Karim A. Calis

Orthopedic Complications of Overweight in Children and Adolescents

OBJECTIVE. Few studies have quantified the prevalence of weight-related orthopedic conditions in otherwise healthy overweight children. The goal of the present investigation was to describe the musculoskeletal consequences of pediatric overweight in a large pediatric cohort of children that included severely overweight children. METHODS. Medical charts from 227 overweight and 128 nonoverweight children and adolescents who were enrolled in pediatric clinical studies at the National Institutes of Health from 1996 to 2004 were reviewed to record pertinent orthopedic medical history and musculoskeletal complaints. Questionnaire data from 183 enrollees (146 overweight) documented difficulties with mobility. In 250, lower extremity alignment was determined by bilateral metaphyseal-diaphyseal and anatomic tibiofemoral angle measurements made from whole-body dual-energy x-ray absorptiometry scans. RESULTS. Compared with nonoverweight children, overweight children reported a greater prevalence of fractures and musculoskeletal discomfort. The most common self-reported joint complaint among those who were questioned directly was knee pain (21.4% overweight vs 16.7% nonoverweight). Overweight children reported greater impairment in mobility than did nonoverweight children (mobility score: 17.0 ± 6.8 vs 11.6 ± 2.8). Both metaphyseal-diaphyseal and anatomic tibiofemoral angle measurements showed greater malalignment in overweight compared with nonoverweight children. CONCLUSIONS. Reported fractures, musculoskeletal discomfort, impaired mobility, and lower extremity malalignment are more prevalent in overweight than nonoverweight children and adolescents. Because they affect the likelihood that children will engage in physical activity, orthopedic difficulties may be part of the cycle that perpetuates the accumulation of excess weight in children.

Orlistat, a New Lipase Inhibitor for the Management of Obesity

Orlistat, a weight‐loss agent with a novel mechanism of action, recently was approved by the Food and Drug Administration for the treatment of obesity. It inhibits gastric and pancreatic lipases in the lumen of the gastrointestinal tract to decrease systemic absorption of dietary fat. In several trials lasting up to 2 years, orlistat was more effective than diet alone for weight reduction and maintenance of lost weight. Orlistat treatment also results in modest improvements in total cholesterol, low‐density lipoprotein, blood pressure, and fasting glucose and insulin concentrations. The major adverse effects are gastrointestinal, usually occur early in therapy, and tend to decrease with continued treatment. Because orlistat may decrease the absorption of fat‐soluble vitamins, a standard multiple‐vitamin supplement is recommended daily during therapy to prevent abnormalities in vitamin serum concentrations. The potential for severe gastrointestinal discomfort and the modest degree of weight loss may limit the agents clinical utility. Its long‐term safety and effectiveness for weight maintenance, cost‐effectiveness of treatment, and overall reduction in obesity‐related morbidity and mortality remain to be determined.

Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome (HPS) consists of oculocutaneous albinism, a platelet storage pool deficiency and, in patients with HPS1 gene mutations, a progressive, fatal pulmonary fibrosis. We investigated the safety and efficacy of an antifibrotic agent, pirfenidone (800 mg, t.i.d.), in treating 21 adult Puerto Rican HPS patients, including 20 homozygous for the same HPS1 mutation. Patients were examined every 4 months for up to 44 months in a randomized, placebo-controlled trial, with rate of change in pulmonary function values as outcome parameters. Using the complete data set of 130 patient admissions, a repeated measures model showed that 11 pirfenidone-treated patients lost FVC at a rate 5% of predicted ( approximately 400 mL) per year slower than 10 placebo-treated patients (p=0.001). A random coefficients model showed no significant difference. However, using data restricted to patients with an initial FVC >50% of predicted, both models showed the pirfenidone group losing FVC (p<0.022), FEV(1) (p<0.0007), TLC (p<0.001), and DL(CO) (p<0.122) at a rate approximately 8%/year slower than the placebo group. Clinical and laboratory side effects were similar in the two groups. Pirfenidone appears to slow the progression of pulmonary fibrosis in HPS patients who have significant residual lung function.

Effects of Orlistat on Fat‐Soluble Vitamins in Obese Adolescents

Study Objectives. To determine whether orlistat causes fat‐soluble vitamin deficiencies in African‐American and Caucasian adolescents.

Effects of Metformin on Body Weight and Body Composition in Obese Insulin-Resistant Children A Randomized Clinical Trial

OBJECTIVE Metformin can decrease adiposity and ameliorate obesity-related comorbid conditions, including abnormalities in glucose homeostasis in adolescents, but there are few data evaluating the efficacy of metformin among younger children. Our objective was to determine whether metformin treatment causes weight loss and improves obesity-related comorbidities in obese children, who are insulin-resistant. RESEARCH DESIGN AND METHODS This study was a randomized double-blind placebo-controlled trial consisting of 100 severely obese (mean BMI 34.6 ± 6.6 kg/m2) insulin-resistant children aged 6–12 years, randomized to 1,000 mg metformin (n = 53) or placebo (n = 47) twice daily for 6 months, followed by open-label metformin treatment for 6 months. All children and their parents participated in a monthly dietitian-administered weight-reduction program. RESULTS Eighty-five percent completed the 6-month randomized phase. Children prescribed metformin had significantly greater decreases in BMI (difference −1.09 kg/m2, CI −1.87 to −0.31, P = 0.006), body weight (difference −3.38 kg, CI −5.2 to −1.57, P < 0.001), BMI Z score (difference between metformin and placebo groups −0.07, CI −0.12 to −0.01, P = 0.02), and fat mass (difference −1.40 kg, CI −2.74 to −0.06, P = 0.04). Fasting plasma glucose (P = 0.007) and homeostasis model assessment (HOMA) insulin resistance index (P = 0.006) also improved more in metformin-treated children than in placebo-treated children. Gastrointestinal symptoms were significantly more prevalent in metformin-treated children, which limited maximal tolerated dosage in 17%. During the 6-month open-label phase, children treated previously with placebo decreased their BMI Z score; those treated continuously with metformin did not significantly change BMI Z score further. CONCLUSIONS Metformin had modest but favorable effects on body weight, body composition, and glucose homeostasis in obese insulin-resistant children participating in a low-intensity weight-reduction program.

Symptomatic cardiotoxicity associated with 5-fluorouracil.

A prospective cohort study was conducted in 35 hospitals with oncology units to determine the incidence of symptomatic cardiotoxicity in patients receiving continuous infusions of 5‐fluorouracil (5‐FU), and to identify risk factors that could contribute to the development of 5‐FU‐associated cardiotoxicity. A sample of 483 patients [197 (41%) women, overall average age ± SD 60.9 ± 11.9 yrs] were followed for one cycle of 5‐FU infusion. Thirty‐eight (7.9%) patients had abrupt termination of the infusion. There were 9 (1.9%) cases of suspected or documented cardiotoxic events. Cardiotoxicity occurred in 7 (3.35%) of 209 patients receiving their first course of 5‐FU and in 2 (0.73%) other patients (p=0.044). Based on univariate analysis, the following patient groups were at elevated risk of cardiotoxicity: those with preexisting cardiac disease (RR=6.83, p=0.0023); patients receiving calcium channel blockers (RR=4.75, p=0.014); those receiving nitrates (RR=9.18, p=0.007); and patients receiving concomitant etoposide (RR=10.32, p=0.022). Patients with underlying cardiac disease require close monitoring while receiving continuous infusions of 5‐FU. They should be observed for signs and symptoms of cardiotoxicity, and vital signs should be measured frequently. Continued reporting of 5‐FU‐associated cardiotoxicity is necessary to identify other patients at risk.

Endothelial function, but not carotid intima-media thickness, is affected early in menopause and is associated with severity of hot flushes.

CONTEXT The effect of early menopause on indices of vascular function has been little studied. OBJECTIVE The objective of the study was to investigate the effect of early menopause on indices of subclinical atherosclerosis and identify predictors of those indices in early menopausal women. DESIGN, SETTING, AND PARTICIPANTS This was a cross-sectional study that included 120 early menopausal women (age range 42-55 yr, <3 yr in menopause) recruited from the menopause outpatient clinic of an academic hospital and 24 age-matched premenopausal women. MAIN OUTCOME MEASURES Brachial artery flow-mediated dilation (FMD) and common carotid intima-media thickness (IMT) were studied. Estrogen receptor (ER)-alpha (rs2234693 T-->C and rs9340799 A-->G) and ERbeta (rs4986938 A-->G) polymorphisms were studied in menopausal women. RESULTS FMD was significantly lower in early menopausal women compared with controls (5.43 +/- 2.53 vs. 8.74 +/- 3.17%, P < 0.001), whereas IMT did not differ between groups (P > 0.8). Severity of hot flushes was the most important independent predictor for FMD (P < 0.001) in menopausal women. Women with moderate/severe/very severe hot flushes had impaired FMD in contrast to women with no/mild hot flushes or controls. Women with no/mild hot flushes did not differ compared with controls. Age and systolic blood pressure were the main determinants of IMT (both P = 0.004). ER polymorphisms were not associated with vascular parameters. CONCLUSIONS Impairment of endothelial function is present in the early menopausal years, whereas carotid IMT is not affected. Severity of hot flushes is the main determinant of endothelial dysfunction in early menopausal women. The studied ER polymorphisms do not offer important information on vascular health in early menopause.

Thrombolytic Therapy with Use of Alteplase (rt-PA) in Peripheral Arterial Occlusive Disease: Review of the Clinical Literature

PURPOSE The clinical literature describing the use of alteplase in the treatment of peripheral arterial occlusive (PAO) disease is reviewed. MATERIALS AND METHODS The literature database was acquired by a MEDLINE search using the Boolean keyword string: tissue plasminogen activator and/or rt-PA and peripheral not animal. A review was performed to identify the dose range of alteplase, technique of infusion, use of anticoagulation, clinical success rates, and risk of complications. RESULTS Forty-six clinical studies were identified. There are few prospective, randomized clinical trials and a lack of standardized protocols and endpoints. Use of catheter-directed infusions of recombinant tissue plasminogen activator (rt-PA) may be beneficial versus surgery in the initial management of acute limb ischemia (< 14 days) and in reducing the magnitude of subsequent surgical or percutaneous revascularization. For patients with chronic limb ischemia (> 14 days), irreversible acute limb ischemia, or advanced diabetic arteriopathy, catheter-directed infusion of rt-PA or other plasminogen activators may be unsuitable. The risk of adverse bleeding appears related to the overall dose and duration of infusion. These risks appear similar to those of urokinase. The role of heparin in increasing adverse bleeding during rt-PA therapy is unclear. CONCLUSIONS There is no generally accepted dose or technique for administering catheter-directed thrombolysis using alteplase; however, several studies have demonstrated its clinical safety and efficacy. Formal studies will be required to determine the optimal dose, technique of infusion, the role of anticoagulation, and complication rates when alteplase is used for PAO disease.

A pharmacokinetic and pharmacodynamic study of delayed- and extended-release hydrocortisone (Chronocort) vs. conventional hydrocortisone (Cortef) in the treatment of congenital adrenal hyperplasia.

Objective  Existing glucocorticoid treatment for congenital adrenal hyperplasia (CAH) is suboptimal and nonphysiological. We compared hormonal profiles during therapy with a new modified‐release hydrocortisone (MR‐HC), Chronocort™, to conventional hydrocortisone (HC), Cortef™, in patients with CAH.

Bone Mineral Density in Estrogen-Deficient Young Women

CONTEXT Osteoporosis primarily affects postmenopausal women. However, young women with estrogen deficiency also are at increased risk for low bone density. OBJECTIVE The aim of the study was to assess bone density and associated risk factors for reduced bone density in young, estrogen-deficient women using primary ovarian insufficiency (POI) as the disease model. DESIGN AND SETTING We conducted a cross-sectional study at a tertiary care research center. PARTICIPANTS We studied women with POI (n = 442), concurrent controls (n = 70), and matched controls from NHANES III (n = 353). PRIMARY OUTCOME MEASURE We measured bone mineral density (BMD) using dual-energy x-ray absorptiometry. RESULTS Patients on average had 2-3% lower BMD at L1-L4, femoral neck, and total hip (P < 0.01 at all sites). The modifiable risk factors for BMD below the expected range for age (Z-score <-2) were: more than 1-yr delay in diagnosis of estrogen deficiency (P = 0.018), low (<32 ng/ml) vitamin D levels (P = 0.002), estrogen replacement nonadherence (P = 0.002), low calcium intake (P = 0.005), and lack of exercise (P = 0.005). As compared to Caucasians, African-American and Asian women with POI were 3.18 and 4.34 times more likely, respectively, to have Z-scores below -2 (P = < 0.0001 for both). Race was an overall risk factor, but on regression modeling, not an independent predictor of low bone density. CONCLUSIONS Women with POI have lower bone density compared to regularly menstruating women. Compared to Caucasians, minority women with estrogen deficiency are more likely to have BMD below the expected range for age. This racial disparity appears to be related to a combined effect of several modifiable risk factors. Delay in diagnosis of POI also contributes to reduced bone density by delaying proper therapy.