Plasma homocysteine, methylenetetrahydrofolate reductase genotypes, and age at onset of symptoms of myocardial ischemia

Elevated fasting plasma homocysteine is a graded risk factor of coronary artery disease (CAD) and may accelerate onset of CAD. Homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is commonly but inconsistently associated with hyperhomocysteinemia. In the present study we examined the possible relation between levels of fasting plasma homocysteine and age at CAD onset in different MTHFR genotypes. We studied 182 patients with CAD, 74 patients with early onset CAD (aged < or = 45 years), and 108 patients with later onset CAD (aged 46 to 65 years). Plasma homocysteine levels in 90 subjects without CAD were used for control. Fasting plasma homocysteine levels in T/T homozygotes with early onset CAD (20.2 +/-12.5 micromol/L) was markedly higher than in T/T homozygotes with later onset CAD (13.4 +/- 6.8 micromol/L) and in patients with early onset CAD who were not T/T homozygotes (11.9 +/- 3.7 micromol/L; p = 0.034 and p = 0.0001, respectively). CAD developed earlier in T/T homozygotes who were hyperhomocysteinemic (>15 micromol/L) than in the T/T homozygotes who were not (p = 0.036). Plasma homocysteine levels had no effect on age at onset of CAD in patients who were non-T/T genotypes. Homocysteine levels in control subjects and in patients who were non-T/T genotypes were comparable and were not influenced by age. The results reveal an inverse relation between the level of fasting plasma homocysteine and age at onset of CAD in T/T homozygotes as opposed to no association in patients who were non-T/T genotypes. Additionally, these results show that hyperhomocysteinemia and the T/T genotype have a stronger effect on the pathogenesis of CAD when they are combined, and that a marked increase (>15 micromol/L) in fasting plasma homocysteine in T/T homozygotes is a risk factor for early onset of CAD.     

Pharmaceutical management of decompensated heart failure syndrome in children: Current state of the art and a new approach

Prompt initiation of appropriate and intensive treatment in children with decompensated heart failure is crucial to avoid irreversible end-organ dysfunction. Initial management of these children includes transfer to the pediatric cardiac intensive care unit, basic hemodynamic monitoring, and establishment of intravenous access. Inotropic support should be instituted peripherally before obtaining central venous and arterial access. The team should be prepared for emergent intubation and initiation of mechanical circulatory support. Two experienced physicians should work together to obtain vascular access and manage sedation, airway control, and cardiovascular support. Acute heart failure syndrome in children may be related to cardiomyopathy, myocarditis, congenital heart disease, and acute rejection post heart transplantation. Each of these causes requires a different approach. Fulminant myocarditis may lead to severe morbidity and requires intensive support, although its outcome is considered to be good. Acute heart failure related to newly diagnosed dilated cardiomyopathy may represent end-stage heart failure; therefore, long-term mechanical circulatory support and heart transplantation may be considered to avoid other end-organ dysfunction. Hypertrophic cardiomyopathy may lead to acute decompensation due to 1) left ventricular outflow obstruction, 2) restrictive physiology leading to pulmonary hypertension, or 3) myocardial is chemia associated with coronary artery bridging. Decompensated heart failure associated with congenital heart disease usually represents end-stage heart failure and requires thorough evaluation for heart transplantation. Children with single-ventricle physiology who develop decompensated heart failure after a Fontan procedure are not candidates for mechanical circulatory support and therefore may not survive to heart transplantation. Acute heart failure due to posttransplantation acute rejection requires aggressive antirejection treatment, which places these patients at significant risk for overwhelming opportunistic infections. In our opinion, mechanical circulatory support should be initiated early in children who present with end-stage heart failure associated with hemodynamic instability to avoid end-organ damage.     

Elevated morbidity and health care use in children with obstructive sleep apnea syndrome.

RATIONALE: Health care use, a reliable measure of morbidity, is noticeably higher 1 yr before obstructive sleep apnea syndrome (OSAS) diagnosis in preschool children. It is not clear at what age OSAS-related morbidity becomes expressed. OBJECTIVE: To explore morbidity and health care use among children with OSAS starting from first year of life. METHODS: Case-control study, starting from the first year of life to date of OSAS diagnosis, among 156 patients (age range, 3-5 yr) and their pair-matched healthy control subjects, by age, sex, primary care physician, and geographic location. MEASUREMENTS: Patients with OSAS underwent nocturnal polysomnography studies. Medical records during hospital visits were reviewed for diagnosis. Variables of health care use were obtained from computerized databases of Clalit Health Care Services, the largest health maintenance organization in Israel. MAIN RESULTS: From the first year of life to date of OSAS diagnosis, children with OSAS had 40% more (p = 0.048) hospital visits, 20% more repeated (two or more) visits (p < 0.0001), and higher consumption of antiinfective and respiratory system drugs (p < 0.0001). Referrals of children with OSAS to otolaryngology surgeons and pediatric pulmonologists were higher from Year 1 (p < 0.0001) to date of OSAS diagnosis, especially in Year 4 (odds ratio, 9.4; 95% confidence interval, 4.2-21.1). The 215% elevation (p < 0.0001) in health care use of the OSAS group was due mainly to higher occurrence of respiratory tract morbidity (p < 0.0001). CONCLUSIONS: Practitioners should be aware that starting in Year 1 until date of diagnosis, children with OSAS have higher health care use, mostly related to respiratory diseases.     

The structure and organization within the membrane of the helices composing the pore-forming domain of Bacillus thuringiensis δ-endotoxin are consistent with an “umbrella-like” structure of the pore

The aim of this study was to elucidate the mechanism of membrane insertion and the structural organization of pores formed by Bacillus thuringiensis δ-endotoxin. We determined the relative affinities for membranes of peptides corresponding to the seven helices that compose the toxin pore-forming domain, their modes of membrane interaction, their structures within membranes, and their orientations relative to the membrane normal. In addition, we used resonance energy transfer measurements of all possible combinatorial pairs of membrane-bound helices to map the network of interactions between helices in their membrane-bound state. The interaction of the helices with the bilayer membrane was also probed by a Monte Carlo simulation protocol to determine lowest-energy orientations. Our results are consistent with a situation in which helices α4 and α5 insert into the membrane as a helical hairpin in an antiparallel manner, while the other helices lie on the membrane surface like the ribs of an umbrella (the “umbrella model”). Our results also support the suggestion that α7 may serve as a binding sensor to initiate the structural rearrangement of the pore-forming domain.     

Interleukin-1 receptor type-1 in non-hematopoietic cells is the target for the pro-atherogenic effects of interleukin-1 in apoE-deficient mice

ObjectiveRecent studies indicate that regulatory T cells (Tregs) attenuate murine atherosclerosis. Since interleukin (IL)-2 induces Tregs proliferation, we tested the impact of L19-IL2, a fusion antibody specific to extra-domain B of fibronectin (ED-B) containing an active human IL-2 molecule, in experimental atherosclerosis.Methods and resultsL19-IL2 or appropriate controls were given intravenously to 6 month old Western diet-fed apoE^?/? mice on day 1, 3, and 5. Human IL-2 was detected on day 7 within atherosclerotic plaques of L19-IL2-treated mice, and magnetic resonance imaging of the plaques showed a significant adventitial gadolinium enhancement on day 7 and 13, suggesting microvascular leakage as a result of the pharmacodynamic activity of L19-IL2. Treatment with L19-IL2 significantly reduced the size of pre-established atherosclerotic plaques at the thoracic aorta (Sudan III stained area) and in the aortic root area (microscopic, morphometric analysis) on day 7 as compared to controls (L19, D1.3-IL2, NaCl) as well as compared to baseline (day 0). Tregs markers Foxp3 and CTLA4 were highly increased in plaques after L19-IL2 treatment compared to controls (p < 0.01), whereas the macrophage marker Mac3 was significantly reduced (p < 0.03). Co-treatment with IL-2-receptor blocking antibody PC61 abrogated L19-IL2-induced plaque reduction compared with IgG control (p < 0.03).ConclusionL19-IL2 delivers functional IL-2 to pre-established atherosclerotic plaques of WD-fed apoE^?/? mice resulting in significant plaque size reduction mediated by local Tregs.     

Endobronchial echinococcosis presenting as non-resolving pneumonia

Hydatid disease of the lungs is caused by larval cysts of the Echinococcus tapeworm. Pulmonary cysts may occasionally invade bronchi or pleura as a result of coughing, trauma, or elevated intra-abdominal pressure. We present the case of a patient evaluated for non-resolving pneumonia whose radiographic and bronchoscopic findings were strikingly similar to those seen in pulmonary tuberculosis with endobronchial invasion; he was ultimately diagnosed with pulmonary echinococcosis. This case underscores the importance of considering unusual diagnoses even when typical features of more common conditions are present.