Early vascular aging in acute ischemic stroke: A systematic review and meta-analysis.

BACKGROUND: While arterial stiffening is a known risk factor for cardiovascular diseases, it remains unclear whether there is an early vascular aging (EVA) in patients who have experienced acute ischemic stroke (AIS). This systematic review and meta-analysis aims to investigate whether patients with AIS exhibit EVA through pulse wave velocity (PWV) measurements shortly after the stroke onset, shedding light on the relationship between arterial stiffness, hypertension, and stroke. METHODS: Thirteen case-control studies were included, comparing PWV measurements between AIS patients and non-AIS individuals. A meta-analysis was performed to compare PWV levels, age, blood pressure, and the prevalence of different cardiovascular risk factors among 1711 AIS patients and 1551 controls. RESULTS: Despite AIS patients showing higher PWV compared to controls (mean difference: 1.72 m/s, 95 % CI: 1.05-2.38, p < 0.001; I2 = 88.3 %), their age did not significantly differ (95 % CI: -0.47-0.94, p = 0.519; I2 = 0 %), suggesting EVA in AIS patients. Moreover, AIS patients exhibited elevated systolic and diastolic blood pressure and had higher odds of smoking, hypertension, diabetes, and male gender compared to controls. CONCLUSIONS: This study's findings underscore the presence of EVA in AIS patients, evident through increased PWV measurements shortly after stroke onset. Notably, smoking, hypertension, and diabetes mellitus emerge as substantial factors contributing to accelerated arterial stiffness within this population.

Decision aids for people with Type 2 diabetes mellitus: an effectiveness rapid review and meta-analysis.

AIMS: To perform a rapid review and meta-analysis of randomized controlled trials (RCTs) evaluating patient decision aids (PtDAs) for people with Type 2 diabetes mellitus. METHODS: We searched Medline and the Cochrane Library for RCTs assessing PtDAs in people with Type 2 diabetes. PtDAs were defined as tools designed to help people engage in decision-making about healthcare options, such as making treatment choices or setting therapeutic goals. The study selection process was facilitated by an automated screening tool to identify RCTs. We classified outcomes into seven domains and conducted meta-analyses using random effects models. RESULTS: We included a total of 15 studies, nine of which were cluster RCTs, that evaluated 10 PtDAs. Thirteen trials compared a PtDA with usual care or usual care plus educational material, whereas two RCTs compared individually tailored vs. non-tailored PtDAs. Meta-analyses showed a favourable effect of PtDAs compared with usual care in reducing decisional conflict [weighted mean difference (WMD) -4.66, 95% confidence interval (CI) -7.93 to -1.39] and in improving knowledge (WMD 20.46, 95% CI 9.13 to 3.77). Use of PtDAs resulted in more active involvement in decision-making during the consultation, although no effect was evident in terms of glycaemic control or self-reported medication adherence. CONCLUSIONS: PtDAs for people with Type 2 diabetes can improve the quality of decision-making and increase knowledge transfer. Interpretation of our findings is attenuated due to limitations related to the rapid review approach, including searching only two databases and performing data extraction and risk of bias assessment by a single reviewer.

Impact of psoriasis flare and remission on quality of life and work productivity: a real-world study in the USA.

Although psoriasis patients often report a negative impact on health-related quality of life (HRQoL) and work productivity, less is known about how disease burden varies between periods of flare and remission. The aim of this study was tocompare HRQoL and work productivity by disease activity level. Data were extracted from Adelphi 2011/2013 Disease Specific Programmes, two real world surveys of US dermatologists and psoriasis patients. HRQoL was measured using the EuroQOL 5-Dimension Health Questionnaire (EQ-5D) and Dermatology Life Quality Index (DLQI). Work productivity was measured using the Work Productivity Activity index (WPAI). Three levels of disease activity were constructed based on physician reports: remission, active not flaring, active, and flaring. Multivariable regression analyses explored the relationship between disease activity, HRQoL and work productivity, controlling for differences in demographics and comorbidities. Out of 681 psoriasis patients 24% were in remission, 62% had active disease without flaring, and 15% experienced active disease and were currently flaring. Greater disease activity was associated with worse HRQoL. EQ-5D scores decreased with more active disease (remission vs. active not flaring vs. active and flaring: 0.93 vs. 0.90 vs. 0.82; p<0.05), while DLQI scores increased (remission vs. active not flaring vs. active and flaring: 2.0 vs. 5.00 vs. 8.7; p<0.05). WPAI scores increased with disease activity indicating increased productivity loss (remission vs. active not flaring vs. active and flaring: 5.9 vs. 14.8 vs. 26.9; p<0.05). The same trends were confirmed by multivariable regression analyses.

Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonists for the management of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.

AIM: To assess the efficacy and safety of recently approved once-weekly glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials comparing any GLP-1 RA licensed for once-weekly dosing (albiglutide, dulaglutide or exenatide extended release) with placebo or other antidiabetic agents. We searched Medline, Embase, the Cochrane Library and grey literature for articles published up to December 2014 and extracted data in duplicate. RESULTS: In our systematic review we included 33 trials with a total of 16 003 participants. Compared with placebo the change in glycated haemoglobin (HbA1c) concentration was -0.66% [six studies; 95% confidence interval (CI) -1.14 to -0.19; I(2) = 88%] with albiglutide, and -1.18% (seven studies; 95% CI -1.34 to -1.02; I(2) = 65%) with dulaglutide. Based on data from placebo-controlled trials, we did not detect statistically significant weight-sparing benefits for albiglutide or dulaglutide. Compared with other antidiabetic agents, once-weekly GLP-1 RAs outperformed sitagliptin, daily exenatide and insulin glargine in terms of HbA1c-lowering (mean differences -0.40%; 95% CI -0.66 to -0.14; I(2) = 85%, -0.44%; 95% CI -0.58 to -0.29; I(2) = 40% and -0.28; 95% CI -0.45 to -0.10; I(2) = 81%, respectively). The main adverse effects of treatment included gastrointestinal and injection site reactions. CONCLUSIONS: Given their dosing scheme and overall efficacy and safety profile, once-weekly GLP-1 RAs are a convenient therapeutic option for use as add-on to metformin.

Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis.

AIM: To assess the efficacy and safety of the novel sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin compared with placebo or other antidiabetic agents in patients with type 2 diabetes. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials. We searched Medline, Embase and the Cochrane Library through December 2013 and grey literature. Two reviewers working independently extracted relevant data and carried out risk-of-bias assessments. We synthesized results using random-effects models and computed weighted mean differences (WMDs) and odds ratios (ORs). RESULTS: We included 10 studies with 6203 participants. Compared with placebo, mean changes in haemoglobin A1c were -0.62% [95% confidence interval (CI) -0.68 to -0.57%] for empagliflozin 10 mg and -0.66% (-0.76 to -0.57%) for empagliflozin 25 mg. Empagliflozin 25 mg daily had glycaemic efficacy similar to metformin or sitagliptin (WMD -0.11%; 95% CI -0.25 to 0.03%), without increasing risk for hypoglycaemia. It was also associated with body weight loss (WMD -1.84; 95% CI -2.30 to -1.38 kg vs. placebo) and had a favourable effect on blood pressure. Incidence of hypoglycaemia with empagliflozin was similar to placebo (OR 1.10; 95% CI 0.87 to 1.39); nevertheless we noted an increased risk for genital tract infections (OR 3.31; 95% CI 1.55 to 7.09). Findings were similar for the 10-mg dosing regimen. CONCLUSIONS: Empagliflozin effectively lowers blood glucose and provides additional clinical benefits including body weight and blood pressure reduction. Ongoing trials will elucidate the long-term safety and effect of empagliflozin on cardiovascular outcomes.

Controversies surrounding the clinical potential of cinnamon for the management of diabetes.

Obesity levels have increased significantly in the past five decades and are predicted to continue rising, resulting in important health implications. In particular, this has translated to an increase in the occurrence of type II diabetes mellitus (T2D). To alleviate associated problems, certain nutraceuticals have been considered as potential adjuncts or alternatives to conventional prescription drugs. Cinnamon, a commonly consumed spice originating from South East Asia, is currently being investigated as a potential preventative supplement and treatment for insulin resistance, metabolic syndrome and T2D. Extensive in vitro evidence has shown that cinnamon may improve insulin resistance by preventing and reversing impairments in insulin signalling in skeletal muscle. In adipose tissue, it has been shown that cinnamon increases the expression of peroxisome proliferator-activated receptors including, PPARγ. This is comparable to the action of commonly used thiazolinediones, which are PPAR agonists. Studies have also shown that cinnamon has potent anti-inflammatory properties. However, numerous human clinical trials with cinnamon have been conducted with varying findings. While some studies have showed no beneficial effect, others have indicated improvements in cholesterol levels, systolic blood pressure, insulin sensitivity and postprandial glucose levels with cinnamon. However, the only measurement consistently improved by cinnamon consumption is fasting glucose levels. While it is still premature to suggest the use of cinnamon supplementation based on the evidence, further investigation into mechanisms of action is warranted. Apart from further characterization of genetic and epigenetic changes in model systems, systematic large-scale clinical trials are required. In this study, we discuss the mechanisms of action of cinnamon in the context of T2D and we highlight some of the associated controversies.

Disparity of histone deacetylase inhibition on repair of radiation-induced DNA damage on euchromatin and constitutive heterochromatin compartments.

Epigenetic regulation of chromatin structure is central to the process of DNA repair. A well-characterized epigenetic feature is the dynamic phosphorylation of the histone H2AX (gammaH2AX) and mobilization of double strand break (DSB) recognition and repair factors to the site. How chromatin structure is altered in response to DNA damage and how such alterations influence DSB repair mechanisms are currently relevant issues. Despite the clear link between histone deacetylases (HDACs) and radiosensitivity, how histone hyperacetylation influence DSB repair remains poorly understood. We have determined the structure of chromatin is a major factor determining radiosensitivity and repair in human cells. Trichostatin A (TSA) enhances radiosensitivity with dose modification factors of 1.2 and 1.9 at 0.2 and 1 microM, respectively. Cells treated with TSA causing hyperacetylation and remodelling on euchromatic alleles coexist with gammaH2AX accumulation in radiosensitized cells. Formation of gammaH2AX on heterochromatin was significantly reduced even when cells were treated with TSA, suggesting that chromatin structure and histone hyperacetylation are pronounced features of radiation sensitivity and repair in euchromatic regions.

Will broad-spectrum histone deacetylase inhibitors be superseded by more specific compounds?

Histone deacetylase (HDAC) inhibitors can induce differentiation, cell cycle and growth arrest or in certain cases apoptosis in cancer cells. In a remarkably short period of time, especially considering that their mechanism of action remains largely undefined, HDAC inhibitors have realized both success and failure as therapeutics for cancer in clinical trials. Notably, the pleiotropic HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and depsipeptide, have shown efficacy in a wide range of cancers, in particular for cutaneous T-cell lymphoma (CTCL), and are progressing in phase II clinical studies. However, evidence is accumulating that specific HDAC enzymes are important with respect to clinical efficacy, calling the usefulness of the classical inhibitors into question. Class I enzymes are being heralded as the most clinically relevant, however, this is still controversial and much of the information is in the private domain. Nevertheless, the potential to alter the expression of a more focused, disease-related subset of genes and to limit adverse effects has prompted the development of isoform-specific HDAC inhibitors. Here, we consider the growing view that broad-spectrum HDAC inhibitors may be superseded by more specific compounds.

Chromatin modifications and DNA double-strand breaks: the current state of play.

The packaging and compaction of DNA into chromatin is important for all DNA-metabolism processes such as transcription, replication and repair. The involvement of chromatin modifications in transcriptional regulation is relatively well characterized, and the distinct patterns of chromatin transitions that guide the process are thought to be the result of a code on the histone proteins (histone code). In contrast to transcription, the intricate link between chromatin and responses to DNA damage has been given attention only recently. It is now emerging that specific ATP-dependent chromatin remodeling complexes (including the Ino80, Swi/Snf and RSC remodelers) and certain constitutive (methylation of lysine 79 of histone H3) and DNA damage-induced covalent histone modifications (the most well characterized being the rapid phosphorylation of histone H2A) facilitate responses to double-strand breaks. Indeed, evidence is already accumulating for a DNA repair-specific histone code. In this review, the recent advances in our understanding of the relationship between chromatin modifications and double-strand break signaling and repair is discussed.

Modulation of cellular radiation responses by histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors are emerging as a new class of targeted cancer chemotherapeutics. Several HDAC inhibitors are currently in clinical trials and promising anticancer effects at well-tolerated doses have been observed for both hematologic and solid cancers. HDAC inhibitors have been shown to induce cell-cycle and growth arrest, differentiation and in certain cases apoptosis in cell cultures and in vivo. However, it is known that these compounds induce varying responses in different cells and biological settings, and identifying their precise mechanisms of action is an area of great interest. Important findings are continually expanding our understanding of the cellular effects of HDAC inhibitors and recent studies will be briefly outlined in this review. In addition to their intrinsic anticancer properties, numerous studies have demonstrated that HDAC inhibitors can modulate cellular responses to other cytotoxic modalities including ionizing radiation, ultraviolet radiation and chemotherapeutic drugs. Hence, there is a growing interest in potential clinical use of HDAC inhibitors in combination with conventional cancer therapies. In this review, the interaction of HDAC inhibitors with other anticancer agents is discussed. The focus of the article is on the different mechanisms by which HDAC inhibitors enhance the sensitivity of cells to the effects of ionizing radiation.

Immunomodulatory effects of histone deacetylase inhibitors.

Histone deacetylase inhibitors (HDACi) have emerged as a new generation of anticancer therapeutics. The classical broad-spectrum HDACi typically alter the cell cycle distribution and induce cell death, apoptosis and differentiation in malignant and transformed cells. This provides the basis for the clinical potential of HDACi in cancer therapy. Currently two compounds, suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza™) and depsipeptide (Romidepsin, Istodax™) have been approved for by the US Food and Drug Administration for the treatment of refractory cutaneous T-cell lymphoma. Apart from clinical application in oncology, HDACi have also been investigated as potential therapeutics for various pathologies including those of the central nervous system (such as Huntington's disease and multiple sclerosis), cardiac conditions (particularly hypertrophy), arthritis and malaria. Further, evidence is accumulating for potent immunomodulatory effects of classical HDACi which is the focus of this review. We review the antiinflammatory effects of HDACi and in particular findings implicating regulation of the innate and adaptive immune systems by HDAC enzymes. The recent findings highlighting the immunomodulatory function of HDAC11 which relates to balancing immune activation versus tolerance are also discussed.

Prevalence of genital chlamydial infection among a community sample of young international backpackers in Sydney, Australia.

We conducted a chlamydia prevalence study from January to June 2009 among a community sample of young international backpackers by recruiting at hostels in Sydney, Australia. Participants completed a questionnaire; men provided a urine sample and women provided a self-collected vaginal swab, which were tested for Chlamydia trachomatis DNA by strand displacement amplification. We recruited 225 men (median age 24 years) and 207 women (median age 23 years). Most (87%) of the travellers came from Europe. A new sexual partner during travel was reported by 67%, and 51% had more than one new sexual partner. Of those reporting a new sexual partner, 40% always used condoms. Prevalence of chlamydia was 3.5% (3.1% in men, 3.9% in women). Previous testing for chlamydia was reported by 40%. Drinking alcohol at hazardous levels was reported by 58% of men and 29% of women. Despite the reporting of new sexual partners and inconsistent condom use, the prevalence of chlamydia in these backpackers was not higher than that found in more general populations, and may relate to good health-care seeking behaviour. Young travellers need education about sexual risks and promotion of condom use prior to travel, and access to public sexual health services.

gammaH2AX: a sensitive molecular marker of DNA damage and repair.

Phosphorylation of the Ser-139 residue of the histone variant H2AX, forming gammaH2AX, is an early cellular response to the induction of DNA double-strand breaks. Detection of this phosphorylation event has emerged as a highly specific and sensitive molecular marker for monitoring DNA damage initiation and resolution. Further, analysis of gammaH2AX foci has numerous other applications including, but not limited to, cancer and aging research. Quantitation of gammaH2AX foci has also been applied as a useful tool for the evaluation of the efficacy of various developmental drugs, particularly, radiation modifying compounds. This review focuses on the current status of gammaH2AX as a marker of DNA damage and repair in the context of ionizing radiation. Although the emphasis is on gamma-radiation-induced gammaH2AX foci, the effects of other genotoxic insults including exposure to ultraviolet rays, oxidative stress and chemical agents are also discussed.

Gestational diabetes mellitus: why screen and how to diagnose.

Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. Women with GDM and their offspring have an increased risk of developing type 2 diabetes mellitus in the future. The global incidence of GDM is difficult to estimate, due to lack of uniform diagnostic criteria. Various diagnostic criteria have been proposed. The benefit of treating GDM has also been controversial. The clinical significance of treating maternal hyperglycemia was made evident in the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. The HAPO study demonstrated that there is a continuous association of maternal glucose levels with adverse pregnancy outcomes and served as the basis for a new set of diagnostic criteria, proposed in 2010 by the International Association of Diabetes and Pregnancy Groups (IADPSG). According to these criteria the diagnosis of GDM is made if there is at least one abnormal value (≥92, 180 and 153 mg/dl for fasting, one-hour and two-hour plasma glucose concentration respectively), after a 75 g oral glucose tolerance test (OGTT).

Experience from the use of absorbable type I collagen as haemostatic agent in obstetric and gynecological operations.

UNLABELLED: During the third stage of labour there are a lot of causes of significant hemorrhage. The commonest causes of acute hemorrhage are the uterine atony, the retained placenta, the lower tract lacerations, uterine rupture, placenta accreta, hereditary coagulopathy. Also, there could be significant bleeding, during caesarian section, usually at the time of removal of the placenta in cases of low lying placenta or placenta previa. A lot of times we have to confront serious hemorrhages in gynecological procedures like hysterectomies in cases of cervical, uterine or ovarian cancers. In order to deal with these problems successfully, general and specific measures are being taken. In cases of atonic uterus when all the other methods are unsuccessful we have to proceed to ligation of the internal iliac artery or even hysterectomy. MATERIAL-METHODS: We have tried to use the hemostatic type I collagen in obstetrical and gynecological cases in order to control the bleeding. We have used the collagen type I totally in 8 cases. Five of them were cases of atonic uterus after normal delivery or caesarian section and three of them were gynecological cases of uterine fibroids and ovarian cancer. RESULTS: By placing the collagen type I over the bleeding surfaces we have realized that in a very short period of time, there has been satisfactory control of the bleeding and immediate clinical improvement of the patient. In four out of five obstetrical cases that we have used the type I collagen, we have managed to avoid the hysterectomy.

Double-strand breaks: signaling pathways and repair mechanisms.

Double-strand breaks arise frequently in the course of endogenous - normal and pathological - cellular DNA metabolism or can result from exogenous agents such as ionizing radiation. It is generally accepted that these lesions represent one of the most severe types of DNA damage with respect to preservation of genomic integrity. Therefore, cells have evolved complex mechanisms that include cell-cycle arrest, activation of various genes, including those associated with DNA repair, and in certain cases induction of the apoptotic pathway to respond to double-strand breaks. In this review we discuss recent progress in our understanding of cellular responses to DNA double-strand breaks. In addition to an analysis of the current paradigms of detection, signaling and repair, insights into the significance of chromatin remodeling in the double-strand break-response pathways are provided.

Cytotoxicity of an 125I-labelled DNA ligand.

The subcellular distribution and cytotoxicity of a DNA-binding ligand [125I]-Hoechst 33258 following incubation of K562 cells with the drug was investigated. The ability of a radical scavenger, dimethyl sulphoxide, to protect cells from the 125I-decay induced cell death was also studied. Three different concentrations and specific activities of the drug were used to provide different ligand : DNA binding ratios. The results demonstrated a trend toward improved delivery of the ligand to the nucleus and to chromatin at higher ligand concentrations, with concomitant increased sensitivity to 125I-decay induced cytotoxicity and decreased protection by dimethyl sulphoxide. This correlation of radiobiological parameters with subcellular drug distribution is consistent with the classical dogma that attributes cytotoxicity to DNA double-stranded breakage in the vicinity of the site of decay, where the high LET nature of the damage confers minimal sensitivity to radical scavenging.