Echocardiographic features of carcinoid heart disease

We reviewed the records of the Mayo Clinic patients with known carcinoid syndrome in whom echocardiographic studies had been done. Nineteen patients had M-mode and 2-dimensional echocardiographic examinations, and 1 patient had an M-mode examination only. Of the 20 patients, 8 had no evidence by echocardiogram of carcinoid heart disease; 2 had changes in the tricuspid valve echogram suggestive of early carcinoid heart disease, and the other 10 patients had the following distinctive echocardiographic findings: (1) the pattern of right ventricular volume overload (enlarged right ventricle with abnormal septal motion); (2) abnormal right-sided valves, including (a) a striking appearance of the tricuspid valve, the leaflets appearing thickened, retracted, and fixed in a semiopen position throughout the cardiac cycle, and (b) thickened, retracted pulmonic valve cusps, when visualized; and (3) the left-sided valves and chambers rarely involved. These echocardiographic features are distinctive of advanced carcinoid heart disease and correlate closely with pathologic findings.     

Non homologous end joining-mediated DNA break repair is impaired in B lymphocytes of aging mice

Aging is an irreversible physiological process characterized by increased risk of diseases, reduced effectiveness of vaccines, and decreased immune responses. One of the most prominent paradigms of aging and age related conditions is the progressive accumulation of un-repaired DNA breaks leading to apoptosis and exhaustion of stem cells. Here we hypothesized that B lymphocytes from old mice have reduced DNA repair mechanisms as a contributing factor for DNA break accumulation. We analyzed class switch recombination (CSR) of naïve B lymphocytes from old and adult mice to delineate the DNA double strand repair mechanisms during aging. In vitro CSR assays and DNA break analysis by labeling phosphorylated histone H2AX showed that old mice had significantly reduced DNA repair efficiency following DNA breaks. Functional efficiency analysis of DNA break repairs using plasmid ligation method showed that B lymphocytes from old mice had poor repair efficiency and increased misrepair of linear plasmid. Diminished DNA repair in old age can contribute to reduced immune cell repertoire and impaired immunity; increased occurrence of cancer; and reduced stem cell reserve.     

HLA-DO increases bacterial superantigen binding to human MHC molecules by inhibiting dissociation of class II-associated invariant chain peptides

HLA-DO (H2-O in mice) is an intracellular non-classical MHC class II molecule (MHCII). It forms a stable complex with HLA-DM (H2-M in mice) and shapes the MHC class II-associated peptide repertoire. Here, we tested the impact of HLA-DO and H2-O on the binding of superantigens (SAgs), which has been shown previously to be sensitive to the structural nature of the class II-bound peptides. We found that the binding of staphylococcal enterotoxin (SE) A and B, as well as toxic shock syndrome toxin 1 (TSST-1), was similar on the HLA-DO⁺ human B cell lines 721.45 and its HLA-DO⁻ counterpart. However, overexpressing HLA-DO in MHC class II⁺ HeLa cells (HeLa-CIITA-DO) improved binding of SEA and TSST-1. Accordingly, knocking down HLA-DO expression using specific siRNAs decreased SEA and TSST-1 binding. We tested directly the impact of the class II-associated invariant chain peptide (CLIP), which dissociation from MHC class II molecules is inhibited by overexpressed HLA-DO. Loading of synthetic CLIP on HLA-DR⁺ cells increased SEA and TSST-1 binding. Accordingly, knocking down HLA-DM had a similar effect. In mice, H2-O deficiency had no impact on SAgs binding to isolated splenocytes. Altogether, our results demonstrate that the sensitivity of SAgs to the MHCII–associated peptide has physiological basis and that the effect of HLA-DO on SEA and TSST-1 is mediated through the inhibition of CLIP release.     

In vivo targeting of human DC‐SIGN drastically enhances CD8+ T‐cell‐mediated protective immunity

Vaccination is one of the oldest yet still most effective methods to prevent infectious diseases. However, eradication of intracellular pathogens and treatment of certain diseases like cancer requiring efficient cytotoxic immune responses remain a medical challenge. In mice, a successful approach to induce strong cytotoxic CD8⁺ T‐cell (CTL) reactions is to target antigens to DCs using specific antibodies against surface receptors in combination with adjuvants. A major drawback for translating this strategy into one for the clinic is the lack of analogous targets in human DCs. DC‐SIGN (DC‐specific‐ICAM3‐grabbing‐nonintegrin/CD209) is a C‐type lectin receptor with potent endocytic capacity and a highly restricted expression on human immature DCs. Therefore, DC‐SIGN represents an ideal candidate for DC targeting. Using transgenic mice that express human DC‐SIGN under the control of the murine CD11c promoter (hSIGN mice), we explored the efficacy of anti‐DC‐SIGN antibodies to target antigens to DCs and induce protective immune responses in vivo. We show that anti‐DC‐SIGN antibodies conjugated to OVA induced strong and persistent antigen‐specific CD4⁺ and CD8⁺ T‐cell responses, which efficiently protected from infection with OVA‐expressing Listeria monocytogenes. Thus, we propose DC targeting via DC‐SIGN as a promising strategy for novel vaccination protocols against intracellular pathogens.     

KATP channels are up-regulated with increasing age in human myometrium

It is well established that ageing is associated with decrease in myometrial efficiency and higher incidence of labour complications. In myometrium, the presence of ATP-sensitive K⁺ (K_ATP) channels has been detected and they could be a factor in regulating uterine quiescence in pregnancy and contractions during labour. Here, we have examined a possibility of ageing-mediated regulation of K_ATP channels in the human myometrium. Myometrial samples were taken from non-pregnant women undergoing hysterectomy (n = 34) and from women undergoing caesarean section in late pregnancy (n = 36). Real time RT-PCR revealed that mRNAs of all known K_ATP channel subunits were present in the human myometrium. In non-pregnant myometrium, ageing up-regulated SUR2B/Kir6.1, subunits forming K_ATP channels in this tissue, without affecting the expression of other channel subunits. In the late pregnant myometrium, the level of subunits that do not form functional K_ATP channels was not affected by age within 20–41 age range. However, uterine SUR2B and Kir6.1 were up-regulated in parturient over 35 years. An ageing-induced increase in those channel subunits was confirmed by Western blotting. Thus, this study suggests that K_ATP channels are up-regulated with increasing age in human myometrium. This may help explain, at least partially, increased rate of birth complications in women aged over 35 years.     

The Misuse of Prescribed Drugs During the Syrian Crisis: a Cross-sectional Study

International Journal of Mental Health and Addiction -     

Eco-friendly microbial route to synthesize cobalt nanoparticles using Bacillus thuringiensis against malaria and dengue vectors

The developments of resistance and persistence to chemical insecticides and concerns about the non-target effects have prompted the development of eco-friendly mosquito control agents. The aim of this study was to investigate the larvicidal activities of synthesized cobalt nanoparticles (Co NPs) using bio control agent, Bacillus thuringiensis against malaria vector, Anopheles subpictus and dengue vector, Aedes aegypti (Diptera: Culicidae). The synthesized Co NPs were characterized by X-ray diffraction (XRD), Fourier transform infrared (FTIR), Field-emission scanning electron microscopy (FESEM) with energy dispersive X-ray spectroscopy, and Transmission electron microscopy (TEM). XRD analysis showed three distinct diffraction peaks at 27.03°, 31.00°, and 45.58° indexed to the planes 102, 122, and 024, respectively on the face-centered cubic cobalt acetate with an average size of 85.3 nm. FTIR spectra implicated role of the peak at 3,436 cm^?1 for O–H hydroxyl group, 2924 cm^?1 for methylene C–H stretch in the formation of Co NPs. FESEM analysis showed the topological and morphological appearance of NPs which were found to be spherical and oval in shape. TEM analysis showed polydispersed and clustered NPs with an average size of 84.81 nm. The maximum larvicidal mortality was observed in the cobalt acetate solution, B. thuringiensis formulation, and synthesized Co NPs against fourth instar larvae of A. subpictus and A. aegypti with LC₅₀ values of 29.16, 8.12, 3.59 mg/L; 34.61, 6.94, and 2.87 mg/L; r ² values of 0.986, 0.933, 0.942; 0.962, 0.957, and 0.922, respectively.     

Entomopathogenic marine actinomycetes as potential and low-cost biocontrol agents against bloodsucking arthropods

A novel approach to control strategies for integrated blood-feeding parasite management is in high demand, including the use of biological control agents. The present study aims to determine the efficacy of optimized crude extract of actinomycetes strain LK1 as biological control agent against the fourth-instar larvae of Anopheles stephensi and Culex tritaeniorhynchus (Diptera: Culicidae) and adults of Haemaphysalis bispinosa, Rhipicephalus (Boophilus) microplus (Acari: Ixodidae), and Hippobosca maculata (Diptera: Hippoboscidae). Antiparasitic activity was optimized using the Plackett–Burman method, and the design was developed using the software Design-Expert version 8.0.7.1. The production of the optimized crude actinomycetes LK1 strain extract was performed using response surface methodology to optimize the process parameters of protease inhibitor activity of marine actinobacteria for the independent variables like pH, temperature, glucose, casein, and NaCl at two levels (?1 and +1). The potential actinomycetes strain was identified as Saccharomonas spp., and the metamodeling surface simulation procedure was followed. It was studied using a computer-generated experimental design, automatic control of simulation experiments, and sequential optimization of the metamodels fitted to a simulation response surface function. The central composite design (CCD) used for the analysis of treatment showed that a second-order polynomial regression model was in good agreement with the experimental results at R ²?=?0.9829 (p?<?0.05). The optimized values of the variables for antioxidant production were pH 6.00, glucose 1.3 %, casein 0.09 %, temperature 31.23 °C, and NaCl 0.10 %. The LK1 strain-optimized crude extract was purified using reversed-phase high-pressure liquid chromatography, and the isolated protease inhibitor showed antiparasitic activity. The antiparasitic activity of optimized crude extract of LK1 was tested against larvae of A. stephensi (LC₅₀?=?31.82 ppm; r ²?=?0.818) and C. tritaeniorhynchus (LC₅₀?=?26.62 ppm; r ²?=?0.790) and adults of H. bispinosa (LC₅₀?=?106.58 ppm; r ²?=?0.871), R. (B.) microplus (LC₅₀?=?92.96 ppm; r ²?=?0.913), and H. maculata (LC₅₀?=?84.90 ppm; r ²?=?0.857).