

Results During a median of 8.2 years of follow-up, 83 men inthe surgery group and 106 men in the watchful-waiting groupdied (P=0.04). In 30 of the 347 men assigned to surgery (8.6percent) and 50 of the 348 men assigned to watchful waiting(14.4 percent), death was due to prostate cancer. The differencein the cumulative incidence of death due to prostate cancerincreased from 2.0 percentage points after 5 years to 5.3 percentagepoints after 10 years, for a relative risk of 0.56 (95 percentconfidence interval, 0.36 to 0.88; P=0.01 by Gray's test). Fordistant metastasis, the corresponding increase was from 1.7to 10.2 percentage points, for a relative risk in the surgerygroup of 0.60 (95 percent confidence interval, 0.42 to 0.86;P=0.004 by Gray's test), and for local progression, the increasewas from 19.1 to 25.1 percentage points, for a relative riskof 0.33 (95 percent confidence interval, 0.25 to 0.44; P<0.001by Gray's test).

Conclusions Radical prostatectomy reduces disease-specific mortality,overall mortality, and the risks of metastasis and local progression.The absolute reduction in the risk of death after 10 years issmall, but the reductions in the risks of metastasis and localtumor progression are substantial.

Saw Palmetto for Benign Prostatic Hyperplasia

2009-01-29T22:55:00.000-08:00

Stephen Bent, M.D., Christopher Kane, M.D., Katsuto Shinohara, M.D., John Neuhaus, Ph.D., Esther S. Hudes, Ph.D., M.P.H., Harley Goldberg, D.O., and Andrew L. Avins, M.D., M.P.H.

ABSTRACT

Background Saw palmetto is used by over 2 million men in theUnited States for the treatment of benign prostatic hyperplasiaand is commonly recommended as an alternative to drugs approvedby the Food and Drug Administration.

Methods In this double-blind trial, we randomly assigned 225men over the age of 49 years who had moderate-to-severe symptomsof benign prostatic hyperplasia to one year of treatment withsaw palmetto extract (160 mg twice a day) or placebo. The primaryoutcome measures were changes in the scores on the AmericanUrological Association Symptom Index (AUASI) and the maximalurinary flow rate. Secondary outcome measures included changesin prostate size, residual urinary volume after voiding, qualityof life, laboratory values, and the rate of reported adverseeffects.

Results There was no significant difference between the sawpalmetto and placebo groups in the change in AUASI scores (meandifference, 0.04 point; 95 percent confidence interval, –0.93to 1.01), maximal urinary flow rate (mean difference, 0.43 mlper minute; 95 percent confidence interval, –0.52 to 1.38),prostate size, residual volume after voiding, quality of life,or serum prostate-specific antigen levels during the one-yearstudy. The incidence of side effects was similar in the twogroups.

Conclusions In this study, saw palmetto did not improve symptomsor objective measures of benign prostatic hyperplasia. (ClinicalTrials.govnumber, NCT00037154 [ClinicalTrials.gov] .)

Cumulative Association of Five Genetic Variants with Prostate Cancer

2009-01-29T22:53:00.000-08:00

S. Lilly Zheng, M.D., Jielin Sun, Ph.D., Fredrik Wiklund, Ph.D., Shelly Smith, M.S., Pär Stattin, M.D., Ph.D., Ge Li, M.D., Hans-Olov Adami, M.D., Ph.D., Fang-Chi Hsu, Ph.D., Yi Zhu, B.S., Katarina Bälter, Ph.D., A. Karim Kader, M.D., Ph.D., Aubrey R. Turner, M.S., Wennuan Liu, Ph.D., Eugene R. Bleecker, M.D., Deborah A. Meyers, Ph.D., David Duggan, Ph.D., John D. Carpten, Ph.D., Bao-Li Chang, Ph.D., William B. Isaacs, Ph.D., Jianfeng Xu, M.D., D.P.H., and Henrik Grönberg, M.D., Ph.D.

ABSTRACT

Background Single-nucleotide polymorphisms (SNPs) in five chromosomalregions — three at 8q24 and one each at 17q12 and 17q24.3— have been associated with prostate cancer. Each SNPhas only a moderate association, but when SNPs are combined,the association may be stronger.

Methods We evaluated 16 SNPs from five chromosomal regions ina Swedish population (2893 subjects with prostate cancer and1781 control subjects) and assessed the individual and combinedassociation of the SNPs with prostate cancer.

Results Multiple SNPs in each of the five regions were associatedwith prostate cancer in single SNP analysis. When the most significantSNP from each of the five regions was selected and includedin a multivariate analysis, each SNP remained significant afteradjustment for other SNPs and family history. Together, thefive SNPs and family history were estimated to account for 46%of the cases of prostate cancer in the Swedish men we studied.The five SNPs plus family history had a cumulative associationwith prostate cancer (P for trend, 3.93x10^–28). In menwho had any five or more of these factors associated with prostatecancer, the odds ratio for prostate cancer was 9.46 (P=1.29x10^–8),as compared with men without any of the factors. The cumulativeeffect of these variants and family history was independentof serum levels of prostate-specific antigen at diagnosis.

Conclusions SNPs in five chromosomal regions plus a family historyof prostate cancer have a cumulative and significant associationwith prostate cancer.

Alfuzosin and Symptoms of Chronic Prostatitis–Chronic Pelvic Pain Syndrome

2009-01-29T22:29:00.000-08:00

J. Curtis Nickel, M.D., John N. Krieger, M.D., Mary McNaughton-Collins, M.D., Rodney U. Anderson, M.D., Michel Pontari, M.D., Daniel A. Shoskes, M.D., Mark S. Litwin, M.D., Richard B. Alexander, M.D., Paige C. White, M.D., Richard Berger, M.D., Robert Nadler, M.D., Michael O'Leary, M.D., Men Long Liong, M.D., Scott Zeitlin, M.D., Shannon Chuai, Ph.D., J. Richard Landis, Ph.D., John W. Kusek, Ph.D., Leroy M. Nyberg, M.D., Anthony J. Schaeffer, M.D., for the Chronic Prostatitis Collaborative Research Network

ABSTRACT

Background In men with chronic prostatitis–chronic pelvicpain syndrome, treatment with alpha-adrenergic receptor blockersearly in the course of the disorder has been reported to beeffective in some, but not all, relatively small randomizedtrials.

Methods We conducted a multicenter, randomized, double-blind,placebo-controlled trial to evaluate the efficacy of alfuzosin,an alpha-adrenergic receptor blocker, in reducing symptoms inmen with chronic prostatitis–chronic pelvic pain syndrome.Participation in the study required diagnosis of the conditionwithin the preceding 2 years and no previous treatment withan alpha-adrenergic receptor blocker. Men were randomly assignedto treatment for 12 weeks with either 10 mg of alfuzosin perday or placebo. The primary outcome was a reduction of at least4 points (from baseline to 12 weeks) in the score on the NationalInstitutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI)(range, 0 to 43; higher scores indicate more severe symptoms).A 4-point decrease is the minimal clinically significant differencein the score.

Results A total of 272 eligible participants underwent randomization,and in both study groups, 49.3% of participants had a decreaseof at least 4 points in their total NIH-CPSI score (rate differenceassociated with alfuzosin, 0.1%; 95% confidence interval, –11.2to 11.0; P=0.99). In addition, a global response assessmentshowed similar response rates at 12 weeks: 33.6% in the placebogroup and 34.8% in the alfuzosin group (P=0.90). The rates ofadverse events in the two groups were also similar.

Conclusions Our findings do not support the use of alfuzosinto reduce the symptoms of chronic prostatitis–chronicpelvic pain syndrome in men who have not received prior treatmentwith an alpha-blocker. (ClinicalTrials.gov number, NCT00103402 [ClinicalTrials.gov] .)

Modulation of Blood Pressure by Central Melanocortinergic Pathways

2009-01-29T22:21:00.000-08:00

Jerry R. Greenfield, M.D., Ph.D., Jeffrey W. Miller, M.D., Julia M. Keogh, B.Sc., Elana Henning, B.Soc.Sc., Julie H. Satterwhite, Ph.D., Gregory S. Cameron, Ph.D., Beatrice Astruc, M.D., John P. Mayer, Ph.D., Soren Brage, Ph.D., Teik Choon See, M.D., David J. Lomas, M.D., Stephen O'Rahilly, M.D., and I. Sadaf Farooqi, M.D., Ph.D.

ABSTRACT

Background Weight gain and weight loss are associated with changesin blood pressure through unknown mechanisms. Central melanocortinergicsignaling is implicated in the control of energy balance andblood pressure in rodents, but there is no information regardingsuch an association with blood pressure in humans.

Methods We assessed blood pressure, heart rate, and urinarycatecholamines in overweight or obese subjects with a loss-of-functionmutation in MC4R, the gene encoding the melanocortin 4 receptor,and in equally overweight control subjects. We also examinedthe effects of an MC4R agonist administered for 7 days in 28overweight or obese volunteers.

Results The prevalence of hypertension was markedly lower inthe MC4R-deficient subjects than in the control subjects (24%vs. 53%, P=0.009). After the exclusion of subjects taking antihypertensivemedications, blood-pressure levels were significantly lowerin MC4R-deficient subjects than in control subjects, with mean(±SE) systolic blood pressures of 123±14 mm Hgand 131±12 mm Hg, respectively (P=0.02), and mean diastolicblood pressures of 73±10 mm Hg and 79±7 mm Hg,respectively (P=0.03). As compared with control subjects, MC4R-deficientsubjects had a lower increase in heart rate on waking (P=0.007),a lower heart rate during euglycemic hyperinsulinemia (P<0.001),and lower 24-hour urinary norepinephrine excretion (P=0.04).The maximum tolerated daily dose of 1.0 mg of the MC4R agonistled to significant increases of 9.3±1.9 mm Hg in systolicblood pressure and of 6.6±1.1 mm Hg in diastolic bloodpressure (P<0.001> with placebo. Differences in blood pressure were not explainedby changes in insulin levels; there were no significant adverseevents.

Conclusions Results of our genetic and pharmacologic studiesimplicate melanocortinergic signaling in the control of humanblood pressure through an insulin-independent mechanism.

Association between Obesity during Pregnancy and Increased Use of Health Care

2009-01-29T22:17:00.000-08:00

Susan Y. Chu, Ph.D., M.S.P.H., Donald J. Bachman, M.S., William M. Callaghan, M.D., M.P.H., Evelyn P. Whitlock, M.D., M.P.H., Patricia M. Dietz, Dr.P.H., M.P.H., Cynthia J. Berg, M.D., M.P.H., Maureen O'Keeffe-Rosetti, M.S., F. Carol Bruce, B.S.N., M.P.H., and Mark C. Hornbrook, Ph.D.

ABSTRACT

Background In the United States, obesity during pregnancy iscommon and increases obstetrical risks. An estimate of the increasein use of health care services associated with obesity duringpregnancy is needed.

Methods We used electronic data systems of a large U.S. group-practicehealth maintenance organization to identify 13,442 pregnanciesamong women 18 years of age or older at the time of conceptionthat resulted in live births or stillbirths. The study periodwas between January 1, 2000, and December 31, 2004. We assessedassociations between measures of use of health care servicesand body-mass index (BMI, defined as the weight in kilogramsdivided by the square of the height in meters) before pregnancyor in early pregnancy. The women were categorized as underweight(BMI <18.5),> to 29.9), obese (BMI 30.0 to 34.9), very obese (BMI 35.0 to39.9), or extremely obese (BMI 40.0). The primary outcome wasthe mean length of hospital stay for delivery.

Results After adjustment for age, race or ethnic group, levelof education, and parity, the mean (±SE) length of hospitalstay for delivery was significantly (P<0.05)> women who were overweight (3.7±0.1 days), obese (4.0±0.1days), very obese (4.1±0.1 days), and extremely obese(4.4±0.1 days) than among women with normal BMI (3.6±0.1days). A higher-than-normal BMI was associated with significantlymore prenatal fetal tests, obstetrical ultrasonographic examinations,medications dispensed from the outpatient pharmacy, telephonecalls to the department of obstetrics and gynecology, and prenatalvisits with physicians. A higher-than-normal BMI was also associatedwith significantly fewer prenatal visits with nurse practitionersand physician assistants. Most of the increase in length ofstay associated with higher BMI was related to increased ratesof cesarean delivery and obesity-related high-risk conditions.

Conclusions Obesity during pregnancy is associated with increaseduse of health care services.

Weight Loss with a Low-Carbohydrate, Mediterranean, or Low-Fat Diet

2009-01-29T22:16:00.000-08:00

Iris Shai, R.D., Ph.D., Dan Schwarzfuchs, M.D., Yaakov Henkin, M.D., Danit R. Shahar, R.D., Ph.D., Shula Witkow, R.D., M.P.H., Ilana Greenberg, R.D., M.P.H., Rachel Golan, R.D., M.P.H., Drora Fraser, Ph.D., Arkady Bolotin, Ph.D., Hilel Vardi, M.Sc., Osnat Tangi-Rozental, B.A., Rachel Zuk-Ramot, R.N., Benjamin Sarusi, M.Sc., Dov Brickner, M.D., Ziva Schwartz, M.D., Einat Sheiner, M.D., Rachel Marko, M.Sc., Esther Katorza, M.Sc., Joachim Thiery, M.D., Georg Martin Fiedler, M.D., Matthias Blüher, M.D., Michael Stumvoll, M.D., Meir J. Stampfer, M.D., Dr.P.H., for the Dietary Intervention Randomized Controlled Trial (DIRECT) Group

ABSTRACT

Background Trials comparing the effectiveness and safety ofweight-loss diets are frequently limited by short follow-uptimes and high dropout rates.

Methods In this 2-year trial, we randomly assigned 322 moderatelyobese subjects (mean age, 52 years; mean body-mass index [theweight in kilograms divided by the square of the height in meters],31; male sex, 86%) to one of three diets: low-fat, restricted-calorie;Mediterranean, restricted-calorie; or low-carbohydrate, non–restricted-calorie.

Results The rate of adherence to a study diet was 95.4% at 1year and 84.6% at 2 years. The Mediterranean-diet group consumedthe largest amounts of dietary fiber and had the highest ratioof monounsaturated to saturated fat (P<0.05> among treatment groups). The low-carbohydrate group consumedthe smallest amount of carbohydrates and the largest amountsof fat, protein, and cholesterol and had the highest percentageof participants with detectable urinary ketones (P<0.05> all comparisons among treatment groups). The mean weight losswas 2.9 kg for the low-fat group, 4.4 kg for the Mediterranean-dietgroup, and 4.7 kg for the low-carbohydrate group (P<0.001for the interaction between diet group and time); among the272 participants who completed the intervention, the mean weightlosses were 3.3 kg, 4.6 kg, and 5.5 kg, respectively. The relativereduction in the ratio of total cholesterol to high-densitylipoprotein cholesterol was 20% in the low-carbohydrate groupand 12% in the low-fat group (P=0.01). Among the 36 subjectswith diabetes, changes in fasting plasma glucose and insulinlevels were more favorable among those assigned to the Mediterraneandiet than among those assigned to the low-fat diet (P<0.001for the interaction among diabetes and Mediterranean diet andtime with respect to fasting glucose levels).

Conclusions Mediterranean and low-carbohydrate diets may beeffective alternatives to low-fat diets. The more favorableeffects on lipids (with the low-carbohydrate diet) and on glycemiccontrol (with the Mediterranean diet) suggest that personalpreferences and metabolic considerations might inform individualizedtailoring of dietary interventions. (ClinicalTrials.gov number,NCT00160108 [ClinicalTrials.gov] .)

Brain-Derived Neurotrophic Factor and Obesity in the WAGR Syndrome

2009-01-29T21:52:00.000-08:00

Joan C. Han, M.D., Qing-Rong Liu, Ph.D., MaryPat Jones, M.S., Rebecca L. Levinn, B.A., Carolyn M. Menzie, B.S., Kyra S. Jefferson-George, Diane C. Adler-Wailes, M.S., Ethan L. Sanford, B.A., Felicitas L. Lacbawan, M.D., George R. Uhl, M.D., Ph.D., Owen M. Rennert, M.D., and Jack A. Yanovski, M.D., Ph.D.

ABSTRACT

Background Brain-derived neurotrophic factor (BDNF) has beenfound to be important in energy homeostasis in animal models,but little is known about its role in energy balance in humans.Heterozygous, variably sized, contiguous gene deletions causinghaploinsufficiency of the WT1 and PAX6 genes on chromosome 11p13,approximately 4 Mb centromeric to BDNF (11p14.1), result inthe Wilms' tumor, aniridia, genitourinary anomalies, and mentalretardation (WAGR) syndrome. Hyperphagia and obesity were observedin a subgroup of patients with the WAGR syndrome. We hypothesizedthat the subphenotype of obesity in the WAGR syndrome is attributableto deletions that induce haploinsufficiency of BDNF.

Methods We studied the relationship between genotype and body-massindex (BMI) in 33 patients with the WAGR syndrome who were recruitedthrough the International WAGR Syndrome Association. The extentof each deletion was determined with the use of oligonucleotidecomparative genomic hybridization.

Results Deletions of chromosome 11p in the patients studiedranged from 1.0 to 26.5 Mb; 58% of the patients had heterozygousBDNF deletions. These patients had significantly higher BMIz scores throughout childhood than did patients with intactBDNF (mean [±SD] z score at 8 to 10 years of age, 2.08±0.45in patients with heterozygous BDNF deletions vs. 0.88±1.28in patients without BDNF deletions; P=0.03). By 10 years ofage, 100% of the patients with heterozygous BDNF deletions (95%confidence interval [CI], 77 to 100) were obese (BMI 95th percentilefor age and sex) as compared with 20% of persons without BDNFdeletions (95% CI, 3 to 56; P<0.001).> for childhood-onset obesity in the WAGR syndrome was locatedwithin 80 kb of exon 1 of BDNF. Serum BDNF concentrations wereapproximately 50% lower among the patients with heterozygousBDNF deletions (P=0.001).

Conclusions Among persons with the WAGR syndrome, BDNF haploinsufficiencyis associated with lower levels of serum BDNF and with childhood-onsetobesity; thus, BDNF may be important for energy homeostasisin humans.

A Randomized, Controlled Trial of Magnesium Sulfate for the Prevention of Cerebral Palsy

2009-01-29T21:51:00.000-08:00

Dwight J. Rouse, M.D., Deborah G. Hirtz, M.D., Elizabeth Thom, Ph.D., Michael W. Varner, M.D., Catherine Y. Spong, M.D., Brian M. Mercer, M.D., Jay D. Iams, M.D., Ronald J. Wapner, M.D., Yoram Sorokin, M.D., James M. Alexander, M.D., Margaret Harper, M.D., John M. Thorp, Jr., M.D., Susan M. Ramin, M.D., Fergal D. Malone, M.D., Marshall Carpenter, M.D., Menachem Miodovnik, M.D., Atef Moawad, M.D., Mary J. O'Sullivan, M.D., Alan M. Peaceman, M.D., Gary D.V. Hankins, M.D., Oded Langer, M.D., Steve N. Caritis, M.D., James M. Roberts, M.D., for the Eunice Kennedy Shriver NICHD Maternal–Fetal Medicine Units Network

ABSTRACT

Background Research suggests that fetal exposure to magnesiumsulfate before preterm birth might reduce the risk of cerebralpalsy.

Methods In this multicenter, placebo-controlled, double-blindtrial, we randomly assigned women at imminent risk for deliverybetween 24 and 31 weeks of gestation to receive magnesium sulfate,administered intravenously as a 6-g bolus followed by a constantinfusion of 2 g per hour, or matching placebo. The primary outcomewas the composite of stillbirth or infant death by 1 year ofcorrected age or moderate or severe cerebral palsy at or beyond2 years of corrected age.

Results A total of 2241 women underwent randomization. The baselinecharacteristics were similar in the two groups. Follow-up wasachieved for 95.6% of the children. The rate of the primaryoutcome was not significantly different in the magnesium sulfategroup and the placebo group (11.3% and 11.7%, respectively;relative risk, 0.97; 95% confidence interval [CI], 0.77 to 1.23).However, in a prespecified secondary analysis, moderate or severecerebral palsy occurred significantly less frequently in themagnesium sulfate group (1.9% vs. 3.5%; relative risk, 0.55;95% CI, 0.32 to 0.95). The risk of death did not differ significantlybetween the groups (9.5% vs. 8.5%; relative risk, 1.12; 95%CI, 0.85 to 1.47). No woman had a life-threatening event.

Conclusions Fetal exposure to magnesium sulfate before anticipatedearly preterm delivery did not reduce the combined risk of moderateor severe cerebral palsy or death, although the rate of cerebralpalsy was reduced among survivors. (ClinicalTrials.gov number,NCT00014989 [ClinicalTrials.gov] .)

Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight

2009-01-29T21:50:00.000-08:00

Brenda H. Morris, M.D., William Oh, M.D., Jon E. Tyson, M.D., M.P.H., David K. Stevenson, M.D., Dale L. Phelps, M.D., T. Michael O'Shea, M.D., M.P.H., Georgia E. McDavid, R.N., Rebecca L. Perritt, M.S., Krisa P. Van Meurs, M.D., Betty R. Vohr, M.D., Cathy Grisby, B.S.N., Qing Yao, Ph.D., Claudia Pedroza, Ph.D., Abhik Das, Ph.D., W. Kenneth Poole, Ph.D., Waldemar A. Carlo, M.D., Shahnaz Duara, M.D., Abbot R. Laptook, M.D., Walid A. Salhab, M.D., Seetha Shankaran, M.D., Brenda B. Poindexter, M.D., Avroy A. Fanaroff, M.D., Michele C. Walsh, M.D., Maynard R. Rasmussen, M.D., Barbara J. Stoll, M.D., C. Michael Cotten, M.D., Edward F. Donovan, M.D., Richard A. Ehrenkranz, M.D., Ronnie Guillet, M.D., Ph.D., Rosemary D. Higgins, M.D., for the NICHD Neonatal Research Network

ABSTRACT

Background It is unclear whether aggressive phototherapy toprevent neurotoxic effects of bilirubin benefits or harms infantswith extremely low birth weight (1000 g or less).

Methods We randomly assigned 1974 infants with extremely lowbirth weight at 12 to 36 hours of age to undergo either aggressiveor conservative phototherapy. The primary outcome was a compositeof death or neurodevelopmental impairment determined for 91%of the infants by investigators who were unaware of the treatmentassignments.

Results Aggressive phototherapy, as compared with conservativephototherapy, significantly reduced the mean peak serum bilirubinlevel (7.0 vs. 9.8 mg per deciliter [120 vs. 168 µmolper liter], P<0.01)> (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI],0.87 to 1.02; P=0.15). Aggressive phototherapy did reduce ratesof neurodevelopmental impairment (26%, vs. 30% for conservativephototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Ratesof death in the aggressive-phototherapy and conservative-phototherapygroups were 24% and 23%, respectively (relative risk, 1.05;95% CI, 0.90 to 1.22). In preplanned subgroup analyses, therates of death were 13% with aggressive phototherapy and 14%with conservative phototherapy for infants with a birth weightof 751 to 1000 g and 39% and 34%, respectively (relative risk,1.13; 95% CI, 0.96 to 1.34), for infants with a birth weightof 501 to 750 g.

Conclusions Aggressive phototherapy did not significantly reducethe rate of death or neurodevelopmental impairment. The rateof neurodevelopmental impairment alone was significantly reducedwith aggressive phototherapy. This reduction may be offset byan increase in mortality among infants weighing 501 to 750 gat birth. (ClinicalTrials.gov number, NCT00114543 [ClinicalTrials.gov] .)

Subthalamic Nucleus Stimulation in Severe Obsessive–Compulsive Disorder

2009-01-29T21:49:00.000-08:00

Luc Mallet, M.D., Ph.D., Mircea Polosan, M.D., Nematollah Jaafari, M.D., Nicolas Baup, M.D., Marie-Laure Welter, M.D., Ph.D., Denys Fontaine, M.D., Ph.D., Sophie Tezenas du Montcel, M.D., Ph.D., Jérôme Yelnik, M.D., Isabelle Chéreau, M.D., Christophe Arbus, M.D., Sylvie Raoul, M.D., Ph.D., Bruno Aouizerate, M.D., Ph.D., Philippe Damier, M.D., Ph.D., Stephan Chabardès, M.D., Ph.D., Virginie Czernecki, Ph.D., Claire Ardouin, Ph.D., Marie-Odile Krebs, M.D., Ph.D., Eric Bardinet, Ph.D., Patrick Chaynes, M.D., Ph.D., Pierre Burbaud, M.D., Ph.D., Philippe Cornu, M.D., Philippe Derost, M.D., Thierry Bougerol, M.D., Ph.D., Benoit Bataille, M.D., Vianney Mattei, M.D., Didier Dormont, M.D., Ph.D., Bertrand Devaux, M.D., Marc Vérin, M.D., Ph.D., Jean-Luc Houeto, M.D., Ph.D., Pierre Pollak, M.D., Ph.D., Alim-Louis Benabid, M.D., Ph.D., Yves Agid, M.D., Ph.D., Paul Krack, M.D., Ph.D., Bruno Millet, M.D., Ph.D., Antoine Pelissolo, M.D., Ph.D., for the STOC Study Group

ABSTRACT

Background Severe, refractory obsessive–compulsive disorder(OCD) is a disabling condition. Stimulation of the subthalamicnucleus, a procedure that is already validated for the treatmentof movement disorders, has been proposed as a therapeutic option.

Methods In this 10-month, crossover, double-blind, multicenterstudy assessing the efficacy and safety of stimulation of thesubthalamic nucleus, we randomly assigned eight patients withhighly refractory OCD to undergo active stimulation of the subthalamicnucleus followed by sham stimulation and eight to undergo shamstimulation followed by active stimulation. The primary outcomemeasure was the severity of OCD, as assessed by the Yale–BrownObsessive Compulsive Scale (Y-BOCS), at the end of two 3-monthperiods. General psychopathologic findings, functioning, andtolerance were assessed with the use of standardized psychiatricscales, the Global Assessment of Functioning (GAF) scale, andneuropsychological tests.

Results After active stimulation of the subthalamic nucleus,the Y-BOCS score (on a scale from 0 to 40, with lower scoresindicating less severe symptoms) was significantly lower thanthe score after sham stimulation (mean [±SD], 19±8vs. 28±7; P=0.01), and the GAF score (on a scale from1 to 90, with higher scores indicating higher levels of functioning)was significantly higher (56±14 vs. 43±8, P=0.005).The ratings of neuropsychological measures, depression, andanxiety were not modified by stimulation. There were 15 seriousadverse events overall, including 1 intracerebral hemorrhageand 2 infections; there were also 23 nonserious adverse events.

Conclusions These preliminary findings suggest that stimulationof the subthalamic nucleus may reduce the symptoms of severeforms of OCD but is associated with a substantial risk of seriousadverse events. (ClinicalTrials.gov number, NCT00169377 [ClinicalTrials.gov] .)

A Functional Genetic Link between Distinct Developmental Language Disorders

2009-01-29T21:46:00.001-08:00

Sonja C. Vernes, D.Phil., Dianne F. Newbury, D.Phil., Brett S. Abrahams, Ph.D., Laura Winchester, B.Sc., Jérôme Nicod, Ph.D., Matthias Groszer, M.D., Maricela Alarcón, Ph.D., Peter L. Oliver, Ph.D., Kay E. Davies, D.Phil., Daniel H. Geschwind, M.D., Ph.D., Anthony P. Monaco, M.D., Ph.D., and Simon E. Fisher, D.Phil.

ABSTRACT

Background Rare mutations affecting the FOXP2 transcriptionfactor cause a monogenic speech and language disorder. We hypothesizedthat neural pathways downstream of FOXP2 influence more commonphenotypes, such as specific language impairment.

Methods We performed genomic screening for regions bound byFOXP2 using chromatin immunoprecipitation, which led us to focuson one particular gene that was a strong candidate for involvementin language impairments. We then tested for associations betweensingle-nucleotide polymorphisms (SNPs) in this gene and languagedeficits in a well-characterized set of 184 families affectedwith specific language impairment.

Results We found that FOXP2 binds to and dramatically down-regulatesCNTNAP2, a gene that encodes a neurexin and is expressed inthe developing human cortex. On analyzing CNTNAP2 polymorphismsin children with typical specific language impairment, we detectedsignificant quantitative associations with nonsense-word repetition,a heritable behavioral marker of this disorder (peak association,P=5.0x10^–5 at SNP rs17236239). Intriguingly, this regioncoincides with one associated with language delays in childrenwith autism.

Conclusions The FOXP2–CNTNAP2 pathway provides a mechanisticlink between clinically distinct syndromes involving disruptedlanguage.

Premyelinating Oligodendrocytes in Chronic Lesions of Multiple Sclerosis

2009-01-29T21:41:00.000-08:00

Ansi Chang, M.D., Wallace W. Tourtellotte, M.D., Ph.D., Richard Rudick, M.D., and Bruce D. Trapp, Ph.D.

ABSTRACT

Background Multiple sclerosis is an inflammatory disease ofthe central nervous system that destroys myelin, oligodendrocytes,and axons. Since most of the lesions of multiple sclerosis arenot remyelinated, enhancement of remyelination is a possibletherapeutic strategy that could perhaps be achieved with thetransplantation of oligodendrocyte-producing cells into thelesions. We investigated the frequency distribution and configurationof oligodendrocytes in chronic lesions of multiple sclerosisto determine whether these factors limit remyelination.

Methods Forty-eight chronic lesions obtained at autopsy from10 patients with multiple sclerosis were examined immunocytochemicallyfor oligodendrocytes and oligodendrocyte progenitor cells. Usingconfocal microscopy, we examined the three-dimensional relationsbetween axons and the processes of premyelinating oligodendrocytes.

Results Thirty-four of the 48 chronic lesions of multiple sclerosiscontained oligodendrocytes with multiple extended processesthat associated with demyelinated axons but failed to myelinatethem. These axons were dystrophic and contained multiple swellings.In some regions, the densities of premyelinating oligodendrocytes(25 per square millimeter of tissue) were similar to those inthe developing rodent brain (23 per square millimeter). In thepatients with disease of long duration (more than 20 years),there were fewer lesions with premyelinating oligodendrocytes(P<0.001).

Conclusions Premyelinating oligodendrocytes are present in chroniclesions of multiple sclerosis, so remyelination is not limitedby an absence of oligodendrocyte progenitors or their failureto generate oligodendrocytes. Our findings suggest that in thechronic lesions of multiple sclerosis, the axons are not receptivefor remyelination. Understanding the cellular interactions betweenpremyelinating oligodendrocytes, axons, and the microenvironmentof lesions of multiple sclerosis may lead to effective strategiesfor enhancing remyelination.

Natural History of Multiple Sclerosis with Childhood Onset

2009-01-29T21:40:00.000-08:00

Christel Renoux, M.D., Sandra Vukusic, M.D., Yann Mikaeloff, M.D., Gilles Edan, M.D., Michel Clanet, M.D., Bénédicte Dubois, M.D., Marc Debouverie, M.D., Bruno Brochet, M.D., Christine Lebrun-Frenay, M.D., Jean Pelletier, M.D., Thibault Moreau, M.D., Catherine Lubetzki, M.D., Patrick Vermersch, M.D., Etienne Roullet, M.D., Laurent Magy, M.D., Marc Tardieu, M.D., Samy Suissa, Ph.D., Christian Confavreux, M.D., for the Adult Neurology Departments KIDMUS Study Group

ABSTRACT

Background The course and prognosis of childhood-onset multiplesclerosis have not been well described.

Methods We used data from 13 adult neurology departments affiliatedwith the European Database for Multiple Sclerosis (EDMUS) networkto identify a cohort of 394 patients who had multiple sclerosiswith an onset at 16 years of age or younger and a comparisongroup of 1775 patients who had multiple sclerosis with an onsetafter 16 years of age. We determined the initial clinical features,the dates of disease onset, and the occurrence of outcomes,including relapse, conversion to secondary progression, andirreversible disability as measured by scores of 4 (limitedwalking ability but ability to walk more than 500 m withoutaid or rest), 6 (ability to walk with unilateral support nomore than 100 m without rest), and 7 (ability to walk no morethan 10 m without rest while using a wall or furniture for support)on the Kurtzke Disability Status Scale (range, 0 to 10; higherscores indicate more severe disability).

Results For patients with childhood-onset multiple sclerosis,the estimated median time from onset to secondary progressionwas 28 years, and the median age at conversion to secondaryprogression was 41 years. The median times from onset to disabilityscores of 4, 6, and 7 were 20.0, 28.9, and 37.0 years, respectively,and the corresponding median ages were 34.6, 42.2, and 50.5years. In comparison with patients with adult-onset disease,those with childhood-onset disease were more likely to be femalethan male (female:male ratio, 2.8 vs. 1.8), were more likelyto have an exacerbating–remitting initial course (98%vs. 84%), took approximately 10 years longer to reach secondaryprogression and irreversible disability, and reached these landmarksat an age approximately 10 years younger (P<0.001> comparisons).

Conclusions Patients with childhood-onset multiple sclerosistake longer to reach states of irreversible disability but doso at a younger age than patients with adult-onset multiplesclerosis.

Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study

2009-01-29T21:35:00.000-08:00

The International Multiple Sclerosis Genetics Consortium

ABSTRACT

Background Multiple sclerosis has a clinically significant heritablecomponent. We conducted a genomewide association study to identifyalleles associated with the risk of multiple sclerosis.

Methods We used DNA microarray technology to identify commonDNA sequence variants in 931 family trios (consisting of anaffected child and both parents) and tested them for association.For replication, we genotyped another 609 family trios, 2322case subjects, and 789 control subjects and used genotypingdata from two external control data sets. A joint analysis ofdata from 12,360 subjects was performed to estimate the overallsignificance and effect size of associations between allelesand the risk of multiple sclerosis.

Results A transmission disequilibrium test of 334,923 single-nucleotidepolymorphisms (SNPs) in 931 family trios revealed 49 SNPs havingan association with multiple sclerosis (P<1x10^–4);of these SNPs, 38 were selected for the second-stage analysis.A comparison between the 931 case subjects from the family triosand 2431 control subjects identified an additional nonoverlapping32 SNPs (P<0.001).> P values (<0.01)> for the second-stage analysis. Of these SNPs, two within theinterleukin-2 receptor gene (IL2RA) were strongly associatedwith multiple sclerosis (P=2.96x10^–8), as were a nonsynonymousSNP in the interleukin-7 receptor gene (IL7RA) (P=2.94x10^–7)and multiple SNPs in the HLA-DRA locus (P=8.94x10^–81).

Conclusions Alleles of IL2RA and IL7RA and those in the HLAlocus are identified as heritable risk factors for multiplesclerosis.

Gene Expression in Fixed Tissues and Outcome in Hepatocellular Carcinoma

2009-01-29T20:39:00.002-08:00

Yujin Hoshida, M.D., Ph.D., Augusto Villanueva, M.D., Masahiro Kobayashi, M.D., Judit Peix, A.S., Derek Y. Chiang, Ph.D., Amy Camargo, B.A., Supriya Gupta, B.S., Jamie Moore, M.A., B.S., Matthew J. Wrobel, M.S., Jim Lerner, B.S., Michael Reich, B.S., Jennifer A. Chan, M.D., Jonathan N. Glickman, M.D., Ph.D., Kenji Ikeda, M.D., Masaji Hashimoto, M.D., Goro Watanabe, M.D., Maria G. Daidone, Ph.D., Sasan Roayaie, M.D., Myron Schwartz, M.D., Swan Thung, M.D., Helga B. Salvesen, M.D., Ph.D., Stacey Gabriel, Ph.D., Vincenzo Mazzaferro, M.D., Jordi Bruix, M.D., Scott L. Friedman, M.D., Hiromitsu Kumada, M.D., Josep M. Llovet, M.D., and Todd R. Golub, M.D.

ABSTRACT

Background It is a challenge to identify patients who, afterundergoing potentially curative treatment for hepatocellularcarcinoma, are at greatest risk for recurrence. Such high-riskpatients could receive novel interventional measures. An obstacleto the development of genome-based predictors of outcome inpatients with hepatocellular carcinoma has been the lack ofa means to carry out genomewide expression profiling of fixed,as opposed to frozen, tissue.

Methods We aimed to demonstrate the feasibility of gene-expressionprofiling of more than 6000 human genes in formalin-fixed, paraffin-embeddedtissues. We applied the method to tissues from 307 patientswith hepatocellular carcinoma, from four series of patients,to discover and validate a gene-expression signature associatedwith survival.

Results The expression-profiling method for formalin-fixed,paraffin-embedded tissue was highly effective: samples from90% of the patients yielded data of high quality, includingsamples that had been archived for more than 24 years. Gene-expressionprofiles of tumor tissue failed to yield a significant associationwith survival. In contrast, profiles of the surrounding nontumoralliver tissue were highly correlated with survival in a trainingset of tissue samples from 82 Japanese patients, and the signaturewas validated in tissues from an independent group of 225 patientsfrom the United States and Europe (P=0.04).

Conclusions We have demonstrated the feasibility of genomewideexpression profiling of formalin-fixed, paraffin-embedded tissuesand have shown that a reproducible gene-expression signaturecorrelated with survival is present in liver tissue adjacentto the tumor in patients with hepatocellular carcinoma.

Peginterferon Alfa-2a and Ribavirin in Latino and Non-Latino Whites with Hepatitis C

2009-01-29T20:39:00.001-08:00

Maribel Rodriguez-Torres, M.D., Lennox J. Jeffers, M.D., Muhammad Y. Sheikh, M.D., Lorenzo Rossaro, M.D., Victor Ankoma-Sey, M.D., Fayez M. Hamzeh, M.D., Ph.D., Paul Martin, M.D., for the Latino Study Group

ABSTRACT

Background Race has been shown to be a factor in the responseto therapy for hepatitis C virus (HCV) infection, and limiteddata suggest that ethnic group may be as well; however, Latinosand other ethnic subpopulations have been underrepresented inclinical trials. We evaluated the effect of Latino ethnic backgroundon the response to treatment with peginterferon alfa-2a andribavirin in patients infected with HCV genotype 1 who had notbeen treated previously.

Methods In a multicenter, open-label, nonrandomized, prospectivestudy, 269 Latino and 300 non-Latino whites with HCV infectionreceived peginterferon alfa-2a, at a dose of 180 µg perweek, and ribavirin, at a dose of 1000 or 1200 mg per day, for48 weeks, and were followed through 72 weeks. The primary endpoint was a sustained virologic response. We enrolled Latinoswhose parents and grandparents spoke Spanish as their primarylanguage; nonwhite Latinos were excluded.

Results Baseline characteristics were similar in the Latinoand non-Latino groups, although higher proportions of Latinopatients were 40 years of age or younger, had a body-mass index(BMI, the weight in kilograms divided by the square of the heightin meters) of more than 27 or more than 30, and had cirrhosis.The rate of sustained virologic response was higher among non-Latinowhites than among Latinos (49% vs. 34%, P<0.001).> of HCV RNA in serum was more frequent in non-Latino whites atweek 4 (P=0.045) and throughout the treatment period (P<0.001for all other comparisons). Latino or non-Latino backgroundwas an independent predictor of the rate of sustained virologicresponse in an analysis adjusted for baseline differences inBMI, cirrhosis, and other characteristics. Adherence to treatmentdid not differ significantly between the two groups. The numbersof patients with adverse events and dose modifications weresimilar in the two groups, but fewer Latino patients discontinuedtherapy because of adverse events.

Conclusions Treatment with peginterferon alfa-2a and ribavirinfor 48 weeks resulted in rates of sustained virologic responseamong patients infected with HCV genotype 1 that were loweramong Latino whites than among non-Latino whites. Strategiesto improve the sustained virologic response in Latinos are needed.(ClinicalTrials.gov number, NCT00107653 [ClinicalTrials.gov] .)

Tenofovir Disoproxil Fumarate versus Adefovir Dipivoxil for Chronic Hepatitis B

2009-01-29T20:36:00.000-08:00

Patrick Marcellin, M.D., E. Jenny Heathcote, M.D., Maria Buti, M.D., Ed Gane, M.D., Robert A. de Man, M.D., Zahary Krastev, M.D., George Germanidis, M.D., Sam S. Lee, M.D., Robert Flisiak, M.D., Kelly Kaita, M.D., Michael Manns, M.D., Iskren Kotzev, M.D., Konstantin Tchernev, M.D., Peter Buggisch, M.D., Frank Weilert, M.D., Oya Ovung Kurdas, M.D., Mitchell L. Shiffman, M.D., Huy Trinh, M.D., Mary Kay Washington, M.D., Jeff Sorbel, M.S., Jane Anderson, Ph.D., Andrea Snow-Lampart, B.S., Elsa Mondou, M.D., Joe Quinn, M.P.H., and Franck Rousseau, M.D.

ABSTRACT

Background Tenofovir disoproxil fumarate (DF) is a nucleotideanalogue and a potent inhibitor of human immunodeficiency virustype 1 reverse transcriptase and hepatitis B virus (HBV) polymerase.

Methods In two double-blind, phase 3 studies, we randomly assignedpatients with hepatitis B e antigen (HBeAg)–negative orHBeAg-positive chronic HBV infection to receive tenofovir DFor adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks.The primary efficacy end point was a plasma HBV DNA level ofless than 400 copies per milliliter (69 IU per milliliter) andhistologic improvement (i.e., a reduction in the Knodell necroinflammationscore of 2 or more points without worsening fibrosis) at week48. Secondary end points included viral suppression (i.e., anHBV DNA level of <400> improvement, serologic response, normalization of alanine aminotransferaselevels, and development of resistance mutations.

Results At week 48, in both studies, a significantly higherproportion of patients receiving tenofovir DF than of thosereceiving adefovir dipivoxil had reached the primary end point(P<0.001).> patients receiving tenofovir DF than patients receiving adefovirdipivoxil (93% vs. 63%, P<0.001)> patients receiving tenofovir DF than patients receiving adefovirdipivoxil (76% vs. 13%, P<0.001).> patients treated with tenofovir DF than those treated with adefovirdipivoxil had normalized alanine aminotransferase levels (68%vs. 54%, P=0.03) and loss of hepatitis B surface antigen (3%vs. 0%, P=0.02). At week 48, amino acid substitutions withinHBV DNA polymerase associated with phenotypic resistance totenofovir DF or other drugs to treat HBV infection had not developedin any of the patients. Tenofovir DF produced a similar HBVDNA response in patients who had previously received lamivudineand in those who had not. The safety profile was similar forthe two treatments in both studies.

Conclusions Among patients with chronic HBV infection, tenofovirDF at a daily dose of 300 mg had superior antiviral efficacywith a similar safety profile as compared with adefovir dipivoxilat a daily dose of 10 mg through week 48. (ClinicalTrials.govnumbers, NCT00116805 [ClinicalTrials.gov] and NCT00117676 [ClinicalTrials.gov] .)

Monoclonal B-Cell Lymphocytosis and Chronic Lymphocytic Leukemia

2009-01-29T20:35:00.000-08:00

Andy C. Rawstron, Ph.D., Fiona L. Bennett, M.Sc., Sheila J.M. O'Connor, Ph.D., Marwan Kwok, B.Sc., James A.L. Fenton, D.Phil., Marieth Plummer, B.Sc., Ruth de Tute, M.Sc., Roger G. Owen, M.D., Stephen J. Richards, Ph.D., Andrew S. Jack, Ph.D., and Peter Hillmen, Ph.D.

ABSTRACT

Background A diagnosis of chronic lymphocytic leukemia (CLL)requires a count of over 5000 circulating CLL-phenotype cellsper cubic millimeter. Asymptomatic persons with fewer CLL-phenotypecells have monoclonal B-cell lymphocytosis (MBL). The goal ofthis study was to investigate the relation between MBL and CLL.

Methods We investigated 1520 subjects who were 62 to 80 yearsof age with a normal blood count and 2228 subjects with lymphocytosis(>4000 lymphocytes per cubic millimeter) for the presenceof MBL, using flow cytometry. Monoclonal B cells were furthercharacterized by means of cytogenetic and molecular analyses.A representative cohort of 185 subjects with CLL-phenotype MBLand lymphocytosis were monitored for a median of 6.7 years (range,0.2 to 11.8).

Results Monoclonal CLL-phenotype B cells were detected in 5.1%of subjects (78 of 1520) with a normal blood count and 13.9%(309 of 2228) with lymphocytosis. CLL-phenotype MBL had a frequencyof 13q14 deletion and trisomy 12 similar to that of CLL andshowed a skewed repertoire of the immunoglobulin heavy variablegroup (IGHV) genes. Among 185 subjects presenting with lymphocytosis,progressive lymphocytosis occurred in 51 (28%), progressiveCLL developed in 28 (15%), and chemotherapy was required in13 (7%). The absolute B-cell count was the only independentprognostic factor associated with progressive lymphocytosis.During follow-up over a median of 6.7 years, 34% of subjects(62 of 185) died, but only 4 of these deaths were due to CLL.Age above 68 years and hemoglobin level below 12.5 g per deciliterwere the only independent prognostic factors for death.

Conclusions The CLL-phenotype cells found in the general populationand in subjects with lymphocytosis have features in common withCLL cells. CLL requiring treatment develops in subjects withCLL-phenotype MBL and with lymphocytosis at the rate of 1.1%per year.

Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia

2009-01-29T20:34:00.001-08:00

Richard F. Schlenk, M.D., Konstanze Döhner, M.D., Jürgen Krauter, M.D., Stefan Fröhling, M.D., Andrea Corbacioglu, Ph.D., Lars Bullinger, M.D., Marianne Habdank, Daniela Späth, Michael Morgan, Ph.D., Axel Benner, M.Sc., Brigitte Schlegelberger, M.D., Gerhard Heil, M.D., Arnold Ganser, M.D., Hartmut Döhner, M.D., for the German–Austrian Acute Myeloid Leukemia Study Group

ABSTRACT

Background Mutations occur in several genes in cytogeneticallynormal acute myeloid leukemia (AML) cells: the nucleophosmingene (NPM1), the fms-related tyrosine kinase 3 gene (FLT3),the CCAAT/enhancer binding protein gene (CEPBA), the myeloid–lymphoidor mixed-lineage leukemia gene (MLL), and the neuroblastomaRAS viral oncogene homolog (NRAS). We evaluated the associationsof these mutations with clinical outcomes in patients.

Methods We compared the mutational status of the NPM1, FLT3,CEBPA, MLL, and NRAS genes in leukemia cells with the clinicaloutcome in 872 adults younger than 60 years of age with cytogeneticallynormal AML. Patients had been entered into one of four trialsof therapy for AML. In each study, patients with an HLA-matchedrelated donor were assigned to undergo stem-cell transplantation.

Results A total of 53% of patients had NPM1 mutations, 31% hadFLT3 internal tandem duplications (ITDs), 11% had FLT3 tyrosinekinase–domain mutations, 13% had CEBPA mutations, 7% hadMLL partial tandem duplications (PTDs), and 13% had NRAS mutations.The overall complete-remission rate was 77%. The genotype ofmutant NPM1 without FLT3-ITD, the mutant CEBPA genotype, andyounger age were each significantly associated with completeremission. Of the 663 patients who received postremission therapy,150 underwent hematopoietic stem-cell transplantation from anHLA-matched related donor. Significant associations were foundbetween the risk of relapse or the risk of death during completeremission and the leukemia genotype of mutant NPM1 without FLT3-ITD(hazard ratio, 0.44; 95% confidence interval [CI], 0.32 to 0.61),the mutant CEBPA genotype (hazard ratio, 0.48; 95% CI, 0.30to 0.75), and the MLL-PTD genotype (hazard ratio, 1.56; 95%CI, 1.00 to 2.43), as well as receipt of a transplant from anHLA-matched related donor (hazard ratio, 0.60; 95% CI, 0.44to 0.82). The benefit of the transplant was limited to the subgroupof patients with the prognostically adverse genotype FLT3-ITDor the genotype consisting of wild-type NPM1 and CEBPA withoutFLT3-ITD.

Conclusions Genotypes defined by the mutational status of NPM1,FLT3, CEBPA, and MLL are associated with the outcome of treatmentfor patients with cytogenetically normal AML.

Reduced Exposure to Calcineurin Inhibitors in Renal Transplantation

2009-01-29T20:29:00.001-08:00

Henrik Ekberg, M.D., Ph.D., Helio Tedesco-Silva, M.D., Alper Demirbas, M.D., tefan Vítko, M.D., Björn Nashan, M.D., Ph.D., Alp Gürkan, M.D., F.A.C.S., Raimund Margreiter, M.D., Christian Hugo, M.D., Josep M. Grinyó, M.D., Ulrich Frei, M.D., Yves Vanrenterghem, M.D., Ph.D., Pierre Daloze, M.D., Philip F. Halloran, M.D., Ph.D., for the ELITE–Symphony Study

ABSTRACT

Background Immunosuppressive regimens with the fewest possibletoxic effects are desirable for transplant recipients. Thisstudy evaluated the efficacy and relative toxic effects of fourimmunosuppressive regimens.

Methods We randomly assigned 1645 renal-transplant recipientsto receive standard-dose cyclosporine, mycophenolate mofetil,and corticosteroids, or daclizumab induction, mycophenolatemofetil, and corticosteroids in combination with low-dose cyclosporine,low-dose tacrolimus, or low-dose sirolimus. The primary endpoint was the estimated glomerular filtration rate (GFR), ascalculated by the Cockcroft–Gault formula, 12 months aftertransplantation. Secondary end points included acute rejectionand allograft survival.

Results The mean calculated GFR was higher in patients receivinglow-dose tacrolimus (65.4 ml per minute) than in the other threegroups (range, 56.7 to 59.4 ml per minute). The rate of biopsy-provenacute rejection was lower in patients receiving low-dose tacrolimus(12.3%) than in those receiving standard-dose cyclosporine (25.8%),low-dose cyclosporine (24.0%), or low-dose sirolimus (37.2%).Allograft survival differed significantly among the four groups(P=0.02) and was highest in the low-dose tacrolimus group (94.2%),followed by the low-dose cyclosporine group (93.1%), the standard-dosecyclosporine group (89.3%), and the low-dose sirolimus group(89.3%). Serious adverse events were more common in the low-dosesirolimus group than in the other groups (53.2% vs. a rangeof 43.4 to 44.3%), although a similar proportion of patientsin each group had at least one adverse event during treatment(86.3 to 90.5%).

Conclusions A regimen of daclizumab, mycophenolate mofetil,and corticosteroids in combination with low-dose tacrolimusmay be advantageous for renal function, allograft survival,and acute rejection rates, as compared with regimens containingdaclizumab induction plus either low-dose cyclosporine or low-dosesirolimus or with standard-dose cyclosporine without induction.(ClinicalTrials.gov number, NCT00231764 [ClinicalTrials.gov] .)

Intensity of Renal Support in Critically Ill Patients with Acute Kidney Injury

2009-01-29T20:28:00.000-08:00

The VA/NIH Acute Renal Failure Trial Network

ABSTRACT

Background The optimal intensity of renal-replacement therapyin critically ill patients with acute kidney injury is controversial.

Methods We randomly assigned critically ill patients with acutekidney injury and failure of at least one nonrenal organ orsepsis to receive intensive or less intensive renal-replacementtherapy. The primary end point was death from any cause by day60. In both study groups, hemodynamically stable patients underwentintermittent hemodialysis, and hemodynamically unstable patientsunderwent continuous venovenous hemodiafiltration or sustainedlow-efficiency dialysis. Patients receiving the intensive treatmentstrategy underwent intermittent hemodialysis and sustained low-efficiencydialysis six times per week and continuous venovenous hemodiafiltrationat 35 ml per kilogram of body weight per hour; for patientsreceiving the less-intensive treatment strategy, the correspondingtreatments were provided thrice weekly and at 20 ml per kilogramper hour.

Results Baseline characteristics of the 1124 patients in thetwo groups were similar. The rate of death from any cause byday 60 was 53.6% with intensive therapy and 51.5% with less-intensivetherapy (odds ratio, 1.09; 95% confidence interval, 0.86 to1.40; P=0.47). There was no significant difference between thetwo groups in the duration of renal-replacement therapy or therate of recovery of kidney function or nonrenal organ failure.Hypotension during intermittent dialysis occurred in more patientsrandomly assigned to receive intensive therapy, although thefrequency of hemodialysis sessions complicated by hypotensionwas similar in the two groups.

Conclusions Intensive renal support in critically ill patientswith acute kidney injury did not decrease mortality, improverecovery of kidney function, or reduce the rate of nonrenalorgan failure as compared with less-intensive therapy involvinga defined dose of intermittent hemodialysis three times perweek and continuous renal-replacement therapy at 20 ml per kilogramper hour. (ClinicalTrials.gov number, NCT00076219 [ClinicalTrials.gov] .)

Preeclampsia and the Risk of End-Stage Renal Disease

2009-01-29T20:26:00.000-08:00

Bjørn Egil Vikse, M.D., Ph.D., Lorentz M. Irgens, M.D., Ph.D., Torbjørn Leivestad, M.D., Ph.D., Rolv Skjærven, Ph.D., and Bjarne M. Iversen, M.D., Ph.D.

ABSTRACT

Background It is unknown whether preeclampsia is a risk markerfor subsequent end-stage renal disease (ESRD).

Methods We linked data from the Medical Birth Registry of Norway,which contains data on all births in Norway since 1967, withdata from the Norwegian Renal Registry, which contains dataon all patients receiving a diagnosis of end-stage renal disease(ESRD) since 1980, to assess the association between preeclampsiain one or more pregnancies and the subsequent development ofESRD. The study population consisted of women who had had afirst singleton birth between 1967 and 1991; we included datafrom up to three pregnancies.

Results ESRD developed in 477 of 570,433 women a mean (±SD)of 17±9 years after the first pregnancy (overall rate,3.7 per 100,000 women per year). Among women who had been pregnantone or more times, preeclampsia during the first pregnancy wasassociated with a relative risk of ESRD of 4.7 (95% confidenceinterval [CI], 3.6 to 6.1). Among women who had been pregnanttwo or more times, preeclampsia during the first pregnancy wasassociated with a relative risk of ESRD of 3.2 (95% CI, 2.2to 4.9), preeclampsia during the second pregnancy with a relativerisk of 6.7 (95% CI, 4.3 to 10.6), and preeclampsia during bothpregnancies with a relative risk of 6.4 (95% CI, 3.0 to 13.5).Among women who had been pregnant three or more times, preeclampsiaduring one pregnancy was associated with a relative risk ofESRD of 6.3 (95% CI, 4.1 to 9.9), and preeclampsia during twoor three pregnancies was associated with a relative risk of15.5 (95% CI, 7.8 to 30.8). Having a low-birth-weight or preterminfant increased the relative risk of ESRD. The results weresimilar after adjustment for possible confounders and afterexclusion of women who had kidney disease, rheumatic disease,essential hypertension, or diabetes mellitus before pregnancy.

Conclusions Although the absolute risk of ESRD in women whohave had preeclampsia is low, preeclampsia is a marker for anincreased risk of subsequent ESRD.

Machine Perfusion or Cold Storage in Deceased-Donor Kidney TransplantationCyril Moers, M.D., Jacqueline M. Smits, M.D., Ph.D., Mark-Hugo J. Maathuis,

2009-01-29T20:25:00.000-08:00

Cyril Moers, M.D., Jacqueline M. Smits, M.D., Ph.D., Mark-Hugo J. Maathuis, M.D., Ph.D., Jürgen Treckmann, M.D., Frank van Gelder, Bogdan P. Napieralski, Margitta van Kasterop-Kutz, Jaap J. Homan van der Heide, M.D., Ph.D., Jean-Paul Squifflet, M.D., Ph.D., Ernest van Heurn, M.D., Ph.D., Günter R. Kirste, M.D., Ph.D., Axel Rahmel, M.D., Ph.D., Henri G.D. Leuvenink, Ph.D., Andreas Paul, M.D., Ph.D., Jacques Pirenne, M.D., Ph.D., and Rutger J. Ploeg, M.D., Ph.D.

ABSTRACT

Background Static cold storage is generally used to preservekidney allografts from deceased donors. Hypothermic machineperfusion may improve outcomes after transplantation, but fewsufficiently powered prospective studies have addressed thispossibility.

Methods In this international randomized, controlled trial,we randomly assigned one kidney from 336 consecutive deceaseddonors to machine perfusion and the other to cold storage. All672 recipients were followed for 1 year. The primary end pointwas delayed graft function (requiring dialysis in the firstweek after transplantation). Secondary end points were the durationof delayed graft function, delayed graft function defined bythe rate of the decrease in the serum creatinine level, primarynonfunction, the serum creatinine level and clearance, acuterejection, toxicity of the calcineurin inhibitor, the lengthof hospital stay, and allograft and patient survival.

Results Machine perfusion significantly reduced the risk ofdelayed graft function. Delayed graft function developed in70 patients in the machine-perfusion group versus 89 in thecold-storage group (adjusted odds ratio, 0.57; P=0.01). Machineperfusion also significantly improved the rate of the decreasein the serum creatinine level and reduced the duration of delayedgraft function. Machine perfusion was associated with lowerserum creatinine levels during the first 2 weeks after transplantationand a reduced risk of graft failure (hazard ratio, 0.52; P=0.03).One-year allograft survival was superior in the machine-perfusiongroup (94% vs. 90%, P=0.04). No significant differences wereobserved for the other secondary end points. No serious adverseevents were directly attributable to machine perfusion.

Conclusions Hypothermic machine perfusion was associated witha reduced risk of delayed graft function and improved graftsurvival in the first year after transplantation. (Current ControlledTrials number, ISRCTN83876362 [controlled-trials.com] .)

Rituximab and Intravenous Immune Globulin for Desensitization during Renal Transplantation

2009-01-29T20:19:00.000-08:00

Ashley A. Vo, Pharm.D., Marina Lukovsky, Pharm.D., Mieko Toyoda, Ph.D., Jennifer Wang, M.D., Nancy L. Reinsmoen, Ph.D., Chih-Hung Lai, Ph.D., Alice Peng, M.D., Rafael Villicana, M.D., and Stanley C. Jordan, M.D.

ABSTRACT

Background Few options for transplantation currently exist forpatients highly sensitized to HLA. This exploratory, open-label,phase 1–2, single-center study examined whether intravenousimmune globulin plus rituximab could reduce anti-HLA antibodylevels and improve transplantation rates.

Methods Between September 2005 and May 2007, a total of 20 highlysensitized patients (with a mean [±SD] T-cell panel-reactiveantibody level, determined by use of the complement-dependentcytotoxicity assay, of 77±19% or with donor-specificantibodies) were enrolled and received treatment with intravenousimmune globulin and rituximab. We recorded rates of transplantation,panel-reactive antibody levels, cross-matching results at thetime of transplantation, survival of patients and grafts, acuterejection episodes, serum creatinine values, adverse eventsand serious adverse events, and immunologic factors.

Results The mean panel-reactive antibody level was 44±30%after the second infusion of intravenous immune globulin (P<0.001for the comparison with the pretreatment level). At study entry,the mean time on dialysis among recipients of a transplant froma deceased donor was 144±89 months (range, 60 to 324).However, the time to transplantation after desensitization was5±6 months (range, 2 to 18). Sixteen of the 20 patients(80%) received a transplant. At 12 months, the mean serum creatininelevel was 1.5±1.1 mg per deciliter (133±97 µmolper liter), and the mean survival rates of patients and graftswere 100% and 94%, respectively. There were no infusion-relatedadverse events or serious adverse events during the study. Long-termmonitoring for infectious complications and neurologic problemsrevealed no unanticipated events.

Conclusions These findings suggest that the combination of intravenousimmune globulin and rituximab may prove effective as a desensitizationregimen for patients awaiting a transplant from either a livingdonor or a deceased donor. Larger and longer trials are neededto evaluate the clinical efficacy and safety of this approach.(ClinicalTrials.gov number, NCT00642655 [ClinicalTrials.gov] .)

Treatment of Patients with the Hypereosinophilic Syndrome with Mepolizumab

2009-01-29T20:18:00.000-08:00

Marc E. Rothenberg, M.D., Ph.D., Amy D. Klion, M.D., Florence E. Roufosse, M.D., Ph.D., Jean Emmanuel Kahn, M.D., Peter F. Weller, M.D., Hans-Uwe Simon, M.D., Ph.D., Lawrence B. Schwartz, M.D., Ph.D., Lanny J. Rosenwasser, M.D., Johannes Ring, M.D., Ph.D., Elaine F. Griffin, D.Phil., Ann E. Haig, B.S.N., Paul I.H. Frewer, M.Sc., Jacqueline M. Parkin, M.B., B.S., Ph.D., Gerald J. Gleich, M.D., for the Mepolizumab HES Study Group

ABSTRACT

Background The hypereosinophilic syndrome is a group of diseasescharacterized by persistent blood eosinophilia, defined as morethan 1500 cells per microliter with end-organ involvement andno recognized secondary cause. Although most patients have aresponse to corticosteroids, side effects are common and canlead to considerable morbidity.

Methods We conducted an international, randomized, double-blind,placebo-controlled trial evaluating the safety and efficacyof an anti–interleukin-5 monoclonal antibody, mepolizumab,in patients with the hypereosinophilic syndrome. Patients werenegative for the FIP1L1–PDGFRA fusion gene and requiredprednisone monotherapy, 20 to 60 mg per day, to maintain a stableclinical status and a blood eosinophil count of less than 1000per microliter. Patients received either intravenous mepolizumabor placebo while the prednisone dose was tapered. The primaryend point was the reduction of the prednisone dose to 10 mgor less per day for 8 or more consecutive weeks.

Results The primary end point was reached in 84% of patientsin the mepolizumab group, as compared with 43% of patients inthe placebo group (hazard ratio, 2.90; 95% confidence interval[CI], 1.59 to 5.26; P<0.001)> activity of the hypereosinophilic syndrome. A blood eosinophilcount of less than 600 per microliter for 8 or more consecutiveweeks was achieved in 95% of patients receiving mepolizumab,as compared with 45% of patients receiving placebo (hazard ratio,3.53; 95% CI, 1.94 to 6.45; P<0.001).> occurred in seven patients receiving mepolizumab (14 events,including one death; mean [±SD] duration of exposure,6.7±1.9 months) and in five patients receiving placebo(7 events; mean duration of exposure, 4.3±2.6 months).

Conclusions Our study shows that treatment with mepolizumab,an agent designed to target eosinophils, can result in corticosteroid-sparingfor patients negative for FIP1L1–PDGFRA who have the hypereosinophilicsyndrome. (ClinicalTrials.gov number, NCT00086658 [ClinicalTrials.gov] .)

An Immunodeficiency Disease with RAG Mutations and Granulomas

2009-01-29T20:17:00.000-08:00

Catharina Schuetz, M.D., Kirsten Huck, M.D., Sonja Gudowius, M.D., Mosaad Megahed, M.D., Oliver Feyen, Ph.D., Bernd Hubner, Ph.D., Dominik T. Schneider, M.D., Burkhard Manfras, M.D., Ulrich Pannicke, Ph.D., Rein Willemze, M.D., Ruth Knüchel, M.D., Ulrich Göbel, M.D., Ansgar Schulz, M.D., Arndt Borkhardt, M.D., Wilhelm Friedrich, M.D., Klaus Schwarz, M.D., and Tim Niehues, M.D.

SUMMARY We describe three unrelated girls who had an immunodeficiencydisease with granulomas in the skin, mucous membranes, and internalorgans. All three girls had severe complications after viralinfections, including B-cell lymphoma associated with Epstein–Barrvirus (EBV). Other findings were hypogammaglobulinemia, a diminishednumber of T and B cells, and sparse thymic tissue on ultrasonography.Molecular analysis revealed that the patients were compoundheterozygotes for mutations in recombination activating gene1 or 2 (RAG1 or RAG2). In each case, both parents were heterozygouscarriers of a RAG mutation. The mutations were associated withreduced function of RAG in vitro (3 to 30% of normal activity).The parents and one sibling in the three families were healthy.

Toll-like Receptor 4 Polymorphisms and Aspergillosis in Stem-Cell Transplantation

2009-01-29T20:11:00.000-08:00

Pierre-Yves Bochud, M.D., Jason W. Chien, M.D., Kieren A. Marr, M.D., Wendy M. Leisenring, Sc.D., Arlo Upton, M.D., Marta Janer, Ph.D., Stephanie D. Rodrigues, Sarah Li, John A. Hansen, M.D., Lue Ping Zhao, Ph.D., Alan Aderem, Ph.D., and Michael Boeckh, M.D.

ABSTRACT

Background Toll-like receptors (TLRs) are essential componentsof the immune response to fungal pathogens. We examined therole of TLR polymorphisms in conferring a risk of invasive aspergillosisamong recipients of allogeneic hematopoietic-cell transplants.

Methods We analyzed 20 single-nucleotide polymorphisms (SNPs)in the toll-like receptor 2 gene (TLR2), the toll-like receptor3 gene (TLR3), the toll-like receptor 4 gene (TLR4), and thetoll-like receptor 9 gene (TLR9) in a cohort of 336 recipientsof hematopoietic-cell transplants and their unrelated donors.The risk of invasive aspergillosis was assessed with the useof multivariate Cox regression analysis. The analysis was replicatedin a validation study involving 103 case patients and 263 matchedcontrols who received hematopoietic-cell transplants from relatedand unrelated donors.

Results In the discovery study, two donor TLR4 haplotypes (S3and S4) increased the risk of invasive aspergillosis (adjustedhazard ratio for S3, 2.20; 95% confidence interval [CI], 1.14to 4.25; P=0.02; adjusted hazard ratio for S4, 6.16; 95% CI,1.97 to 19.26; P=0.002). The haplotype S4 was present in carriersof two SNPs in strong linkage disequilibrium (1063 A/G [D299G]and 1363 C/T [T399I]) that influence TLR4 function. In the validationstudy, donor haplotype S4 also increased the risk of invasiveaspergillosis (adjusted odds ratio, 2.49; 95% CI, 1.15 to 5.41;P=0.02); the association was present in unrelated recipientsof hematopoietic-cell transplants (odds ratio, 5.00; 95% CI,1.04 to 24.01; P=0.04) but not in related recipients (odds ratio,2.29; 95% CI, 0.93 to 5.68; P=0.07). In the discovery study,seropositivity for cytomegalovirus (CMV) in donors or recipients,donor positivity for S4, or both, as compared with negativeresults for CMV and S4, were associated with an increase inthe 3-year probability of invasive aspergillosis (12% vs. 1%,P=0.02) and death that was not related to relapse (35% vs. 22%,P=0.02).

Conclusions This study suggests an association between the donorTLR4 haplotype S4 and the risk of invasive aspergillosis amongrecipients of hematopoietic-cell transplants from unrelateddonors.

Feasibility of Treating Prehypertension with an Angiotensin-Receptor Blocker

2009-01-29T20:08:00.000-08:00

Stevo Julius, M.D., Sc.D., Shawna D. Nesbitt, M.D., Brent M. Egan, M.D., Michael A. Weber, M.D., Eric L. Michelson, M.D., Niko Kaciroti, Ph.D., Henry R. Black, M.D., Richard H. Grimm, Jr., M.D., Ph.D., Franz H. Messerli, M.D., Suzanne Oparil, M.D., M. Anthony Schork, Ph.D., for the Trial of Preventing Hypertension (TROPHY) Study Investigators

ABSTRACT

Background Prehypertension is considered a precursor of stage1 hypertension and a predictor of excessive cardiovascular risk.We investigated whether pharmacologic treatment of prehypertensionprevents or postpones stage 1 hypertension.

Methods Participants with repeated measurements of systolicpressure of 130 to 139 mm Hg and diastolic pressure of 89 mmHg or lower, or systolic pressure of 139 mm Hg or lower anddiastolic pressure of 85 to 89 mm Hg, were randomly assignedto receive two years of candesartan (Atacand, AstraZeneca) orplacebo, followed by two years of placebo for all. When a participantreached the study end point of stage 1 hypertension, treatmentwith antihypertensive agents was initiated. Both the candesartangroup and the placebo group were instructed to make changesin lifestyle to reduce blood pressure throughout the trial.

Results A total of 409 participants were randomly assigned tocandesartan, and 400 to placebo. Data on 772 participants (391in the candesartan group and 381 in the placebo group; meanage, 48.5 years; 59.6 percent men) were available for analysis.During the first two years, hypertension developed in 154 participantsin the placebo group and 53 of those in the candesartan group(relative risk reduction, 66.3 percent; P<0.001).> years, hypertension had developed in 240 participants in theplacebo group and 208 of those in the candesartan group (relativerisk reduction, 15.6 percent; P<0.007).> occurred in 3.5 percent of the participants assigned to candesartanand 5.9 percent of those receiving placebo.

Conclusions Over a period of four years, stage 1 hypertensiondeveloped in nearly two thirds of patients with untreated prehypertension(the placebo group). Treatment of prehypertension with candesartanappeared to be well tolerated and reduced the risk of incidenthypertension during the study period. Thus, treatment of prehypertensionappears to be feasible. (ClinicalTrials.gov number, NCT00227318 [ClinicalTrials.gov] .)

Treatment of Hypertension in Patients 80 Years of Age or Older

2009-01-29T20:04:00.000-08:00

Nigel S. Beckett, M.B., Ch.B., Ruth Peters, Ph.D., Astrid E. Fletcher, Ph.D., Jan A. Staessen, M.D., Ph.D., Lisheng Liu, M.D., Dan Dumitrascu, M.D., Vassil Stoyanovsky, M.D., Riitta L. Antikainen, M.D., Ph.D., Yuri Nikitin, M.D., Craig Anderson, M.D., Ph.D., Alli Belhani, M.D., Françoise Forette, M.D., Chakravarthi Rajkumar, M.D., Ph.D., Lutgarde Thijs, M.Sc., Winston Banya, M.Sc., Christopher J. Bulpitt, M.D., for the HYVET Study Group

ABSTRACT

Background Whether the treatment of patients with hypertensionwho are 80 years of age or older is beneficial is unclear. Ithas been suggested that antihypertensive therapy may reducethe risk of stroke, despite possibly increasing the risk ofdeath.

Methods We randomly assigned 3845 patients from Europe, China,Australasia, and Tunisia who were 80 years of age or older andhad a sustained systolic blood pressure of 160 mm Hg or moreto receive either the diuretic indapamide (sustained release,1.5 mg) or matching placebo. The angiotensin-converting–enzymeinhibitor perindopril (2 or 4 mg), or matching placebo, wasadded if necessary to achieve the target blood pressure of 150/80mm Hg. The primary end point was fatal or nonfatal stroke.

Results The active-treatment group (1933 patients) and the placebogroup (1912 patients) were well matched (mean age, 83.6 years;mean blood pressure while sitting, 173.0/90.8 mm Hg); 11.8%had a history of cardiovascular disease. Median follow-up was1.8 years. At 2 years, the mean blood pressure while sittingwas 15.0/6.1 mm Hg lower in the active-treatment group thanin the placebo group. In an intention-to-treat analysis, activetreatment was associated with a 30% reduction in the rate offatal or nonfatal stroke (95% confidence interval [CI], –1to 51; P=0.06), a 39% reduction in the rate of death from stroke(95% CI, 1 to 62; P=0.05), a 21% reduction in the rate of deathfrom any cause (95% CI, 4 to 35; P=0.02), a 23% reduction inthe rate of death from cardiovascular causes (95% CI, –1to 40; P=0.06), and a 64% reduction in the rate of heart failure(95% CI, 42 to 78; P<0.001).> were reported in the active-treatment group (358, vs. 448 inthe placebo group; P=0.001).

Conclusions The results provide evidence that antihypertensivetreatment with indapamide (sustained release), with or withoutperindopril, in persons 80 years of age or older is beneficial.(ClinicalTrials.gov number, NCT00122811 [ClinicalTrials.gov] .)

Modulation of Blood Pressure by Central Melanocortinergic Pathways

2009-01-29T19:59:00.000-08:00

ABSTRACT

Conclusions Results of our genetic and pharmacologic studiesimplicate melanocortinergic signaling in the control of humanblood pressure through an insulin-independent mechanism.

Effects of Torcetrapib in Patients at High Risk for Coronary Events

2009-01-29T09:43:00.000-08:00

Philip J. Barter, M.D., Ph.D., Mark Caulfield, M.D., M.B., B.S., Mats Eriksson, M.D., Ph.D., Scott M. Grundy, M.D., Ph.D., John J.P. Kastelein, M.D., Ph.D., Michel Komajda, M.D., Jose Lopez-Sendon, M.D., Ph.D., Lori Mosca, M.D., M.P.H., Ph.D., Jean-Claude Tardif, M.D., David D. Waters, M.D., Charles L. Shear, Dr.P.H., James H. Revkin, M.D., Kevin A. Buhr, Ph.D., Marian R. Fisher, Ph.D., Alan R. Tall, M.B., B.S., Bryan Brewer, M.D., Ph.D., for the ILLUMINATE Investigators

ABSTRACT

Background Inhibition of cholesteryl ester transfer protein(CETP) has been shown to have a substantial effect on plasmalipoprotein levels. We investigated whether torcetrapib, a potentCETP inhibitor, might reduce major cardiovascular events. Thetrial was terminated prematurely because of an increased riskof death and cardiac events in patients receiving torcetrapib.

Methods We conducted a randomized, double-blind study involving15,067 patients at high cardiovascular risk. The patients receivedeither torcetrapib plus atorvastatin or atorvastatin alone.The primary outcome was the time to the first major cardiovascularevent, which was defined as death from coronary heart disease,nonfatal myocardial infarction, stroke, or hospitalization forunstable angina.

Results At 12 months in patients who received torcetrapib, therewas an increase of 72.1% in high-density lipoprotein cholesteroland a decrease of 24.9% in low-density lipoprotein cholesterol,as compared with baseline (P<0.001> in addition to an increase of 5.4 mm Hg in systolic blood pressure,a decrease in serum potassium, and increases in serum sodium,bicarbonate, and aldosterone (P<0.001> There was also an increased risk of cardiovascular events (hazardratio, 1.25; 95% confidence interval [CI], 1.09 to 1.44; P=0.001)and death from any cause (hazard ratio, 1.58; 95% CI, 1.14 to2.19; P=0.006). Post hoc analyses showed an increased risk ofdeath in patients treated with torcetrapib whose reduction inpotassium or increase in bicarbonate was greater than the medianchange.

Conclusions Torcetrapib therapy resulted in an increased riskof mortality and morbidity of unknown mechanism. Although therewas evidence of an off-target effect of torcetrapib, we cannotrule out adverse effects related to CETP inhibition. (ClinicalTrials.govnumber, NCT00134264 [ClinicalTrials.gov] .)

A Comparison of Bare-Metal and Drug-Eluting Stents for Off-Label Indications

2009-01-29T09:38:00.000-08:00

Oscar C. Marroquin, M.D., Faith Selzer, Ph.D., Suresh R. Mulukutla, M.D., David O. Williams, M.D., Helen A. Vlachos, M.Sc., Robert L. Wilensky, M.D., Jean-François Tanguay, M.D., Elizabeth M. Holper, M.D., J. Dawn Abbott, M.D., Joon S. Lee, M.D., Conrad Smith, M.D., William D. Anderson, M.D., Sheryl F. Kelsey, Ph.D., and Kevin E. Kip, Ph.D.

ABSTRACT

Background Recent reports suggest that off-label use of drug-elutingstents is associated with an increased incidence of adverseevents. Whether the use of bare-metal stents would yield differentresults is unknown.

Methods We analyzed data from 6551 patients in the NationalHeart, Lung, and Blood Institute Dynamic Registry accordingto whether they were treated with drug-eluting stents or bare-metalstents and whether use was standard or off-label. Patients werefollowed for 1 year for the occurrence of cardiovascular eventsand death. Off-label use was defined as use in restenotic lesions,lesions in a bypass graft, left main coronary artery disease,or ostial, bifurcated, or totally occluded lesions, as wellas use in patients with a reference-vessel diameter of lessthan 2.5 mm or greater than 3.75 mm or a lesion length of morethan 30 mm.

Results Off-label use occurred in 54.7% of all patients withbare-metal stents and 48.7% of patients with drug-eluting stents.As compared with patients with bare-metal stents, patients withdrug-eluting stents had a higher prevalence of diabetes, hypertension,renal disease, previous percutaneous coronary intervention andcoronary-artery bypass grafting, and multivessel coronary arterydisease. One year after intervention, however, there were nosignificant differences in the adjusted risk of death or myocardialinfarction in patients with drug-eluting stents as comparedwith those with bare-metal stents, whereas the risk of repeatrevascularization was significantly lower among patients withdrug-eluting stents.

Conclusions Among patients with off-label indications, the useof drug-eluting stents was not associated with an increasedrisk of death or myocardial infarction but was associated witha lower rate of repeat revascularization at 1 year, as comparedwith bare-metal stents. These findings support the use of drug-elutingstents for off-label indications.

The Effect of Aprotinin on Outcome after Coronary-Artery Bypass Grafting

2009-01-29T09:37:00.000-08:00

Andrew D. Shaw, M.B., Mark Stafford-Smith, M.D., William D. White, M.P.H., Barbara Phillips-Bute, Ph.D., Madhav Swaminathan, M.D., Carmelo Milano, M.D., Ian J. Welsby, M.B., Solomon Aronson, M.D., Joseph P. Mathew, M.D., Eric D. Peterson, M.D., M.P.H., and Mark F. Newman, M.D.

ABSTRACT

Background Aprotinin has recently been associated with adverseoutcomes in patients undergoing cardiac surgery. We reviewedour experience with this agent in patients undergoing cardiacsurgery at Duke University Medical Center.

Methods We retrieved data on 10,275 consecutive patients undergoingsurgical coronary revascularization at Duke between January1, 1996, and December 31, 2005. We fit data to a logistic-regressionmodel predicting each patient's likelihood of receiving aprotininon the basis of preoperative characteristics and to models predictinglong-term survival (up to 10 years) and decline in renal function,as measured by increases in serum creatinine levels.

Results A total of 1343 patients (13.2%) received aprotinin,6776 patients (66.8%) received aminocaproic acid, and 2029 patients(20.0%) received no antifibrinolytic therapy. All patients underwentcoronary-artery bypass grafting, and 1181 patients (11.5%) underwentcombined coronary-artery bypass grafting and valve surgery.In the risk-adjusted model, survival was worse among patientstreated with aprotinin, with a main-effects hazard ratio fordeath of 1.32 (95% confidence interval [CI], 1.12 to 1.55) forthe comparison with patients receiving no antifibrinolytic therapy(P=0.003) and 1.27 (95% CI, 1.10 to 1.46) for the comparisonwith patients receiving aminocaproic acid (P=0.004). As comparedwith the use of aminocaproic acid or no antifibrinolytic agent,aprotinin use was also associated with a larger risk-adjustedincrease in the serum creatinine level (P<0.001)> with a greater risk-adjusted incidence of dialysis (P=0.56).

Conclusions Patients who received aprotinin had a higher mortalityrate and larger increases in serum creatinine levels than thosewho received aminocaproic acid or no antifibrinolytic agent.

Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death

2009-01-29T09:26:00.000-08:00

Sebastian Schneeweiss, M.D., Sc.D., John D. Seeger, Pharm.D., Dr.P.H., Joan Landon, M.P.H., and Alexander M. Walker, M.D., Dr.P.H.

ABSTRACT

Background Aprotinin (Trasylol) is used to mitigate bleedingduring coronary-artery bypass grafting (CABG). Accumulatingevidence suggests that this practice increases mortality.

Methods Using electronic administrative records of the PremierPerspective Comparative Database, we studied hospitalized patientswith operating-room charges for the use of aprotinin (33,517patients) or aminocaproic acid (44,682 patients) on the dayCABG was performed. We tabulated the numbers of patients witha hospital-discharge status of death and performed three typesof analyses: a multivariable logistic-regression analysis (primaryanalysis); propensity-score matching in the highly selectedsubcohort of patients who received full amounts of the studydrug, who underwent CABG by surgeons who performed 50 or moreCABG surgeries during the study period, and for whom informationon 10 additional covariates was available because the surgeryoccurred on hospital day 3 or later; and an instrumental-variableanalysis of data from patients whose surgeons showed a strongpreference for one of the two study drugs.

Results In all, 1512 of the 33,517 aprotinin recipients (4.5%)and 1101 of the 44,682 aminocaproic acid recipients (2.5%) died.After adjustment for 41 characteristics of patients and hospitals,the estimated risk of death was 64% higher in the aprotiningroup than in the aminocaproic acid group (relative risk, 1.64;95% confidence interval [CI], 1.50 to 1.78). In the first 7days after surgery, the adjusted relative risk of in-hospitaldeath in the aprotinin group was 1.78 (95% CI, 1.56 to 2.02).The relative risk in a propensity-score–matched analysiswas 1.32 (95% CI, 1.08 to 1.63). In the instrumental-variableanalysis, the use of aprotinin was found to be associated withan excess risk of death of 1.59 per 100 patients (95% CI, 0.14to 3.04). Postoperative revascularization and dialysis weremore frequent among recipients of aprotinin than among recipientsof aminocaproic acid.

Conclusions Patients who received aprotinin alone on the dayof CABG surgery had a higher mortality than patients who receivedaminocaproic acid alone. Characteristics of neither the patientsnor the surgeons explain the difference, which persisted throughseveral approaches to control confounding.

Effect of Screening and Adjuvant Therapy on Mortality from Breast Cancer

2009-01-29T09:10:00.000-08:00

Donald A. Berry, Ph.D., Kathleen A. Cronin, Ph.D., Sylvia K. Plevritis, Ph.D., Dennis G. Fryback, Ph.D., Lauren Clarke, M.S., Marvin Zelen, Ph.D., Jeanne S. Mandelblatt, Ph.D., Andrei Y. Yakovlev, Ph.D., J. Dik F. Habbema, Ph.D., Eric J. Feuer, Ph.D., for the Cancer Intervention and Surveillance Modeling Network (CISNET) Collaborators

ABSTRACT

Background We used modeling techniques to assess the relativeand absolute contributions of screening mammography and adjuvanttreatment to the reduction in breast-cancer mortality in theUnited States from 1975 to 2000.

Methods A consortium of investigators developed seven independentstatistical models of breast-cancer incidence and mortality.All seven groups used the same sources to obtain data on theuse of screening mammography, adjuvant treatment, and benefitsof treatment with respect to the rate of death from breast cancer.

Results The proportion of the total reduction in the rate ofdeath from breast cancer attributed to screening varied in theseven models from 28 to 65 percent (median, 46 percent), withadjuvant treatment contributing the rest. The variability acrossmodels in the absolute contribution of screening was largerthan it was for treatment, reflecting the greater uncertaintyassociated with estimating the benefit of screening.

Conclusions Seven statistical models showed that both screeningmammography and treatment have helped reduce the rate of deathfrom breast cancer in the United States.

Concordance among Gene-Expression–Based Predictors for Breast Cancer

2009-01-29T08:53:00.000-08:00

Cheng Fan, M.S., Daniel S. Oh, Ph.D., Lodewyk Wessels, Ph.D., Britta Weigelt, Ph.D., Dimitry S.A. Nuyten, M.D., Andrew B. Nobel, Ph.D., Laura J. van't Veer, Ph.D., and Charles M. Perou, Ph.D.

ABSTRACT

Background Gene-expression–profiling studies of primarybreast tumors performed by different laboratories have resultedin the identification of a number of distinct prognostic profiles,or gene sets, with little overlap in terms of gene identity.

Methods To compare the predictions derived from these gene setsfor individual samples, we obtained a single data set of 295samples and applied five gene-expression–based models:intrinsic subtypes, 70-gene profile, wound response, recurrencescore, and the two-gene ratio (for patients who had been treatedwith tamoxifen).

Results We found that most models had high rates of concordancein their outcome predictions for the individual samples. Inparticular, almost all tumors identified as having an intrinsicsubtype of basal-like, HER2-positive and estrogen-receptor–negative,or luminal B (associated with a poor prognosis) were also classifiedas having a poor 70-gene profile, activated wound response,and high recurrence score. The 70-gene and recurrence-scoremodels, which are beginning to be used in the clinical setting,showed 77 to 81 percent agreement in outcome classification.

Conclusions Even though different gene sets were used for prognosticationin patients with breast cancer, four of the five tested showedsignificant agreement in the outcome predictions for individualpatients and are probably tracking a common set of biologicphenotypes.

Mammographic Density and the Risk and Detection of Breast Cancer

2009-01-29T08:48:00.000-08:00

Norman F. Boyd, M.D., D.Sc., Helen Guo, M.Sc., Lisa J. Martin, Ph.D., Limei Sun, M.Sc., Jennifer Stone, M.Sc., Eve Fishell, M.D., F.R.C.P.C., Roberta A. Jong, M.D., F.R.C.P.C., Greg Hislop, M.D., F.R.C.P.C., Anna Chiarelli, Ph.D., Salomon Minkin, Ph.D., and Martin J. Yaffe, Ph.D.

ABSTRACT

Background Extensive mammographic density is associated withan increased risk of breast cancer and makes the detection ofcancer by mammography difficult, but the influence of densityon risk according to method of cancer detection is unknown.

Methods We carried out three nested case–control studiesin screened populations with 1112 matched case–controlpairs. We examined the association of the measured percentageof density in the baseline mammogram with risk of breast cancer,according to method of cancer detection, time since the initiationof screening, and age.

Results As compared with women with density in less than 10%of the mammogram, women with density in 75% or more had an increasedrisk of breast cancer (odds ratio, 4.7; 95% confidence interval[CI], 3.0 to 7.4), whether detected by screening (odds ratio,3.5; 95% CI, 2.0 to 6.2) or less than 12 months after a negativescreening examination (odds ratio, 17.8; 95% CI, 4.8 to 65.9).Increased risk of breast cancer, whether detected by screeningor other means, persisted for at least 8 years after study entryand was greater in younger than in older women. For women youngerthan the median age of 56 years, 26% of all breast cancers and50% of cancers detected less than 12 months after a negativescreening test were attributable to density in 50% or more ofthe mammogram.

Conclusions Extensive mammographic density is strongly associatedwith the risk of breast cancer detected by screening or betweenscreening tests. A substantial fraction of breast cancers canbe attributed to this risk factor.

Lifestyle, Diabetes, and Cardiovascular Risk Factors 10 Years after Bariatric Surgery

2009-01-29T02:34:00.000-08:00

Lars Sjöström, M.D., Ph.D., Anna-Karin Lindroos, Ph.D., Markku Peltonen, Ph.D., Jarl Torgerson, M.D., Ph.D., Claude Bouchard, Ph.D., Björn Carlsson, M.D., Ph.D., Sven Dahlgren, M.D., Ph.D., Bo Larsson, M.D., Ph.D., Kristina Narbro, Ph.D., Carl David Sjöström, M.D., Ph.D., Marianne Sullivan, Ph.D., Hans Wedel, Ph.D., for the Swedish Obese Subjects Study Scientific Group

ABSTRACT

Background Weight loss is associated with short-term ameliorationand prevention of metabolic and cardiovascular risk, but whetherthese benefits persist over time is unknown.

Methods The prospective, controlled Swedish Obese Subjects Studyinvolved obese subjects who underwent gastric surgery and contemporaneouslymatched, conventionally treated obese control subjects. We nowreport follow-up data for subjects (mean age, 48 years; meanbody-mass index, 41) who had been enrolled for at least 2 years(4047 subjects) or 10 years (1703 subjects) before the analysis(January 1, 2004). The follow-up rate for laboratory examinationswas 86.6 percent at 2 years and 74.5 percent at 10 years.

Results After two years, the weight had increased by 0.1 percentin the control group and had decreased by 23.4 percent in thesurgery group (P<0.001).> by 1.6 percent and decreased by 16.1 percent, respectively (P<0.001).Energy intake was lower and the proportion of physically activesubjects higher in the surgery group than in the control groupthroughout the observation period. Two- and 10-year rates ofrecovery from diabetes, hypertriglyceridemia, low levels ofhigh-density lipoprotein cholesterol, hypertension, and hyperuricemiawere more favorable in the surgery group than in the controlgroup, whereas recovery from hypercholesterolemia did not differbetween the groups. The surgery group had lower 2- and 10-yearincidence rates of diabetes, hypertriglyceridemia, and hyperuricemiathan the control group; differences between the groups in theincidence of hypercholesterolemia and hypertension were undetectable.

Conclusions As compared with conventional therapy, bariatricsurgery appears to be a viable option for the treatment of severeobesity, resulting in long-term weight loss, improved lifestyle,and, except for hypercholesterolemia, amelioration in risk factorsthat were elevated at baseline.

Premature Birth and Later Insulin Resistance

2009-01-29T02:33:00.000-08:00

Paul L. Hofman, M.B., Ch.B., Fiona Regan, M.B., B.S., Wendy E. Jackson, M.B., Ch.B., Craig Jefferies, M.B., Ch.B., David B. Knight, M.B., B.S., Elizabeth M. Robinson, M.Sc., and Wayne S. Cutfield, M.D.

ABSTRACT

Background Term infants who are small for gestational age appearprone to the development of insulin resistance during childhood.We hypothesized that insulin resistance, a marker of type 2diabetes mellitus, would be prevalent among children who hadbeen born prematurely, irrespective of whether they were appropriatefor gestational age or small for gestational age.

Methods Seventy-two healthy prepubertal children 4 to 10 yearsof age were studied: 50 who had been born prematurely (32 weeks'gestation or less), including 38 with a birth weight that wasappropriate for gestational age (above the 10th percentile)and 12 with a birth weight that was low (i.e., who were small)for gestational age, and 22 control subjects (at least 37 weeks'gestation, with a birth weight above the 10th percentile). Insulinsensitivity was measured with the use of paired insulin andglucose data obtained by frequent measurements during intravenousglucose-tolerance tests.

Results Children who had been born prematurely, whether theirweight was appropriate or low for gestational age, had an isolatedreduction in insulin sensitivity as compared with controls (appropriate-for-gestational-agegroup, 14.2x10^–4 per minute per milliunit per liter [95percent confidence interval, 11.5 to 16.2]; small-for-gestational-agegroup, 12.9x10^–4 per minute per milliunit per liter [95percent confidence interval, 9.7 to 17.4]; and control group,21.6x10^–4 per minute per milliunit per liter [95 percentconfidence interval, 17.1 to 27.4]; P=0.002). There were nosignificant differences in insulin sensitivity between the twopremature groups (P=0.80). As compared with controls, both groupsof premature children had a compensatory increase in acute insulinrelease (appropriate-for-gestational-age group, 2002 pmol perliter [95 percent confidence interval, 2153 to 2432]; small-for-gestational-agegroup, 2253 pmol per liter [95 percent confidence interval,1622 to 3128]; and control group, 1148 pmol per liter [95 percentconfidence interval, 875 to 1500]; P<0.001).

Conclusions Like children who were born at term but who weresmall for gestational age, children who were born prematurelyhave an isolated reduction in insulin sensitivity, which maybe a risk factor for type 2 diabetes mellitus.

Childhood Vaccination and Type 1 Diabetes

2009-01-29T02:32:00.000-08:00

Anders Hviid, M.Sc., Michael Stellfeld, M.D., Jan Wohlfahrt, M.Sc., and Mads Melbye, M.D., Ph.D.

ABSTRACT

Background A link between childhood vaccinations and the developmentof type 1 diabetes has been proposed.

Methods We evaluated a cohort comprising all children born inDenmark from January 1, 1990, through December 31, 2000, forwhom detailed information on vaccinations and type 1 diabeteswas available. Using Poisson regression models, we estimatedrate ratios according to vaccination status, including the trendassociated with the number of doses, among all children andin a subgroup of children who had siblings with type 1 diabetes.Given recent claims of clustering of cases of diabetes two tofour years after vaccination, we also estimated rate ratiosduring the period after vaccination.

Results Type 1 diabetes was diagnosed in 681 children during4,720,517 person-years of follow-up. The rate ratio for type1 diabetes among children who received at least one dose ofvaccine, as compared with unvaccinated children, was 0.91 (95percent confidence interval, 0.74 to 1.12) for Haemophilus influenzaetype b vaccine; 1.02 (95 percent confidence interval, 0.75 to1.37) for diphtheria, tetanus, and inactivated poliovirus vaccine;0.96 (95 percent confidence interval, 0.71 to 1.30) for diphtheria,tetanus, acellular pertussis, and inactivated poliovirus vaccine;1.06 (95 percent confidence interval, 0.80 to 1.40) for whole-cellpertussis vaccine; 1.14 (95 percent confidence interval, 0.90to 1.45) for measles, mumps, and rubella vaccine; and 1.08 (95percent confidence interval, 0.74 to 1.57) for oral poliovirusvaccine. The development of type 1 diabetes in genetically predisposedchildren (defined as those who had siblings with type 1 diabetes)was not significantly associated with vaccination. Furthermore,there was no evidence of any clustering of cases two to fouryears after vaccination with any vaccine.

Conclusions These results do not support a causal relation betweenchildhood vaccination and type 1 diabetes.

International Trial of the Edmonton Protocol for Islet Transplantation

2009-01-29T02:30:00.000-08:00

A.M. James Shapiro, M.D., Ph.D., Camillo Ricordi, M.D., Bernhard J. Hering, M.D., Hugh Auchincloss, M.D., Robert Lindblad, M.D., R. Paul Robertson, M.D., Antonio Secchi, M.D., Mathias D. Brendel, M.D., Thierry Berney, M.D., Daniel C. Brennan, M.D., Enrico Cagliero, M.D., Rodolfo Alejandro, M.D., Edmond A. Ryan, M.D., Barbara DiMercurio, R.N., Philippe Morel, M.D., Kenneth S. Polonsky, M.D., Jo-Anna Reems, Ph.D., Reinhard G. Bretzel, M.D., Federico Bertuzzi, M.D., Tatiana Froud, M.D., Raja Kandaswamy, M.D., David E.R. Sutherland, M.D., Ph.D., George Eisenbarth, M.D., Ph.D., Miriam Segal, Ph.D., Jutta Preiksaitis, M.D., Gregory S. Korbutt, Ph.D., Franca B. Barton, M.S., Lisa Viviano, R.N., Vicki Seyfert-Margolis, Ph.D., Jeffrey Bluestone, Ph.D., and Jonathan R.T. Lakey, Ph.D.

ABSTRACT

Background Islet transplantation offers the potential to improveglycemic control in a subgroup of patients with type 1 diabetesmellitus who are disabled by refractory hypoglycemia. We conductedan international, multicenter trial to explore the feasibilityand reproducibility of islet transplantation with the use ofa single common protocol (the Edmonton protocol).

Methods We enrolled 36 subjects with type 1 diabetes mellitus,who underwent islet transplantation at nine international sites.Islets were prepared from pancreases of deceased donors andwere transplanted within 2 hours after purification, withoutculture. The primary end point was defined as insulin independencewith adequate glycemic control 1 year after the final transplantation.

Results Of the 36 subjects, 16 (44%) met the primary end point,10 (28%) had partial function, and 10 (28%) had complete graftloss 1 year after the final transplantation. A total of 21 subjects(58%) attained insulin independence with good glycemic controlat any point throughout the trial. Of these subjects, 16 (76%)required insulin again at 2 years; 5 of the 16 subjects whoreached the primary end point (31%) remained insulin-independentat 2 years.

Conclusions Islet transplantation with the use of the Edmontonprotocol can successfully restore long-term endogenous insulinproduction and glycemic stability in subjects with type 1 diabetesmellitus and unstable control, but insulin independence is usuallynot sustainable. Persistent islet function even without insulinindependence provides both protection from severe hypoglycemiaand improved levels of glycated hemoglobin. (ClinicalTrials.govnumber, NCT00014911 [ClinicalTrials.gov] .)

Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes

2009-01-29T02:27:00.000-08:00

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group

ABSTRACT

Background Intensive diabetes therapy aimed at achieving nearnormoglycemia reduces the risk of microvascular and neurologiccomplications of type 1 diabetes. We studied whether the useof intensive therapy as compared with conventional therapy duringthe Diabetes Control and Complications Trial (DCCT) affectedthe long-term incidence of cardiovascular disease.

Methods The DCCT randomly assigned 1441 patients with type 1diabetes to intensive or conventional therapy, treating themfor a mean of 6.5 years between 1983 and 1993. Ninety-threepercent were subsequently followed until February 1, 2005, duringthe observational Epidemiology of Diabetes Interventions andComplications study. Cardiovascular disease (defined as nonfatalmyocardial infarction, stroke, death from cardiovascular disease,confirmed angina, or the need for coronary-artery revascularization)was assessed with standardized measures and classified by anindependent committee.

Results During the mean 17 years of follow-up, 46 cardiovasculardisease events occurred in 31 patients who had received intensivetreatment in the DCCT, as compared with 98 events in 52 patientswho had received conventional treatment. Intensive treatmentreduced the risk of any cardiovascular disease event by 42 percent(95 percent confidence interval, 9 to 63 percent; P=0.02) andthe risk of nonfatal myocardial infarction, stroke, or deathfrom cardiovascular disease by 57 percent (95 percent confidenceinterval, 12 to 79 percent; P=0.02). The decrease in glycosylatedhemoglobin values during the DCCT was significantly associatedwith most of the positive effects of intensive treatment onthe risk of cardiovascular disease. Microalbuminuria and albuminuriawere associated with a significant increase in the risk of cardiovasculardisease, but differences between treatment groups remained significant(P0.05) after adjusting for these factors.

Conclusions Intensive diabetes therapy has long-term beneficialeffects on the risk of cardiovascular disease in patients withtype 1 diabetes.

Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy

2009-01-29T02:26:00.002-08:00

Steven E. Kahn, M.B., Ch.B., Steven M. Haffner, M.D., Mark A. Heise, Ph.D., William H. Herman, M.D., M.P.H., Rury R. Holman, F.R.C.P., Nigel P. Jones, M.A., Barbara G. Kravitz, M.S., John M. Lachin, Sc.D., M. Colleen O'Neill, B.Sc., Bernard Zinman, M.D., F.R.C.P.C., Giancarlo Viberti, M.D., F.R.C.P., for the ADOPT Study Group

ABSTRACT

Background The efficacy of thiazolidinediones, as compared withother oral glucose-lowering medications, in maintaining long-termglycemic control in type 2 diabetes is not known.

Methods We evaluated rosiglitazone, metformin, and glyburideas initial treatment for recently diagnosed type 2 diabetesin a double-blind, randomized, controlled clinical trial involving4360 patients. The patients were treated for a median of 4.0years. The primary outcome was the time to monotherapy failure,which was defined as a confirmed level of fasting plasma glucoseof more than 180 mg per deciliter (10.0 mmol per liter), forrosiglitazone, as compared with metformin or glyburide. Prespecifiedsecondary outcomes were levels of fasting plasma glucose andglycated hemoglobin, insulin sensitivity, and -cell function.

Results Kaplan–Meier analysis showed a cumulative incidenceof monotherapy failure at 5 years of 15% with rosiglitazone,21% with metformin, and 34% with glyburide. This representsa risk reduction of 32% for rosiglitazone, as compared withmetformin, and 63%, as compared with glyburide (P<0.001> both comparisons). The difference in the durability of the treatmenteffect was greater between rosiglitazone and glyburide thanbetween rosiglitazone and metformin. Glyburide was associatedwith a lower risk of cardiovascular events (including congestiveheart failure) than was rosiglitazone (P<0.05),> associated with metformin was similar to that with rosiglitazone.Rosiglitazone was associated with more weight gain and edemathan either metformin or glyburide but with fewer gastrointestinalevents than metformin and with less hypoglycemia than glyburide(P<0.001>

Conclusions The potential risks and benefits, the profile ofadverse events, and the costs of these three drugs should allbe considered to help inform the choice of pharmacotherapy forpatients with type 2 diabetes. (ClinicalTrials.gov number, NCT00279045 [ClinicalTrials.gov] .)

Effect of Ramipril on the Incidence of Diabetes

2009-01-29T02:26:00.001-08:00

The DREAM Trial Investigators

ABSTRACT

Background Previous studies have suggested that blockade ofthe renin–angiotensin system may prevent diabetes in peoplewith cardiovascular disease or hypertension.

Methods In a double-blind, randomized clinical trial with a2-by-2 factorial design, we randomly assigned 5269 participantswithout cardiovascular disease but with impaired fasting glucoselevels (after an 8-hour fast) or impaired glucose toleranceto receive ramipril (up to 15 mg per day) or placebo (and rosiglitazoneor placebo) and followed them for a median of 3 years. We studiedthe effects of ramipril on the development of diabetes or death,whichever came first (the primary outcome), and on secondaryoutcomes, including regression to normoglycemia.

Results The incidence of the primary outcome did not differsignificantly between the ramipril group (18.1%) and the placebogroup (19.5%; hazard ratio for the ramipril group, 0.91; 95%confidence interval [CI], 0.81 to 1.03; P=0.15). Participantsreceiving ramipril were more likely to have regression to normoglycemiathan those receiving placebo (hazard ratio, 1.16; 95% CI, 1.07to 1.27; P=0.001). At the end of the study, the median fastingplasma glucose level was not significantly lower in the ramiprilgroup (102.7 mg per deciliter [5.70 mmol per liter]) than inthe placebo group (103.4 mg per deciliter [5.74 mmol per liter],P=0.07), though plasma glucose levels 2 hours after an oralglucose load were significantly lower in the ramipril group(135.1 mg per deciliter [7.50 mmol per liter] vs. 140.5 mg perdeciliter [7.80 mmol per liter], P=0.01).

Conclusions Among persons with impaired fasting glucose levelsor impaired glucose tolerance, the use of ramipril for 3 yearsdoes not significantly reduce the incidence of diabetes or deathbut does significantly increase regression to normoglycemia.(ClinicalTrials.gov number, NCT00095654 [ClinicalTrials.gov] .)

Glucose Regulation in Young Adults with Very Low Birth Weight

2009-01-29T02:24:00.002-08:00

Petteri Hovi, M.D., Sture Andersson, M.D., Ph.D., Johan G. Eriksson, M.D., Ph.D., Anna-Liisa Järvenpää, M.D., Ph.D., Sonja Strang-Karlsson, M.D., Outi Mäkitie, M.D., Ph.D., and Eero Kajantie, M.D., Ph.D.

ABSTRACT

Background The association between small size at birth and impairedglucose regulation later in life is well established in personsborn at term. Preterm birth with very low birth weight (<1500g) is also associated with insulin resistance in childhood.If insulin resistance persists into adulthood, preterm birthwith very low birth weight also may be associated with an increasedrisk of disease in adulthood. We assessed glucose toleranceand insulin sensitivity and measured serum lipid levels andblood pressure in young adults with very low birth weight.

Methods We performed a standard 75-g oral glucose-tolerancetest, measuring insulin and glucose concentrations at baselineand at 120 minutes in 163 young adults (age range, 18 to 27years) with very low birth weight and in 169 subjects who hadbeen born at term and were not small for gestational age. Thetwo groups were similar with regard to age, sex, and birth hospital.We measured blood pressure and serum lipid levels, and in 150very-low-birth-weight subjects and 136 subjects born at term,we also measured body composition by means of dual-energy x-rayabsorptiometry.

Results As compared with the subjects born at term, the very-low-birth-weightsubjects had a 6.7% increase in the 2-hour glucose concentration(95% confidence interval [CI], 0.8 to 12.9), a 16.7% increasein the fasting insulin concentration (95% CI, 4.6 to 30.2),a 40.0% increase in the 2-hour insulin concentration (95% CI,17.5 to 66.8), an 18.9% increase in the insulin-resistance indexdetermined by homeostatic model assessment (95% CI, 5.7 to 33.7),and an increase of 4.8 mm Hg in systolic blood pressure (95%CI, 2.1 to 7.4). Adjustment for the lower lean body mass inthe very-low-birth-weight subjects did not attenuate these relationships.

Conclusions Young adults with a very low birth weight have higherindexes of insulin resistance and glucose intolerance and higherblood pressure than those born at term.

Hyperglycemia and Adverse Pregnancy Outcomes

2009-01-29T02:24:00.001-08:00

The HAPO Study Cooperative Research Group

ABSTRACT

Background It is controversial whether maternal hyperglycemialess severe than that in diabetes mellitus is associated withincreased risks of adverse pregnancy outcomes.

Methods A total of 25,505 pregnant women at 15 centers in ninecountries underwent 75-g oral glucose-tolerance testing at 24to 32 weeks of gestation. Data remained blinded if the fastingplasma glucose level was 105 mg per deciliter (5.8 mmol perliter) or less and the 2-hour plasma glucose level was 200 mgper deciliter (11.1 mmol per liter) or less. Primary outcomeswere birth weight above the 90th percentile for gestationalage, primary cesarean delivery, clinically diagnosed neonatalhypoglycemia, and cord-blood serum C-peptide level above the90th percentile. Secondary outcomes were delivery before 37weeks of gestation, shoulder dystocia or birth injury, needfor intensive neonatal care, hyperbilirubinemia, and preeclampsia.

Results For the 23,316 participants with blinded data, we calculatedadjusted odds ratios for adverse pregnancy outcomes associatedwith an increase in the fasting plasma glucose level of 1 SD(6.9 mg per deciliter [0.4 mmol per liter]), an increase inthe 1-hour plasma glucose level of 1 SD (30.9 mg per deciliter[1.7 mmol per liter]), and an increase in the 2-hour plasmaglucose level of 1 SD (23.5 mg per deciliter [1.3 mmol per liter]).For birth weight above the 90th percentile, the odds ratioswere 1.38 (95% confidence interval [CI], 1.32 to 1.44), 1.46(1.39 to 1.53), and 1.38 (1.32 to 1.44), respectively; for cord-bloodserum C-peptide level above the 90th percentile, 1.55 (95% CI,1.47 to 1.64), 1.46 (1.38 to 1.54), and 1.37 (1.30 to 1.44);for primary cesarean delivery, 1.11 (95% CI, 1.06 to 1.15),1.10 (1.06 to 1.15), and 1.08 (1.03 to 1.12); and for neonatalhypoglycemia, 1.08 (95% CI, 0.98 to 1.19), 1.13 (1.03 to 1.26),and 1.10 (1.00 to 1.12). There were no obvious thresholds atwhich risks increased. Significant associations were also observedfor secondary outcomes, although these tended to be weaker.

Conclusions Our results indicate strong, continuous associationsof maternal glucose levels below those diagnostic of diabeteswith increased birth weight and increased cord-blood serum C-peptidelevels.

GAD Treatment and Insulin Secretion in Recent-Onset Type 1 Diabetes

2009-01-29T02:22:00.002-08:00

Johnny Ludvigsson, M.D., Ph.D., Maria Faresjö, Ph.D., Maria Hjorth, M.Sc., Stina Axelsson, M.Sc., Mikael Chéramy, M.Sc., Mikael Pihl, M.Sc., Outi Vaarala, M.D., Ph.D., Gun Forsander, M.D., Ph.D., Sten Ivarsson, M.D., Ph.D., Calle Johansson, M.D., Agne Lindh, M.D., Nils-Östen Nilsson, M.D., Jan Åman, M.D., Ph.D., Eva Örtqvist, M.D., Ph.D., Peter Zerhouni, M.Sc., and Rosaura Casas, Ph.D.

ABSTRACT

Background The 65-kD isoform of glutamic acid decarboxylase(GAD) is a major autoantigen in patients with type 1 diabetesmellitus. This trial assessed the ability of alum-formulatedGAD (GAD-alum) to reverse recent-onset type 1 diabetes in patients10 to 18 years of age.

Methods We randomly assigned 70 patients with type 1 diabeteswho had fasting C-peptide levels above 0.1 nmol per liter (0.3ng per milliliter) and GAD autoantibodies, recruited within18 months after receiving the diagnosis of diabetes, to receivesubcutaneous injections of 20 µg of GAD-alum (35 patients)or placebo (alum alone, 35 patients) on study days 1 and 30.At day 1 and months 3, 9, 15, 21, and 30, patients underwenta mixed-meal tolerance test to stimulate residual insulin secretion(measured as the C-peptide level). The effect of GAD-alum onthe immune system was also studied.

Results Insulin secretion gradually decreased in both studygroups. The study treatment had no significant effect on changein fasting C-peptide level after 15 months (the primary endpoint). Fasting C-peptide levels declined from baseline levelssignificantly less over 30 months in the GAD-alum group thanin the placebo group (–0.21 vs. –0.27 nmol per liter[–0.62 vs. –0.81 ng per milliliter], P=0.045), asdid stimulated secretion measured as the area under the curve(–0.72 vs. –1.02 nmol per liter per 2 hours [–2.20vs. –3.08 ng per milliliter per 2 hours], P=0.04). Noprotective effect was seen in patients treated 6 months or moreafter receiving the diagnosis. Adverse events appeared to bemild and similar in frequency between the two groups. The GAD-alumtreatment induced a GAD-specific immune response.

Conclusions GAD-alum may contribute to the preservation of residualinsulin secretion in patients with recent-onset type 1 diabetes,although it did not change the insulin requirement. (ClinicalTrials.govnumber, NCT00435981 [ClinicalTrials.gov] .)

Early Insulin Therapy in Very-Low-Birth-Weight Infants

2009-01-29T02:22:00.001-08:00

Kathryn Beardsall, M.R.C.P., Sophie Vanhaesebrouck, M.D., Amanda L. Ogilvy-Stuart, D.M., Christine Vanhole, Ph.D., Christopher R. Palmer, Ph.D., Mirjam van Weissenbruch, Ph.D., Paula Midgley, M.D., Michael Thompson, F.R.C.P., Marta Thio, M.D., Luc Cornette, M.D., Iviano Ossuetta, M.R.C.P., Isabel Iglesias, M.D., Claire Theyskens, M.D., Miranda de Jong, M.D., Jag S. Ahluwalia, F.R.C.P.C.H., Francis de Zegher, Ph.D., and David B. Dunger, M.D.

ABSTRACT

Background Studies involving adults and children being treatedin intensive care units indicate that insulin therapy and glucosecontrol may influence survival. Hyperglycemia in very-low-birth-weightinfants is also associated with morbidity and mortality. Thisinternational randomized, controlled trial aimed to determinewhether early insulin replacement reduced hyperglycemia andaffected outcomes in such neonates.

Methods In this multicenter trial, we assigned 195 infants tocontinuous infusion of insulin at a dose of 0.05 U per kilogramof body weight per hour with 20% dextrose support and 194 tostandard neonatal care on days 1 to 7. The efficacy of glucosecontrol was assessed by continuous glucose monitoring. The primaryoutcome was mortality at the expected date of delivery. Thestudy was discontinued early because of concerns about futilitywith regard to the primary outcome and potential harm.

Results As compared with infants in the control group, infantsin the early-insulin group had lower mean (±SD) glucoselevels (6.2±1.4 vs. 6.7±2.2 mmol per liter [112±25vs. 121±40 mg per deciliter], P=0.007). Fewer infantsin the early-insulin group had hyperglycemia for more than 10%of the first week of life (21% vs. 33%, P=0.008). The early-insulingroup had significantly more carbohydrate infused (51±13vs. 43±10 kcal per kilogram per day, P<0.001)> less weight loss in the first week (standard-deviation scorefor change in weight, –0.55±0.52 vs. –0.70±0.47;P=0.006). More infants in the early-insulin group had episodesof hypoglycemia (defined as a blood glucose level of <2.6mmol per liter [47 mg per deciliter] for >1 hour) (29% inthe early-insulin group vs. 17% in the control group, P=0.005),and the increase in hypoglycemia was significant in infantswith birth weights of more than 1 kg. There were no differencesin the intention-to-treat analyses for the primary outcome (mortalityat the expected date of delivery) and the secondary outcome(morbidity). In the intention-to-treat analysis, mortality at28 days was higher in the early-insulin group than in the controlgroup (P=0.04).

Conclusions Early insulin therapy offers little clinical benefitin very-low-birth-weight infants. It reduces hyperglycemia butmay increase hypoglycemia (Current Controlled Trials number,ISRCTN78428828 [controlled-trials.com] .)

Genotype Score in Addition to Common Risk Factors for Prediction of Type 2 Diabetes

2009-01-29T02:21:00.000-08:00

James B. Meigs, M.D., M.P.H., Peter Shrader, M.S., Lisa M. Sullivan, Ph.D., Jarred B. McAteer, B.A., Caroline S. Fox, M.D., M.P.H., Josée Dupuis, Ph.D., Alisa K. Manning, M.A., Jose C. Florez, M.D., Ph.D., Peter W.F. Wilson, M.D., Ralph B. D'Agostino, Sr., Ph.D., and L. Adrienne Cupples, Ph.D.

ABSTRACT

Background Multiple genetic loci have been convincingly associatedwith the risk of type 2 diabetes mellitus. We tested the hypothesisthat knowledge of these loci allows better prediction of riskthan knowledge of common phenotypic risk factors alone.

Methods We genotyped single-nucleotide polymorphisms (SNPs)at 18 loci associated with diabetes in 2377 participants ofthe Framingham Offspring Study. We created a genotype scorefrom the number of risk alleles and used logistic regressionto generate C statistics indicating the extent to which thegenotype score can discriminate the risk of diabetes when usedalone and in addition to clinical risk factors.

Results There were 255 new cases of diabetes during 28 yearsof follow-up. The mean (±SD) genotype score was 17.7±2.7among subjects in whom diabetes developed and 17.1±2.6among those in whom diabetes did not develop (P<0.001).> sex-adjusted odds ratio for diabetes was 1.12 per risk allele(95% confidence interval, 1.07 to 1.17). The C statistic was0.534 without the genotype score and 0.581 with the score (P=>0.01).In a model adjusted for sex and self-reported family historyof diabetes, the C statistic was 0.595 without the genotypescore and 0.615 with the score (P=0.11). In a model adjustedfor age, sex, family history, body-mass index, fasting glucoselevel, systolic blood pressure, high-density lipoprotein cholesterollevel, and triglyceride level, the C statistic was 0.900 withoutthe genotype score and 0.901 with the score (P=0.49). The genotypescore resulted in the appropriate risk reclassification of,at most, 4% of the subjects.

Conclusions A genotype score based on 18 risk alleles predictednew cases of diabetes in the community but provided only a slightlybetter prediction of risk than knowledge of common risk factorsalone.

Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes

2009-01-29T02:20:00.001-08:00

William Duckworth, M.D., Carlos Abraira, M.D., Thomas Moritz, M.S., Domenic Reda, Ph.D., Nicholas Emanuele, M.D., Peter D. Reaven, M.D., Franklin J. Zieve, M.D., Ph.D., Jennifer Marks, M.D., Stephen N. Davis, M.D., Rodney Hayward, M.D., Stuart R. Warren, J.D., Pharm.D., Steven Goldman, M.D., Madeline McCarren, Ph.D., M.P.H., Mary Ellen Vitek, William G. Henderson, Ph.D., Grant D. Huang, M.P.H., Ph.D., for the VADT Investigator

ABSTRACT

Background The effects of intensive glucose control on cardiovascularevents in patients with long-standing type 2 diabetes mellitusremain uncertain.

Methods We randomly assigned 1791 military veterans (mean age,60.4 years) who had a suboptimal response to therapy for type2 diabetes to receive either intensive or standard glucose control.Other cardiovascular risk factors were treated uniformly. Themean number of years since the diagnosis of diabetes was 11.5,and 40% of the patients had already had a cardiovascular event.The goal in the intensive-therapy group was an absolute reductionof 1.5 percentage points in the glycated hemoglobin level, ascompared with the standard-therapy group. The primary outcomewas the time from randomization to the first occurrence of amajor cardiovascular event, a composite of myocardial infarction,stroke, death from cardiovascular causes, congestive heart failure,surgery for vascular disease, inoperable coronary disease, andamputation for ischemic gangrene.

Results The median follow-up was 5.6 years. Median glycatedhemoglobin levels were 8.4% in the standard-therapy group and6.9% in the intensive-therapy group. The primary outcome occurredin 264 patients in the standard-therapy group and 235 patientsin the intensive-therapy group (hazard ratio in the intensive-therapygroup, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P=0.14).There was no significant difference between the two groups inany component of the primary outcome or in the rate of deathfrom any cause (hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P=0.62).No differences between the two groups were observed for microvascularcomplications. The rates of adverse events, predominantly hypoglycemia,were 17.6% in the standard-therapy group and 24.1% in the intensive-therapygroup.

Conclusions Intensive glucose control in patients with poorlycontrolled type 2 diabetes had no significant effect on therates of major cardiovascular events, death, or microvascularcomplications. (ClinicalTrials.gov number, NCT00032487 [ClinicalTrials.gov] .)

Clinical Risk Factors, DNA Variants, and the Development of Type 2 Diabetes

2009-01-29T02:16:00.000-08:00

Valeriya Lyssenko, M.D., Anna Jonsson, M.Sc., Peter Almgren, M.Sc., Nicoló Pulizzi, M.D., Bo Isomaa, M.D., Tiinamaija Tuomi, M.D., Göran Berglund, M.D., David Altshuler, M.D., Peter Nilsson, M.D., and Leif Groop, M.D.

ABSTRACT

Background Type 2 diabetes mellitus is thought to develop froman interaction between environmental and genetic factors. Weexamined whether clinical or genetic factors or both could predictprogression to diabetes in two prospective cohorts.

Methods We genotyped 16 single-nucleotide polymorphisms (SNPs)and examined clinical factors in 16,061 Swedish and 2770 Finnishsubjects. Type 2 diabetes developed in 2201 (11.7%) of thesesubjects during a median follow-up period of 23.5 years. Wealso studied the effect of genetic variants on changes in insulinsecretion and action over time.

Results Strong predictors of diabetes were a family historyof the disease, an increased body-mass index, elevated liver-enzymelevels, current smoking status, and reduced measures of insulinsecretion and action. Variants in 11 genes (TCF7L2, PPARG, FTO,KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX)were significantly associated with the risk of type 2 diabetesindependently of clinical risk factors; variants in 8 of thesegenes were associated with impaired beta-cell function. Theaddition of specific genetic information to clinical factorsslightly improved the prediction of future diabetes, with aslight increase in the area under the receiver-operating-characteristiccurve from 0.74 to 0.75; however, the magnitude of the increasewas significant (P=1.0x10^–4). The discriminative powerof genetic risk factors improved with an increasing durationof follow-up, whereas that of clinical risk factors decreased.

Conclusions As compared with clinical risk factors alone, commongenetic variants associated with the risk of diabetes had asmall effect on the ability to predict the future developmentof type 2 diabetes. The value of genetic factors increased withan increasing duration of follow-up.

Lung Transplantation and Survival in Children with Cystic Fibrosis

2009-01-29T02:14:00.000-08:00

Theodore G. Liou, M.D., Frederick R. Adler, Ph.D., David R. Cox, Ph.D., and Barbara C. Cahill, M.D.

ABSTRACT

Background The effects of lung transplantation on the survivaland quality of life in children with cystic fibrosis are uncertain.

Methods We used data from the U.S. Cystic Fibrosis FoundationPatient Registry and from the Organ Procurement and TransplantationNetwork to identify children with cystic fibrosis who were onthe waiting list for lung transplantation during the periodfrom 1992 through 2002. We performed proportional-hazards survivalmodeling, using multiple clinically relevant covariates thatwere available before the children were on the waiting listand the interactions of these covariates with lung transplantationas a time-dependent covariate. The data were insufficient inquality and quantity for a retrospective quality-of-life analysis.

Results A total of 248 of the 514 children on the waiting listunderwent lung transplantation in the United States during theperiod from 1992 through 2002. Proportional-hazards modelingidentified four variables besides transplantation that wereassociated with changes in survival. Burkholderia cepacia infectionwas associated with a trend toward decreased survival, regardlessof whether the patient underwent transplantation. A diagnosisof diabetes before the patient was placed on the waiting listdecreased survival while the patient was on the waiting listbut did not decrease survival after transplantation, whereasolder age did not affect waiting-list survival but decreasedpost-transplantation survival. Staphylococcus aureus infectionincreased waiting-list survival but decreased post-transplantationsurvival. Using age, diabetes status, and S. aureus infectionstatus as covariates, we estimated the effect of transplantationon survival for each patient group, expressed as a hazard factorof less than 1 for a benefit and more than 1 for a risk of harm.Five patients had a significant estimated benefit, 283 patientshad a significant risk of harm, 102 patients had an insignificantbenefit, and 124 patients had an insignificant risk of harmassociated with lung transplantation.

Conclusions Our analyses estimated clearly improved survivalfor only 5 of 514 patients on the waiting list for lung transplantation.Prolongation of life by means of lung transplantation shouldnot be expected in children with cystic fibrosis. A prospective,randomized trial is needed to clarify whether and when patientsderive a survival and quality-of-life benefit from lung transplantation.

Phenotype and Course of Hutchinson–Gilford Progeria Syndrome

2009-01-29T02:13:00.000-08:00

Melissa A. Merideth, M.D., M.P.H., Leslie B. Gordon, M.D., Ph.D., Sarah Clauss, M.D., Vandana Sachdev, M.D., Ann C.M. Smith, M.A., Monique B. Perry, M.D., Carmen C. Brewer, Ph.D., Christopher Zalewski, M.A., H. Jeffrey Kim, M.D., Beth Solomon, M.S., Brian P. Brooks, M.D., Ph.D., Lynn H. Gerber, M.D., Maria L. Turner, M.D., Demetrio L. Domingo, D.D.S., Thomas C. Hart, D.D.S., Jennifer Graf, M.S., James C. Reynolds, M.D., Andrea Gropman, M.D., Jack A. Yanovski, M.D., Ph.D., Marie Gerhard-Herman, M.D. Francis S. Collins, M.D., Ph.D., Elizabeth G. Nabel, M.D., Richard O. Cannon, III, M.D., William A. Gahl, M.D., Ph.D., and Wendy J. Introne, M.D.

ABSTRACT

Background Hutchinson–Gilford progeria syndrome is a rare,sporadic, autosomal dominant syndrome that involves prematureaging, generally leading to death at approximately 13 yearsof age due to myocardial infarction or stroke. The genetic basisof most cases of this syndrome is a change from glycine GGCto glycine GGT in codon 608 of the lamin A (LMNA) gene, whichactivates a cryptic splice donor site to produce abnormal laminA; this disrupts the nuclear membrane and alters transcription.

Methods We enrolled 15 children between 1 and 17 years of age,representing nearly half of the world's known patients withHutchinson–Gilford progeria syndrome, in a comprehensiveclinical protocol between February 2005 and May 2006.

Results Clinical investigations confirmed sclerotic skin, jointcontractures, bone abnormalities, alopecia, and growth impairmentin all 15 patients; cardiovascular and central nervous systemsequelae were also documented. Previously unrecognized findingsincluded prolonged prothrombin times, elevated platelet countsand serum phosphorus levels, measured reductions in joint rangeof motion, low-frequency conductive hearing loss, and functionaloral deficits. Growth impairment was not related to inadequatenutrition, insulin unresponsiveness, or growth hormone deficiency.Growth hormone treatment in a few patients increased heightgrowth by 10% and weight growth by 50%. Cardiovascular studiesrevealed diminishing vascular function with age, including elevatedblood pressure, reduced vascular compliance, decreased ankle–brachialindexes, and adventitial thickening.

Conclusions Establishing the detailed phenotype of Hutchinson–Gilfordprogeria syndrome is important because advances in understandingthis syndrome may offer insight into normal aging. Abnormallamin A (progerin) appears to accumulate with aging in normalcells. (ClinicalTrials.gov number, NCT00094393 [ClinicalTrials.gov] .)

Etanercept Treatment for Children and Adolescents with Plaque Psoriasis

2009-01-29T02:12:00.000-08:00

Amy S. Paller, M.D., Elaine C. Siegfried, M.D., Richard G. Langley, M.D., Alice B. Gottlieb, M.D., Ph.D., David Pariser, M.D., Ian Landells, M.D., Adelaide A. Hebert, M.D., Lawrence F. Eichenfield, M.D., Vaishali Patel, Pharm.D., M.S., Kara Creamer, M.S., Angelika Jahreis, M.D., Ph.D., for the Etanercept Pediatric Psoriasis Study Group

ABSTRACT

Background Etanercept, a soluble tumor necrosis factor receptor,has been shown to lessen disease severity in adult patientswith psoriasis. We assessed the efficacy and safety of etanerceptin children and adolescents with moderate-to-severe plaque psoriasis.

Methods In this 48-week study, 211 patients with psoriasis (4to 17 years of age) were initially randomly assigned to a double-blindtrial of 12 once-weekly subcutaneous injections of placebo or0.8 mg of etanercept per kilogram of body weight (to a maximumof 50 mg), followed by 24 weeks of once-weekly open-label etanercept.At week 36, 138 patients underwent a second randomization toplacebo or etanercept to investigate the effects of withdrawaland retreatment. The primary end point was 75% or greater improvementfrom baseline in the psoriasis area-and-severity index (PASI75) at week 12. Secondary end points included PASI 50, PASI90, physician's global assessment of clear or almost clear ofdisease, and safety assessments.

Results At week 12, 57% of patients receiving etanercept achievedPASI 75, as compared with 11% of those receiving placebo (P<0.001).A significantly higher proportion of patients in the etanerceptgroup than in the placebo group had PASI 50 (75% vs. 23%), PASI90 (27% vs. 7%), and a physician's global assessment of clearor almost clear (53% vs. 13%) at week 12 (P<0.001).> 36, after 24 weeks of open-label etanercept, rates of PASI 75were 68% and 65% for patients initially assigned to etanerceptand placebo, respectively. During the withdrawal period fromweek 36 to week 48, response was lost by 29 of 69 patients (42%)assigned to placebo at the second randomization. Four seriousadverse events (including three infections) occurred in threepatients during treatment with open-label etanercept; all resolvedwithout sequelae.

Conclusions Etanercept significantly reduced disease severityin children and adolescents with moderate-to-severe plaque psoriasis.(ClinicalTrials.gov number, NCT00078819 [ClinicalTrials.gov] .)

Severe Anemia in Malawian Children

2009-01-29T02:11:00.001-08:00

Job C.J. Calis, M.D., Kamija S. Phiri, M.D., E. Brian Faragher, Ph.D., Bernard J. Brabin, F.R.C.P.C.H., Imelda Bates, M.D., Luis E. Cuevas, M.D., Rob J. de Haan, Ph.D., Ajib I. Phiri, M.D., Pelani Malange, M.Sc., Mirriam Khoka, B.Sc., Paul J.M. Hulshof, M.Sc., Lisette van Lieshout, Ph.D., Marcel G.H.M. Beld, Ph.D., Yik Y. Teo, Ph.D., Kirk A. Rockett, Ph.D., Anna Richardson, B.Sc., Dominic P. Kwiatkowski, F.R.C.P., Malcolm E. Molyneux, F.R.C.P., and Michaël Boele van Hensbroek, M.D.

ABSTRACT

Background Severe anemia is a major cause of sickness and deathin African children, yet the causes of anemia in this populationhave been inadequately studied.

Methods We conducted a case–control study of 381 preschoolchildren with severe anemia (hemoglobin concentration, <5.0g per deciliter) and 757 preschool children without severe anemiain urban and rural settings in Malawi. Causal factors previouslyassociated with severe anemia were studied. The data were examinedby multivariate analysis and structural equation modeling.

Results Bacteremia (adjusted odds ratio, 5.3; 95% confidenceinterval [CI], 2.6 to 10.9), malaria (adjusted odds ratio, 2.3;95% CI, 1.6 to 3.3), hookworm (adjusted odds ratio, 4.8; 95%CI, 2.0 to 11.8), human immunodeficiency virus infection (adjustedodds ratio, 2.0; 95% CI, 1.0 to 3.8), the G6PD^{–202/–376}genetic disorder (adjusted odds ratio, 2.4; 95% CI, 1.3 to 4.4),vitamin A deficiency (adjusted odds ratio, 2.8; 95% CI, 1.3to 5.8), and vitamin B₁₂ deficiency (adjusted odds ratio, 2.2;95% CI, 1.4 to 3.6) were associated with severe anemia. Folatedeficiency, sickle cell disease, and laboratory signs of anabnormal inflammatory response were uncommon. Iron deficiencywas not prevalent in case patients (adjusted odds ratio, 0.37;95% CI, 0.22 to 0.60) and was negatively associated with bacteremia.Malaria was associated with severe anemia in the urban site(with seasonal transmission) but not in the rural site (wheremalaria was holoendemic). Seventy-six percent of hookworm infectionswere found in children under 2 years of age.

Conclusions There are multiple causes of severe anemia in Malawianpreschool children, but folate and iron deficiencies are notprominent among them. Even in the presence of malaria parasites,additional or alternative causes of severe anemia should beconsidered.

Severe Anemia in Malawian Children

2009-01-29T02:11:00.000-08:00

ABSTRACT

Background Severe anemia is a major cause of sickness and deathin African children, yet the causes of anemia in this populationhave been inadequately studied.

Shared Genetic Causes of Cardiac Hypertrophy in Children and Adults

2009-01-29T02:09:00.002-08:00

Hiroyuki Morita, M.D., Heidi L. Rehm, Ph.D., Andres Menesses, M.D., Barbara McDonough, R.N., Amy E. Roberts, M.D., Raju Kucherlapati, Ph.D., Jeffrey A. Towbin, M.D., J.G. Seidman, Ph.D., and Christine E. Seidman, M.D.

ABSTRACT

Background The childhood onset of idiopathic cardiac hypertrophythat occurs without a family history of cardiomyopathy can portenda poor prognosis. Despite morphologic similarities to geneticcardiomyopathies of adulthood, the contribution of geneticsto childhood-onset hypertrophy is unknown.

Methods We assessed the family and medical histories of 84 children(63 boys and 21 girls) with idiopathic cardiac hypertrophy diagnosedbefore 15 years of age (mean [±SD] age, 6.99±6.12years). We sequenced eight genes: MYH7, MYBPC3, TNNT2, TNNI3,TPM1, MYL3, MYL2, and ACTC. These genes encode sarcomere proteinsthat, when mutated, cause adult-onset cardiomyopathies. We alsosequenced PRKAG2 and LAMP2, which encode metabolic proteins;mutations in these genes can cause early-onset ventricular hypertrophy.

Results We identified mutations in 25 of 51 affected childrenwithout family histories of cardiomyopathy and in 21 of 33 affectedchildren with familial cardiomyopathy. Among 11 of the 25 childrenwith presumed sporadic disease, 4 carried new mutations and7 inherited the mutations. Mutations occurred predominantly(in >75% of the children) in MYH7 and MYBPC3; significantlymore MYBPC3 missense mutations were detected than occur in adult-onsetcardiomyopathy (P<0.005).> contractile function correlated with familial or genetic status.Cardiac transplantation and sudden death were more prevalentamong mutation-positive than among mutation-negative children;implantable cardioverter–defibrillators were more frequent(P=0.007) in children with family histories that were positivefor the mutation.

Conclusions Genetic causes account for about half of presumedsporadic cases and nearly two thirds of familial cases of childhood-onsethypertrophy. Childhood-onset hypertrophy should prompt geneticanalyses and family evaluations.

Hypothermia Therapy after Traumatic Brain Injury in Children

2009-01-29T02:09:00.001-08:00

James S. Hutchison, M.D., Roxanne E. Ward, B.A., Jacques Lacroix, M.D., Paul C. Hébert, M.D., M.H.Sc., Marcia A. Barnes, Ph.D., Desmond J. Bohn, M.B., Peter B. Dirks, M.D., Steve Doucette, M.Sc., Dean Fergusson, Ph.D., Ronald Gottesman, M.D., Ari R. Joffe, M.D., Haresh M. Kirpalani, M.B., M.Sc., Philippe G. Meyer, M.D., Kevin P. Morris, M.D., David Moher, Ph.D., Ram N. Singh, M.D., Peter W. Skippen, M.D., for the Hypothermia Pediatric Head Injury Trial Investigators and the Canadian Critical Care Trials Group

ABSTRACT

Background Hypothermia therapy improves survival and the neurologicoutcome in animal models of traumatic brain injury. However,the effect of hypothermia therapy on the neurologic outcomeand mortality among children who have severe traumatic braininjury is unknown.

Methods In a multicenter, international trial, we randomly assignedchildren with severe traumatic brain injury to either hypothermiatherapy (32.5°C for 24 hours) initiated within 8 hours afterinjury or to normothermia (37.0°C). The primary outcomewas the proportion of children who had an unfavorable outcome(i.e., severe disability, persistent vegetative state, or death),as assessed on the basis of the Pediatric Cerebral PerformanceCategory score at 6 months.

Results A total of 225 children were randomly assigned to thehypothermia group or the normothermia group; the mean temperaturesachieved in the two groups were 33.1±1.2°C and 36.9±0.5°C,respectively. At 6 months, 31% of the patients in the hypothermiagroup, as compared with 22% of the patients in the normothermiagroup, had an unfavorable outcome (relative risk, 1.41; 95%confidence interval [CI], 0.89 to 2.22; P=0.14). There were23 deaths (21%) in the hypothermia group and 14 deaths (12%)in the normothermia group (relative risk, 1.40; 95% CI, 0.90to 2.27; P=0.06). There was more hypotension (P=0.047) and morevasoactive agents were administered (P<0.001)> group during the rewarming period than in the normothermia group.Lengths of stay in the intensive care unit and in the hospitaland other adverse events were similar in the two groups.

Conclusions In children with severe traumatic brain injury,hypothermia therapy that is initiated within 8 hours after injuryand continued for 24 hours does not improve the neurologic outcomeand may increase mortality. (Current Controlled Trials number,ISRCTN77393684 [controlled-trials.com] .)

Long-Term Medical and Social Consequences of Preterm Birth

2009-01-29T02:07:00.000-08:00

Dag Moster, M.D., Ph.D., Rolv Terje Lie, Ph.D., and Trond Markestad, M.D., Ph.D.

ABSTRACT

Background Advances in perinatal care have increased the numberof premature babies who survive. There are concerns, however,about the ability of these children to cope with the demandsof adulthood.

Methods We linked compulsory national registries in Norway toidentify children of different gestational-age categories whowere born between 1967 and 1983 and to follow them through 2003in order to document medical disabilities and outcomes reflectingsocial performance.

Results The study included 903,402 infants who were born aliveand without congenital anomalies (1822 born at 23 to 27 weeksof gestation, 2805 at 28 to 30 weeks, 7424 at 31 to 33 weeks,32,945 at 34 to 36 weeks, and 858,406 at 37 weeks or later).The proportions of infants who survived and were followed toadult life were 17.8%, 57.3%, 85.7%, 94.6%, and 96.5%, respectively.Among the survivors, the prevalence of having cerebral palsywas 0.1% for those born at term versus 9.1% for those born at23 to 27 weeks of gestation (relative risk for birth at 23 to27 weeks of gestation, 78.9; 95% confidence interval [CI], 56.5to 110.0); the prevalence of having mental retardation, 0.4%versus 4.4% (relative risk, 10.3; 95% CI, 6.2 to 17.2); andthe prevalence of receiving a disability pension, 1.7% versus10.6% (relative risk, 7.5; 95% CI, 5.5 to 10.0). Among thosewho did not have medical disabilities, the gestational age atbirth was associated with the education level attained, income,receipt of Social Security benefits, and the establishment ofa family, but not with rates of unemployment or criminal activity.

Conclusions In this cohort of people in Norway who were bornbetween 1967 and 1983, the risks of medical and social disabilitiesin adulthood increased with decreasing gestational age at birth.

GAD Treatment and Insulin Secretion in Recent-Onset Type 1 Diabetes

2009-01-29T02:06:00.000-08:00

ABSTRACT

Preemptive Use of High-Dose Fluticasone for Virus-Induced Wheezing in Young Children

2009-01-29T02:02:00.000-08:00

Francine M. Ducharme, M.D., Chantal Lemire, M.D., Francisco J.D. Noya, M.D., G. Michael Davis, M.D., Nathalie Alos, M.D., Hélène Leblond, M.D., Cheryl Savdie, M.Sc., Jean-Paul Collet, M.D., Ph.D., Lyudmyla Khomenko, Ph.D., Georges Rivard, M.D., and Robert W. Platt, Ph.D.

ABSTRACT

Background Although virus-induced wheezing is common in preschool-agechildren, optimal management remains elusive. We examined theefficacy and safety of preemptive treatment with high-dose fluticasonein reducing the severity of recurrent virus-induced wheezingin children.

Methods We randomly assigned 129 children who were 1 to 6 yearsof age to receive 750 µg of fluticasone propionate (ex-valve[manufacturer-measured] dose) or placebo twice daily, beginningat the onset of an upper respiratory tract infection and continuingfor a maximum of 10 days, over a period of 6 to 12 months. Theprimary outcome was rescue oral corticosteroid use. Secondaryoutcomes included symptoms, use of β₂-agonists, acute carevisits, hospitalizations, discontinuation of the study drug,change in growth and bone mineral density, basal cortisol level,and adverse events.

Results Over a median period of 40 weeks, 8% of upper respiratorytract infections in the fluticasone group led to treatment withrescue systemic corticosteroids, as compared with 18% in theplacebo group (odds ratio, 0.49; 95% confidence interval [CI],0.30 to 0.83). Children who were treated with fluticasone, ascompared with those who were given placebo, had smaller mean(±SD) gains from baseline in height (6.23±2.62cm [unadjusted value]; z score, –0.19 ±0.42 vs.6.56±2.90 cm [unadjusted value]; z score, 0.00±0.48;difference between groups in z score from baseline to end point,–0.24 [95% CI, –0.40 to –0.08]) and in weight(1.53±1.17 kg [unadjusted value]; z score, –0.15±0.48vs. 2.17±1.79 kg [unadjusted value]; z score, 0.11±0.43;difference between groups in z score from baseline to end point,–0.26 [95% CI, –0.41 to –0.09]). There wereno significant differences between the groups in basal cortisollevel, bone mineral density, or adverse events.

Conclusions In preschool-age children with moderate-to-severevirus-induced wheezing, preemptive treatment with high-dosefluticasone as compared with placebo reduced the use of rescueoral corticosteroids. Treatment with fluticasone was associatedwith a smaller gain in height and weight. Given the potentialfor overuse, this preventive approach should not be adoptedin clinical practice until long-term adverse effects are clarified.(ClinicalTrials.gov number, NCT00238927 [ClinicalTrials.gov] .)

Oral Prednisolone for Preschool Children with Acute Virus-Induced Wheezing

2009-01-29T01:58:00.000-08:00

Jayachandran Panickar, M.D., M.R.C.P.C.H., Monica Lakhanpaul, M.D., F.R.C.P.C.H., Paul C. Lambert, Ph.D., Priti Kenia, M.B., B.S., M.R.C.P.C.H., Terence Stephenson, D.M., F.R.C.P.C.H., Alan Smyth, M.D., F.R.C.P.C.H., and Jonathan Grigg, M.D., F.R.C.P.C.H.

ABSTRACT

Background Attacks of wheezing induced by upper respiratoryviral infections are common in preschool children between theages of 10 months and 6 years. A short course of oral prednisoloneis widely used to treat preschool children with wheezing whopresent to a hospital, but there is conflicting evidence regardingits efficacy in this age group.

Methods We conducted a randomized, double-blind, placebo-controlledtrial comparing a 5-day course of oral prednisolone (10 mg oncea day for children 10 to 24 months of age and 20 mg once a dayfor older children) with placebo in 700 children between theages of 10 months and 60 months. The children presented to threehospitals in England with an attack of wheezing associated witha viral infection; 687 children were included in the intention-to-treatanalysis (343 in the prednisolone group and 344 in the placebogroup). The primary outcome was the duration of hospitalization.Secondary outcomes were the score on the Preschool RespiratoryAssessment Measure, albuterol use, and a 7-day symptom score.

Results There was no significant difference in the durationof hospitalization between the placebo group and the prednisolonegroup (13.9 hours vs. 11.0 hours; ratio of geometric means,0.90; 95% confidence interval, 0.77 to 1.05) or in the intervalbetween hospital admission and signoff for discharge by a physician.In addition, there was no significant difference between thetwo study groups for any of the secondary outcomes or for thenumber of adverse events.

Conclusions In preschool children presenting to a hospital withmild-to-moderate wheezing associated with a viral infection,oral prednisolone was not superior to placebo. (Current ControlledTrials number, ISRCTN58363576 [controlled-trials.com] .)

Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture

2009-01-29T01:39:00.000-08:00

Kenneth W. Lyles, M.D., Cathleen S. Colón-Emeric, M.D., M.H.Sc., Jay S. Magaziner, Ph.D., Jonathan D. Adachi, M.D., Carl F. Pieper, D.P.H., Carlos Mautalen, M.D., Lars Hyldstrup, M.D., D.M.Sc., Chris Recknor, M.D., Lars Nordsletten, M.D., Ph.D., Kathy A. Moore, R.N., Catherine Lavecchia, M.S., Jie Zhang, Ph.D., Peter Mesenbrink, Ph.D., Patricia K. Hodgson, B.A., Ken Abrams, M.D., John J. Orloff, M.D., Zebulun Horowitz, M.D., Erik Fink Eriksen, M.D., D.M.Sc., Steven Boonen, M.D., Ph.D., for the HORIZON Recurrent Fracture Trial

ABSTRACT

Background Mortality is increased after a hip fracture, andstrategies that improve outcomes are needed.

Methods In this randomized, double-blind, placebo-controlledtrial, 1065 patients were assigned to receive yearly intravenouszoledronic acid (at a dose of 5 mg), and 1062 patients wereassigned to receive placebo. The infusions were first administeredwithin 90 days after surgical repair of a hip fracture. Allpatients (mean age, 74.5 years) received supplemental vitaminD and calcium. The median follow-up was 1.9 years. The primaryend point was a new clinical fracture.

Results The rates of any new clinical fracture were 8.6% inthe zoledronic acid group and 13.9% in the placebo group, a35% risk reduction with zoledronic acid (P=0.001); the respectiverates of a new clinical vertebral fracture were 1.7% and 3.8%(P=0.02), and the respective rates of new nonvertebral fractureswere 7.6% and 10.7% (P=0.03). In the safety analysis, 101 of1054 patients in the zoledronic acid group (9.6%) and 141 of1057 patients in the placebo group (13.3%) died, a reductionof 28% in deaths from any cause in the zoledronic acid group(P=0.01). The most frequent adverse events in patients receivingzoledronic acid were pyrexia, myalgia, and bone and musculoskeletalpain. No cases of osteonecrosis of the jaw were reported, andno adverse effects on the healing of fractures were noted. Therates of renal and cardiovascular adverse events, includingatrial fibrillation and stroke, were similar in the two groups.

Conclusions An annual infusion of zoledronic acid within 90days after repair of a low-trauma hip fracture was associatedwith a reduction in the rate of new clinical fractures and improvedsurvival. (ClinicalTrials.gov number, NCT00046254 [ClinicalTrials.gov] .)

Outcomes of Allergy to Insect Stings in Children, with and without Venom Immunotherapy

2009-01-29T01:24:00.000-08:00

David B.K. Golden, M.D., Anne Kagey-Sobotka, Ph.D., Philip S. Norman, M.D., Robert G. Hamilton, Ph.D., and Lawrence M. Lichtenstein, M.D., Ph.D.

ABSTRACT

Background Children are thought to "outgrow" the allergy toinsect stings, but there are no reports documenting the naturalhistory of this reaction. We studied the outcome of allergicreactions to insect stings in childhood 10 to 20 years afterwardin patients who had not received venom immunotherapy and inthose who had been treated.

Methods Between 1978 and 1985, we diagnosed allergic reactionto insect stings in 1033 children, of whom 356 received venomimmunotherapy. We conducted a survey of these patients by telephoneand mail between January 1997 and January 2000, to determinethe outcome of stings that occurred in the period from 1987through 1999.

Results Of the 1033 patients, 512 patients (50 percent) responded,with a mean follow-up period of 18 years, a mean duration ofvenom immunotherapy of 3.5 years in treated patients, and anincidence of stings of 43 percent. Systemic reactions occurredless frequently in patients who had received venom immunotherapy(2 of 64 patients, or 3 percent) than in untreated patients(19 of 111 patients, or 17 percent; P=0.007). Patients witha history of moderate-to-severe reactions had a higher rateof reaction if they had not been treated (7 of 22 patients,or 32 percent) than if they had received venom immunotherapy(2 of 43 patients, or 5 percent; P=0.007). In patients who hadbeen treated and who had a history of mild (cutaneous) systemicreaction (i.e., one with only cutaneous manifestations), noneof the 21 subjects who received stings had a systemic reaction.

Conclusions A clinically important number of children do notoutgrow allergic reactions to insect stings. Venom immunotherapyin children leads to a significantly lower risk of systemicreaction to stings even 10 to 20 years after treatment is stopped,and this prolonged benefit is greater than the benefit seenin adults.

Outbreak of Adverse Reactions Associated with Contaminated Heparin

2009-01-29T01:21:00.000-08:00

David B. Blossom, M.D., Alexander J. Kallen, M.D., M.P.H., Priti R. Patel, M.D., M.P.H., Alexis Elward, M.D., M.P.H., Luke Robinson, B.S., Ganpan Gao, Ph.D., Robert Langer, Sc.D., Kiran M. Perkins, M.D., Jennifer L. Jaeger, M.D., Katie M. Kurkjian, D.V.M., M.P.H., Marilyn Jones, R.N., M.P.H., Sarah F. Schillie, M.D., M.P.H., Nadine Shehab, Pharm.D., Daniel Ketterer, M.D., Ganesh Venkataraman, Ph.D., Takashi Kei Kishimoto, Ph.D., Zachary Shriver, Ph.D., Ann W. McMahon, M.D., K. Frank Austen, M.D., Steven Kozlowski, M.D., Arjun Srinivasan, M.D., George Turabelidze, M.D., Ph.D., Carolyn V. Gould, M.D., Matthew J. Arduino, Dr.P.H., and Ram Sasisekharan, Ph.D.

ABSTRACT

Background In January 2008, the Centers for Disease Controland Prevention began a nationwide investigation of severe adversereactions that were first detected in a single hemodialysisfacility. Preliminary findings suggested that heparin was apossible cause of the reactions.

Methods Information on clinical manifestations and on exposurewas collected for patients who had signs and symptoms that wereconsistent with an allergic-type reaction after November 1,2007. Twenty-one dialysis facilities that reported reactionsand 23 facilities that reported no reactions were included ina case–control study to identify facility-level risk factors.Unopened heparin vials from facilities that reported reactionswere tested for contaminants.

Results A total of 152 adverse reactions associated with heparinwere identified in 113 patients from 13 states from November19, 2007, through January 31, 2008. The use of heparin manufacturedby Baxter Healthcare was the factor most strongly associatedwith reactions (present in 100.0% of case facilities vs. 4.3%of control facilities, P<0.001).> by Baxter from facilities that reported reactions containeda contaminant identified as oversulfated chondroitin sulfate(OSCS). Adverse reactions to the OSCS-contaminated heparin wereoften characterized by hypotension, nausea, and shortness ofbreath occurring within 30 minutes after administration. Of130 reactions for which information on the heparin lot was available,128 (98.5%) occurred in a facility that had OSCS-contaminatedheparin on the premises. Of 54 reactions for which the lot numberof administered heparin was known, 52 (96.3%) occurred afterthe administration of OSCS-contaminated heparin.

Conclusions Heparin contaminated with OSCS was epidemiologicallylinked to adverse reactions in this nationwide outbreak. Thereported clinical features of many of the cases further supportthe conclusion that contamination of heparin with OSCS was thecause of the outbreak.

Reduced Lung Function at Birth and the Risk of Asthma at 10 Years of Age

2009-01-29T01:18:00.000-08:00

Geir Håland, M.D., Karin C. Lødrup Carlsen, M.D., Ph.D., Leiv Sandvik, Ph.D., Chandra Sekhar Devulapalli, M.D., Monica Cheng Munthe-Kaas, M.D., Morten Pettersen, M.D., Kai-Håkon Carlsen, M.D., Ph.D., for ORAACLE

ABSTRACT

Background Reduced lung function in early infancy has been associatedwith later obstructive airway diseases. We assessed whetherreduced lung function shortly after birth predicts asthma 10years later.

Methods We conducted a prospective birth cohort study of healthyinfants in which we measured lung function shortly after birthwith the use of tidal breathing flow-volume loops (the fractionof expiratory time to peak tidal expiratory flow to total expiratorytime [t_PTEF/t_E]) in 802 infants and passive respiratory mechanics,including respiratory-system compliance, in 664 infants. At10 years of age, 616 children (77%) were reassessed by measuringlung function, exercise-induced bronchoconstriction, and bronchialhyperresponsiveness (by means of a methacholine challenge) andby conducting a structured interview to determine whether therewas a history of asthma or current asthma.

Results As compared with children whose t_PTEF/t_E shortly afterbirth was above the median, children whose t_PTEF/t_E was at orbelow the median were more likely at 10 years of age to havea history of asthma (24.3% vs. 16.2%, P=0.01), to have currentasthma (14.6% vs. 7.5%, P=0.005), and to have severe bronchialhyperresponsiveness, defined as a methacholine dose of lessthan 1.0 µmol causing a 20% fall in the forced expiratoryvolume in 1 second (FEV₁) (9.1% vs. 4.9%, P=0.05). As comparedwith children whose respiratory-system compliance was abovethe median, children with respiratory compliance at or belowthe median more often had a history of asthma (27.4% vs. 14.8%;P=0.001) and current asthma (15.0% vs. 7.7%, P=0.009), althoughthis measure was not associated with later measurements of lungfunction. At 10 years of age, t_PTEF/t_E at birth correlated weaklywith the maximal midexpiratory flow rate (r=0.10, P=0.01) butnot with FEV₁ or forced vital capacity.

Conclusions Reduced lung function at birth is associated withan increased risk of asthma by 10 years of age.

Improving the Management of Chronic Disease at Community Health Centers

2009-01-29T01:17:00.000-08:00

Bruce E. Landon, M.D., M.B.A., LeRoi S. Hicks, M.D., M.P.H., A. James O'Malley, Ph.D., Tracy A. Lieu, M.D., M.P.H., Thomas Keegan, Ph.D., Barbara J. McNeil, M.D., Ph.D., and Edward Guadagnoli, Ph.D.

ABSTRACT

Background The Health Disparities Collaboratives of the HealthResources and Services Administration (HRSA) were designed toimprove care in community health centers, where many patientsfrom ethnic and racial minority groups and uninsured patientsreceive treatment.

Methods We performed a controlled preintervention and postinterventionstudy of community health centers participating in quality-improvementcollaboratives (the Health Disparities Collaboratives sponsoredby the HRSA) for the care of patients with diabetes, asthma,or hypertension. We enrolled 9658 patients at 44 interventioncenters that had participated in the collaboratives and 20 centersthat had not participated (external control centers). Each interventioncenter also served as an internal control for another condition.Quality measures were abstracted from medical records at eachhealth center. We created overall quality scores by standardizingand averaging the scores from all of the applicable measures.Changes in quality were evaluated with the use of hierarchicalregression models that controlled for patient characteristics.

Results Overall, the intervention centers had considerably greaterimprovement than the external and internal control centers inthe composite measures of quality for the care of patients withasthma and diabetes, but not for those with hypertension. Ascompared with the external control centers, the interventioncenters had significant improvements in the measures of preventionand screening, including a 21% increase in foot examinationsfor patients with diabetes, and in disease treatment and monitoring,including a 14% increase in the use of antiinflammatory medicationfor asthma and a 16% increase in the assessment of glycatedhemoglobin. There was no improvement, however, in any of theintermediate outcomes assessed (urgent care or hospitalizationfor asthma, control of glycated hemoglobin levels for diabetes,and control of blood pressure for hypertension).

Conclusions The Health Disparities Collaboratives significantlyimproved the processes of care for two of the three conditionsstudied. There was no improvement in the clinical outcomes studied.

Asthma Control during the Year after Bronchial Thermoplasty

2009-01-29T01:16:00.000-08:00

Gerard Cox, M.B., Neil C. Thomson, M.D., Adalberto S. Rubin, M.D., Robert M. Niven, M.D., Paul A. Corris, M.D., Hans Christian Siersted, M.D., Ronald Olivenstein, M.D., Ian D. Pavord, M.D., David McCormack, M.D., Rekha Chaudhuri, M.D., John D. Miller, M.D., Michel Laviolette, M.D., for the AIR Trial Study Group

ABSTRACT

Background Bronchial thermoplasty is a bronchoscopic procedureto reduce the mass of airway smooth muscle and attenuate bronchoconstriction.We examined the effect of bronchial thermoplasty on the controlof moderate or severe persistent asthma.

Methods We randomly assigned 112 subjects who had been treatedwith inhaled corticosteroids and long-acting ₂-adrenergic agonists(LABA) and in whom asthma control was impaired when the LABAwere withdrawn to either bronchial thermoplasty or a controlgroup. The primary outcome was the frequency of mild exacerbations,calculated during three scheduled 2-week periods of abstinencefrom LABA at 3, 6, and 12 months. Airflow, airway responsiveness,asthma symptoms, the number of symptom-free days, use of rescuemedication, and scores on the Asthma Quality of Life Questionnaire(AQLQ) and the Asthma Control Questionnaire (ACQ) were alsoassessed.

Results The mean rate of mild exacerbations, as compared withbaseline, was reduced in the bronchial-thermoplasty group butwas unchanged in the control group (change in frequency persubject per week, –0.16±0.37 vs. 0.04±0.29;P=0.005). At 12 months, there were significantly greater improvementsin the bronchial-thermoplasty group than in the control groupin the morning peak expiratory flow (39.3±48.7 vs. 8.5±44.2liters per minute), scores on the AQLQ (1.3±1.0 vs. 0.6±1.1)and ACQ (reduction, 1.2±1.0 vs. 0.5±1.0), thepercentage of symptom-free days (40.6±39.7 vs. 17.0±37.9),and symptom scores (reduction, 1.9±2.1 vs. 0.7±2.5)while fewer puffs of rescue medication were required. Valuesfor airway responsiveness and forced expiratory volume in 1second did not differ significantly between the two groups.Adverse events immediately after treatment were more commonin the bronchial-thermoplasty group than in the control groupbut were similar during the period from 6 weeks to 12 monthsafter treatment.

Conclusions Bronchial thermoplasty in subjects with moderateor severe asthma results in an improvement in asthma control.(ClinicalTrials.gov number, NCT00214526 [ClinicalTrials.gov] .)

Childhood Asthma after Bacterial Colonization of the Airway in Neonates

2009-01-29T01:07:00.000-08:00

Hans Bisgaard, M.D., D.M.Sc., Mette Northman Hermansen, M.D., Frederik Buchvald, M.D., Ph.D., Lotte Loland, M.D., Ph.D., Liselotte Brydensholt Halkjaer, M.D., Ph.D., Klaus Bønnelykke, M.D., Martin Brasholt, M.D., Andreas Heltberg, M.D., Nadja Hawwa Vissing, M.D., Sannie Vester Thorsen, M.Sc., Malene Stage, M.Sc., and Christian Bressen Pipper, M.Sc., Ph.D.

ABSTRACT

Background Pathological features of the airway in young childrenwith severe recurrent wheeze suggest an association betweenbacterial colonization and the initiating events of early asthma.We conducted a study to investigate a possible association betweenbacterial colonization of the hypopharynx in asymptomatic neonatesand later development of recurrent wheeze, asthma, and allergyduring the first 5 years of life.

Methods The subjects were children from the Copenhagen ProspectiveStudy on Asthma in Childhood birth cohort who were born to motherswith asthma. Aspirates from the hypopharyngeal region of asymptomatic1-month-old infants were cultured for Streptococcus pneumoniae,Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcusaureus. Wheeze was monitored prospectively on diary cards duringthe first 5 years of life. Blood eosinophil count and totalIgE and specific IgE were measured at 4 years of age. Lung functionwas measured and asthma was diagnosed at 5 years of age.

Results Hypopharyngeal samples were cultured from 321 neonatesat 1 month of age. Twenty-one percent of the infants were colonizedwith S. pneumoniae, M. catarrhalis, H. influenzae, or a combinationof these organisms; colonization with one or more of these organisms,but not colonization with S. aureus, was significantly associatedwith persistent wheeze (hazard ratio, 2.40; 95% confidence interval[CI], 1.45 to 3.99), acute severe exacerbation of wheeze (hazardratio, 2.99; 95% CI, 1.66 to 5.39), and hospitalization forwheeze (hazard ratio, 3.85; 95% CI, 1.90 to 7.79). Blood eosinophilcounts and total IgE at 4 years of age were significantly increasedin children colonized neonatally with S. pneumoniae, M. catarrhalis,H. influenzae, or a combination of these organisms, but specificIgE was not significantly affected. The prevalence of asthmaand the reversibility of airway resistance after ₂-agonist administrationat 5 years of age were significantly increased in the childrencolonized neonatally with these organisms as compared with thechildren without such colonization (33% vs. 10% and 23% vs.18%, respectively).

Conclusions Neonates colonized in the hypopharyngeal regionwith S. pneumoniae, H. influenzae, or M. catarrhalis, or witha combination of these organisms, are at increased risk forrecurrent wheeze and asthma early in life.

A Chitinase-like Protein in the Lung and Circulation of Patients with Severe Asthma

2009-01-29T01:05:00.000-08:00

Geoffrey L. Chupp, M.D., Chun Geun Lee, M.D., Ph.D., Nizar Jarjour, M.D., Yun Michael Shim, M.D., Carole T. Holm, R.N., Susan He, M.D., James D. Dziura, Ph.D., M.P.H., Jennifer Reed, Ph.D., Anthony J. Coyle, Ph.D., Peter Kiener, Ph.D., Mark Cullen, M.D., Martine Grandsaigne, Marie-Christine Dombret, M.D., Michel Aubier, M.D., Marina Pretolani, Ph.D., and Jack A. Elias, M.D.

ABSTRACT

Background The evolutionarily conserved 18-glycosyl-hydrolasefamily contains true chitinases and chitinase-like proteinsthat lack enzymatic activity. Acidic mammalian chitinase hasrecently been associated with animal models of asthma. The relatedchitinase-like protein, YKL-40 (also called human cartilageglycoprotein 39 [HCgp-39] and chitinase 3–like 1), canbe readily measured in the serum. However, its relationshipto asthma has not been evaluated.

Methods We quantified serum YKL-40 levels in three cohorts ofpatients with asthma — one recruited from the patientpopulation at Yale University, one from the University of Paris,and one from the University of Wisconsin — as well asin controls from the surrounding communities. In the Paris cohort,immunohistochemical analysis and morphometric quantitation wereused to evaluate the locus of expression of YKL-40 in the lung.The clinical characteristics of the patients with high serumor lung YKL-40 levels were also evaluated.

Results Serum YKL-40 levels were significantly elevated in patientswith asthma as compared with controls. In the Paris cohort,lung YKL-40 levels were elevated and were correlated with circulatingYKL-40 levels (r=0.55, P<0.001)> (measured as the thickness of the subepithelial basement membrane)(r=0.51, P=0.003). In all three cohorts, serum YKL-40 levelscorrelated positively with the severity of asthma and inverselywith the forced expiratory volume in 1 second. Patients withelevated levels of YKL-40 had significantly more frequent rescue-inhaleruse, greater oral corticosteroid use, and a greater rate ofhospitalization than patients with lower levels.

Conclusions YKL-40 is found in increased quantities in the serumand lungs in a subgroup of patients with asthma, in whom expressionof chitinase in both compartments correlates with the severityof asthma. The recovery of YKL-40 from these patients indicateseither a causative or a sentinel role for this molecule in asthma.

Respiratory Effects of Exposure to Diesel Traffic in Persons with Asthma

2009-01-29T00:49:00.000-08:00

James McCreanor, M.R.C.P., Paul Cullinan, M.D., Mark J. Nieuwenhuijsen, Ph.D., James Stewart-Evans, M.Sc., Eleni Malliarou, M.Sc., Lars Jarup, Ph.D., Robert Harrington, M.S., Magnus Svartengren, M.D., In-Kyu Han, M.P.H., Pamela Ohman-Strickland, Ph.D., Kian Fan Chung, M.D., and Junfeng Zhang, Ph.D.

ABSTRACT

Background Air pollution from road traffic is a serious healthhazard, and people with preexisting respiratory disease maybe at increased risk. We investigated the effects of short-termexposure to diesel traffic in people with asthma in an urban,roadside environment.

Methods We recruited 60 adults with either mild or moderateasthma to participate in a randomized, crossover study. Eachparticipant walked for 2 hours along a London street (OxfordStreet) and, on a separate occasion, through a nearby park (HydePark). We performed detailed real-time exposure, physiological,and immunologic measurements.

Results Participants had significantly higher exposures to fineparticles (<2.5> particles, elemental carbon, and nitrogen dioxide on OxfordStreet than in Hyde Park. Walking for 2 hours on Oxford Streetinduced asymptomatic but consistent reductions in the forcedexpiratory volume in 1 second (FEV₁) (up to 6.1%) and forcedvital capacity (FVC) (up to 5.4%) that were significantly largerthan the reductions in FEV₁ and FVC after exposure in Hyde Park(P=0.04 and P=0.01, respectively, for the overall effect ofexposure, and P<0.005> greater in subjects with moderate asthma than in those withmild asthma. These changes were accompanied by increases inbiomarkers of neutrophilic inflammation (sputum myeloperoxidase,4.24 ng per milliliter after exposure in Hyde Park vs. 24.5ng per milliliter after exposure on Oxford Street; P=0.05) andairway acidification (maximum decrease in pH, 0.04% after exposurein Hyde Park and 1.9% after exposure on Oxford Street; P=0.003).The changes were associated most consistently with exposuresto ultrafine particles and elemental carbon.

Conclusions Our observations serve as a demonstration and explanationof the epidemiologic evidence that associates the degree oftraffic exposure with lung function in asthma

Asthma in Children - Overview

2009-01-28T08:26:00.000-08:00

Is this topic for you?

This topic provides information about asthma in children. If you are looking for information about asthma in teens and adults, see the topic Asthma in Teens and Adults.
What is asthma?

Asthma makes it hard for your child to breathe. It causes swelling and inflammation in the airways that lead to the lungs. When asthma flares up, the airways tighten and become narrower. This keeps the air from passing through easily and makes it hard for your child to breathe. These flare ups are also called asthma attacks or exacerbations.

Asthma affects children in different ways. Some children only have asthma attacks during allergy season, when they breathe in cold air, or when they exercise. Others have many bad attacks that send them to the doctor often.

Even if your child has few asthma attacks, you still need to treat the asthma. If the swelling and irritation in your child’s airways isn't controlled, asthma could lower your child's quality of life, prevent your child from exercising, and increase your child's risk of going to the hospital.

Even though asthma is a lifelong disease, treatment can control it and keep your child healthy. Many children with asthma play sports and live healthy, active lives.
What causes asthma?

Experts do not know exactly what causes asthma. But there are some things we do know:
Asthma runs in families.
Asthma is much more common in people with allergies, though not everyone with allergies gets asthma. And not everyone with asthma has allergies.
Pollution may cause asthma or make it worse.
What are the symptoms?

Symptoms of asthma can be mild or severe. When your child has asthma, he or she may:
Wheeze, making a loud or soft whistling noise that occurs when the airways narrow.
Cough a lot.
Feel tightness in the chest.
Feel short of breath.
Have trouble sleeping because of coughing and wheezing.
Quickly get tired during exercise.

Many children with asthma have symptoms that are worse at night.
How is asthma diagnosed?

Along with doing a physical exam and asking about your child’s symptoms, your doctor may order tests such as:
Spirometry. Doctors use this test to diagnose and keep track of asthma in children age 5 and older. It measures how quickly your child can move air in and out of the lungs and how much air is moved. Spirometry is not used with babies and small children. In those cases, the doctor usually will listen for wheezing and will ask how often the child wheezes or coughs.
Peak expiratory flow (PEF). This shows how fast your child can breathe out when trying his or her hardest.
A chest X-ray to see if another disease is causing your child’s symptoms.
Allergy tests, if your doctor thinks your child’s symptoms may be caused by allergies.

Allergic Reaction Causes

2009-01-28T08:24:00.000-08:00

Almost anything can trigger an allergic reaction.

The body's immune system has a patrol of white blood cells, which produce antibodies.

When the body is exposed to an antigen, a complex set of reactions begins.

The white blood cells produce an antibody specific to that antigen. This is called "sensitization."

The job of the antibodies is to detect and destroy substances that cause disease and sickness. In allergic reactions, the antibody is called immunoglobulin E, or IgE.

This antibody promotes production and release of chemicals and hormones called "mediators."

Histamine is one well-known mediator.

Mediators have effects on local tissue and organs in addition to activating more white blood cell defenders. It is these effects that cause the symptoms of the reaction.

If the release of the mediators is sudden or extensive, the allergic reaction may also be sudden and severe.

Your allergic reactions are unique to you. For example, your body may have learned to be allergic to poison ivy from repeated exposure.

Most people are aware of their particular allergy triggers and reactions.

Certain foods, vaccines and medications, latex rubber, aspirin, shellfish, dust, pollen, mold, animal dander, and poison ivy are famous allergens.

Bee stings, fire ant stings, penicillin, and peanuts are known for causing dramatic reactions that can be serious and involve the whole body.

Minor injuries, hot or cold temperatures, exercise, or even emotions may be triggers.

Often, the specific allergen cannot be identified unless you have had a similar reaction in the past.

Allergies and the tendency to have allergic reactions run in some families. You may have allergies even if they do not run in your family.

Many people who have one trigger tend to have other triggers as well.

People with certain medical conditions are more likely to have allergic reactions.

Severe allergic reaction in the past

Asthma

Lung conditions that affect breathing, such as chronic obstructive pulmonary disease (COPD)

Nasal polyps

Frequent infections of the nasal sinuses, ears, or respiratory tract

Sensitive skin

What Are Allergies?

2009-01-28T08:18:00.000-08:00

Allergies are an abnormal response of the immune system. People who have allergies have an immune system that reacts to a usually harmless substance in the environment. This substance (pollen, mold, animal dander, etc.) is called an allergen.

Allergies are a very common problem, affecting at least 2 out of every 10 Americans.
What Happens During an Allergic Reaction?

When a person is exposed to an allergen, a series of events takes place:
The body starts to produce a specific type of antibody, called IgE, to bind the allergen.
The antibodies attach to a form of blood cell called a mast cell. Mast cells can be found in the airways, in the GI tract, and elsewhere. The presence of mast cells in the airways and GI tract makes these areas more susceptible to allergen exposure.
The allergens bind to the IgE, which is attached to the mast cell. This triggers a reaction that allows the mast cells to release a variety of chemicals including histamine, which causes most of the symptoms of an allergy, including itchiness or runny nose.

If the allergen is in the air, the allergic reaction will likely occur in the eyes, nose and lungs. If the allergen is ingested, the allergic reaction often occurs in the mouth, stomach, and intestines. Sometimes enough chemicals are released from the mast cells to cause a reaction throughout the body, such as hives, decreased blood pressure, shock, or loss of consciousness.
What Are the Symptoms of Allergies?

Allergy symptoms can be categorized as mild, moderate, or severe (anaphylactic).
Mild reactions include those symptoms that affect a specific area of the body such as a rash, itchy, watery eyes, and some congestion. Mild reactions do not spread to other parts of the body.
Moderate reactions include symptoms that spread to other parts of the body. These may include itchiness or difficulty breathing.
A severe reaction, called anaphylaxis, is a rare, life-threatening emergency in which the response to the allergen is intense and affects the whole body. It may begin with the sudden onset of itching of the eyes or face and progress within minutes to more serious symptoms, including abdominal pain, cramps, vomiting, and diarrhea, as well as varying degrees of swellings that can make breathing and swallowing difficult. Mental confusion or dizziness may also be symptoms, since anaphylaxis causes a quick drop in blood pressure.
Does Everyone Have Allergies?

No. Most allergies are inherited, which means they are passed on to children by their parents. People inherit a tendency to be allergic, although not to any specific allergen. When one parent is allergic, their child has a 50% chance of having allergies. That risk jumps to 75% if both parents have allergies.