Effect of calcium on the hemolytic activity of Stichodactyla helianthus toxin sticholysin II on human erythrocytes

Sticholysin II (St II) is a toxin from the sea anemona Stichodactyla helianthus that produces erythrocytes lysis at low concentration and its activity depends on the presence of calcium. Calcium may act modifying toxin interaction with erythrocyte membranes or activating cellular processes which may result in a modified St II lytic action. In this study we are reporting that, in the presence of external K⁺, extracellular calcium decreased St II activity on erythrocytes. On the other hand an increase of intracellular calcium promotes Sty II lytic activity. The effect of intracellular calcium was specifically studied in relation to membrane lipid translocation elicited by scramblases and how this action influence St II lytic activity on erythrocytes. We used 0.5 mmol/L calcium and 10 mmol/L A23187, as calcium ionophore, for scramblases activation and found increased St II activity associated to increase of intracellular calcium. N-ethyl maleimide (activator) and 4,4′-diisothiocyanatostilbene-2,2′-disulfonate (inhibitor) were used as scramblases modulators in the assays which produced an increase and a decrease of the calcium effect, respectively. Results reported suggest an improved St II membrane pore-forming capacity promoted by intracellular calcium associated to membrane phospholipids translocation.     

Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6

Fetal loss in animals and humans is frequently associated with inflammatory conditions. D6 is a promiscuous chemokine receptor with decoy function, expressed in lymphatic endothelium, that recognizes and targets to degradation most inflammatory CC chemokines. Here, we report that D6 is expressed in placenta on invading extravillous trophoblasts and on the apical side of syncytiotrophoblast cells, at the very interface between maternal blood and fetus. Exposure of D6-/- pregnant mice to LPS or antiphospholipid autoantibodies results in higher levels of inflammatory CC chemokines and increased leukocyte infiltrate in placenta, causing an increased rate of fetal loss, which is prevented by blocking inflammatory chemokines. Thus, the promiscuous decoy receptor for inflammatory CC chemokines D6 plays a nonredundant role in the protection against fetal loss caused by systemic inflammation and antiphospholipid antibodies.     

The interplay between microRNAs and the neurotrophin receptor tropomyosin-related kinase C controls proliferation of human neuroblastoma cells

MicroRNAs (miRNAs) are tiny noncoding RNAs whose function as modulators of gene expression is crucial for the proper control of cell growth and differentiation. Although the profile of miRNA expression has been defined for many different cellular systems, the elucidation of the regulatory networks in which they are involved is only just emerging. In this work, we identify a crucial role for three neuronal miRNAs (9, 125a, and 125b) in controlling human neuroblastoma cell proliferation. We show that these molecules act in an additive manner by repressing a common target, the truncated isoform of the neurotrophin receptor tropomyosin-related kinase C, and we demonstrate that the down-regulation of this isoform is critical for regulating neuroblastoma cell growth. Consistently with their function, these miRNAs were found to be down-modulated in primary neuroblastoma tumors.     

Rapid detection of beta-Thalassemia alleles in Egypt using naturally or amplified created restriction sites and direct sequencing: a step in disease control

beta-Thalassemia (thal), the most common genetic disorder in Egypt, is a major health problem with an estimated carrier rate of 9-10%. This study, aimed at describing the beta-globin gene mutations in the Suez Canal area, an important Egyptian region, to provide a foundation for a disease control program. We studied 44 beta-thalassemic patients (and their relatives) from 35 families living in this region. The commonest mutations were genetically diagnosed using naturally or amplified created restriction sites. Less frequent mutations were characterized by denaturing gradient gel electrophoresis (DGGE) and direct sequencing. Twelve different mutations were identified in 51 unrelated chromosomes. The three most frequent mutations were IVS-I-110 (G-->A), IVS-I-1 (G-->A) and IVS-I-6 (T-->C). The spectrum of rarer mutations was heterogeneous and differed from that reported in other areas of Egypt. We also identified the first homozygous case of a rare mutation, codon 24 (-G; +CAC), displaying a thalassemia major phenotype. Parental consanguinity was high (60.6%) with 35.7% of the compound heterozygous patients having consanguineous parents. These data provide insights for the distribution of beta-thal alleles in this region, and could be used as a basis for genetic counseling and prenatal diagnosis.     

Obstructive sleep apnea and resistant hypertension: a case-control study

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) has been linked to resistant hypertension, but the magnitude of this association and its independence of confounding have not been established. METHODS: Case patients were 63 patients with resistant hypertension (BP >or= 140/90 mm Hg using at least three BP-lowering drugs, including a diuretic), and control subjects were 63 patients with controlled BP receiving drug treatment. The primary outcome was the frequency of OSAS (apnea-hypopnea index [AHI] >or= 10 episodes per hour) determined with a portable home monitor. The comparison of AHI episodes in patients truly normotensive, truly hypertensive, and in patients with white coat or masked hypertension, based on BP determined at office and by ambulatory BP monitoring (ABPM) was a secondary outcome. RESULTS: Case patients and control subjects were well matched for confounding factors. OSAS was present in 45 case patients (71%) and in 24 control subjects (38%) [p < 0.001]. In a logistic regression model, OSAS was strongly and independently associated with resistant hypertension (odds ratio, 4.8; 95% confidence interval, 2.0 to 11.7). The AHI of case patients with normal BP in ABPM (white coat hypertension) and control subjects with abnormal BP in ABPM (masked hypertension) was intermediate between the AHI of individuals with normal and abnormal BP measures in both settings (p < 0.001). CONCLUSIONS: The magnitude and independence of the risk of OSAS for resistant hypertension strengthen the concept that OSAS is a risk factor for resistant hypertension. Comorbid OSAS should be considered in patients with resistant hypertension.     

Nearly identical strains of human herpesvirus 8 in couples discordant for Kaposi's sarcoma

Transmission of human herpesvirus 8 (HHV-8) may occur through various routes including breastfeeding and sexual intercourse. We attempted to detect HHV-8 infection in nine HIV-positive couples discordant for Kaposi's sarcoma who maintained a monogamous sexual relationship for at least one year. By quantitative real-time polymerase chain reaction and HHV-8 genotyping we provide strong evidence for the sexual transmission of HHV-8 in this unique cohort.     

Cell and molecular biology of Notch

Notch signalling is a cell-cell communication process, which allows the establishment of patterns of gene expression and differentiation, regulates binary cell fate choice and the maintenance of stem cell populations. So far, the data published has elucidated the main players in the Notch signalling pathway. However, its regulatory mechanisms are exhibiting an increasing complexity which could account for the multitude of roles it has during development and in adult organisms. In this review, we will describe the multiple roles of Notch and how various factors can regulate Notch signalling.     

Erosive arthropathy: clinical variance in lupus erythematosus and association with anti-CCP case series and review of the literature

OBJECTIVE: To describe the occurrence of erosive arthropathy in systemic lupus erythematosus (SLE) and its relationship to anti-CCP antibodies. METHODS: Retrospective medical record review of a case series of five female patients with SLE and erosive arthropathies. RESULTS: The initial disease presentation in all patients was a polyarthritis. Anti-CCP antibodies were detected in 4 out of 5 (80%) patients, 2 of whom had a positive rheumatoid factor. CONCLUSION: Erosive arthritis was strongly associated with the presence of anti-CCP antibodies in these patients with SLE, who presented with polyarthritis. Anti-CCP in patients with SLE may be a marker of a more severe joint disease.     

Genes, environments, development and asthma: a reappraisal.

Significant advances have been made in our understanding of the role of genetic variation in determining complex human phenotypes such as asthma. It is now well established that there is no single "gene for asthma", in the way that the cystic fibrosis transmembrane receptor is the "gene for cystic fibrosis". It is also clear that among all genetic variants eventually found to be associated with asthma, only a few will be replicated, and in the same direction, in the majority of well-performed studies. Current evidence suggests that most asthma-related polymorphisms determine risk for the disease in a context-dependent manner, i.e. they interact with environmental factors, with polymorphisms in other genes and with the specific developmental phase of the disease in which the association is tested. Elucidating these complex interactions will allow us to understand better the heterogeneity of the disease and thus to develop therapeutic tools tailored to the specific form of the disease in each patient.