Hearing and vision:the age old problem

Opticians and audiologists tend to see the same people. Many factors that are associated with poorer vision, whether hereditary, pre-natal, or post-natal, are also associated with poorer hearing. The most common factor is simply old age. According to the Royal National Institute for Deaf People (RNID), more than half of all people aged over 60 have some degree of hearing loss and are gradually losing their hearing as part of the ageing process – a process known as presbycusis.

Psychosoziale Merkmale der Arbeit, Überforderungserleben und Depressivität

Die vorliegende Studie untersuchte die im Job-Demand-Control-Support-Modell und Effort-Reward-Imbalance-Modell beschriebenen Tätigkeitsmerkmale in Bezug auf Depressivität in einer Stichprobe von 265 Erwerbstätigen. Anhand konfirmatorischer Faktorenanalysen wurden Gemeinsamkeiten und Unterschiede beider Modelle geprüft. Anschließend wurde die Bedeutung der nachweisbaren Tätigkeitsmerkmale für die Vorhersage von Depressivität getestet und untersucht, inwieweit die Effekte durch Überforderungserleben mediiert werden. Die Analysen zeigten, dass die Modelle sowohl gemeinsame (Arbeitsintensität bzw. berufliche Anforderungen) als auch distinkte Arbeitsmerkmale (Tätigkeitsspielraum, Arbeitsplatzsicherheit, beruflicher Status, soziale Anerkennung) erfassen. Hohe Arbeitsintensität, geringe Arbeitsplatzsicherheit und fehlende soziale Anerkennung standen in signifikantem Zusammenhang mit Depressivität. Anders als erwartet war der berufliche Status positiv mit Depressivität assoziiert, während für den Tätigkeitsspielraum keine signifikanten Effekte nachweisbar waren. Das Pfadmodell bestätigte sowohl direkte als auch durch Überforderungserleben vermittelte Zusammenhänge zwischen den Tätigkeitsmerkmalen und Depressivität (39 % Varianzaufklärung). Die Ergebnisse bieten eine Grundlage für die Identifizierung potenzieller Risikofaktoren für das Auftreten depressiver Symptome am Arbeitsplatz. This study examined the job characteristics in the Job-Demand-Control-Support Model and in the Effort-Reward Imbalance Model with regard to depression in a sample of 265 employees. First, we tested by means of confirmatory factor analysis similarities and differences of the two models. Secondly, job characteristics were introduced as predictors in a path model to test their relation with depression. Furthermore, we examined whether the associations were mediated by the experience of excessive demands. Our analyses showed the demand/effort component to be one common factor, while decision latitude and reward (subdivided into the three facets of job security, social recognition, and status-related reward) remained distinctive components. Employees with high job demands/effort, low job security, low social recognition, but high status-related rewards reported higher depression scores. Unexpectedly, status-related rewards were positively associated with depression, while we found no significant effects for decision latitude. The path models confirmed direct as well as mediation effects (through experienced excessive demands) between job characteristics and depression (39 % explained variance in depression). Our results could be useful to identify possible job-related risk factors for depression.

The MIMIC model and formative variables:problems and solutions

The use of the multiple indicators, multiple causes model to operationalize formative variables (the formative MIMIC model) is advocated in the methodological literature. Yet, contrary to popular belief, the formative MIMIC model does not provide a valid method of integrating formative variables into empirical studies and we recommend discarding it from formative models. Our arguments rest on the following observations. First, much formative variable literature appears to conceptualize a causal structure between the formative variable and its indicators which can be tested or estimated. We demonstrate that this assumption is illogical, that a formative variable is simply a researcher-defined composite of sub-dimensions, and that such tests and estimates are unnecessary. Second, despite this, researchers often use the formative MIMIC model as a means to include formative variables in their models and to estimate the magnitude of linkages between formative variables and their indicators. However, the formative MIMIC model cannot provide this information since it is simply a model in which a common factor is predicted by some exogenous variables—the model does not integrate within it a formative variable. Empirical results from such studies need reassessing, since their interpretation may lead to inaccurate theoretical insights and the development of untested recommendations to managers. Finally, the use of the formative MIMIC model can foster fuzzy conceptualizations of variables, particularly since it can erroneously encourage the view that a single focal variable is measured with formative and reflective indicators. We explain these interlinked arguments in more detail and provide a set of recommendations for researchers to consider when dealing with formative variables.

Mechanism of attenuation of muscle protein degradation induced by tumor necrosis factor-alpha and angiotensin II by beta-hydroxy-beta-methylbutyrate

Both tumor necrosis factor-alpha (TNF-alpha)/interferon-gamma (IFN-gamma) and angiotensin II (ANG II) induced an increase in total protein degradation in murine myotubes, which was completely attenuated by treatment with beta-hydroxy-beta-methylbutyrate (HMB; 50 microM). There was an increase in formation of reactive oxygen species (ROS) within 30 min, as well as an increase in the activity of both caspase-3 and -8, and both effects were attenuated by HMB. Moreover, inhibitors of caspase-3 and -8 completely attenuated both ROS formation and total protein degradation induced by TNF-alpha/IFN-gamma and ANG II. There was an increased autophosphorylation of double-stranded RNA-dependent protein kinase (PKR), which was attenuated by the specific caspase-3 and -8 inhibitors. Neither ROS formation or protein degradation occurred in myotubes expressing a catalytically inactive PKR variant, PKRDelta6, in response to TNF-alpha/IFN-gamma, compared with myotubes expressing wild-type PKR, although there was still activation of caspase-3 and -8. HMB also attenuated activation of PKR, suggesting that it was important in protein degradation. Formation of ROS was attenuated by rotenone, an inhibitor of the mitochondrial electron transport chain, nitro-l-arginine methyl ester, an inhibitor of nitric oxide synthase, and SB 203580, a specific inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), which also attenuated total protein degradation. Activation of p38 MAPK by PKR provides the link to ROS formation. These results suggest that TNF-alpha/IFN-gamma and ANG II induce muscle protein degradation by a common signaling pathway, which is attenuated by HMB, and that this involves the initial activation of caspase-3 and -8, followed by autophosphorylation and activation of PKR, which then leads to increased ROS formation via activation of p38 MAPK. Increased ROS formation is known to induce protein degradation through the ubiquitin-proteasome pathway.

Statnote 11: the two-factor analysis of variance

Experiments combining different groups or factors are a powerful method of investigation in applied microbiology. ANOVA enables not only the effect of individual factors to be estimated but also their interactions; information which cannot be obtained readily when factors are investigated separately. In addition, combining different treatments or factors in a single experiment is more efficient and often reduces the number of replications required to estimate treatment effects adequately. Because of the treatment combinations used in a factorial experiment, the degrees of freedom (DF) of the error term in the ANOVA is a more important indicator of the ‘power’ of the experiment than simply the number of replicates. A good method is to ensure, where possible, that sufficient replication is present to achieve 15 DF for each error term of the ANOVA. Finally, in a factorial experiment, it is important to define the design of the experiment in detail because this determines the appropriate type of ANOVA. We will discuss some of the common variations of factorial ANOVA in future statnotes. If there is doubt about which ANOVA to use, the researcher should seek advice from a statistician with experience of research in applied microbiology.

Hypoxia induces dilated cardiomyopathy in the chick embryo:mechanism, intervention, and long-term consequences

Background - Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos. Methods - Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine. Principal Findings - Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF165 to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype. Conclusions/Significance - Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood.

Induction of apoptosis by a cachectic-factor in murine myotubes and inhibition by eicosapentaenoic acid

Treatment of C2C12 myotubes with a tumour-derived proteolysis-inducing factor (PIF) at concentrations between 1 and 10 nM was shown to stimulate the activity of the apoptotic initiator caspases-8 and -9 and the apoptotic effector caspases-2,-3 and -6. This increased caspase activity was attenuated in myotubes pretreated with 50 μM eicosapentaenoic acid (EPA). At least part of the increase in caspase activity may be related to the increased proteasome proteolytic activity, since a caspase-3 inhibitor completely attenuated the PIF-induced increase in 'chymotrypsin-like' enzyme activity, the predominant proteolytic activity of the proteasome. However, Western blot analysis showed that PIF induced an increase in expression of the active form of caspase-3, which was also attenuated by EPA. Further Western blot analysis showed PIF increased the cytosolic content of cytochrome c, as well as expression of the pro-apoptotic protein bax but not the antiapoptotic protein bcl-2, which were both attenuated by 50 μM EPA. Induction of apoptosis by PIF in murine myotubes was confirmed by an increase in free nucleasomes formation and increased DNA fragmentation evidenced by a nucleasomal ladder typical of apoptotic cells. This process was again inhibited by pre-incubation with EPA. These results suggest that in addition to activating the proteasome, PIF induces apoptosis in C2C12 myotubes, possibly through the common intermediate arachidonic acid. Both of these processes would contribute to the loss of skeletal muscle in cancer cachexia.

Common variants of the TCF7L2 gene are associated with increased risk of type 2 diabetes mellitus in a UK-resident South Asian population

Background - Recent studies have implicated variants of the transcription factor 7-like 2 (TCF7L2) gene in genetic susceptibility to type 2 diabetes mellitus in several different populations. The aim of this study was to determine whether variants of this gene are also risk factors for type 2 diabetes development in a UK-resident South Asian cohort of Punjabi ancestry. Methods - We genotyped four single nucleotide polymorphisms (SNPs) of TCF7L2 (rs7901695, rs7903146, rs11196205 and rs12255372) in 831 subjects with diabetes and 437 control subjects. Results - The minor allele of each variant was significantly associated with type 2 diabetes; the greatest risk of developing the disease was conferred by rs7903146, with an allelic odds ratio (OR) of 1.31 (95% CI: 1.11 – 1.56, p = 1.96 × 10-3). For each variant, disease risk associated with homozygosity for the minor allele was greater than that for heterozygotes, with the exception of rs12255372. To determine the effect on the observed associations of including young control subjects in our data set, we reanalysed the data using subsets of the control group defined by different minimum age thresholds. Increasing the minimum age of our control subjects resulted in a corresponding increase in OR for all variants of the gene (p ≤ 1.04 × 10-7). Conclusion - Our results support recent findings that TCF7L2 is an important genetic risk factor for the development of type 2 diabetes in multiple ethnic groups.

Can hydrogen sulfide prevent preeclampsia and fetal growth restriction?

The exact aetiology of preeclampsia is unknown, but there is a good association with an imbalance in angiogenic growth factors and abnormal placentation [1]. Hydrogen sulphide (H2S), a gaseous messenger produced mainly by cystathionine γ-lyase (CSE), is pro-angiogenic vasodilator [2] and [3]. We hypothesized that a reduction in CSE activity may alter the angiogenic balance in pregnancy and induce abnormal placentation and maternal hypertension. Plasma levels of H2S were significantly decreased in preeclamptic women (p < 0.01), which was associated with reduced CSE message and protein expression in human placenta as determined by real-time PCR and immunohistochemistry. Inhibition of CSE activity by DL-propargylglycine (PAG) in first trimester (8–12 weeks gestation) human placental explants had reduced placenta growth factor (PlGF) production as assessed by ELISA and inhibited trophoblast invasion in vitro. Endothelial CSE knockdown by siRNA transfection increased the endogenous release of soluble fms-Like tyrosine kinase-1 (sFlt-1) and soluble endoglin, (sEng) from human umbilical vein endothelial cells while adenoviral-mediated CSE overexpression inhibited their release. Administration of PAG to pregnant mice induced hypertension, liver damage, and promoted abnormal labyrinth vascularisation in the placenta and decreased fetal growth. Finally, a slow releasing, H2S-generating compound, GYY4137, inhibited circulating sFlt-1 and sEng levels and restored fetal growth that was compromised by PAG-treatment demonstrating that the effect of CSE inhibitor was due to inhibition of H2S production. These results imply that endogenous H2S is required for healthy placental vasculature and a decrease in of CSE/H2S activity may contribute to the pathogenesis of preeclampsia. References [1] S. Ahmad, A. Ahmed, Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia, Circ Res., 95 (2004), pp. 884–891. [2] G. Yang, et al., H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase, Science, 322 (2008), pp. 587–590. [3] A. Papapetropoulos, et al., Hydrogen sulfide is an endogenous stimulator of angiogenesis, Proc Natl Acad Sci USA, 106 (2009), pp. 21972–21977.

Hydrogen sulphide rescues preeclampsia-like phenotype aggravated by high sFlt-1 in placenta growth factor (PlGF) deficiency

Placenta growth factor (PlGF) deficient mice are fertile at a Mendelian ratio. Interestingly, low maternal plasma levels of PlGF are strongly associated with early onset of preeclampsia, a pregnancy hypertensive disorder characterised by high blood pressure, proteinuria and fetal growth restriction. PlGF is increasingly being recognised as an early diagnostic biomarker, but the physiological importance of PlGF in the pathogenesis of preeclampsia is unknown. We investigated whether the decreased levels of PlGF in pregnancy exacerbate the fetal growth restriction associated with preeclampsia in the presence of high sFlt-1 and the potential of hydrogen sulphide to ameliorate these effects. Pregnant PlGF−/− mice were injected with adenovirus encoding sFlt-1 (Ad-sFlt-1) at 1 × 109 pfu/ml at E10.5 and mean arterial blood pressure (MAP), biochemical and histological analysis of maternal kidney, placenta and embryos were assessed at the end of pregnancy. Ad-sFlt-1 significantly increased MAP and induced severe glomerular endotheliosis in PlGF−/− mice compared to wild-type animals. Soluble Flt-1 also significantly elevated albumin–creatinine ratio and increased levels of urinary kidney injury molecule-1, a marker for proximal tubule injury. Furthermore, sFlt-1 over expression increased fetal resorption rate in the PlGF−/− mice and promoted abnormal placental vascularisation. To determine whether placental PlGF is critical for preventing fetal growth restriction associated with preeclampsia, we generated haploinsufficient PlGF+/− placentas and embryos in dams and exposed to high sFlt-1 environment. These mothers showed reduced fetal resorption, gestational hypertension and proteinuria when compared to pregnant PlGF−/− mice. Furthermore, treatment with hydrogen sulphide-releasing agent, GYY4137, significantly reduced resorption, hypertension and proteinuria observed in Ad-sFlt-1 treated pregnant PlGF−/− mice. Our study shows that placental PlGF is a critical protective factor against the damaging effects of high sFlt-1 associated with preeclampsia and activation of the hydrogen sulphide pathway may rescue preeclampsia phenotypes even under low PlGF environment.

Dysregulation of placental cystathionine-β-synthase promotes fetal growth restriction

Fetal growth restriction (FGR) is characterized by the birth weight and body mass below the tenth percentile for gestational age. FGR is a major cause of perinatal morbidity and mortality and babies born with FGR are prone to develop cardiovascular diseases later in life. The underlying pathology of FGR is inadequate placental transfer of nutrients from mother to fetus, which can be caused by placental insufficiency. Hydrogen sulfide (H2S), a gaseous messenger is produced endogenously by cystathionine-lyase (Cth), cystathionine-β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST), which are present in human placenta. Recently, we demonstrated that the dysregulation of H2S/Cth pathway is associated with preeclampsia and blockade of CSE activity induces preeclampsia-like condition in pregnant mice. We hypothesized that defect in H2S pathways promote FGR and H2S donor restores fetal growth in mice where CBS or CSE activity has been compromised. Western blotting and qPCR revealed that placental CBS expressions were significantly reduced in women with FGR. ELISA analysis showed reduced placental growth factor production (PlGF) from first trimester (8–12 weeks gestation) human placental explants following inhibition of CBS activity by aminooxyacetic acid (AOA). Administration of AOA to pregnant mice had no effects on blood pressure, but caused fetal growth restriction. This was associated with reduced PlGF production. Histological analysis revealed a reduction in the placental junction zone, within which trophoblast giant cells and glycogen cells were less prominent in CBS inhibitor treated mice. These results imply that placental CBS is required for placental development and that dysregulation of CBS activity may contribute to the pathogenesis of FGR but not preeclampsia.

Hydrogen sulphide rescues preeclampsia-like phenotype aggravated by high sFlt-1 in Placenta Growth Factor (PlGF) deficiency

INTRODUCTION: Low circulating levels of placenta growth factor (PlGF) is strongly associated with the onset of preeclampsia, a maternal hypertensive disorder characterized by high blood pressure and proteinuria after 20 weeks of gestation. Although, PlGF-deficient mice are born healthy and fertile at a Mendelian ratio, the physiological importance of PlGF in the pathogenesis of preeclampsia is unclear. We hypothesised that decreased levels of PlGF in pregnancy exacerbates the fetal growth restriction associated with preeclampsia in the presence of high sFlt-1. METHODS: Pregnant PlGF-/- mice were injected with adenovirus encoding sFlt-1 (Ad-sFlt-1) at high (i) 1.5x109 pfu/ml and low (ii) 0.5x109 pfu/ml doses. Mean arterial blood pressure (MBP), biochemical and histological assessments of maternal kidney, placenta and embryos were performed. RESULTS: Ad-sFlt-1 significantly increased MBP and induced severe glomerular endotheliosis in PlGF-/- mice at E10.5 gestation compared to wild-type animals. High sFlt-1 also significantly elevated albumincreatinine ratio and increased levels of urinary kidney injury molecule-1, a marker for proximal tubule injury.At a high dose of sFlt-1, there was complete fetal resorption in the pregnant PlGF-/- mice, and even the lower dose of sFlt-1 induced severe fetal resorption and abnormal placental vascularization. Hydrogen sulphide-releasing agent, GYY4137, significantly reduced resorption, hypertension and proteinuria in Ad-sFlt-1 treated pregnant PlGF-/- mice. To determine if placental PlGF is critical for preventing fetal growth restriction associated with preeclampsia, we generated haploinsufficient PlGF+/- placentas and embryos were generated in wild-time dams and exposed to high sFlt-1 environment. This resulted in reduced fetal resorption, gestational hypertension and proteinuria when compared to pregnant PlGF-/- mice. CONCLUSIONS: Placental PlGF is a critical protective factor against the damaging effects of high sFlt-1 in preeclampsia and the hydrogen sulphide pathway may rescue preeclampsia phenotypes.