Increased risk for metachronous gastric adenocarcinoma following gastric MALT lymphoma-A US population-based study

Gastric mucosa-associated lymphoid tissue lymphoma (gMALT) and gastric adenocarcinoma (GC) are long-term complications of chronic Helicobacter pylori (HP) gastritis. Treatment of HP infection induces remission in most patients with gMALT. Endoscopic follow-up is not currently endorsed after complete remission. However, the risk of GC in these patients is unclear. OBJECTIVE: The objective of this study is to estimate GC risk in gMALT patients. METHODS: The National Cancer Institute Surveillance, Epidemiology and End Results 13 (SEER) database-Nov 2014 Sub (1992-2012) was used to identify adult patients diagnosed with gMALT between 1992 and 2012. The standardized incidence ratio of second primary GC after a latency period of 12 months was calculated and compared to a reference SEER cohort of identical age, sex and time period. The risk of GC in these patients was also stratified by latency period (five years) and age. RESULTS: We identified 2195 cases of gMALT lymphoma, and 20 (0.91%) of them subsequently developed GC with a relative risk (RR) of 4.32 (95% CI 2.64-6.67) compared to the American population. The median latency time was five years and the risk was maintained afterward (RR 4.92, 95% CI 2.45-8.79). When stratified by age group the risk was highest for the 45-64 group (RR 14.04, 95% CI 5.64-28.93). CONCLUSION: gMALT lymphoma is associated with an increased risk of metachronous gastric adenocarcinoma. The risk is still present after more than five years of follow-up. Further studies may clarify the most adequate follow-up strategy.info:eu-repo/semantics/publishedVersio

Raquitismo hipofosfatêmico ligado ao X: uma nova mutação

Phosphopenic rickets may be caused by mutations in the PHEX gene (phosphate regulating endopeptidase homolog X-linked). Presently, more than 500 mutations in the PHEX gene have been found to cause hypophosphatemic rickets. The authors report a clinical case of a 4-year-old girl with unremarkable family history, who presented with failure to thrive and bowing of the legs. Laboratory tests showed hypophosphatemia, elevated alkaline phosphatase, normal calcium, mildly elevated PTH and normal levels of 25(OH)D and 1.25(OH)D. The radiological study showed bone deformities of the radius and femur. Clinical diagnosis of phosphopenic rickets was made and the genetic study detected a heterozygous likely pathogenic variant of the PHEX gene: c.767_768del (p.Thr256Serfs*7). This variant was not previously described in the literature or databases. Knowledge about new mutations can improve patient’s outcome. Genetic analysis can help to establish a genotype-phenotype correlation.info:eu-repo/semantics/publishedVersio

Intensive Blood Pressure Treatment Reduced Stroke Risk in Patients With Albuminuria in the SPRINT Trial

Background and Purpose- Albuminuria is associated with stroke risk among individuals with diabetes. However, the association of albuminuria with incident stroke among nondiabetic patients is less clear. Methods- We performed a post hoc analysis of the SPRINT (Systolic Blood Pressure Intervention Trial), which examined the effect of higher versus lower intensity blood pressure management on mortality in 8913 participants without diabetes. We fit unadjusted and adjusted Cox proportional hazards models to estimate the association of baseline albuminuria (urinary albumin-to-creatinine ratio ≥30 mg/g versus<30 mg/g) with stroke risk. We also assessed effect modification according to treatment arms. Results- Mean age was 68±9 years, 35% were female, and 30% were black. Median follow-up was 3.2 years, and 19% patients had baseline albuminuria. Incident stroke occurred in 129 individuals during follow-up. Albuminuria was associated with increased stroke risk (unadjusted hazard ratio, 2.24; 95% CI, 1.55-3.23; adjusted hazard ratio 1.73; 95% CI, 1.17-2.56). The association of albuminuria with incident stroke differed according to the randomized treatment arm (P interaction=0.03). In the intensive treatment arm, the association of albuminuria and stroke was nonsignificant (unadjusted hazard ratio, 1.25; 95% CI, 0.69-2.28), whereas, in the standard treatment arm, it was significant (unadjusted hazard ratio, 3.44; 95% CI, 2.11-5.61). Conclusions- In a post hoc analysis of SPRINT, baseline albuminuria (versus not) was associated with a higher risk of incident stroke, but this relationship appeared to be restricted to those in the standard treatment arm. Further studies are required to conclusively determine if reduction of albuminuria in itself is beneficial in reducing stroke risk. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01206062.info:eu-repo/semantics/publishedVersio

Hydrodynamics of the VanA-type VanS histidine kinase: an extended solution conformation and first evidence for interactions with vancomycin

VanA-type resistance to glycopeptide antibiotics in clinical enterococci is regulated by the VanSARA two-component signal transduction system. The nature of the molecular ligand that is recognised by the VanSA sensory component has not hitherto been identified. Here we employ purified, intact and active VanSA membrane protein (henceforth referred to as VanS) in analytical ultracentrifugation experiments to study VanS oligomeric state and conformation in the absence and presence of vancomycin. A combination of sedimentation velocity and sedimentation equilibrium in the analytical ultracentrifuge (SEDFIT, SEDFIT-MSTAR and MULTISIG analysis) showed that VanS in the absence of the ligand is almost entirely monomeric (molar mass M = 45.7 kDa) in dilute aqueous solution with a trace amount of high molar mass material (M ~ 200 kDa). The sedimentation coefficient s suggests the monomer adopts an extended conformation in aqueous solution with an equivalent aspect ratio of ~ (12+2). In the presence of vancomycin over a 33% increase in the sedimentation coefficient is observed with the appearance of additional higher s components, demonstrating an interaction, an observation consistent with our circular dichroism measurements. The two possible causes of this increase in s – either a ligand induced dimerization and/or compaction of the monomer are considered

Measuring macroscopic brain connections in vivo

Decades of detailed anatomical tracer studies in non-human animals point to a rich and complex organization of long-range white matter connections in the brain. State-of-the art in vivo imaging techniques are striving to achieve a similar level of detail in humans, but multiple technical factors can limit their sensitivity and fidelity. In this review, we mostly focus on magnetic resonance imaging of the brain. We highlight some of the key challenges in analyzing and interpreting in vivo connectomics data, particularly in relation to what is known from classical neuroanatomy in laboratory animals. We further illustrate that, despite the challenges, in vivo imaging methods can be very powerful and provide information on connections that is not available by any other means

Major Depletion of Plasmacytoid Dendritic Cells in HIV-2 Infection, an Attenuated Form of HIV Disease

Plasmacytoid dendritic cells (pDC) provide an important link between innate and acquired immunity, mediating their action mainly through IFN-α production. pDC suppress HIV-1 replication, but there is increasing evidence suggesting they may also contribute to the increased levels of cell apoptosis and pan-immune activation associated with disease progression. Although having the same clinical spectrum, HIV-2 infection is characterized by a strikingly lower viremia and a much slower rate of CD4 decline and AIDS progression than HIV-1, irrespective of disease stage. We report here a similar marked reduction in circulating pDC levels in untreated HIV-1 and HIV-2 infections in association with CD4 depletion and T cell activation, in spite of the undetectable viremia found in the majority of HIV-2 patients. Moreover, the same overexpression of CD86 and PD-L1 on circulating pDC was found in both infections irrespective of disease stage or viremia status. Our observation that pDC depletion occurs in HIV-2 infected patients with undetectable viremia indicates that mechanisms other than direct viral infection determine the pDC depletion during persistent infections. However, viremia was associated with an impairment of IFN-α production on a per pDC basis upon TLR9 stimulation. These data support the possibility that diminished function in vitro may relate to prior activation by HIV virions in vivo, in agreement with our finding of higher expression levels of the IFN-α inducible gene, MxA, in HIV-1 than in HIV-2 individuals. Importantly, serum IFN-α levels were not elevated in HIV-2 infected individuals. In conclusion, our data in this unique natural model of “attenuated” HIV immunodeficiency contribute to the understanding of pDC biology in HIV/AIDS pathogenesis, showing that in the absence of detectable viremia a major depletion of circulating pDC in association with a relatively preserved IFN-α production does occur

In Vitro Surfactant Structure-Toxicity Relationships: Implications for Surfactant Use in Sexually Transmitted Infection Prophylaxis and Contraception

Background The need for woman-controlled, cheap, safe, effective, easy-to-use and easy-to-store topical applications for prophylaxis against sexually transmitted infections (STIs) makes surfactant-containing formulations an interesting option that requires a more fundamental knowledge concerning surfactant toxicology and structure-activity relationships. Methodology/Principal Findings We report in vitro effects of surfactant concentration, exposure time and structure on the viability of mammalian cell types typically encountered in the vagina, namely, fully polarized and confluent epithelial cells, confluent but non-polarized epithelial-like cells, dendritic cells, and human sperm. Representatives of the different families of commercially available surfactants – nonionic (Triton X-100 and monolaurin), zwitterionic (DDPS), anionic (SDS), and cationic (CnTAB (n = 10 to 16), C12PB, and C12BZK) – were examined. Triton X-100, monolaurin, DDPS and SDS were toxic to all cell types at concentrations around their critical micelle concentration (CMC) suggesting a non-selective mode of action involving cell membrane destabilization and/or destruction. All cationic surfactants were toxic at concentrations far below their CMC and showed significant differences in their toxicity toward polarized as compared with non-polarized cells. Their toxicity was also dependent on the chemical nature of the polar head group. Our results suggest an intracellular locus of action for cationic surfactants and show that their structure-activity relationships could be profitably exploited for STI prophylaxis in vaginal gel formulations. The therapeutic indices comparing polarized epithelial cell toxicity to sperm toxicity for all surfactants examined, except C12PB and C12BZK, does not justify their use as contraceptive agents. C12PB and C12BZK are shown to have a narrow therapeutic index recommending caution in their use in contraceptive formulations. Conclusions/Significance Our results contribute to understanding the mechanisms involved in surfactant toxicity, have a predictive value with regard to their safety, and may be used to design more effective and less harmful surfactants for use in topical applications for STI prophylaxis.Foundation for Science and Technology of the Portuguese Ministry of Science and Higher Educatio

The Role of Research in Viral Disease Eradication and Elimination Programs: Lessons for Malaria Eradication

Using their experiences from, and analysis of, global campaigns to eradicate smallpox, poliomyelitis, and measles, Myron Levine and colleagues derive lessons for malaria eradication