Comparative evaluation of Schistosoma mansoni,Schistosoma intercalatum,and Schistosoma haematobium alkaline phosphatase antigenicity by the alkaline phosphatase immunoassay (APIA)

To know if alkaline phosphatase (AP) from schistosomes other than Schistosoma mansoni can be used as diagnostic marker for schistosomiasis in alkaline phosphatase immunocapture assay (APIA), we comparatively tested n-butanol extracts of adult worm membranes from a Venezuelan (JL) strain of S. mansoni (Ven/AWBE/Sm); a Cameroonian (EDEN) strain of Schistosoma intercalatum (Cam/AWBE/Si) and a Yemeni strain of Schistosoma haematobium (Yem/AWBE/Sh). APIA was evaluated with sera of patients from Venezuela, Senegal, and Gabon infected with S. mansoni, from Gabon infected with S. intercalatum or S. haematobium, from Chine infected with Schistosoma japonicum and from Cambodian patients infected with Schistosoma mekongi. Results indicate that 92.5 % (37/40) of Venezuela sera, 75 % (15/20) of Senegal sera, 39.5 % (17/43) of S. haematobium sera, and 19.2 % (5/26) S. intercalatum sera were APIA-positive with the Ven/AWBE/Sm preparation. APIA with the Cam/AWBE/Si preparation showed that 53.8 % of S. intercalatum-positive sera had anti-AP antibodies, and 51.2 %?S. haematobium-positive sera cross-immunocapturing the S. intercalatum AP. APIA performed with Yem/AWBE/Sh showed that 55.8 %?S. haematobium sera were positive. Only two out of nine S. japonicum sera were APIA-positive with the Ven/AWBE/Sm and Cam/AWBE/Si, and no reaction was observed with Cambodian S. mekongi-positive sera. AP activity was shown to be present in all the schistosome species/strains studied. The use of APIA as a tool to explore the APs antigenicity and the presence of Schistosoma sp. infections through the detection of anti-Schistosoma sp. AP antibodies in a host, allowed us to demonstrate the antigenicity of APs of S. mansoni, S. intercalatum, and S. haematobium.     

Daily versus thrice-weekly interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected persons: a multicenter randomized controlled trial

Among HIV-infected persons, chronic hepatitis C virus (HCV) infection causes substantial morbidity and mortality. However, few studies have evaluated the safety and efficacy of interferon alfa (IFN) and ribavirin (RBV) therapy in co-infected persons. Accordingly, a randomized, controlled, open-label, multicenter trial was conducted to establish the safety, tolerability, and efficacy of IFN alfa-2b 3 mIU daily plus RBV 800 mg/d compared with IFN alfa-2b 3 mIU thrice weekly (TIW) plus RBV 800 mg/d in HCV treatment-naive, HIV-infected subjects with compensated liver disease and stable HIV disease. The primary endpoint was sustained virologic response (SVR), defined as an undetectable HCV RNA level 24 weeks after discontinuation of HCV therapy. At study entry, subjects in both groups were similar with respect to age, gender, HCV genotype, and HIV disease status. Of 180 randomized subjects, 162 received at least 1 dose of study medication, constituting the modified intention-to-treat population. After 12 weeks of therapy, 122 (75%) had serum HCV RNA levels assessed; of these subjects, early virologic response (undetectable HCV RNA or >2 log10 decrease from baseline) was observed in 33 (42%) and 13 (16%) of subjects taking daily and TIW IFN, respectively (P < 0.001). SVR was observed in 15 (19.0%) and 7 (8.4%) of subjects taking daily and TIW IFN, respectively (P = 0.05). Adverse events were similar in both groups. However, while no deaths or opportunistic infections were observed, nearly 30% of subjects stopped treatment due to adverse events and 7 subjects experienced a serious adverse event. In conclusion, SVR was achieved in 19% of HIV/HCV coinfected subjects treated with daily IFN plus RBV, but the effectiveness of therapy was substantially diminished by relatively high rates of treatment-related toxicity.     

The prevalence of vitamin D abnormalities in South Asians with type 2 diabetes mellitus in the UK

Background: The high prevalence of both hypovitaminosis D and type 2 diabetes (T2DM) in the Asian community is well recognised, but the impact of diabetes on vitamin D status and vice versa, has not been well reported. Aims: To determine the prevalence of hypovitaminosis D in Asian patients with T2DM and its impact on glycaemic control. Methods: A cross‐sectional study was conducted in a tertiary referral centre in the UK. Two hundred and ten Asian patients aged more than 40 years were included (170 with and 40 without T2DM). Each had a standard bone profile (serum calcium, phosphate and alkaline phosphatase), serum parathyroid hormone and 25‐hydroxycholecalciferol. Results: The prevalence of low serum 25‐hydroxyvitamin D (< 50 nmol/l) was high in the group as a whole (> 80%) and more common in diabetics compared with controls (83% vs. 70%; p = 0.07). This was particularly so in men (82.5% vs. 57.9%; p = 0.02). HbA1c was higher in women with vitamin D deficiency (< 12.5 nmol/l) (8.11 ± 1.11% vs. 7.33 ± 1.32%, p = 0.046). In logistic regression analysis, T2DM was an independent predictor of hypovitaminosis D. In linear regression analysis, vitamin D deficiency was independently related to HbA1c in women with T2DM. Conclusions: Hypovitaminosis D remains a major public health issue in the Asian population and is exaggerated in patients with T2DM. The fact that vitamin D deficient women had higher HbA1c levels raises the possibility that vitamin D replacement may improve glycaemic control.     

Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244

CONTEXT: Activating mutations in the BRAF gene, primarily at V600E, are associated with poorer outcomes in patients with papillary thyroid cancer. MAPK kinase (MEK), immediately downstream of BRAF, is a promising target for ras-raf-MEK-ERK pathway inhibition. OBJECTIVE: The objective of the investigation was to study the efficacy of a MEK1/2 inhibitor in thyroid cancer preclinical models with defined BRAF mutation status. EXPERIMENTAL DESIGN: After treatment with the potent MEK 1/2 inhibitor AZD6244, MEK inhibition and cell growth were examined in four BRAF mutant (V600E) and two BRAF wild-type thyroid cancer cell lines and in xenografts from a BRAF mutant cell line. RESULTS: AZD6244 potently inhibited MEK 1/2 activity in thyroid cancer cell lines regardless of BRAF mutation status, as evidenced by reduced ERK phosphorylation. Four BRAF mutant lines exhibited growth inhibition at low doses of the drug, with GI50 concentrations ranging from 14 to 50 nm, predominantly via a G0/G1 arrest, comparable with findings in a sensitive BRAF mutant melanoma cell line. In contrast, two BRAF wild-type lines were significantly less sensitive, with GI50 values greater than 200 nm. Nude mouse xenograft tumors derived from the BRAF mutant line ARO exhibited dose-dependent growth inhibition by AZD6244, with effective treatment at 10 mg/kg by oral gavage. This effect was primarily cytostatic and associated with marked inhibition of ERK phosphorylation. CONCLUSION: AZD6244 inhibits the MEK-ERK pathway across a spectrum of thyroid cancer cells. MEK inhibition is cytostatic in papillary thyroid cancer and anaplastic thyroid cancer cells bearing a BRAF mutation and may have less impact on thyroid cancer cells lacking this mutation.     

Characterization of wild-type recombinant Bet v 1a as a candidate vaccine against birch pollen allergy

BACKGROUND: We describe the production in Escherichia coli as a recombinant protein of clinical grade wild-type Bet v 1a (rBet v 1a), to be used as a candidate vaccine against birch pollen allergy. METHODS: This recombinant protein was purified by hydrophobic interaction and ion exchange chromatography and characterized by SDS-PAGE, immunoprint and circular dichroism in parallel with natural Bet v 1 (nBet v 1) purified from a birch pollen extract. We also compared rBet v 1 and nBet v 1 for their capacity to induce histamine release from basophils and to stimulate T lymphocyte proliferation. RESULTS: rBet v 1a appears in SDS-PAGE as an 18-kDa monomeric protein, whereas purified nBet v 1 comprises a mixture of isoforms (resolving as three distinct bands and six spots after 1-dimensional and 2-dimensional electrophoresis, respectively). Both recombinant and natural purified Bet v 1 molecules are recognized by IgE from birch pollen-allergic patients as well as anti-Bet v 1 murine monoclonal antibodies, suggesting that the recombinant protein is correctly folded in a native configuration. Circular dichroism analysis confirmed that the two Bet v 1 molecules exhibit similar 3-dimensional structures, even if rBet v 1a appears more compact and stable in thermodenaturation/renaturation experiments. Both rBet v 1 and nBet v 1 induce the degranulation of sensitized basophils and proliferation of Bet v 1-specific T lymphocytes in a similar manner. CONCLUSIONS: On the basis of these structural and biological properties, rBet v 1a is a valid candidate vaccine against birch pollen allergy, currently evaluated in humans.     

Evidence for opioid involvement in the regulation of song production in male European starlings (Sturnus vulgaris)

Many social animals vocalize at high rates, suggesting that vocal communication is highly motivated and rewarding. In songbirds, much is known about the neural control of vocal behavior; however, little is known about neurobiological mechanisms regulating the motivation to communicate. This study examined a possible role for opioid neuropeptides in motivation and reward associated with song production in male European starlings (Sturnus vulgaris). Peripheral opioid blockade facilitated male song production. Furthermore, methionine-enkephalin immunolabeled fiber densities within brain regions in which opioids are known to regulate motivation and reward (i.e., the medial preoptic nucleus and ventral tegmental area) related positively to male song production. These data suggest that song production might be regulated by opioid activity within motivation and reward neural systems.     

HLA-B27 and genetic predisposing factors in spondyloarthropathies

With the mapping of the human genome having been completed, our ability to investigate and ideally better understand the genetic basis of rheumatic diseases is advancing at a rapid pace. Substantial evidence strongly favors a direct role for HLA-B27 in genetic susceptibility to ankylosing spondylitis and related spondyloarthropathies, although the underlying molecular basis has yet to be identified. HLA-B27 contributes only 16 to 50% of the total genetic risk for the disease, clearly indicating that other genes must be involved. However, no other putative disease genes have yet been absolutely proven. Potential genes include MHC (HLA class II, low molecular weight proteasome [LMP], transporter associated with antigen processing (TAP), tumor necrosis factor [TNF]-alpha, and major histocompatibility complex class I chain-related gene A (MICA), as well as non-MHC genes (IL-1RA, IL-6, IL-10, and CYP2D6). Genome-wide screens have identified other chromosomal areas of interest: 1p, 2q, 6p, 9q, 10q, 16q, and 19q. However, different studies have given conflicting results. HLA-B27 itself is a serologic specificity, which encompasses 25 different alleles that encode 23 different products (proteins): HLA-B*2701 to B*2723. These alleles may have evolved from the most widespread subtype, B*2705, and two of them, B*2706 in Southeast Asia and B*2709 in Sardinia, seem not to be associated with ankylosing spondylitis. The distinction between the disease associated and nonassociated subtypes may provide clues to the actual role of B27 in disease pathogenesis.     

2型糖尿病患者勃起功能障碍患病率及西地那非的疗效和安全性评价

目的调查内分泌门诊中糖尿病患者阴茎勃起功能障碍(ED)患病率,并评价西地那非(万艾可)在糖尿病合并ED患者中的疗效和安全性。方法多中心收集2型糖尿病男性患者6193例,入选6178例,患者签署知情同意书后,根据国际勃起功能指数表(IIEF5)患者进行自我评分。对3个月内服用3剂万艾可的患者除要求填写治疗前的IIEF5表评分外,还要求填写治疗后的总体疗效问题回答表,以评价万艾可治疗的疗效,并记录患者服药后的不良事件以评价其安全性。结果国内42家医院内分泌门诊2型糖尿病患者中ED的患病率为75.2%,其中重度、中度和轻度ED分别为9.1%、17.2%、48.9%。该受检人群中ED的知晓率为85.0%,但治疗率仅为9.4%。多因素回归分析显示患者年龄、糖尿病病程、血糖控制不佳(HbA1C>6.5%)与糖尿病患者ED的发生独立相关。共有389例患者服用万艾可治疗,治疗后患者IIEF5总评分和各问题的评分均显著高于治疗前(P<0.01);根据IIEF5评分,治疗后重、中度ED患者例数明显少于治疗前(P<0.01)。根据总体疗效评估问题的回答,给予万艾可治疗后勃起功能改善率达86.4%。对安全性评价显示服用万艾可后出现的与药物有关的不良事件主要是颜面潮红、头痛、心悸和口干等,大多为轻度。结论在2型糖尿病患者中ED是常见的合并症,万艾可治疗糖尿病合并ED疗效确切,并有良好的安全性。