Defective regulatory and effector T cell functions in patients with FOXP3 mutations

The autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is caused by mutations in the forkhead box protein P3 (FOXP3) gene. In the mouse model of FOXP3 deficiency, the lack of CD4+ CD25+ Tregs is responsible for lethal autoimmunity, indicating that FOXP3 is required for the differentiation of this Treg subset. We show that the number and phenotype of CD4+ CD25+ T cells from IPEX patients are comparable to those of normal donors. CD4+ CD25high T cells from IPEX patients who express FOXP3 protein suppressed the in vitro proliferation of effector T cells from normal donors, when activated by "weak" TCR stimuli. In contrast, the suppressive function of CD4+ CD25high T cells from IPEX patients who do not express FOXP3 protein was profoundly impaired. Importantly, CD4+ CD25high T cells from either FOXP3+ or FOXP3- IPEX patients showed altered suppression toward autologous effector T cells. Interestingly, IL-2 and IFN-gamma production by PBMCs from IPEX patients was significantly decreased. These findings indicate that FOXP3 mutations in IPEX patients result in heterogeneous biological abnormalities, leading not necessarily to a lack of differentiation of CD4+ CD25high Tregs but rather to a dysfunction in these cells and in effector T cells.     

Adiponectin and insulin sensitivity in primary aldosteronism

BACKGROUND: A high prevalence of metabolic syndrome has been reported in primary aldosteronism. Low levels of adiponectin, an adipokine with insulin-sensitizing properties, are considered a hallmark of the metabolic syndrome. We evaluated the relationship between adiponectin and insulin sensitivity in primary aldosteronism, with and without metabolic syndrome, compared with essential hypertension. METHODS: Forty patients with primary aldosteronism and 40 matched patients with low-renin essential hypertension (LREH) were studied. Patients with type 2 diabetes were excluded. Each group was divided into two subsets: one including patients with metabolic syndrome and one including patients without metabolic syndrome (ie, hypertension alone or associated with another component of the syndrome). RESULTS: Insulin resistance, defined by increased homeostasis model assessment (HOMA index), was higher in patients with primary aldosteronism than in those with LREH only in the absence of metabolic syndrome (P<.01), whereas in the subsets bearing the syndrome it was similar. Adiponectin levels were lower in primary aldosteronism than in patients with LREH (P<.01). Like HOMA index, the difference was maintained (P<.01) only in the subsets without metabolic syndrome. Adiponectin levels were inversely correlated with HOMA index and positively correlated with potassium levels both in primary aldosteronism (P<.001) or in LREH (P<.05) groups. CONCLUSIONS: Lower adiponectin as well as lower insulin sensitivity in primary aldosteronism compared with LREH seem to result from both direct (aldosterone excess) and indirect (hypokalemia) mechanisms. Therapeutic interventions aimed at correcting both potassium and adiponectin levels by specific antihypertensive agents might improve insulin sensitivity, providing better cardiovascular protection in primary aldosteronism.     

Evaluation of pulmonary atresia with 64-slice multidetector computed tomography (MDCT)

Pulmonary atresia with ventricular septal defect is a complex congenital heart disease. We report a case of a 46-year-old woman with pulmonary atresia and ventricular septal defect, surgically treated when she was 15 years old with an implant of a conduit between ascending aorta and left pulmonary branch. A 64-slice computed tomography was performed to assess the conduit patency. The contrast enhanced MDCT study showed the conduit was pervious and correctly connected with an enlarged left pulmonary artery implant of a conduit between ascending aorta and left pulmonary branch.     

Phylogeny of human T cell lymphotropic virus type 1 in Peru: a high degree of evolutionary relatedness with South African isolates

We investigated the prevalence and molecular epidemiology of human T cell lymphotropic virus type 1 in Peruvian HIV-1-positive subjects, and found a 10.1% prevalence in a consecutive series of 318 HIV-1-positive patients living in Lima. Phylogenetic analysis of the long terminal repeat of 10 patient isolates showed that all of them belonged to the HTLV-1aA (Transcontinental) subgroup. Although the majority of the Peruvian sequences included in the analysis formed a clade with other Latin American sequences, the isolates of three patients clustered significantly with South African strains. These data show a high prevalence of HTLV-1 infection in HIV-1-positive subjects living in Lima and confirm the presence in Latin America of HTLV-1 strains probably arising from South Africa.     

Effects of montelukast treatment and withdrawal on fractional exhaled nitric oxide and lung function in children with asthma

BACKGROUND: Leukotriene receptor antagonists (LTRAs) reduce fractional exhaled nitric oxide (Feno) concentrations in children with asthma, but the effect of LTRA withdrawal on Feno and lung function is unknown. We aimed to study the effect of treatment and withdrawal of montelukast, a LTRA, on airway inflammation as reflected by Feno and lung function in children with asthma. METHODS: A double-blind, randomized, placebo controlled, parallel group study was undertaken in 14 atopic children with mild persistent asthma who were treated with oral montelukast (5 mg/d for 4 weeks) and 12 atopic children with mild persistent asthma who received matching placebo. A follow-up visit was performed 2 weeks after montelukast or placebo withdrawal. RESULTS: Montelukast reduced Feno concentrations by 17% (p = 0.067), an effect that was more pronounced (35%) [p = 0.0029] when children with seasonal atopy who were exposed to relevant allergens during the treatment phase were excluded from analysis (n = 3). Compared to those at the end of treatment, Feno concentrations were increased 2 weeks after montelukast withdrawal (p = 0.023) concomitant with a reduction in absolute FEV(1) values (p = 0.011), FEV(1) percentage of predicted values (p = 0.006), FEV(1)/FVC ratio (p = 0.002), and forced expiratory flow at 25% to 75% of FVC values (p = 0.021). These changes were not observed in the placebo group. CONCLUSIONS: LTRAs reduce Feno concentrations in children with asthma, and withdrawal can result in increased Feno values and worsening of lung function in children with asthma.     

Structural motifs of biomolecules

Biomolecular structures are assemblies of emergent anisotropic building modules such as uniaxial helices or biaxial strands. We provide an approach to understanding a marginally compact phase of matter that is occupied by proteins and DNA. This phase, which is in some respects analogous to the liquid crystal phase for chain molecules, stabilizes a range of shapes that can be obtained by sequence-independent interactions occurring intra- and intermolecularly between polymeric molecules. We present a singularity-free self-interaction for a tube in the continuum limit and show that this results in the tube being positioned in the marginally compact phase. Our work provides a unified framework for understanding the building blocks of biomolecules.     

Neutropenia induced by platelet-activating factor (PAF-acether) released from neutrophils: The inhibitory effect of prostacyclin (PGI2)

Soluble and phagocytic stimuli released PAF-acether from PMN leucocytes, as determined by chromatography and bioassay by platelet aggregation. The same material caused aggregation of human and rabbit PMN leucocytesin vitro which was inhibited by ETYA and PGI₂. PGI₂ also inhibited PAF-acether release by PMN leucocytes and,in vivo, PGI₂ abolished not only PAF-acether-induced, but also immune complex or C5a-induced thrombocytopenia and neutropenia in rabbits. These data suggest that PAF-acether may be involved in activation of both platelets and PMN leucocytesin vivo.     

Oral Specific Desensitization in Food-Allergic Children

The possibility of obtaining oral desensitization in patients with food allergy is still a matter of debate. We decided to evaluate the safety and efficacy of standardized protocols for oral desensitization with the most common food allergens. Forty-two children (ages up to 16 years) diagnosed as affected by food allergy (on the basis of clinical history, skin prick tests, measurement of specific IgE, and double-blind, placebo-controlled food challenge) underwent a sublingual-oral desensitizing treatment according to new standardized protocols. The control group consisted of 10 patients who followed an elimination diet. The treatment was successfully completed by 85.7% of the patients. Specific IgE showed a significant decrease, while specific IgG₄ showed a significant increase, in all treated patients. The immunological modifications observed in our patients lead us to hypothesize that oral tolerance may be mediated by the same mechanisms as those involved in traditional desensitizing treatments for respiratory and insect sting allergy.