Relation of circulating oxidized LDL to obesity and insulin resistance in children

Kelly AS, Jacobs DR Jr, Sinaiko AR, Moran A, Steffen LM, Steinberger J. Relation of circulating oxidized LDL to obesity and insulin resistance in children. Introduction: Circulating oxidized low‐density lipoprotein (LDL), a marker of oxidative stress, is associated with obesity, insulin resistance, metabolic syndrome, and cardiovascular disease in adults. However, little is known about its relation to insulin resistance and cardiovascular risk factors in children. The purpose of this study was to assess the relation of oxidative stress, measured by circulating oxidized LDL, with measures of adiposity and insulin resistance in children. Methods: Oxidized LDL, measures of body fatness (body mass index: BMI, percent body fat, waist circumference, percent trunk fat, abdominal visceral and subcutaneous fat), insulin resistance with euglycemic insulin clamp (Mlbm), blood pressure, and blood lipids were obtained in 78 children. Oxidized LDL was compared between normal weight children (BMI < 85th percentile) and overweight/obese children (BMI ≥ 85th percentile) and levels were evaluated for associations with body fatness and insulin resistance. Results: Oxidized LDL levels were significantly higher in overweight/obese vs. normal weight children (p < 0.0001). Oxidized LDL was significantly correlated with BMI, percent body fat, waist circumference, percent trunk fat, abdominal visceral fat, and abdominal subcutaneous fat (all p‐values <0.0001). Moreover, oxidized LDL was negatively correlated with Mlbm, even after adjustment for adiposity (p < 0.01). Conclusions: Oxidized LDL is significantly associated with adiposity and with insulin resistance, independent of body fatness, in children. Oxidative stress may be independently related to the development of insulin resistance early in life, especially in obese youth.     

Azygous vein to right atrium bypass graft in a patient with idiopathic fibrosing mediastinitis and symptomatic superior and inferior vena cava obstructions

We report an unusual case of a patient with diminished cardiac output caused by systemic venous occlusions of unclear etiology with a history of idiopathic fibrosing mediastinitis and retroperitoneal fibrosis. On thoracic, abdominal, and pelvic venograms, the patient was previously known to have superior vena caval and infrarenal inferior vena caval occlusions. Subsequent studies revealed retrograde flow through the azygous and hemiazygous veins and numerous caval-portal anastomoses providing venous return from the upper and lower extremities. After an extensive hypercoagulable state work-up, no abnormalities were found. To relieve the symptoms, the patient underwent an elective right thoracotomy with azygous vein to right atrial bypass graft. The patient has had complete amelioration of the disabling symptoms and participates in many activities that he could not tolerate previously. Because this condition and procedure are unreported, we present a novel surgical treatment option to palliate symptoms caused by concurrent superior and inferior caval obstructions by improving venous return to the heart.     

Endocrine complications of cystic fibrosis

Patients with cystic fibrosis (CF) are now living longer, with a median survival of 32 years in 2000. With longer life expectancy and improved treatments for pulmonary disease, other complications of CF are becoming more apparent. The primary endocrine complications affecting adolescents with CF include (1) poor growth and pubertal development, (2) CF-related diabetes, and (3) poor bone mineralization. This chapter discusses pathophysiology, screening, and treatment of endocrine complications of CF.     

Phylogenetic relationships of southern African West Nile virus isolates

Phylogenetic relationships were examined for 29 southern African West Nile virus (formal name West Nile virus [WNV]) isolates from various sources in four countries from 1958 to 2001. In addition, sequence data were retrieved from GenBank for another 23 WNV isolates and Kunjin and Japanese encephalitis viruses. All isolates belonged to two lineages. Lineage 1 isolates were from central and North Africa, Europe, Israel, and North America; lineage 2 isolates were from central and southern Africa and Madagascar. No strict correlation existed between grouping and source of virus isolate, pathogenicity, geographic distribution, or year of isolation. Some southern African isolates have been associated with encephalitis in a human, a horse, and a dog and with fatal hepatitis in a human and death of an ostrich chick.     

Comparison of contractile responses to donitriptan and sumatriptan in the human middle meningeal and coronary arteries

Donitriptan is a potent, high efficacy agonist at 5-HT(1B/1D) receptors. We investigated the contractile effects of donitriptan and sumatriptan on human isolated blood vessels of relevance to therapeutic efficacy in migraine (middle meningeal artery) and coronary adverse events (coronary artery). Furthermore, using the concentration-response curves in the middle meningeal artery, we predicted the plasma concentration needed for the therapeutic effect of donitriptan. Both donitriptan and sumatriptan contracted the middle meningeal artery with similar apparent efficacy (E(max): 103+/-8% and 110+/-12%, respectively), but the potency of donitriptan (pEC(50): 9.07+/-0.14) was significantly higher than that of sumatriptan (pEC(50): 7.41+/-0.08). In the coronary artery, the contraction to donitriptan was biphasic with a significantly higher maximal response (E(max): 29+/-6%) than sumatriptan (E(max): 14+/-2%; pEC(50): 5.71+/-0.16), yielding two distinct pEC(50) values (8.25+/-0.16 and 5.60+/-0.24). Incubation with the 5-HT(2) receptor antagonist ketanserin (10 microM) eliminated the low affinity component of the concentration-response curve of donitriptan and the resultant E(max) and pEC(50) were 9+/-2% and 7.33+/-0.21, respectively. Ketanserin was without effect on the sumatriptan-induced contraction. Based on the middle meningeal artery contraction, concentrations (C(max)) of donitriptan that may be expected to have a therapeutic efficacy equivalent to that of 50 and 100 mg sumatriptan are predicted to be around 2.5 and 4.3 nM, respectively. Such concentrations are likely to induce only a small coronary artery contraction of 2.9+/-1.5% and 3.8+/-2.0%, respectively; these are not different from those by C(max) concentrations of sumatriptan (1.7+/-0.4% or 2.2+/-0.4%). The present results suggest that, like sumatriptan, donitriptan exhibits cranioselectivity and would be effective in aborting migraine attacks with a similar coronary side-effect profile as sumatriptan.     

Polymorphism of roxifiban

Roxifiban was found to exist in two polymorphic forms. The polymorphs were detected by X-ray powder diffraction and solid-state carbon nuclear magnetic resonance. A slight difference between the two polymorphs was also detected by isothermal microcalorimetry. However, no differences were observed by differential scanning calorimetry, infrared, or Raman spectroscopy. Solubility studies as a function of temperature in a discriminating solvent system permitted characterization of the thermodynamics of the polymorphs. The enthalpy of solution at 25 degrees C was 8.1 kcal/mol and 8.9 kcal/mol for Form I and Form II, respectively, and the thermodynamic transition point was 132 degrees C. The data confirm that the polymorphs are enantiotropic. Form II is the thermodynamically stable crystal form over the practical range of drug substance storage and handling and dosage form processing and storage. However, Form I has been kinetically stable after storage for more than 36 months at 25 degrees C/60% relative humidity with no conversion to Form II occurring.     

The relative utility of cardiac troponin I,creatine kinase-MBmass,and myosin light chain-1 in the long-term risk stratification of patients with chest pain

BACKGROUND: Sensitive and specific cardiac markers convey important short-term prognostic information about patients with an acute coronary syndrome. There are, however, few data assessing their value as long-term predictors. HYPOTHESIS: The aim of the current study was to assess the relative value of three such markers and clinical characteristics in determining the long-term prognosis of patients with chest pain. METHODS: Cardiac troponin I (cTnI), myosin light chain-(MLC-1), and creatine kinase-MBmass levels were obtained on admission (0 h) and at 4, 8, 16, and 24 h in 208 patients with chest pain. Eligible subjects were determined, at the time of hospital admission, to be at >7% risk of acute myocardial infarction (MI), but without new ST-segment elevation on their presenting electrocardiogram. Follow-up was performed a median of 28 (range 1-46) months later. The primary study endpoint was death or nonfatal MI, subsequent to the index admission. RESULTS: Cardiac TnI levels > or = 0.2 ng/ml (odds ratio [OR] 1.93, 95% confidence interval [CI] 1.09-3.40) and MLC-1 levels > or = 1 ng/ml (OR 3.24, 95% CI 1.83-5.73) were both significant predictors of death or MI during long-term follow-up; MLC-1 was, however, the only independent biochemical predictor (OR 2.11,95% CI 1.14-3.93). CONCLUSIONS: Both cTnl and MLC-1 predict the long-term outcome of patients with chest pain, but, in this cohort, MLC-1 proved to be a better predictor of mortality and nonfatal acute MI.     

Effectiveness of medical resident education in mechanical ventilation

Specific methods of mechanical ventilation management reduce mortality and lower health care costs. However, in the face of a predicted deficit of intensivists, it is unclear whether residency programs are training internists to provide effective care for patients who require mechanical ventilation. To evaluate these educational outcomes, we administered a validated 19-item case-based test and survey to resident physicians at 31 diverse U.S. internal medicine residency programs nationwide. Of 347 senior residents, 259 (75%) responded. The mean test score was 74% correct (SD, 14%; range, 37 to 100%). Important items representing evidence-based standards of critical care answered incorrectly were as follows: use of appropriate tidal volume in the acute respiratory distress syndrome (48% incorrect), identifying a patient ready for a weaning trial (38% incorrect), and recognizing indication for noninvasive ventilation (27% incorrect). Most accurately identified pneumothorax (86% correct) and increased intrathoracic positive end-expiratory pressure (93% correct). Better scores were associated with "closed" versus "open" intensive care unit organization (76 versus 71% correct, p = 0.001), resident perception of greater versus lesser ventilator knowledge (79 versus 71% correct, p = 0.001), and graduation from a U.S. versus international medical school (75 versus 69% correct, p = 0.033). Although overall training satisfaction correlated strongly with program use of learning objectives (r = 0.89, p < 0.0001), only 46% reported being satisfied with their mechanical ventilation training. We conclude that senior residents may not be gaining essential evidence-based knowledge needed to provide effective care for patients who require mechanical ventilation. Residency programs should emphasize evidence-based learning objectives to guide mechanical ventilation instruction.     

Renal segmental tubular response to salt during the normal menstrual cycle

BACKGROUND: It has been suggested that women gain weight and develop peripheral edema during the luteal phase of the menstrual cycle because they tend to retain sodium and water. However, there is actually no clear evidence for physiological, cyclic variations in renal sodium handling during the menstrual cycle. We prospectively assessed the changes in segmental renal sodium handling occurring during the menstrual cycle in response to changes in salt intake. METHODS: Thirty-five normotensive women were enrolled. Seventeen women were randomized and studied in the follicular and 18 in the luteal phases of their menstrual cycle. All women were assigned at random to receive a low (40 mmol/day) or a high (250 mmol/day) sodium diet for seven days on two consecutive menstrual cycles. Renal sodium handling and hemodynamics were measured at the end of each diet period. RESULTS: The changes in sodium intake induced comparable variations in sodium excretion in both phases of the menstrual cycle. In the follicular phase, the increase in salt intake was associated with no change in renal hemodynamics, an increased fractional excretion of lithium (FELi) and a decreased fractional distal reabsorption of sodium (FDRNa), suggesting that sodium reabsorption is reduced both in the proximal and the distal tubules. In contrast, in the luteal phase, the renal response to salt was characterized by a significant renal vasodilation and a marked salt escape from the distal nephron, compared to the women investigated in the follicular phase (P < 0.01). Sodium reabsorption by the proximal nephron was not reduced as indicated by the unchanged FELi. CONCLUSIONS: These results show that the segmental renal handling of sodium differs markedly in the two phases of the menstrual cycle. They suggest that the female hormones modulate the renal handling of sodium at the proximal and distal segments of the nephron in young normotensive women.