Cardiac-specific suppression of NF-kappa B signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system

Activation of NF-kappa B signaling in the heart may be protective or deleterious depending on the pathological context. in diabetes, the role of NF-kappa B in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-kappa B modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated I kappa B-alpha in the heart (3M mice), which prevented activation of canonical NF-kappa B signaling. Diabetes was developed by streptozotocin injections in wild-type (WT) and 3M mice. Diabetic WT mice developed systolic and diastolic cardiac dysfunction by the 12th week, as measured by echocardiography. in contrast, cardiac function was preserved in 3M mice up to 24 wk of diabetes. Diabetes induced an elevation in cardiac oxidative stress in diabetic WT mice but not 3M mice compared with nondiabetic control mice. in diabetic WT mice, an increase in the phospholamban/sarco(endo) plasmic reticulum Ca2+-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca2+ handling. Significantly, renin-angiotensin system activity was suppressed in diabetic 3M mice compared with an increase in WT animals. in conclusion, these results demonstrate that inhibition of NF-kappa B signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca2+ handling and inhibition of the cardiac renin-angiotensin system.National Heart, Lung, and Blood InstituteTexas A&M Hlth Sci Ctr, Div Mol Cardiol, Dept Med, Coll Med, Temple, TX USABaylor Scott & White Hlth, Temple, TX USACent Texas Vet Hlth Care Syst, Temple, TX USAUniversidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilLoyola Univ Chicago, Maywood, IL USAUniversidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilNational Heart, Lung, and Blood Institute: 5-R01-HL-090817Web of Scienc

Angiotensin type 1a receptor-deficient mice develop diabetes-induced cardiac dysfunction, which is prevented by renin-angiotensin system inhibitors

BACKGROUND: Diabetes-induced organ damage is significantly associated with the activation of the renin-angiotensin system (RAS). Recently, several studies have demonstrated a change in the RAS from an extracellular to an intracellular system, in several cell types, in response to high ambient glucose levels. In cardiac myocytes, intracellular angiotensin (ANG) II synthesis and actions are ACE and AT(1) independent, respectively. However, a role of this system in diabetes-induced organ damage is not clear. METHODS: To determine a role of the intracellular ANG II in diabetic cardiomyopathy, we induced diabetes using streptozotocin in AT(1a) receptor deficient (AT(1a)-KO) mice to exclude any effects of extracellular ANG II. Further, diabetic animals were treated with a renin inhibitor aliskiren, an ACE inhibitor benazeprilat, and an AT(1) receptor blocker valsartan. RESULTS: AT(1a)-KO mice developed significant diastolic and systolic dysfunction following 10 wks of diabetes, as determined by echocardiography. All three drugs prevented the development of cardiac dysfunction in these animals, without affecting blood pressure or glucose levels. A significant down regulation of components of the kallikrein-kinin system (KKS) was observed in diabetic animals, which was largely prevented by benazeprilat and valsartan, while aliskiren normalized kininogen expression. CONCLUSIONS: These data indicated that the AT(1a) receptor, thus extracellular ANG II, are not required for the development of diabetic cardiomyopathy. The KKS might contribute to the beneficial effects of benazeprilat and valsartan in diabetic cardiomyopathy. A role of intracellular ANG II is suggested by the inhibitory effects of aliskiren, which needs confirmation in future studies

STrengthening the REporting of Genetic Association Studies (STREGA)— An Extension of the STROBE Statement

Julian Little and colleagues present the STREGA recommendations, which are aimed at improving the reporting of genetic association studies

Global patterns in monthly activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus: a systematic analysis

Background: Influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus are the most common viruses associated with acute lower respiratory infections in young children (<5 years) and older people (≥65 years). A global report of the monthly activity of these viruses is needed to inform public health strategies and programmes for their control. Methods: In this systematic analysis, we compiled data from a systematic literature review of studies published between Jan 1, 2000, and Dec 31, 2017; online datasets; and unpublished research data. Studies were eligible for inclusion if they reported laboratory-confirmed incidence data of human infection of influenza virus, respiratory syncytial virus, parainfluenza virus, or metapneumovirus, or a combination of these, for at least 12 consecutive months (or 52 weeks equivalent); stable testing practice throughout all years reported; virus results among residents in well-defined geographical locations; and aggregated virus results at least on a monthly basis. Data were extracted through a three-stage process, from which we calculated monthly annual average percentage (AAP) as the relative strength of virus activity. We defined duration of epidemics as the minimum number of months to account for 75% of annual positive samples, with each component month defined as an epidemic month. Furthermore, we modelled monthly AAP of influenza virus and respiratory syncytial virus using site-specific temperature and relative humidity for the prediction of local average epidemic months. We also predicted global epidemic months of influenza virus and respiratory syncytial virus on a 5° by 5° grid. The systematic review in this study is registered with PROSPERO, number CRD42018091628. Findings: We initally identified 37 335 eligible studies. Of 21 065 studies remaining after exclusion of duplicates, 1081 full-text articles were assessed for eligibility, of which 185 were identified as eligible. We included 246 sites for influenza virus, 183 sites for respiratory syncytial virus, 83 sites for parainfluenza virus, and 65 sites for metapneumovirus. Influenza virus had clear seasonal epidemics in winter months in most temperate sites but timing of epidemics was more variable and less seasonal with decreasing distance from the equator. Unlike influenza virus, respiratory syncytial virus had clear seasonal epidemics in both temperate and tropical regions, starting in late summer months in the tropics of each hemisphere, reaching most temperate sites in winter months. In most temperate sites, influenza virus epidemics occurred later than respiratory syncytial virus (by 0·3 months [95% CI −0·3 to 0·9]) while no clear temporal order was observed in the tropics. Parainfluenza virus epidemics were found mostly in spring and early summer months in each hemisphere. Metapneumovirus epidemics occurred in late winter and spring in most temperate sites but the timing of epidemics was more diverse in the tropics. Influenza virus epidemics had shorter duration (3·8 months [3·6 to 4·0]) in temperate sites and longer duration (5·2 months [4·9 to 5·5]) in the tropics. Duration of epidemics was similar across all sites for respiratory syncytial virus (4·6 months [4·3 to 4·8]), as it was for metapneumovirus (4·8 months [4·4 to 5·1]). By comparison, parainfluenza virus had longer duration of epidemics (6·3 months [6·0 to 6·7]). Our model had good predictability in the average epidemic months of influenza virus in temperate regions and respiratory syncytial virus in both temperate and tropical regions. Through leave-one-out cross validation, the overall prediction error in the onset of epidemics was within 1 month (influenza virus −0·2 months [−0·6 to 0·1]; respiratory syncytial virus 0·1 months [−0·2 to 0·4]). Interpretation: This study is the first to provide global representations of month-by-month activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus. Our model is helpful in predicting the local onset month of influenza virus and respiratory syncytial virus epidemics. The seasonality information has important implications for health services planning, the timing of respiratory syncytial virus passive prophylaxis, and the strategy of influenza virus and future respiratory syncytial virus vaccination. Funding: European Union Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU)

Study of fundamental problem in Singapore's healthcare system.

The report studies about queues for primary healthcare services in Singapore. We investigate the contributing factors of queues for healthcare services and discuss the elements of demand and supply of healthcare services in Singapore. Finally we conducted a case study on Singapore's primary healthcare services

A cost analysis of Outpatient Parenteral Antibiotic Therapy (OPAT): an Asian perspective

The concept of Outpatient Parenteral Antibiotic Therapy (OPAT) is relatively new in Asia. This study compared the actual costs and outcomes of care involving OPAT with conventional inpatient-only care at a university hospital in Singapore. Actual costs were obtained for selected patients enrolled in OPAT after 1 January 2005 and these costs were directly compared with those of age-, gender- and diagnosis-matched patients managed as inpatients only prior to the availability of OPAT in the preceding 12 months. Outcomes of patients were also considered. The OPAT and inpatient-only groups comprised 72 and 93 enrolments, respectively. Mean treatment duration for OPAT patients was 42.5 days versus 19 days for those receiving inpatient-only care (P < 0.001). The mean total treatment cost for OPAT and inpatient-only care was US$12 736 and$12 403, respectively (P = 0.706). Mean cost per day for care including an OPAT episode was US$278 versus$457 per day for inpatient-only care (P < 0.001). There was no difference in outcomes between the two groups. OPAT is a viable alternative to inpatient care as it is safe, effective and results in lower daily costs. The trend to longer treatment courses is worthy of further review

Color-sharing Bonus

Color repetitions in a visual scene boost memory for its elements, a phenomenon known as the color-sharing effect. This may occur because improved perceptual organization reduces information load or because the repetitions capture attention. The implications of these explanations differ drastically for both the theoretical meaning of this effect and its potential value for applications in design of visual materials. If repetitions capture attention to the exclusion of other details, this should be considered when deciding whether to use repetitions in graphic designs. We manipulated the availability of general attention during a visual memory task by comparing groups of participants engaged in meaningless speech or attention-demanding continuous arithmetic. We also tracked eye movements as an implicit indicator of selective attention. Estimated memory capacity was always higher when color duplicates were tested, and under full attention conditions this bonus spilled over to the unique colors too. Analyses of gazes showed that with full attention, participants tended to glance earlier at duplicate colors during stimulus presentation but looked more at unique colors during the retention interval. This pattern of results suggests that the color-sharing bonus occurs because efficient perceptual organization of the display is enhanced by strategic attention allocation when attention is available