Menopausal hormone therapy does not play a major role in left ventricular hypertrophy

Objectives

Left ventricular hypertrophy (LVH) is a precursor of morbidity and mortality in women. Use of menopausal hormone therapy (MHT) might be associated with decreased left ventricular mass (LVM) and lower risk of LVH, although results of previous observational and clinical studies are inconclusive. Therefore, we analyzed the association between MHT use and either LVM indexed to height^2.7 (LVMI) or LVH determined echocardiographically.

Methods

Data from women aged ≥ 45 years recruited for the population-based Study of Health in Pomerania were used for cross-sectional (n = 975) and longitudinal (n = 675; 361 women without LVH at baseline) analyses. Information on ever (past and current) and never use of MHT were obtained. Linear (LVMI) or logistic (LVH) regression analyses were performed while controlling for potential confounders.

Results

Crude and age-adjusted analyses suggested an association between ever use of MHT and lower odds for LVH. This association was no longer significant in fully adjusted models. Compared to women who never used MHT, the odds ratios of LVH for ever MHT users were 0.97 [95%-confidence interval (95%-CI) 0.71–1.30] in cross-sectional and 0.70 (95%-CI 0.44–1.11) in longitudinal fully adjusted analyses. Similarly, results with an alternative classification of MHT use (never, past, and current) indicated no significant associations with LVH after full adjustment.

Conclusions

This study provides little evidence of an association between MHT use and LVH. Differences in lifestyle or health-related factors between never and MHT users could provide an explanation, in part, for the presumptive protective benefit of MHT on LVH.     

The NOD2 receptor does not play a major role in the pathogenesis of Group B Streptococcus in mice

Group B Streptococcus (GBS) capsular type III is an important agent of life-threatening invasive infections. It has been previously shown that encapsulated GBS is easily internalized by dendritic cells (DCs) and this internalization has an impact on cytokine production. The intracellular receptors or pathways underlying this response are not well understood. In this work, we investigated the role of NOD2 in the pathogenesis of GBS using a mouse model of infection. NOD2^−/− mice showed similar levels of survival and bacteremia than control mice. Interestingly, ex vivo analysis of total spleen cells from infected animals showed that the absence of NOD2 results in reduced production of inflammatory cytokines. However this abridged inflammatory response does not seem to improve mouse survival. In conclusion, we demonstrated that NOD2 is not a crucial receptor to fight GBS infection and only partially contributes to the inflammatory response.     

Association analyses of the INSIG2 polymorphism in the obesity and cholesterol levels of Korean populations

Background  

While INSIG2 has been reported to be associated with BMI in many populations, conflicting results have prevented consensus over its role. In analyses of mice and cell cultures the gene has been found to be involved in the regulation of cholesterol synthesis; however, no relationship has been found with cholesterol metabolism in human epidemiological research. Therefore, this study attempts to assess the effect of rs7566605 near INSIG2 on both obesity- and cholesterol-related traits in Koreans.     

Phagocytosis does not play a major role in naturally acquired transmission-blocking immunity to Plasmodium falciparum malaria

Phagocytosis of Plasmodium falciparum sexual stages in vitro and within the mosquito midgut was assayed in order to assess its role in transmission-blocking immunity to malaria. Both monocytes/macrophages (MM) and polymorphonuclear neutrophils (PMN) phagocytosed malarial gametes in vitro, but levels of phagocytosis were low. Intraerythrocytic gametocytes were not susceptible to phagocytosis. In vitro phagocytosis was positively correlated with levels of antibodies against the gamete surface proteins Pfs230 and Pfs48/45. Immunoglobulin G (IgG) subclass analysis revealed that phagocytosis was correlated with levels of antigamete IgG1. In vivo membrane-feeding experiments were performed in the presence of both pooled and individual malaria immune sera. The phagocytic process proceeded less efficiently in vivo than in vitro, which may be related to the lower ambient temperature (26 degrees C, compared with 37 degrees C). Finally, although we found a correlation between the ability of a serum to promote phagocytosis in vitro and the presence of antibodies against transmission-blocking target antigens, we were unable to demonstrate a role for MM- or PMN-mediated phagocytosis in reduction of infectivity of the malarial parasite to mosquitoes.     

The vagal afferent pathway does not play a major role in the induction of satiety by intestinal fatty acid in rats

Intestinal infusion of long-chain fatty acids (LCFAs) strongly suppresses food intake and gut motility. Vagal afferents and cholecystokinin (CCK) signaling pathway are considered to play important roles in intestinal LCFA-induced satiety. Here, we first investigated the influence of vagus nerve on satiety following intestinal LCFA infusion in rats. Jejunal infusion of linoleic acid (LA) at 200 μL/h for 7 h suppressed food intake and the effect lasted for 24 h. The satiety induced by jejunal LA infusion occurred in a dose dependent manner. In contrast, the anorectic effect induced by octanoic acid, a medium-chain fatty acid, was weaker than that induced by LA. The reduction in food intake induced by jejunal LA infusion was not attenuated in rats treated with vagotomy, the ablation of bilateral subdiaphragmatic vagal trunks. Jejunal LA-induced satiety could also be observed in rats with bilateral midbrain transections, which ablates fibers between the hindbrain and hypothalamus. These findings suggest that the vagus nerve and fibers ascending from the hindbrain to the hypothalamus do not play a major role in intestinal LCFA-induced satiety. Jejunal LA infusion also reduced food intake in CCK-A receptor-deficient OLETF rats, suggesting that CCK signaling pathway is not critical for intestinal LCFA-induced anorexia. In conclusion, this study indicates that the vagus nerve and the CCK signaling pathway do not play major roles in conveying satiety signals induced by intestinal LCFA to the brain in rats.     

Complement does not play a role in promotingBabesia rodhaini infections in Balb/C mice

A critical role of C3 and the C3b receptor for the erythrocyte invasion and the development of the parasitemia ofB. rodhaini in rats has been described recently (Jack and Ward 1980a). In the present study the influence of the C system onB. rodhaini infection in Balb/C mice is documented. Depletion of serum C3 to less than 5% of the normal level by treatment of mice with CoF, the C3 inactivator isolated from cobra venom, did not affect the course ofB. rodhaini parasitaemia. Treatment of mice with trypan blue, a reagent that inactivates the C3b receptor on human polymorphonuclear leukocytes, inhibited the development of parasitemia. However, whenB. rodhaini parasitized erythrocytes were incubated in vitro with trypan blue and subsequently tested for the in vivo and in vitro replication of the parasites, this old-fashioned therapy for babesiosis in cattle showed its babesiacidal activity. This indicates that the inhibition of parasite development by trypan blue is caused by its parasitotoxicity. These data suggest that the C system does not play an essential role in the development ofB. rodhaini infection of the Balb/C mouse.List of Abbreviations VSB veronal saline buffer, pH 7.4, containing 0.15 mM Ca²⁺ and 0.5 mM Mg²⁺ - EDTA-GVB veronal saline buffer, containing 1 g gelatin/l and 10 mM EDTA - EDTA ethylenediamine/tetraacetic/acid - C complement - CoF cobra venom factor - E₄₁₂ extinction at 412 nm - CH₅₀ units of total hemolytic complement activity in serum - RaRBC rabbit red blood cells - PBS phosphate buffered saline - EAC₁₄₂₃ sheep erythrocytes coated with rabbit amboceptor and human complement components C₁, C₄, C₂ and C₃ - S.D. standard deviation - SEM standard error of the mean - SRBC sheep red blood cells     

The common genetic variant upstream of INSIG2 gene is not associated with obesity in Indian population

The high incidence of obesity has resulted in increased morbidity and mortality worldwide. Obesity, a common lifestyle disorder, is caused by multiple factors with heredity playing a strong causal role. Recently, a genetic variation upstream of insulin-induced gene 2 (INSIG2) (rs7566605) has been reported to be associated with obesity in four separate cohorts. Because the lifestyle and food preferences of a large proportion of Indian population differ from the rest of the world, we studied the impact of this polymorphism with body mass index (BMI). The study consisted of two cohorts--1577 healthy individuals from three major linguistic lineages in India and 610 coronary artery disease cases and controls. In the two cohorts studied, no significant association was observed between the polymorphism and BMI. However, frequency of homozygous variant genotype was higher in non-obese individuals as compared with obese individuals in both cohorts although the difference was marginally significant only in the case-control cohort under the assumption of a recessive model. Furthermore, regardless of age and sex, mean BMI did not vary with genotype under the assumptions of recessive model. Thus, in contrast to earlier reports, the variant upstream of INSIG2 is not a determinant of BMI in Indian population.     

Testosterone decrease does not play a major role in the suppression of hippocampal cell proliferation following social defeat stress in rats

Stress of social defeat in rodents is known to have a strong and long-lasting effect on brain, physiology and behavior, which bears similarities with certain human stress related psychopathologies. Previous experiments in this lab showed that social defeat stress suppresses testosterone secretion and causes a lasting desensitization of the serotonergic 5-HT_1A receptors. Testosterone supplementation in socially stressed tree shrews prevented a decrease in hippocampal 5-HT_1A receptor binding. These receptors are hypothesized to play an important role in neurogenesis in this brain structure. We designed the present experiment to test if social defeat reduces hippocampal cell proliferation and neurogenesis in rats and if testosterone supplementation can prevent this reduction. The results indicate that repeated social defeat stress on 5 successive days induces a significant drop in plasma testosterone levels in male rats and suppresses hippocampal cell proliferation 24 h and 3 weeks after the end of the stress period. Testosterone supplementation prevented the social stress induced drop in plasma testosterone levels. The hormone supplementation also reduced the negative effect of stress on hippocampal BrdU labeling at 3 weeks post-defeat. This effect was, however, rather weak and was caused by the tendency of the hormone in itself to suppress proliferation and the failure to fully recover the proliferation rate. Survival of dentate gyrus cells that either proliferated prior to the stress period or 24 h after the last defeat was not affected by the social defeats. Thus the stress-induced lowering of hippocampal cell proliferation is not likely to be caused by transient inhibition of testosterone secretion during social stress.     

GIGYF2 has no major role in Parkinson genetic etiology in a Belgian population

Missense mutations were identified in the Grb10-Interacting GYF Protein-2 gene (GIGYF2), located in the chromosomal region 2q36-q37, in familial Parkinson disease (PD) patients of European descent. To determine the contribution of GIGYF2 mutations in an extended (N = 305) Belgian series of both familial and sporadic PD patients, we sequenced all 32 coding and non-coding exons of GIGYF2. In three sporadic PD patients we identified two novel heterozygous missense mutations (c.1907A>G, p.Tyr636Cys and c.2501G>A, p.Arg834Gln), that were absent from control individuals (N = 360). However, since we lack genetic as well as functional data supporting their pathogenic nature, we cannot exclude that these variants are benign polymorphisms. Together, our results do not support a role for GIGYF2 in the genetic etiology of Belgian PD.     

Oxytocin receptor (OXTR) does not play a major role in the aetiology of autism: Genetic and molecular studies

Oxytocin (OXT) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. It is postulated that OXT reduces activation of the amygdala, inhibiting social anxiety, indicating a neural mechanism for the effects of OXT in social cognition. Genetic variation at the oxytocin receptor gene (OXTR) has been reported to be associated with autism. We examined 18 SNPs at the OXTR gene for association in three independent autism samples from Ireland, Portugal and the United Kingdom. We investigated cis-acting genetic effects on OXTR expression in lymphocytes and amygdala region of the brain using an allelic expression imbalance (AEI) assay and by investigating the correlation between RNA levels and genotype in the amygdala region. No marker survived multiple correction for association with autism in any sample or in a combined sample (n = 436). Results from the AEI assay performed in the lymphoblast cell lines highlighted two SNPs associated with relative allelic abundance in OXTR (rs237897 and rs237895). Two SNPs were found to be effecting cis-acting variation through AEI in the amygdala. One was weakly correlated with total gene expression (rs13316193) and the other was highlighted in the lymphoblast cell lines (rs237895). Data presented here does not support the role of common genetic variation in OXTR in the aetiology of autism spectrum disorders in Caucasian samples.     

The MMP2 rs243865-T allele is not a major genetic factor for rheumatoid arthritis in the French Caucasian population

The MMP2 rs243865-T allele was recently suggested to be associated with rheumatoid arthritis (RA) in a case-control study. MMP2 is a positional RA candidate gene. Our aim was to test rs243865 in a French family based study. No significant result was shown. The MMP2 rs243865-T allele is not a major rheumatoid arthritis genetic factor in this population.     

The BDNF rs6265 variant may interact with overweight and obesity to influence obesity-related physical,metabolic and behavioural traits in Pakistani individuals

Background: The association of the variant rs6265 (G>A) in the brain-derived neurotrophic factor (BDNF) gene with obesity and other obesity-related parameters is not known for the Pakistani population. Moreover, the effects of interaction between BDNF rs6265 and overweight/obesity on obesity-related traits have never been investigated before.

Aim: To find the association of the BDNF rs6265 with obesity and related traits and to explore the effect of rs6265?×?obesity interaction on obesity-related traits in Pakistanis.

Subjects and methods: The study involved a total of 606 subjects, including 306 overweight and obese (OW/OB) cases and 300 normal weight (NW) controls. The genotyping of the BDNF rs6265 was done and obesity-related anthropometric, physical, behavioural and metabolic parameters were determined. Statistical analyses using SPSS software were performed to find the associations.

Results: The study revealed a lack of association of the BDNF rs6265 with obesity and obesity-related traits. On the other hand, the interaction between the BDNF rs6265 and overweight/obesity was found to be significantly associated with some of the obesity-related anomalous traits. However, no association between rs6265 and these anomalous traits was seen in either group when the association test was performed in NW and OW/OB groups separately.

Conclusion: The BDNF rs6265, in the presence of obesity, may be associated with elevated risk of anomalous metabolic, behavioural and physical traits and obesity-related co-morbidities, but it needs to be validated in a significantly larger Pakistani sample population.     

RIT2 variant is not associated with Parkinson's disease in a Taiwanese population

Recent genome-wide association studies of Parkinson's disease (PD) have identified the rs12456492 variant of the novel susceptibility loci, RIT2, as being associated with disease risk in a large white population. Studies among Asians are scarce. We genotyped RIT2 rs12456492 variant in a total of 1000 participants, comprising 500 patients with PD and 500 control subjects in a Taiwanese population. The frequency of GA/AA genotype was slightly higher in PD patients compared with controls, but was without statistical significance (odds ratio = 1.03, 95% confidence interval = 0.73–1.46, p = 0.86). We failed to replicate the RIT2 rs12456492 variant as a genetic risk factor for PD in our population.     

The major risk alleles of age-related macular degeneration (AMD) in CFH do not play a major role in rheumatoid arthritis (RA)

Because activation of the alternative pathway (AP) of the complement system is an important aspect of both age-related macular degeneration (AMD) and rheumatoid arthritis (RA), we wished to address the question whether genetic risk factors of the AP inhibitor complement factor H (CFH) for AMD would also be risk factors for RA. For this purpose we genotyped single nucleotide polymorphisms (SNPs) in a Dutch set of RA patients and controls. Similarly, a meta-analysis using a Spanish cohort of RA as well as six large genome-wide association studies (GWAS) studies was performed. For these SNPs we analysed more than 6000 patients and 20,000 controls. The CFH variants, I62V, Y402H, IVS1 and IVS10, known to associate strongly with AMD, did not show a significant association with the risk of developing RA despite a strong statistical power to detect such differences. In conclusion, the major risk alleles of AMD in CFH do not have a similar effect on developing RA.     

CD62L is required for the priming of encephalitogenic T cells but does not play a major role in the effector phase of experimental autoimmune encephalomyelitis

CD62L (l ‐selectin, mel 14) regulates naïve T cell homing into lymph nodes and the migration of leucocytes to sites of inflammation. The requirement of CD62L in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, has been demonstrated previously. However, it remains controversial as to whether CD62L is required for the induction or the effector phase of EAE. It is also unclear whether other non‐T effector cells need CD62L to enter the central nervous system (CNS) parenchyma and exert their damaging effects on myelin. We report that mice with a targeted mutation of CD62L are resistant to Myelin oligodendrocyte glycoprotein peptide‐induced EAE. CD62L‐deficient mice had no peptide‐specific T cell responses in the draining lymph nodes and had lower levels of peptide‐specific T cell responses in spleens at a later time point. Adoptive transfer studies showed that CD62L‐deficient mice were fully susceptible to adoptive transfer EAE induced by either wildtype or CD62L‐deficient T cells. Moreover, CD62L‐deficient, F4/80⁺ macrophages can be efficiently recruited into the CNS parenchyma. These data suggest that CD62L is required for the induction of encephalitogenic T cells during EAE development, but is not required by T and non‐T effector cells to attack the CNS parenchyma.     

C4B null alleles are not associated with genetic polymorphisms in the adjacent gene CYP21A2 in autism

Background  

Research indicates that the etiology of autism has a strong genetic component, yet so far the search for genes that contribute to the disorder, including several whole genome scans, has led to few consistent findings. However, three studies indicate that the complement C4B gene null allele (i.e. the missing or nonfunctional C4B gene) is significantly more frequent in individuals with autism. Due to the close proximity of the CYP21A2 gene to the C4B locus (3 kb) it was decided to examine samples from autistic subjects, including many with known C4B null alleles for common CYP21A2 mutations.     

PLCL1 rs7595412 variation is not associated with hip bone size variation in postmenopausal Danish women

Background  

Bone size (BS) variation is under strong genetic control and plays an important role in determining bone strength and fracture risk. Recently, a genome-wide association study identified polymorphisms associated with hip BS variation in the PLCL1 (phospholipase c-like 1) locus. Carriers of the major A allele of the most significant polymorphism, rs7595412, have around 17% larger hip BS than non-carriers. We therefore hypothesized that this polymorphism may also influence postmenopausal complications.