RAAS gene polymorphisms influence progression of pediatric hypertrophic cardiomyopathy

Hypertrophic Cardiomyopathy (HCM) is a disease with variable rate of progression. Young age is an independent risk factor for poor outcome in HCM. The influence of renin–angiotensin–aldosterone (RAAS) genotype on the progression of HCM in children is unknown. Children with HCM (n = 65) were enrolled prospectively across two centers (2001–2005). All subjects were genotyped for five RAAS gene polymorphisms previously associated with LV hypertrophy (pro-LVH): AGT M235T, ACE DD, CMA-1903 A/G, AGTR1 1666 A/C and CYP11B2-344 C/T. Linear regression models, based on maximum likelihood estimates, were created to assess the independent effect of RAAS genotype on LV hypertrophy (LVH). Forty-six subjects were homozygous for <2 and 19 were homozygous for ≥2 pro-LVH RAAS polymorphisms. Mean age at presentation was 9.6 ± 6 years. Forty children had follow-up echocardiograms after a median of 1.5 years. Indexed LV mass (LVMI) and LV mass z-scores were higher at presentation and follow-up in subjects with ≥2 pro-LVH genotypes compared to those with <2 (P < 0.05). Subjects with ≥2 pro-LVH genotypes also demonstrated a greater increase in septal thickness (IVST) and in LV outflow tract (LVOT) obstruction on follow-up (P < 0.05). On multivariate analysis, a higher number of pro-LVH genotypes was associated with a larger effect size (P < 0.05). Pro-LVH RAAS gene polymorphisms are associated with progressive septal hypertrophy and LVOT obstruction in children with HCM. Identification of RAAS modifier genes may help to risk-stratify patients with HCM. This work was presented in part at the Annual Scientific Sessions of the American Heart Association, New Orleans, November 2004.     

Structural and Functional Analyses of the Human PDH Complex Suggest a “Division-of-Labor” Mechanism by Local E1 and E3 Clusters

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Seed Dispersal by Avian Frugivores: Non‐random Heterogeneity at Fine Scales

Seed dispersal studies have primarily examined dispersal as a function of distance from the parent tree and/or heterogeneity in dispersal due to animal use of nesting, roosting and sleeping sites. However, non‐random heterogeneity in seed dispersal is also likely to result from the post‐foraging behavior and movement of frugivores which prefer certain trees. To characterize variation in seed rain at fine scales, we studied the dispersal curve of Prunus ceylanica, a primarily bird‐dispersed species. We compared seed rain at conspecifics, heterospecific fruiting trees with similar frugivore assemblages, emergent trees, and the landscape surrounding these trees. Seed rain of P. ceylanica was found to peak globally under the canopy of conspecifics but to peak locally under the canopy and immediate neighborhood of heterospecific fruiting trees. Our results demonstrate that seed rain is highly clumped even at fine spatial scales. A large proportion of seeds are dispersed in specific, localized regions. This variation can have important implications for plant population dynamics and might significantly alter the impact of post‐dispersal processes. Seed dispersal models may need to incorporate this heterogeneity to explain manifestations of spatially explicit dynamics like mixed species ‘orchards’.     

C-Reactive Protein (CRP), Interferon Gamma-Inducible Protein 10 (IP-10), and Lipopolysaccharide (LPS) Are Associated with Risk of Tuberculosis after Initiation of Antiretroviral Therapy in Resource-Limited Settings

ObjectiveThe association between pre-antiretroviral (ART) inflammation and immune activation and risk for incident tuberculosis (TB) after ART initiation among adults is uncertain.DesignNested case-control study (n = 332) within ACTG PEARLS trial of three ART regimens among 1571 HIV-infected, treatment-naïve adults in 9 countries. We compared cases (participants with incident TB diagnosed by 96 weeks) to a random sample of controls (participants who did not develop TB, stratified by country and treatment arm).MethodsWe measured pre-ART C-reactive protein (CRP), EndoCab IgM, ferritin, interferon gamma (IFN-γ), interleukin 6 (IL-6), interferon gamma-inducible protein 10 (IP-10), lipopolysaccharide (LPS), soluble CD14 (sCD14), tumor necrosis factor alpha (TNF-α), and CD4/DR+/38+ and CD8/DR+/38+ T cells. Markers were defined according to established cutoff definitions when available, 75th percentile of measured values when not, and detectable versus undetectable for LPS. Using logistic regression, we measured associations between biomarkers and incident TB, adjusting for age, sex, study site, treatment arm, baseline CD4 and log10 viral load. We assessed the discriminatory value of biomarkers using receiver operating characteristic (ROC) analysis.ResultsSeventy-seven persons (4.9%) developed incident TB during follow-up. Elevated baseline CRP (aOR 3.25, 95% CI: 1.55–6.81) and IP-10 (aOR 1.89, 95% CI: 1.05–3.39), detectable plasma LPS (aOR 2.39, 95% CI: 1.13–5.06), and the established TB risk factors anemia and hypoalbuminemia were independently associated with incident TB. In ROC analysis, CRP, albumin, and LPS improved discrimination only modestly for TB risk when added to baseline routine patient characteristics including CD4 count, body mass index, and prior TB.ConclusionIncident TB occurs commonly after ART initiation. Although associated with higher post-ART TB risk, baseline CRP, IP-10, and LPS add limited value to routine patient characteristics in discriminating who develops active TB. Besides determining ideal cutoffs for these biomarkers, additional biomarkers should be sought that predict TB disease in ART initiators.     

Immunologic Predictors of Liver Transplantation Outcomes in HIV-HCV Co-Infected Persons

Liver disease is a leading cause of mortality among HIV-infected persons in the highly active anti-retroviral therapy (HAART) era. Hepatitis C Virus (HCV) co-infection is prevalent in, and worsened by HIV; consequently many co-infected persons require liver transplantation (LT). Despite the need, post-LT outcomes are poor in co-infection. We examined predictors of outcomes post-LT. Immunologic biomarkers of immune activation, microbial translocation, and Th1/Th2 skewing were measured pre-LT in participants enrolled in a cohort of HIV infected persons requiring solid organ transplant (HIVTR). Predictive biomarkers were analyzed in Cox-proportional hazards models; multivariate models included known predictors of outcome and biomarkers from univariate analyses. Sixty-nine HIV-HCV co-infected persons with available pre-LT samples were tested: median (IQR) CD4+ T-cell count was 286 (210–429) cells mm^-3; 6 (9%) had detectable HIV RNA. Median (IQR) follow-up was 2.1 (0.7–4.0) years, 29 (42%) people died, 35 (51%) had graft loss, 22 (32%) were treated for acute rejection, and 14 (20%) had severe recurrent HCV. In multivariate models, sCD14 levels were significantly lower in persons with graft loss post-LT (HR 0.10 [95%CI 0.02–0.68]). IL-10 levels were higher in persons with rejection (HR 2.10 [95%CI 1.01–4.34]). No markers predicted severe recurrent HCV. Monocyte activation pre-LT may be mechanistically linked to graft health in HIV-HCV co-infection.     

Variation in condylar morphology in different malocclusion among Indians

Temporo-mandibular joint (TMJ) joint and the condyle of mandible are observed in the radiographs of the skull and the jaw. Therefore, it is of interest to assess the predictability of four different shapes of condyle in skeletal class I, II and III malocclusion. The four commonly visualized shapes are oval, bird beak, diamond and crooked were assessed using an ortho pantomogram (OPG). Each of the malocclusion was visualized for different shapes of the condyle. 987 OPGs were radiographically evaluated and the morphology of 1974 condylar heads was visualized. The shapes of the condyles were grouped under four different types. Data shows that oval shaped condyle was most common followed by bird beak. There was variability in the diamond and crooked shape and was lesser than the other types. Thus, the shapes of the condyle are useful predictable guide in deciding the nature of the occlusion.     

Efficacy of zirconium oxide nanoparticles coated on stainless steel and nickel titanium wires in orthodontic treatment

It is of particular intrigue to synthesize, analyze anti-bacterial, anti-inflammatory activity, cytotoxicity effect of clove and cardamom reinforced zirconium oxide nanoparticles to coat the orthodontic archwires and study its ramifications. Characterization of nanoparticles was done using Transmission electron microscopic analysis (TEM). Antimicrobial activity was assessed using agar well diffusion method. Cytotoxic effect was assessed using Brine Shrimp Assay. Anti-inflammatory activity was completed using Bovine Serum Albumin (BSA). A Digital magnetic stirrer with a hot plate was used to coat orthodontic arch wires such as NiTi and SS. TEM spherical shape was of size 5 -20 nm. Minimal cytotoxicity was observed at 50 µL. Anti-inflammatory property was fair. Antimicrobial activity against Lactobacillus species, streptococcus mutans staphylococcus aureus and Candida albicans was recorded. NiTi and SS showed a colour shift from silver to orange red with a uniform surface coating on wires. Thus, green synthesized zirconium oxide nanoparticles have potent antimicrobial, anti-inflammatory properties with minimal cytotoxicity for further consideration as nano-coatings on orthodontic archwires such as NiTi and Stainless Steel.     

Characterization of a novel microfluidic platform for the isolation of rare single cells to enable CTC analysis from head and neck squamous cell carcinoma patients

Detailed examination of tumor components is leading‐edge to establish personalized cancer therapy. Accompanying research on cell‐free DNA, the cell count of circulating tumor cells (CTCs) in patient blood is seen as a crucial prognostic factor. The potential of CTC analysis is further not limited to the determination of the overall survival rate but sheds light on understanding inter‐ and intratumoral heterogeneity. In this regard, commercial CTC isolation devices combining an efficient enrichment of rare cells with a droplet deposition of single cells for downstream analysis are highly appreciated. The Liquid biopsy platform CTCelect was developed to realize a fully‐automated enrichment and single cell dispensing of CTCs from whole blood without pre‐processing. We characterized each process step with two different carcinoma cell lines demonstrating up to 87 % enrichment (n = 10) with EpCAM coupled immunomagnetic beads, 73 % optical detection and dispensing efficiency (n = 5). 40 to 56.7 % of cells were recovered after complete isolation from 7.5 ml untreated whole blood (n = 6). In this study, CTCelect enabled automated dispensing of single circulating tumor cells from HNSCC patient samples, qPCR‐based confirmation of tumor‐related biomarkers and immunostaining. Finally, the platform was compared to commercial CTC isolation technologies to highlight advantages and limitations of CTCelect. This system offers new possibilities for single cell screening in cancer diagnostics, individual therapy approaches and real‐time monitoring.     

Essential role of Rnd1 in innate immunity during viral and bacterial infections

Intracellular and cell surface pattern-recognition receptors (PRRs) are an essential part of innate immune recognition and host defense. Here, we have compared the innate immune responses between humans and bats to identify a novel membrane-associated protein, Rnd1, which defends against viral and bacterial infection in an interferon-independent manner. Rnd1 belongs to the Rho GTPase family, but unlike other small GTPase members, it is constitutively active. We show that Rnd1 is induced by pro-inflammatory cytokines during viral and bacterial infections and provides protection against these pathogens through two distinct mechanisms. Rnd1 counteracts intracellular calcium fluctuations by inhibiting RhoA activation, thereby inhibiting virus internalisation. On the other hand, Rnd1 also facilitates pro-inflammatory cytokines IL-6 and TNF-α through Plxnb1, which are highly effective against intracellular bacterial infections. These data provide a novel Rnd1-mediated innate defense against viral and bacterial infections.Subject terms: Viral infection, Pattern recognition receptors