Clustering of risk factors and social class in childhood and adulthood in British women's heart and health study: cross sectional analysis

Objective To examine co-occurrence and clustering of risk factors used in the Framingham equation by social class in childhood and adult life.Design Cross sectional study.Setting 23 towns across England, Wales, and Scotland.Participants 2936 women aged 60-79 years.Main outcome measures Prevalence of risk factors (hypertension, obesity, smoking, left ventricular hypertrophy on electrocardiography, diabetes, and low concentration of high density cholesterol); ratios of observed to expected frequencies of clusters of risk factors.Results Risk factors were more common in women from manual social classes in either childhood or adult life, and the co-occurrence of three or four of these risk factors was greater among more disadvantaged groups. Within the four socioeconomic groups, these risk factors occurred together more than would be expected from their individual frequency distributions, indicating that they were clustered. The extent of this clustering was similar in all four social class groups.Conclusions Clustering of risk factors included in the Framingham risk function occurs in all social class groups, but the lack of social patterning makes it unlikely that clustering is an explanation of socioeconomic inequalities in cardiovascular disease. As the proportion of women with co-occurrence of risk factors is greatest in those from manual social class in childhood, this measure of socioeconomic position might prove useful in risk prediction.     

Scanning electron microscopic analysis of intramyocellular lipid droplets in an animal model of type 2 diabetes

Objective: To evaluate the accumulation pattern of intramyocellular lipids (IMCLs) in striated muscle during the development and progression of diabetes, using a novel scanning electron microscopic method. Methods and Procedures: Hyperglycemia was induced by feeding diabetes‐prone (DP) Psammomys obesus a high‐energy (HE) diet. Lipid accumulation within gastrocnemius muscle fibers was assessed in formalin‐fixed muscle samples during the development of hyperglycemia using high resolution imaging in a scanning electron microscope. We evaluated the temporal relationship between changes in IMCL quantity and morphology and the altered glucose metabolism and assessed the effect of reversal of hyperglycemia on IMCL level and morphology. Diabetes‐resistant (DR) P. obesus served as controls. Results: Lipid accumulation in the muscle fibers of DP animals was increased with the development of hyperglycemia. This was characterized by increased lipid density as well as by an abundance of large lipid droplets. Reversal of the phenotype resulted in the disappearance of large lipid droplets. The IMCL level and the distribution of lipid droplet size were similar in muscles of both the normoglycemic DR and DP animals, with an abundance of small lipid droplets. This profile was changed following a HE diet only in the DP animals. Discussion: Lipid accumulation in the muscle of P. obesus during the development of hyperglycemia is characterized by increased quantity and accumulation of large lipid droplets. These changes were reversible upon normalization of blood glucose. The evaluated methodology is a useful tool for the study of the dynamics of lipid accumulation in different metabolic conditions.     

Impact of NHS walk-in centres on the workload of other local healthcare providers: time series analysis

ObjectivesTo assess the impact of NHS walk-in centres on the workload of local accident and emergency departments, general practices, and out of hours services.DesignTime series analysis in walk-in centre sites with no-treatment control series in matched sites.SettingWalk-in centres and matched control towns without walk-in centres in England.Participants20 accident and emergency departments, 40 general practices, and 14 out of hours services within 3 km of a walk-in centre or the centre of a control town.ResultsA reduction in consultations at emergency departments (–175 (95% confidence interval –387 to 36) consultations per department per month) and general practices (–19.8 (−53.3 to 13.8) consultations per 1000 patients per month) close to walk-in centres became apparent, although these reductions were not statistically significant. Walk-in centres did not have any impact on consultations on out of hours services.ConclusionIt will be necessary to assess the impact of walk-in centres in a larger number of sites and over a prolonged period, to determine whether they reduce the demand on other local NHS providers.

What is already known on this topic

One of the objectives for NHS walk-in centres was to reduce demand on other NHS services, particularly general practitioners'' services and accident and emergency departmentsStudies of walk-in centres in North America have indicated that such centres do not reduce demand on other healthcare servicesStudies of minor injuries units in the United Kingdom (which have some similarities with walk-in centres) indicate that these units substitute mainly for consultations in accident and emergency departments

What this study adds

The data imply that walk-in centres may moderate the increasing demand on general practice and reduce the number of consultations in accident and emergency departmentsThe high level of background variability in consultation rates means that any impact of a walk-in centre is not statistically significantTo draw robust conclusions about the impact of walk-in centres on other health providers will require study of a large number of sites over an extended period of time     

Comparative analysis of vertebrate <Emphasis Type="Italic">Shh</Emphasis> genes identifies novel conserved non-coding sequence

Abstract The puffer fish Takifugu rubripes (Fugu), with its compact genome, is an ideal model organism for comparative genomics. Sonic hedgehog (Shh) is a key protein in the patterning of differentiating cells during embryonic development. We have sequenced the Fugu Shh gene and compared it with the mammalian and zebrafish orthologs, identifying a number of novel conserved, non-coding sequences upstream of exon one and within the two introns. Additional conserved sequences serve to delineate activator regions and enhancers previously characterized through functional analysis. Control elements can thus be rapidly and effectively predicted by comparative methodology in its own right as well as complementing other, functional methods. This work demonstrates the value of using Fugu in comparative genomics, which has allowed identification of new putative regulatory elements, as well as corroborating enhancers identified by the more traditional deletion mapping method.     

Neurogenic exacerbation of microglial and astrocyte responses to Neisseria meningitidis and Borrelia burgdorferi

Although glial cells are recognized for their roles in maintaining neuronal function, there is growing appreciation of the ability of resident CNS cells to initiate and/or augment inflammation following trauma or infection. The tachykinin, substance P (SP), is well known to augment inflammatory responses at peripheral sites and its presence throughout the CNS raises the possibility that this neuropeptide might serve a similar function within the brain. In support of this hypothesis, we have recently demonstrated the expression of high affinity receptors for SP (Neurokinin-1 (NK-1) receptors) on microglia and shown that this tachykinin can significantly elevate bacterially induced inflammatory prostanoid production by isolated cultures of these cells. In the present study, we demonstrate that endogenous SP/NK-1R interactions are an essential component in the initiation and/or progression of CNS inflammation in vivo following exposure to two clinically relevant bacterial CNS pathogens, Neisseria meningitidis and Borrelia burgdorferi. We show that in vivo elevations in inflammatory cytokine production and decreases in the production of an immunosuppressive cytokine are markedly attenuated in mice genetically deficient in the expression of the NK-1R or in mice treated with a specific NK-1R antagonist. Furthermore, we have used isolated cultures of microglia and astrocytes to demonstrate that SP can augment inflammatory cytokine production by these resident CNS cell types following exposure to either of these bacterial pathogens. Taken together, these studies indicate a potentially important role for neurogenic exacerbation of resident glial immune responses in CNS inflammatory diseases, such as bacterial meningitis.     

Design and synthesis of 2-pyridones as novel inhibitors of the Bacillus anthracis enoyl-ACP reductase

Enoyl-ACP reductase (ENR), the product of the FabI gene, from Bacillus anthracis (BaENR) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis. A number of novel 2-pyridone derivatives were synthesized and shown to be potent inhibitors of BaENR.     

Factors released from embryonic stem cells inhibit apoptosis in H9c2 cells through PI3K/Akt but not ERK pathway

We recently reported that embryonic stem cells-conditioned medium (ES-CM) contains antiapoptotic factors that inhibit apoptosis in the cardiac myoblast H9c2 cells. However, the mechanisms of inhibited apoptosis remain elusive. In this report, we provide evidence for the novel mechanisms involved in the inhibition of apoptosis provided by ES-CM. ES-CM from mouse ES cells was generated. Apoptosis was induced after exposure with H(2)O(2) (400 mum) in H9c2 cells followed by the replacement with ES-CM or culture medium. H9c2 cells treated with H(2)O(2) were exposed to ES-CM, and ES-CM plus cell survival protein phosphatidylinositol 3-kinase/Akt inhibitor, LY-294002, or extracellular signal-regulated kinase (ERK1/2) inhibitor, PD-98050. After 24 h, H9c2 cells treated with ES-CM demonstrated a significant increase in cell survival. ES-CM significantly inhibited (P < 0.05) apoptosis determined by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining, apoptotic ELISA, and caspase-3 activity. Importantly, enhanced cell survival and inhibited apoptosis with ES-CM was abolished with LY-294002. In contrast, PD-98050 shows no effect on ES-CM-increased cell survival. Furthermore, H(2)O(2)-induced apoptosis is associated with decreased levels of phosphorylated (p)Akt activity. Following treatment with ES-CM, we observed a decrease in apoptosis with an increase in pAkt, and the increased activity was attenuated with the Akt inhibitor, suggesting that the Akt pathway is involved in the decreased apoptosis and cell survival provided by ES-CM. In contrast, we observed no change in ES-CM-decreased apoptosis or pERK with PD-98050. In conclusion, we suggest that ES-CM inhibited apoptosis and is mediated by Akt but not the ERK pathway.     

Intradermal angiotensin II administration attenuates the local cutaneous vasodilator heating response

The vasodilation response to local cutaneous heating is nitric oxide (NO) dependent and blunted in postural tachycardia but reversed by angiotensin II (ANG II) type 1 receptor (AT(1)R) blockade. We tested the hypothesis that a localized infusion of ANG II attenuates vasodilation to local heating in healthy volunteers. We heated the skin of a calf to 42 degrees C and measured local blood flow to assess the percentage of maximum cutaneous vascular conductance (%CVC(max)) in eight healthy volunteers aged 19.5-25.5 years. Initially, two experiments were performed; in one, Ringer solution was perfused in three catheters, the response to heating was measured, 2 microg/l losartan, 10 mM nitro-l-arginine (NLA), or NLA + losartan was added to perfusate, and the heat response was remeasured; in another, 10 microM ANG II was given, the heat response was measured, losartan, NLA, or NLA + losartan was added to ANG II, and the heat response was reassessed. The heat response decreased with ANG II, particularly the plateau phase (47 +/- 5 vs. 84 +/- 3 %CVC(max)). Losartan increased baseline conductance in both experiments (from 8 +/- 1 to 20 +/- 2 and 12 +/- 1 to 24 +/- 3). Losartan increased the ANG II response (83 +/- 4 vs. 91 +/- 6 in Ringer). NLA decreased both angiotensin and Ringer responses (31 +/- 4 vs. 43 +/- 3). NLA + losartan blunted the Ringer response (48 +/- 2), but the ANG II response (74 +/- 5) increased. In a second set of experiments, we used dose responses to ANG II (0.1 nM to 10 microM) with and without NLA + losartan to confirm graded responses. Sodium ascorbate (10 mM) restored the ANG II-blunted heating plateau. NO synthase and AT(1)R inhibition cause an NO-independent angiotensin-mediated vasodilation with local heating. ANG II mediates the AT(1)R blunting of local heating, which is not exclusively NO dependent, and is improved by antioxidant supplementation.