Non-Communicable Disease Risk Factors among Employees and Their Families of a Saudi University: An Epidemiological Study

ObjectivesTo assess the prevalence of noncommunicable disease (NCD) risk factors among Saudi university employees and their families; to estimate the cardiovascular risk (CVR) amongst the study population in the following 10years.MethodsThe NCD risk factors prevalence was estimated using a cross-sectional approach for a sample of employees and their families aged ≥ 18 years old, in a Saudi university (Riyadh in Kingdom of Saudi Arabia; KSA). WHO STEPwise standardized tools were used to estimate NCD risk factors and the Framingham Coronary Heart Risk Score calculator was used to calculate the CVR.ResultsFive thousand and two hundred subjects were invited, of whom 4,500 participated in the study, providing a response rate of 87%. The mean age of participants was 39.3±13.4 years. The majority of participants reported low fruit/vegetables consumption (88%), and physically inactive (77%). More than two thirds of the cohort was found to be either overweight or obese (72%), where 36% were obese, and 59% had abdominal obesity. Of the total cohort, 22–37% were found to suffer from dyslipidaemia, 22% either diabetes or hypertension, with rather low reported current tobacco use (12%). One quarter of participants was estimated to have >10% risk to develop cardiovascular disease within the following 10-years.ConclusionThe prevalence of NCD risk factors was found to be substantially high among the university employees and their families in this study.     

Autophagy in mammalian cells

Autophagy is a regulated process for the degradation of cellular components that has been well conserved in eukaryotic cells. The discovery of autophagy-regulating proteins in yeast has been important in understanding this process. Although many parallels exist between fungi and mammals in the regulation and execution of autophagy, there are some important differences. The preautophagosomal structure found in yeast has not been identified in mammals, and it seems that there may be multiple origins for autophagosomes, including endoplasmic reticulum, plasma membrane and mitochondrial outer membrane. The maturation of the phagophore is largely dependent on 5’-AMP activated protein kinase and other factors that lead to the dephosphorylation of mammalian target of rapamycin. Once the process is initiated, the mammalian phagophore elongates and matures into an autophagosome by processes that are similar to those in yeast. Cargo selection is dependent on the ubiquitin conjugation of protein aggregates and organelles and recognition of these conjugates by autophagosomal receptors. Lysosomal degradation of cargo produces metabolites that can be recycled during stress. Autophagy is an impor-tant cellular safeguard during starvation in all eukaryotes; however, it may have more complicated, tissue specific roles in mammals. With certain exceptions, autophagy seems to be cytoprotective, and defects in the process have been associated with human disease.     

Immediate and one-year outcome of patients presenting with Acute Coronary Syndrome complicated by stroke: Findings from the 2nd Gulf Registry of Acute Coronary Events (Gulf RACE-2)

ABSTRACT: BACKGROUND: Stroke is a potential complication of acute coronary syndrome (ACS). The aim of this study was to identify the prevalence, risk factors predisposing to stroke, in-hospital and 1-year mortality among patients presenting with ACS in the Middle East. METHODS: For a period of 9 months in 2008 to 2009, 7,930 consecutive ACS patients were enrolled from 65 hospitals in 6 Middle East countries. RESULTS: The prevalence of in-hospital stroke following ACS was 0.70%. Most cases were ST segment elevation MI-related (STEMI) and ischemic stroke in nature. Patients with in-hospital stroke were 5 years older than patients without stroke and were more likely to have hypertension (66% vs. 47.6%, P = 0.001). There were no differences between the two groups in regards to gender, other cardiovascular risk factors, or prior cardiovascular disease. Patients with stroke were more likely to present with atypical symptoms, advanced Killip class and less likely to be treated with evidence-based therapies. Independent predictors of stroke were hypertension, advanced killip class, ACS type --STEMI and cardiogenic shock. Stroke was associated with increased risk of in-hospital (39.3% vs. 4.3%) and one-year mortality (52% vs. 12.3%). CONCLUSION: There is low incidence of in-hospital stroke in Middle-Eastern patients presenting with ACS but with very high in-hospital and one-year mortality rates. Stroke patients were less likely to be appropriately treated with evidence-based therapy. Future work should be focused on reducing the risk and improving the outcome of this devastating complication.     

Effects of cathepsins B and L inhibition on postischemic protein alterations in the brain

The effects of selective inhibition of cathepsins B and L on postischemic protein alterations in the brain were investigated in a rat model of middle cerebral artery occlusion (MCAO). Cathepsin B activity increased predominantly in the subcortical region of the ischemic hemisphere where the levels of collapsing mediator response protein 2, heat shock cognate 70 kDa protein, 60 kDa heat shock protein, protein disulfide isomerase A3 and albumin, were found to be significantly elevated. Postischemic treatment with Cbz-Phe-Ser(OBzl)-CHN₂, cysteine protease inhibitor 1 (CP-1), reduced infarct volume, neurological deficits and cathepsin B activity as well as the amount of heat shock proteins and albumin found in the brain. Our data strongly suggests that the decrease in heat shock protein levels and the significant reduction of serum albumin leakage into the brain following acute treatment with CP-1 is indicative of less secondary ischemic damage, which ultimately, is related to less cerebral tissue loss and improved neurological recovery of the animals.     

Mechanisms of Topoisomerase I (TOP1) Gene Copy Number Increase in a Stage III Colorectal Cancer Patient Cohort

Background

Topoisomerase I (Top1) is the target of Top1 inhibitor chemotherapy. The TOP1 gene, located at 20q12-q13.1, is frequently detected at elevated copy numbers in colorectal cancer (CRC). The present study explores the mechanism, frequency and prognostic impact of TOP1 gene aberrations in stage III CRC and how these can be detected by fluorescent in situ hybridization (FISH).

Methods

Nine CRC cell line metaphase spreads were analyzed by FISH with a TOP1 probe in combination with a reference probe covering either the centromeric region of chromosome 20 (CEN-20) or chromosome 2 (CEN-2). Tissue sections from 154 chemonaive stage III CRC patients, previously studied with TOP1/CEN-20, were analyzed with TOP1/CEN-2. Relationships between biomarker status and overall survival (OS), time to recurrence (TTR) in CRC and time to local recurrence (LR; rectal cancer only) were determined.

Results

TOP1 aberrations were observed in four cell line metaphases. In all cell lines CEN-2 was found to reflect chromosomal ploidy levels and therefore the TOP1/CEN-2 probe combination was selected to identify TOP1 gene gains (TOP1/CEN-2≥1.5). One hundred and three patients (68.2%) had TOP1 gain, of which 15 patients (14.6%) harbored an amplification (TOP1/CEN-20≥2.0). TOP1 gene gain did not have any association with clinical endpoints, whereas TOP1 amplification showed a non-significant trend towards longer TTR (multivariate HR: 0.50, p = 0.08). Once amplified cases were segregated from other cases of gene gain, non-amplified gene increases (TOP1/CEN-2≥1.5 and TOP1/CEN-20<2.0) showed a trend towards shorter TTR (univariate HR: 1.57, p = 0.07).

Conclusions

TOP1 gene copy number increase occurs frequently in stage III CRC in a mechanism that often includes CEN-20. Using CEN-2 as a measurement for tumor ploidy levels, we were able to discriminate between different mechanisms of gene gain, which appeared to differ in prognostic impact. TOP1 FISH guidelines have been updated.     

A large kindred of pulmonary fibrosis associated with a novel ABCA3 gene variant

Background

Interstitial lung disease occurring in children is a condition characterized by high frequency of cases due to genetic aberrations of pulmonary surfactant homeostasis, that are also believed to be responsible of a fraction of familial pulmonary fibrosis. To our knowledge, ABCA3 gene was not previously reported as causative agent of fibrosis affecting both children and adults in the same kindred.

Methods

We investigated a large kindred in which two members, a girl whose interstitial lung disease was first recognized at age of 13, and an adult, showed a diffuse pulmonary fibrosis with marked differences in terms of morphology and imaging. An additional, asymptomatic family member was detected by genetic analysis. Surfactant abnormalities were investigated at biochemical, and genetic level, as well as by cell transfection experiments.

Results

Bronchoalveolar lavage fluid analysis of the patients revealed absence of surfactant protein C, whereas the gene sequence was normal. By contrast, sequence of the ABCA3 gene showed a novel homozygous G > A transition at nucleotide 2891, localized within exon 21, resulting in a glycine to aspartic acid change at codon 964. Interestingly, the lung specimens from the girl displayed a morphologic usual interstitial pneumonitis-like pattern, whereas the specimens from one of the two adult patients showed rather a non specific interstitial pneumonitis-like pattern.

Conclusions

We have detected a large kindred with a novel ABCA3 mutation likely causing interstitial lung fibrosis affecting either young and adult family members. We suggest that ABCA3 gene should be considered in genetic testing in the occurrence of familial pulmonary fibrosis.     

Changes in soluble factor-mediated CD8+ cell-derived antiviral activity in cynomolgus macaques infected with simian immunodeficiency virus SIVmac251: relationship to biological markers of progression

Cross-sectional studies have shown that the capacity of CD8+ cells from human immunodeficiency virus (HIV)-infected patients and simian immunodeficiency virus (SIV) SIVmac-infected macaques to suppress the replication of human and simian immunodeficiency viruses in vitro depends on the clinical stage of disease, but little is known about changes in this antiviral activity over time in individual HIV-infected patients or SIV-infected macaques. We assessed changes in the soluble factor-mediated noncytolytic antiviral activity of CD8+ cells over time in eight cynomolgus macaques infected with SIVmac251 to determine the pathophysiological role of this activity. CD8+ cell-associated antiviral activity increased rapidly in the first week after viral inoculation and remained detectable during the early phase of infection. The net increase in antiviral activity of CD8+ cells was correlated with plasma viral load throughout the 15 months of follow-up. CD8+ cells gradually lost their antiviral activity over time and acquired virus replication-enhancing capacity. Levels of antiviral activity correlated with CD4+ T-cell counts after viral set point. Concentrations of beta-chemokines and interleukin-16 in CD8+ cell supernatants were not correlated with this antiviral activity, and alpha-defensins were not detected. The soluble factor-mediated antiviral activity of CD8+ cells was neither cytolytic nor restricted to major histocompatibility complex. This longitudinal study strongly suggests that the increase in noncytolytic antiviral activity from baseline and the maintenance of this increase over time in cynomolgus macaques depend on both viral replication and CD4+ T cells.     

Gender Disparities in the Presentation,Management and Outcomes of Acute Coronary Syndrome Patients: Data from the 2nd Gulf Registry of Acute Coronary Events (Gulf RACE-2)

Background

Gender-related differences in mortality of acute coronary syndrome (ACS) have been reported. The extent and causes of these differences in the Middle-East are poorly understood. We studied to what extent difference in outcome, specifically 1-year mortality are attributable to demographic, baseline clinical differences at presentation, and management differences between female and male patients.

Methodology/Principal Findings

Baseline characteristics, treatment patterns, and 1-year mortality of 7390 ACS patients in 65 hospitals in 6 Arabian Gulf countries were evaluated during 2008–2009, as part of the 2nd Gulf Registry of Acute Coronary Events (Gulf RACE-2). Women were older (61.3±11.8 vs. 55.6±12.4; P<0.001), more overweight (BMI: 28.1±6.6 vs. 26.7±5.1; P<0.001), and more likely to have a history of hypertension, hyperlipidemia or diabetes. Fewer women than men received angiotensin-converting enzyme inhibitors (ACE), aspirin, clopidogrel, beta blockers or statins at discharge. They also underwent fewer invasive procedures including angiography (27.0% vs. 34.0%; P<0.001), percutaneous coronary intervention (PCI) (10.5% vs. 15.6%; P<0.001) and reperfusion therapy (6.9% vs. 20.2%; P<0.001) than men. Women were at higher unadjusted risk for in-hospital death (6.8% vs. 4.0%, P<0.001) and heart failure (HF) (18% vs. 11.8%, P<0.001). Both 1-month and 1-year mortality rates were higher in women than men (11% vs. 7.4% and 17.3% vs. 11.4%, respectively, P<0.001). Both baseline and management differences contributed to a worse outcome in women. Together these variables explained almost all mortality disparities.

Conclusions/Significance

Differences between genders in mortality appeared to be largely explained by differences in prognostic variables and management patterns. However, the origin of the latter differences need further study.     

5-Hydroxy-5-methylhydantoin DNA lesion, a molecular trap for DNA glycosylases

DNA base-damage recognition in the base excision repair (BER) is a process operating on a wide variety of alkylated, oxidized and degraded bases. DNA glycosylases are the key enzymes which initiate the BER pathway by recognizing and excising the base damages guiding the damaged DNA through repair synthesis. We report here biochemical and structural evidence for the irreversible entrapment of DNA glycosylases by 5-hydroxy-5-methylhydantoin, an oxidized thymine lesion. The first crystal structure of a suicide complex between DNA glycosylase and unrepaired DNA has been solved. In this structure, the formamidopyrimidine-(Fapy) DNA glycosylase from Lactococcus lactis (LlFpg/LlMutM) is covalently bound to the hydantoin carbanucleoside-containing DNA. Coupling a structural approach by solving also the crystal structure of the non-covalent complex with site directed mutagenesis, this atypical suicide reaction mechanism was elucidated. It results from the nucleophilic attack of the catalytic N-terminal proline of LlFpg on the C5-carbon of the base moiety of the hydantoin lesion. The biological significance of this finding is discussed.