Montelukast for Chronic Asthma in 6- to 14-Year-Old Children: A Randomized, Double-blind Trial

Context.— Leukotrienes are important mediators of asthma by causing bronchoconstriction, mucous secretion, and increased vascular permeability. Studies using compounds that block leukotrienes have demonstrated improvement in asthma control in adults and adolescents, but children younger than 12 years, for whom asthma is the most common chronic disease, have not been studied. Objective.— To determine the clinical effect of montelukast, a leukotriene receptor antagonist, in 6- to 14-year-old children with asthma. Design.— Eight-week, multicenter, randomized, double-blind study. Setting.— Forty-seven outpatient centers at private practices and academic medical centers in the United States and Canada. Patients.— A total of 336 children with forced expiratory volume in 1 second (FEV₁) between 50% to 85% of the predicted value, at least 15% reversibility after inhaled -agonist administration, a minimal predefined level of daytime asthma symptoms, and daily -agonist use. Concomitant inhaled corticosteroids at a constant daily dose were used by 39% of patients receiving montelukast and 33% receiving placebo. Intervention.— After a 2-week placebo run-in period, patients received either montelukast (5-mg chewable tablet) or matching-image placebo once daily at bedtime for 8 weeks. Main Outcome Measure.— Morning FEV₁ percent change from baseline. Results.— Mean morning FEV₁ increased from 1.85 L to 2.01 L in the montelukast group and from 1.85 L to 1.93 L in the placebo group. This represents an 8.23% (95% confidence interval [CI], 6.33% to 10.13%) increase from baseline in the montelukast group and a 3.58% (95% CI, 1.29% to 5.87%) increase from baseline in the placebo group (P<.001 for montelukast vs placebo). Conclusion.— Montelukast improves morning FEV₁ in 6- to 14-year-old children with chronic asthma.      

Effect of calcium carbonate on the absorption of levothyroxine

Context  The effect of calcium carbonate on the absorption of levothyroxine has not been studied systematically. Such a potential drug interaction merits investigation because concurrent treatment with both drugs is common, particularly in postmenopausal women. Objective  To investigate the potential interference of calcium carbonate in the absorption of levothyroxine. Design  Prospective cohort study conducted from November 1998 to June 1999, supplemented with an in vitro study of thyroxine (T₄) binding to calcium carbonate. Setting  Veterans Affairs Medical Center in West Los Angeles, Calif. Patients  Twenty patients (age range, 27-78 years; n=11 men) with hypothyroidism who were taking a stable long-term regimen of levothyroxine were included in the study. All patients had serum free T₄ and thyrotropin values in the normal range before beginning the study. Intervention  Subjects were instructed to take 1200 mg/d of elemental calcium as calcium carbonate, ingested with their levothyroxine, for 3 months. Main Outcome Measures  Levels of free T₄, total T₄, total triiodothyronine (T₃), and thyrotropin, measured in all subjects at baseline (while taking levothyroxine alone), at 2 and 3 months (while taking calcium carbonate and levothyroxine), and 2 months after calcium carbonate discontinuation (while continuing to take levothyroxine). Results  Mean free T₄ and total T₄ levels were significantly reduced during the calcium period and increased after calcium discontinuation. Mean free T₄ levels were 17 pmol/L (1.3 ng/dL) at baseline, 15 pmol/L (1.2 ng/dL) during the calcium period, and 18 pmol/L (1.4 ng/dL) after calcium discontinuation (overall P<.001); mean total T₄ levels were 118 nmol/L (9.2 µg/dL) at baseline, 111 nmol/L (8.6 µg/dL) during the calcium period, and 120 nmol/L (9.3 µg/dL) after calcium discontinuation (overall P=.03). Mean thyrotropin levels increased significantly, from 1.6 mIU/L at baseline to 2.7 mIU/L during the calcium period, and decreased to 1.4 mIU/L after calcium discontinuation (P=.008). Twenty percent of patients had serum thyrotropin levels higher than the normal range during the calcium period; the highest observed level was 7.8 mIU/L. Mean T₃ levels did not change during the calcium period. The in vitro study of T₄ binding to calcium showed that adsorption of T₄ to calcium carbonate occurs at acidic pH levels. Conclusions  This study of 20 patients receiving long-term levothyroxine replacement therapy indicates that calcium carbonate reduces T₄ absorption and increases serum thyrotropin levels. Levothyroxine adsorbs to calcium carbonate in an acidic environment, which may reduce its bioavailability.      

Human Cardiovascular and Metabolic Response to Acute, Severe Isovolemic Anemia

Context.— Although concern over the risks of red blood cell transfusion has resulted in several practice guidelines for transfusion, lack of data regarding the physiological effects of anemia in humans has caused uncertainty regarding the blood hemoglobin (Hb) concentration requiring treatment. Objective.— To test the hypothesis that acute isovolemic reduction of blood Hb concentration to 50 g/L in healthy resting humans would produce inadequate cardiovascular compensation and result in tissue hypoxia secondary to inadequate oxygen transport. Design.— Before and after interventional study. Setting.— Academic tertiary care medical center. Participants.— Conscious healthy patients (n=11) prior to anesthesia and surgery and volunteers not undergoing surgery (n=21). Interventions.— Aliquots of blood (450-900 mL) were removed to reduce blood Hb concentration from 131 (2) g/L to 50 (1) g/L [mean (SE)]. Isovolemia was maintained with 5% human albumin and/or autologous plasma. Cardiovascular parameters, arterial and mixed venous oxygen content, oxyhemoglobin saturation, and arterial blood lactate were measured before and after removal of each aliquot of blood. Electrocardiogram and, in a subset, Holter monitor were monitored continuously. Main Outcome Measures.— "Critical" oxygen delivery (TO₂) as assessed by oxygen consumption (O₂), plasma lactate concentration, and ST changes on electrocardiogram. Results.— Acute, isovolemic reduction of Hb concentration decreased systemic vascular resistance and TO₂ and increased heart rate, stroke volume, and cardiac index (each P<.001). We did not find evidence of inadequate oxygenation: O₂ increased slightly from a mean (SD) of 3.07 (0.44) mL of oxygen per kilogram per minute (mL O₂·kg^-1·min^-1) to 3.42 (0.54) Ml O₂·kg^-1·min^-1 (P<.001) and plasma lactate concentration did not change (0.81 [0.11] mmol/L to 0.62 [0.19] mmol/L;P=.09). Two subjects developed significant ST changes on Holter monitor: one apparently related to body position or activity, the other to an increase in heart rate (at an Hb concentration of 46-53 g/L); both occurred in young women and resolved without sequelae. Conclusions.— Acute isovolemic reduction of blood Hb concentration to 50 g/L in conscious healthy resting humans does not produce evidence of inadequate systemic TO₂, as assessed by lack of change of O₂ and plasma lactate concentration. Analysis of Holter readings suggests that at this Hb concentration in this resting healthy population, myocardial ischemia would occur infrequently.      

Folate and Vitamin B6 From Diet and Supplements in Relation to Risk of Coronary Heart Disease Among Women

Context.— Hyperhomocysteinemia is caused by genetic and lifestyle influences, including low intakes of folate and vitamin B₆. However, prospective data relating intake of these vitamins to risk of coronary heart disease (CHD) are not available. Objective.— To examine intakes of folate and vitamin B₆ in relation to the incidence of nonfatal myocardial infarction (MI) and fatal CHD. Design.— Prospective cohort study. Setting and Patients.— In 1980, a total of 80082 women from the Nurses' Health Study with no previous history of cardiovascular disease, cancer, hypercholesterolemia, or diabetes completed a detailed food frequency questionnaire from which we derived usual intake of folate and vitamin B₆. Main Outcome Measure.— Nonfatal MI and fatal CHD confirmed by World Health Organization criteria. Results.— During 14 years of follow-up, we documented 658 incident cases of nonfatal MI and 281 cases of fatal CHD. After controlling for cardiovascular risk factors, including smoking and hypertension and intake of alcohol, fiber, vitamin E, and saturated, polyunsaturated, and trans fat, the relative risks (RRs) of CHD between extreme quintiles were 0.69 (95% confidence interval [CI], 0.55-0.87) for folate (median intake, 696 µg/d vs 158 µg/d) and 0.67 (95% CI, 0.53-0.85) for vitamin B₆ (median intake, 4.6 mg/d vs 1.1 mg/d). Controlling for the same variables, the RR was 0.55 (95% CI, 0.41-0.74) among women in the highest quintile of both folate and vitamin B₆ intake compared with the opposite extreme. Risk of CHD was reduced among women who regularly used multiple vitamins (RR=0.76; 95% CI, 0.65-0.90), the major source of folate and vitamin B₆, and after excluding multiple vitamin users, among those with higher dietary intakes of folate and vitamin B₆. In a subgroup analysis, compared with nondrinkers, the inverse association between a high-folate diet and CHD was strongest among women who consumed up to 1 alcoholic beverage per day (RR =0.69; 95% CI, 0.49-0.97) or more than 1 drink per day (RR=0.27; 95% CI, 0.13-0.58). Conclusion.— These results suggest that intake of folate and vitamin B₆ above the current recommended dietary allowance may be important in the primary prevention of CHD among women.      

Effects of Raloxifene on Serum Lipids and Coagulation Factors in Healthy Postmenopausal Women

Context.— Raloxifene is a selective estrogen receptor modulator that has estrogen-agonistic effects on bone and estrogen-antagonistic effects on breast and uterus. Objective.— To identify the effects of raloxifene on markers of cardiovascular risk in postmenopausal women, and to compare them with those induced by hormone replacement therapy (HRT). Design.— Double-blind, randomized, parallel trial. Setting.— Eight sites in the United States. Participants.— 390 healthy postmenopausal women recruited by advertisement. Intervention.— Participants were randomized to receive 1 of 4 treatments: raloxifene, 60 mg/d; raloxifene, 120 mg/d; HRT (conjugated equine estrogen, 0.625 mg/d, and medroxyprogesterone acetate, 2.5 mg/d); or placebo. Main Outcome Measures.— Change and percent change from baseline of lipid levels and coagulation parameters after 3 months and 6 months of treatment. Results.— At the last visit completed, compared with placebo, both dosages of raloxifene significantly lowered low-density lipoprotein cholesterol (LDL-C) by 12% (P<.001), similar to the 14% reduction with HRT (P<.001). Both dosages of raloxifene significantly lowered lipoprotein(a) by 7% to 8% (P<.001), less than the 19% decrease with HRT (P<.001). Raloxifene increased high-density lipoprotein-2 cholesterol (HDL₂-C) by 15% to 17% (P<.05), less than the 33% increase with HRT (P<.001). Raloxifene did not significantly change high-density lipoprotein cholesterol (HDL-C), triglycerides, or plasminogen activator inhibitor-1 (PAI-1); whereas HRT increased HDL-C by 11% and triglycerides by 20%, and decreased PAI-1 by 29% (for all, P< .001). Raloxifene significantly lowered fibrinogen by 12% to 14% (P<.001), unlike HRT, which had no effect. Neither treatment changed fibrinopeptide A or prothrombin fragment 1 and 2. Conclusions.— Raloxifene favorably alters biochemical markers of cardiovascular risk by decreasing LDL-C, fibrinogen, and lipoprotein(a), and by increasing HDL₂-C without raising triglycerides. In contrast to HRT, raloxifene had no effect on HDL-C and PAI-1, and a lesser effect on HDL₂-C and lipoprotein(a). Further clinical trials are necessary to determine whether these favorable biochemical effects are associated with protection against cardiovascular disease.      

Effect of Prolonged Methylprednisolone Therapy in Unresolving Acute Respiratory Distress Syndrome: A Randomized Controlled Trial

Context.— No pharmacological therapeutic protocol has been found effective in modifying the clinical course of acute respiratory distress syndrome (ARDS) and mortality remains greater than 50%. Objective.— To determine the effects of prolonged methylprednisolone therapy on lung function and mortality in patients with unresolving ARDS. Design.— Randomized, double-blind, placebo-controlled trial. Setting.— Medical intensive care units of 4 medical centers. Participants.— Twenty-four patients with severe ARDS who had failed to improve lung injury score (LIS) by the seventh day of respiratory failure. Interventions.— Sixteen patients received methylprednisolone and 8 received placebo. Methylprednisolone dose was initially 2 mg/kg per day and the duration of treatment was 32 days. Four patients whose LIS failed to improve by at least 1 point after 10 days of treatment were blindly crossed over to the alternative treatment. Main Outcome Measures.— Primary outcome measures were improvement in lung function and mortality. Secondary outcome measures were improvement in multiple organ dysfunction syndrome (MODS) and development of nosocomial infections. Results.— Physiological characteristics at the onset of ARDS were similar in both groups. At study entry (day 9 [SD, 3] of ARDS), the 2 groups had similar LIS, ratios of PaO₂ to fraction of inspired oxygen (FIO₂), and MODS scores. Changes observed by study day 10 for methylprednisolone vs placebo were as follows: reduced LIS (mean [SEM], 1.7 [0.1] vs 3.0 [0.2]; P<.001); improved ratio of PaO₂ to FIO₂ (mean [SEM], 262 [19] vs 148 [35]; P<.001); decreased MODS score (mean [SEM], 0.7 [0.2] vs 1.8 [0.3]; P<.001); and successful extubation (7 vs 0; P=.05). For the treatment group vs the placebo group, mortality associated with the intensive care unit was 0 (0%) of 16 vs 5 (62%) of 8 (P=.002) and hospital-associated mortality was 2 (12%) of 16 vs 5 (62%) of 8 (P=.03). The rate of infections per day of treatment was similar in both groups, and pneumonia was frequently detected in the absence of fever. Conclusions.— In this study, prolonged administration of methylprednisolone in patients with unresolving ARDS was associated with improvement in lung injury and MODS scores and reduced mortality.      

Intensity and Amount of Physical Activity in Relation to Insulin Sensitivity: The Insulin Resistance Atherosclerosis Study

Context.— Exercise training is associated with improved insulin sensitivity (S_I), but the potential impact of habitual, nonvigorous activity is uncertain. Objective.— To determine whether habitual, nonvigorous physical activity, as well as vigorous and overall activity, is associated with better S_I. Design.— A multicultural epidemiologic study. Setting.— The Insulin Resistance Atherosclerosis Study, conducted in Oakland, Calif; Los Angeles, Calif; the San Luis Valley, Colo; and San Antonio, Tex. Participants.— A total of 1467 men and women of African American, Hispanic, and non-Hispanic white ethnicity, aged 40 to 69 years, with glucose tolerance ranging from normal to mild non–insulin-dependent diabetes mellitus. Main Outcome Measure.— Insulin sensitivity as measured by an intravenous glucose tolerance test. Results.— The mean S_I for individuals who participated in vigorous activity 5 or more times per week was 1.59 min^-1·µU^-1·mL^-1·10^-4 (95% confidence interval [CI], 1.39-1.79) compared with 0.90 (95% CI, 0.83-0.97) for those who rarely or never participated in vigorous activity, after adjusting for potential confounders (P<.001). When habitual physical activity (estimated energy expenditure [EEE]) was assessed by 1-year recall of activities, the correlation coefficient between S_I and total EEE was 0.14 (P<.001). After adjustment for confounders, vigorous and nonvigorous levels of EEE (metabolic equivalent levels 6.0 and <6.0, respectively) were each positively and independently associated with S_I (P.01 for each). The association was attenuated after adjustment for the potential mediators, body mass index (a measure of weight in kilograms divided by the square of the height in meters), and waist-to-hip ratio. Results were similar for subgroups of sex, ethnicity, and diabetes. Conclusions.— Increased participation in nonvigorous as well as overall and vigorous physical activity was associated with significantly higher S_I. These findings lend further support to current public health recommendations for increased moderate-intensity physical activity on most days.      

Intensive Lifestyle Changes for Reversal of Coronary Heart Disease

Context.— The Lifestyle Heart Trial demonstrated that intensive lifestyle changes may lead to regression of coronary atherosclerosis after 1 year. Objectives.— To determine the feasibility of patients to sustain intensive lifestyle changes for a total of 5 years and the effects of these lifestyle changes (without lipid-lowering drugs) on coronary heart disease. Design.— Randomized controlled trial conducted from 1986 to 1992 using a randomized invitational design. Patients.— Forty-eight patients with moderate to severe coronary heart disease were randomized to an intensive lifestyle change group or to a usual-care control group, and 35 completed the 5-year follow-up quantitative coronary arteriography. Setting.— Two tertiary care university medical centers. Intervention.— Intensive lifestyle changes (10% fat whole foods vegetarian diet, aerobic exercise, stress management training, smoking cessation, group psychosocial support) for 5 years. Main Outcome Measures.— Adherence to intensive lifestyle changes, changes in coronary artery percent diameter stenosis, and cardiac events. Results.— Experimental group patients (20 [71%] of 28 patients completed 5-year follow-up) made and maintained comprehensive lifestyle changes for 5 years, whereas control group patients (15 [75%] of 20 patients completed 5-year follow-up) made more moderate changes. In the experimental group, the average percent diameter stenosis at baseline decreased 1.75 absolute percentage points after 1 year (a 4.5% relative improvement) and by 3.1 absolute percentage points after 5 years (a 7.9% relative improvement). In contrast, the average percent diameter stenosis in the control group increased by 2.3 percentage points after 1 year (a 5.4% relative worsening) and by 11.8 percentage points after 5 years (a 27.7% relative worsening) (P=.001 between groups. Twenty-five cardiac events occurred in 28 experimental group patients vs 45 events in 20 control group patients during the 5-year follow-up (risk ratio for any event for the control group, 2.47 [95% confidence interval, 1.48-4.20]). Conclusions.— More regression of coronary atherosclerosis occurred after 5 years than after 1 year in the experimental group. In contrast, in the control group, coronary atherosclerosis continued to progress and more than twice as many cardiac events occurred.      

Triiodothyronine levels in athyreotic individuals during levothyroxine therapy

Jacqueline Jonklaas, MD, PhD; Bruce Davidson, MD; Supna Bhagat, MD; Steven J. Soldin, PhD

JAMA. 2008;299(7):769-777.

Context  Thyroidal production of triiodothyronine (T₃) is absent in athyreotic patients, leading to the suggestion that T₃ deficiency may be unavoidable during levothyroxine (LT₄) therapy. However, trials evaluating therapy with combined LT₄ and T₃ have failed to demonstrate any consistent advantage of combination therapy.

Objective  To determine whether T₃ levels in patients treated with LT₄ therapy were truly lower than in the same patients with native thyroid function.

Design, Setting, and Patients  A prospective study conducted in the General Clinical Research Center, Georgetown University Medical Center, Washington, DC, between January 30, 2004, and June 20, 2007, of 50 euthyroid study participants aged 18 to 65 years who were scheduled for total thyroidectomy for goiter, benign nodular disease, suspected thyroid cancer, or known thyroid cancer. Following thyroidectomy, patients were prescribed LT₄. Patients with benign thyroid disease and thyroid cancer were treated to achieve a normal and suppressed serum thyroid-stimulating hormone (TSH) level, respectively. The LT₄ dose was adjusted as necessary postoperatively to achieve the desired TSH goal.

Main Outcome Measure  Thyroxine (tetraiodothyronine [T₄]), T₃, and TSH levels were measured twice preoperatively and twice postoperatively.

Results  By the end of the study, there were no significant decreases in T₃ concentrations in patients receiving LT₄ therapy compared with their prethyroidectomy T₃ levels (mean, 127.2 ng/dL; 95% confidence interval [CI], 119.5-134.9 ng/dL vs 129.3 ng/dL; 95% CI, 121.9-136.7 ng/dL; P = .64). However, free T₄ concentrations were significantly higher in patients treated with LT₄ therapy (mean, 1.41 ng/dL; 95% CI, 1.33-1.49 ng/dL) compared with their native free T₄ levels (1.05 ng/dL; 95% CI, 1.00-1.10 ng/dL; P < .001). Serum TSH values of 4.5 mIU/L or less were achieved in 94% of patients by the end of the study. The T₃ concentrations were lower in the subgroup of patients whose therapy had not resulted in a TSH level of 4.5 mIU/L or less (P < .001).

Conclusion  In our study, normal T₃ levels were achieved with traditional LT₄ therapy alone in patients who had undergone near-total or total thyroidectomy, which suggests that T₃ administration is not necessary to maintain serum T₃ values at their endogenous prethyroidectomy levels.

     

Influence of a Child's Sex on Medulloblastoma Outcome

Context.— Aggressive treatment of medulloblastoma, the most common pediatric brain tumor, has not improved survival. Identifying better prognostic indicators may warrant less morbid therapy. Objective.— To investigate the role of sex on outcome of medulloblastoma. Design.— Retrospective study of significant factors for survival with a median follow-up of 82 months. Setting.— University medical center. Patients.— A total of 109 consecutive, pediatric patients treated for primary medulloblastoma from 1970 to 1995 with surgery and postoperative radiotherapy and, after 1979, chemotherapy. Main Outcome Measures.— Factors independently associated with survival. Results.— The final multivariate model predicting improved survival included sex (hazard ratio, 0.52; 95% confidence interval [CI], 0.29-0.92; P=.03; favoring female), metastases at presentation (hazard ratio, 2.01; 95% CI, 1.14-3.52; P=.02), and extent of surgical resection (hazard ratio, 0.60; 95% CI, 0.34-1.04; P=.07; favoring greater resection). The overall, 5-year freedom from progression was 40% and survival was 49%. Radiotherapy dose (P=.72), and chemotherapy (P=.90) did not significantly affect a disease outcome. Conclusions.— The sex of the child was an important predictor for survival of medulloblastoma; girls had a much better outcome. The difference in survival between sexes should be evaluated in prospective, clinical trials.      

Perioperative Blood Transfusion and Postoperative Mortality

Context.— The risks of blood transfusion have been studied extensively but the benefits and the hemoglobin concentration at which patients should receive a transfusion have not. Objective.— To determine the effect of perioperative transfusion on 30- and 90-day postoperative mortality. Design.— Retrospective cohort study. Setting.— A total of 20 US hospitals between 1983 and 1993. Participants.— A total of 8787 consecutive hip fracture patients, aged 60 years or older, who underwent surgical repair. Main Outcome Measures.— Primary outcome was 30-day postoperative mortality; secondary outcome was 90-day postoperative mortality. The "trigger" hemoglobin level was defined as the lowest hemoglobin level prior to the first transfusion during the time period or, for patients in the nontranfused group, as the lowest hemoglobin level during the time period. Results.— Overall 30-day mortality was 4.6% (n=402; 95% confidence interval [CI], 4.1%-5.0%); overall 90-day mortality was 9.0% (n=788; 95% CI, 8.4%-9.6%). A total of 42% of patients (n=3699) received a postoperative transfusion. Among patients with trigger hemoglobin levels between 80 and 100 g/L (8.0 and 10.0 g/dL), 55.6% received a transfusion, while 90.5% of patients with hemoglobin levels less than 80 g/L (8.0 g/dL) received postoperative transfusions. Postoperative transfusion did not influence 30- or 90-day mortality after adjusting for trigger hemoglobin level, cardiovascular disease, and other risk factors for death: for 30-day mortality, the adjusted odds ratio (OR) was 0.96 (95% CI, 0.74-1.26); for 90-day mortality, the adjusted hazard ratio was 1.08 (95% CI, 0.90-1.29). Similarly, 30-day mortality after surgery did not differ between those who received a preoperative transfusion and those who did not (adjusted OR, 1.23; 95% CI, 0.81-1.89). Conclusions.— Perioperative transfusion in patients with hemoglobin levels 80 g/L (8.0 g/dL) or higher did not appear to influence the risk of 30- or 90-day mortality in this elderly population. At hemoglobin concentrations of less than 80 g/L (8.0 g/dL), 90.5% of patients received a transfusion, precluding further analysis of the association of transfusion and mortality.      

Pulmonary Infiltrates, Eosinophilia, and Cardiomyopathy Following Corticosteroid Withdrawal in Patients With Asthma Receiving Zafirlukast

Context.— Zafirlukast is a potent leukotriene antagonist that recently was approved for the treatment of asthma. As use of this drug increases, adverse events that occur at low frequency or in populations not studied in premarketing clinical trials may become evident. Objective.— To describe a clinical syndrome associated with zafirlukast therapy. Design.— Case series. Patients.— Eight adults (7 women and 1 man) with steroid-dependent asthma who received zafirlukast. Main Outcome Measures.— Development of a clinical syndrome characterized by pulmonary infiltrates, cardiomyopathy, and eosinophilia following the withdrawal of corticosteroid treatment. Results.— The clinical syndrome developed while patients were receiving zafirlukast from 3 days to 4 months and from 3 days to 3 months after corticosteroid withdrawal. All 8 patients developed leukocytosis (range, 14.5-27.6x10⁹/L) with eosinophilia (range, 0.19-0.71). Six patients had fever (temperature >38.5°C), 7 had muscle pain, 6 had sinusitis, and 6 had biopsy evidence of eosinophilic tissue infiltration. The clinical syndrome improved with discontinuation of zafirlukast treatment and reinitiation of corticosteroid treatment or addition of cyclophosphamide treatment. Comment.— Development of pulmonary infiltrates, cardiomyopathy, and eosinophilia may have occurred independent of zafirlukast use or may have resulted from an allergic response to this medication. We suspect that these patients may have had a primary eosinophilic infiltrative disorder that had been clinically recognized as asthma, was quelled by steroid treatment, and was unmasked following corticosteroid withdrawal facilitated by zafirlukast.      

Nebulized Budesonide and Oral Dexamethasone for Treatment of Croup: A Randomized Controlled Trial

Context.— The effectiveness of glucocorticoids for patients with croup is well established but it remains uncertain which glucocorticoid regimen is most effective. Objective.— To determine the effectiveness of 3 glucocorticoid regimens in patients with croup. Design.— Randomized controlled trial with parallel design. Setting.— Emergency departments of 2 Canadian pediatric tertiary care hospitals. Participants.— Children with a clinical syndrome consistent with croup, aged 3 months to 5 years, with a croup score of 2 or greater following at least 15 minutes of mist therapy. Interventions.— Oral dexamethasone, 0.6 mg/kg, and nebulized placebo; oral placebo and nebulized budesonide, 2 mg; or oral dexamethasone, 0.6 mg/kg, and nebulized budesonide, 2 mg. Main Outcome Measures.— Westley croup score (primary outcome), hospital admission rates, time spent in the emergency department, return visits to the emergency department, or ongoing symptoms at 1 week. Results.— The mean change in the croup score from baseline to the final study assessment was -2.3 (95% confidence interval [CI], -2.6 to -2.0) in the budesonide group (n=65), -2.4 (95% CI, -2.6 to -2.2) in the dexamethasone group (n=69), and -2.4 (95% CI, -2.7 to -2.1) in the budesonide and dexamethasone group (n=64, P=.70). Conclusions.— Based on the similar outcomes in the 3 groups, oral dexamethasone is the preferred intervention because of its ease of administration, lower cost, and more widespread availability.      

Bartenders' Respiratory Health After Establishment of Smoke-Free Bars and Taverns

Context.— The association between environmental tobacco smoke (ETS) exposure and respiratory symptoms has not been well established in adults. Objective.— To study the respiratory health of bartenders before and after legislative prohibition of smoking in all bars and taverns by the state of California. Design.— Cohort of bartenders interviewed before and after smoking prohibition. Setting and Participants.— Bartenders at a random sample of bars and taverns in San Francisco. Main Outcome Measures.— Interviews assessed respiratory symptoms, sensory irritation symptoms, ETS exposure, personal smoking, and recent upper respiratory tract infections. Spirometric assessment included forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC) measurements. Results.— Fifty-three of 67 eligible bartenders were interviewed. At baseline, all 53 bartenders reported workplace ETS exposure. After the smoking ban, self-reported ETS exposure at work declined from a median of 28 to 2 hours per week (P<.001). Thirty-nine bartenders (74%) initially reported respiratory symptoms. Of those symptomatic at baseline, 23 (59%) no longer had symptoms at follow-up (P<.001). Forty-one bartenders (77%) initially reported sensory irritation symptoms. At follow-up, 32 (78%) of these subjects had resolution of symptoms (P<.001). After prohibition of workplace smoking, we observed improvement in mean FVC (0.189 L; 95% confidence interval [CI], 0.082-0.296 L; 4.2% change) and, to a lesser extent, mean FEV₁ (0.039 L; 95% CI, -0.030 to 0.107 L; 1.2% change). Complete cessation of workplace ETS exposure (compared with continued exposure) was associated with improved mean FVC (0.287 L; 95% CI, 0.088-0.486; 6.8% change) and mean FEV₁ (0.142 L; 95% CI, 0.020-0.264 L; 4.5% change), after controlling for personal smoking and recent upper respiratory tract infections. Conclusion.— Establishment of smoke-free bars and taverns was associated with a rapid improvement of respiratory health.      

Distribution of and factors associated with serum homocysteine levels in children: Child and Adolescent Trial for Cardiovascular Health

Context  Although evidence suggests that homocysteine is a risk factor for cardiovascular disease in adults, little information exists on homocysteine levels in children. Objectives  To describe the distribution of serum homocysteine concentrations among children and to examine the association between homocysteine levels and several characteristics, including serum levels of folic acid and vitamins B₁₂ and B₆. Design  Cross-sectional analysis. Setting  School-based cohort from California, Louisiana, Minnesota, and Texas. Participants  A total of 3524 US schoolchildren, aged 13 and 14 years, from the Child and Adolescent Trial for Cardiovascular Health (completed in 1994). Measurement was conducted in 1997. Main Outcome Measure  Nonfasting serum total homocysteine concentration. Results  The distribution of homocysteine values ranged from 0.1 to 25.7 µmol/L (median, 4.9 µmol/L). Geometric mean homocysteine concentration was significantly higher in boys (5.22 µmol/L) than girls (4.84 µmol/L); blacks (5.51 µmol/L) than whites (4.96 µmol/L) or Hispanics (4.93 µmol/L); nonusers of multivitamins (5.09 µmol/L) than users (4.82 µmol/L); and smokers (5.19 µmol/L) than nonsmokers (5.00 µmol/L). Serum homocysteine was significantly inversely correlated with serum levels of folic acid (r=-0.36; P=.001), vitamin B₁₂ (r=-0.21; P=.001), and vitamin B₆ (r=-0.18; P=.001). Serum homocysteine was not significantly associated with serum lipid levels or family history of cardiovascular disease and was only weakly related to body mass index and systolic blood pressure. After multivariate adjustment, homocysteine remained independently associated with sex, race, serum folic acid and vitamin B₁₂ levels, and systolic blood pressure. Conclusions  The distribution of homocysteine levels in children is substantially lower than that observed for adults; however, a small percentage of children are still potentially at elevated risk for future cardiovascular disease. Serum folic acid may be an important determinant of homocysteine levels in children.      

Genetic Studies on Chromosome 12 in Late-Onset Alzheimer Disease

Context.— The only genetic locus universally accepted to be important as a risk factor for late-onset Alzheimer disease (AD) is the apolipoprotein E (APOE) locus on chromosome 19. However, this locus does not account for all the risk in late-onset disease, and a recent report has suggested a second locus on chromosome 12p11-12. Objective.— To look for evidence of linkage on chromosome 12 and to test for the presence of the new locus in an independent sample of familial late-onset AD cases. Design.— Retrospective cohort study. As part of a 20-centimorgan genome screen (approximately equal to 200 markers), we tested a series of 18 genetic markers on chromosome 12 and carried out multipoint, nonparametric lod score and exclusion analyses. Setting.— Clinic populations in the continental United States selected from the National Institute of Mental Health AD Genetics Consortium. Patients.— We selected samples for DNA analysis from affected sibling pairs, 497 subjects from 230 families with 2 or more affected individuals with probable or definite AD with onset ages older than 60 years (mean±SD, 75±6 years). Within the families, we used the 2 probable or definitely affected individuals. In families with more than 2 such cases available, we used all of them; in families with only 2 such cases in which unaffected individuals were available, we also sampled the oldest unaffected individual and used genotype data from this unaffected individual to check for nonpaternity and genotyping errors. Main Outcome Measure.— Presence of linkage or locus on chromosome 12. Results.— Although linkage analyses confirmed the presence of a genetic susceptibility factor at the APOE locus in these families with late-onset AD, we were unable to confirm the presence of a locus close to the marker D12S1042. A moderate lod score (1.91) was found near D12S98 close to the ₂-macroglobulin locus in the affected pairs in which both members did not possess an APOE 4 allele. Conclusions.— APOE remains the only locus established to be a risk factor for late-onset AD. We were unable to confirm that a locus on chromosome 12p11-12 has a major effect on risk for late-onset AD, although an effect smaller than that for APOE cannot be excluded.      

Simultaneous vs Sequential Initiation of Therapy With Indinavir, Zidovudine, and Lamivudine for HIV-1 Infection: 100-Week Follow-up

Context.— Combination antiretroviral therapy can markedly suppress human immunodeficiency virus (HIV) replication but the duration of HIV suppression varies among patients. Objective.— To compare the antiretroviral effect of a 3-drug regimen started simultaneously or sequentially in patients with HIV infection. Design.— A multicenter, randomized, double-blind study, modified after at least 24 weeks of blinded therapy to provide open-label 3-drug therapy with follow-up through 100 weeks. Setting.— Four clinical research units Patients.— Ninety-seven patients with HIV infection who had taken zidovudine for at least 6 months with serum HIV RNA level of at least 20000 copies/mL and CD4 cell count of 0.05 to 0.40x10⁹/L. Interventions.— Patients were initially randomized to receive 1 of 3 antiretroviral regimens: indinavir, 800 mg every 8 hours; zidovudine, 200 mg every 8 hours and lamivudine, 150 mg every 12 hours; or all 3 drugs. After at least 24 weeks of blinded therapy, all patients received open-label 3-drug therapy. Main Outcome Measures.— Antiretroviral activity was assessed by changes in HIV RNA level and CD4 cell count from baseline. Data through 100 weeks were summarized. Results.— Simultaneous initiation of indinavir, zidovudine, and lamivudine suppressed HIV RNA in 78% (25/32) of contributing patients to less than 500 copies/mL and increased CD4 cell count to a median of 0.209x10⁹/L above baseline at 100 weeks. When these 3 drugs were initiated sequentially, only 30% to 45% of contributing patients (10 of 33 in the zidovudine-lamivudine group and 13 of 29 in the indinavir group, respectively) had a sustained reduction in HIV RNA to less than 500 copies/mL, and median CD4 cell count increased to 0.101 to 0.163x10⁹/L above baseline at 100 weeks. Conclusions.— A 3-drug combination of indinavir, zidovudine, and lamivudine started simultaneously has durable antiretroviral activity for at least 2 years. Sequential initiation of the same 3 drugs is much less effective.      

Health Economic Benefits and Quality of Life During Improved Glycemic Control in Patients With Type 2 Diabetes Mellitus: A Randomized, Controlled, Double-Blind Trial

Context.— Although the long-term health benefits of good glycemic control in patients with diabetes are well documented, shorter-term quality of life (QOL) and economic savings generally have been reported to be minimal or absent. Objective.— To examine short-term outcomes of glycemic control in type 2 diabetes mellitus (DM). Design.— Double-blind, randomized, placebo-controlled, parallel trial. Setting.— Sixty-two sites in the United States. Participants.— A total of 569 male and female volunteers with type 2 DM. Intervention.— After a 3-week, single-blind placebo-washout period, participants were randomized to diet and titration with either 5 to 20 mg of glipizide gastrointestinal therapeutic system (GITS) (n=377) or placebo (n=192) for 12 weeks. Main Outcome Measures.— Change from baseline in glucose and hemoglobin A_1c (HbA_1c) levels and symptom distress, QOL, and health economic indicators by questionnaires and diaries. Results.— After 12 weeks, mean (±SE) HbA_1c and fasting blood glucose levels decreased with active therapy (glipizide GITS) vs placebo (7.5%±0.1% vs 9.3%±0.1% and 7.0±0.1 mmol/L [126±2 mg/dL] vs 9.3±0.2 mmol/L [168±4 mg/dL], respectively; P<.001). Quality-of-life treatment differences (SD units) for symptom distress (+0.59; P<.001), general perceived health (+0.36; P=.004), cognitive functioning (+0.34; P=.005), and the overall visual analog scale (VAS) (+0.24; P=.04) were significantly more favorable for active therapy. Subscales of acuity (+0.38; P=.002), VAS emotional health (+0.35; P =.003), general health (+0.27; P =.01), sleep (+0.26; P =.04), depression (+0.25; P =.05), disorientation and detachment (+0.23; P =.05), and vitality (+0.22; P =.04) were most affected. Favorable health economic outcomes for glipizide GITS included higher retained employment (97% vs 85%; P<.001), greater productive capacity (99% vs 87%; P<.001), less absenteeism (losses=$24 vs $115 per worker per month; P <.001), fewer bed-days (losses=$1539 vs $1843 per 1000 person-days; P=.05), and fewer restricted-activity days (losses=$2660 vs $4275 per 1000 person-days; P=.01). Conclusions.— Improved glycemic control of type 2 DM is associated with substantial short-term symptomatic, QOL, and health economic benefits.      

Vitamins for chronic disease prevention in adults: scientific review

Context  Although vitamin deficiency is encountered infrequently in developed countries, inadequate intake of several vitamins is associated with chronic disease. Objective  To review the clinically important vitamins with regard to their biological effects, food sources, deficiency syndromes, potential for toxicity, and relationship to chronic disease. Data Sources and Study Selection  We searched MEDLINE for English-language articles about vitamins in relation to chronic diseases and their references published from 1966 through January 11, 2002. Data Extraction  We reviewed articles jointly for the most clinically important information, emphasizing randomized trials where available. Data Synthesis  Our review of 9 vitamins showed that elderly people, vegans, alcohol-dependent individuals, and patients with malabsorption are at higher risk of inadequate intake or absorption of several vitamins. Excessive doses of vitamin A during early pregnancy and fat-soluble vitamins taken anytime may result in adverse outcomes. Inadequate folate status is associated with neural tube defect and some cancers. Folate and vitamins B₆ and B₁₂ are required for homocysteine metabolism and are associated with coronary heart disease risk. Vitamin E and lycopene may decrease the risk of prostate cancer. Vitamin D is associated with decreased occurrence of fractures when taken with calcium. Conclusions  Some groups of patients are at higher risk for vitamin deficiency and suboptimal vitamin status. Many physicians may be unaware of common food sources of vitamins or unsure which vitamins they should recommend for their patients. Vitamin excess is possible with supplementation, particularly for fat-soluble vitamins. Inadequate intake of several vitamins has been linked to chronic diseases, including coronary heart disease, cancer, and osteoporosis.      

Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake

Context  Adequate vitamin D status for optimum bone health has received increased recognition in recent years; however, the ideal intake is not known. Serum 25-hydroxyvitamin D is the generally accepted indicator of vitamin D status, but no universal reference level has been reached. Objective  To investigate the relative importance of high calcium intake and serum 25-hydroxyvitamin D for calcium homeostasis, as determined by serum intact parathyroid hormone (PTH). Design, Setting, and Participants  Cross-sectional study of 2310 healthy Icelandic adults who were divided equally into 3 age groups (30-45 years, 50-65 years, or 70-85 years) and recruited from February 2001 to January 2003. They were administered a semi-quantitative food frequency questionnaire, which assessed vitamin D and calcium intake. Participants were further divided into groups according to calcium intake (<800 mg/d, 800-1200 mg/d, and >1200 mg/d) and serum 25-hydroxyvitamin D level (<10 ng/mL, 10-18 ng/mL, and >18 ng/mL). Main Outcome Measure  Serum intact PTH as determined by calcium intake and vitamin D. Results  A total of 944 healthy participants completed all parts of the study. After adjusting for relevant factors, serum PTH was lowest in the group with a serum 25-hydroxyvitamin D level of more than 18 ng/mL but highest in the group with a serum 25-hydroxyvitamin D level of less than 10 ng/mL. At the low serum 25-hydroxyvitamin D level (<10 ng/mL), calcium intake of less than 800 mg/d vs more than 1200 mg/d was significantly associated with higher serum PTH (P = .04); and at a calcium intake of more than 1200 mg/d, there was a significant difference between the lowest and highest vitamin D groups (P = .04). Conclusions  As long as vitamin D status is ensured, calcium intake levels of more than 800 mg/d may be unnecessary for maintaining calcium metabolism. Vitamin D supplements are necessary for adequate vitamin D status in northern climates.