Analysis of IL28B variants in an Egyptian population defines the 20 kilobases minimal region involved in spontaneous clearance of hepatitis C virus

Spontaneous clearance of hepatitis C virus (HCV) occurs in ~30% of acute infections. Host genetics play a major role in HCV clearance, with a strong effect of single nucleotide polymorphisms (SNPs) of the IL28B gene already found in different populations, mostly infected with viral genotypes 1 and 3. Egypt has the highest prevalence of HCV infection in the world, which is mostly due to viral genotype 4. We investigated the role of several IL28B SNPs in HCV spontaneous clearance in an Egyptian population. We selected nine SNPs within the IL28B genomic region covering the linkage disequilibrium (LD) block known to be associated with HCV clearance in European populations. These SNPs were genotyped in 261 HCV-infected Egyptian subjects (130 with spontaneous clearance and 131 with chronic infection). The most associated SNPs were rs12979860 (P = 1.6 × 10(-7)) and the non-synonymous IL28B SNP, rs8103142 (P = 1.6 × 10(-7)). Interestingly, three SNPs at the two bounds of the region were monomorphic, reducing the size of the LD block in which the causal variants are potentially located to ～20 kilobases. HCV clearance in Egypt was associated with a region of IL28B smaller than that identified in European populations, and involved the non-synonymous IL28B SNP, rs8103142.     

The effect of ghrelin pretreatment on epididymal sperm quality and tissue antioxidant enzyme activities after testicular ischemia/reperfusion in rats

Ghrelin, the endogenous ligand for growth hormone secretagogue receptor, has been reported to prevent ischemia/reperfusion (I/R) injury in various tissues by its antioxidant activity. Therefore, this study was aimed to investigate the effect of ghrelin on sperm quality and antioxidant enzyme activity in a rat testicular ischemia/reperfusion injury model. Forty-two male Wistar rats were divided into groups control, I/R, and I/R plus ghrelin. The right testes were rotated 720° for 1 h and were allowed to reperfuse for 4 h and 30 days thereafter. Ghrelin (40 nmol/kg IP) or vehicle (physiological saline) was administrated 15 min before reperfusion. After 4 h of reperfusion, a right orchiectomy was performed to measure the biochemical parameters. In addition, the sperm was collected from the epididymis after 30 days of reperfusion, and sperm characteristics were examined. The malondialdehyde levels of the testis tissues were significantly increased, but a statistically significant decrease was found in the superoxide dismutase, glutathione peroxidase, and catalase activities in the I/R group as compared with the control, indicating I/R injury. The sperm evaluation showed a significant reduction in all characteristics resulted from I/R compared with the control. In the ghrelin-treated group, the malondialdehyde values were significantly lowered, and only enzyme activity of glutathione peroxidase showed significant increases compared with the I/R group. Ghrelin significantly enhanced sperm motility, movement, and concentration but did not prevent I/R-induced reduction in membrane integrity in the testes of rats compared to the I/R group. Our results suggest that ghrelin treatment has a protective role on IR-induced testicular injury, and this effect may be due to its antioxidant properties.     

Trends in Asthma-Related Direct Medical Costs from 2002 to 2007 in British Columbia,Canada: A Population Based-Cohort Study

Background

Asthma-related health resource use and costs may be influenced by increasing asthma prevalence, changes to asthma management guidelines, and new medications over the last decade. The objective of this work was to analyze direct asthma-related medical costs, and trends in total and per-patient costs of hospitalizations, physician visits, and medications.

Methods

A cohort of asthma patients from British Columbia (BC), Canada, was created. Asthma patients were identified using a validated case definition. Costs for hospitalizations, physician visits, and medications were calculated from billing records (in 2008 Canadian dollars). Trends in total and per-patient costs over the study period were analyzed using Generalized Linear Models.

Results

398,235 patients satisfied the asthma case definition (mid-point prevalence 8.0%). Patients consumed $315.9 million (M) in direct asthma-related health resources between 2002 and 2007. Hospitalizations, physician visits, and medication costs accounted for 16.0%, 15.7% and 68.2% of total costs, respectively. Cost of asthma increased from $49.4 M in 2002 to $54.7 M in 2007. Total annual costs attributable to hospitalizations and physician visits decreased (−39.8% and −25.5%, respectively; p<0.001), while medication costs increased (+38.7%; p<0.001).

Interpretation

This population-based analysis shows that the total direct cost of asthma in BC has increased since 2002, mainly due to a rise in asthma prevalence and cost of medication. Combination therapy with inhaled corticosteroids/long-acting beta-agonists has become a significant component of the cost of asthma. Although billing records capture only a fraction of the true burden of asthma, the simultaneous increase in medication costs and reductions in hospitalization and physician visit costs provides valuable insight for policy makers into the shifts in asthma-related resource use.     

The lavender plumage colour in Japanese quail is associated with a complex mutation in the region of MLPH that is related to differences in growth, feed consumption and body temperature

ABSTRACT: BACKGROUND: The lavender phenotype in quail is a dilution of both eumelanin and phaeomelanin in feathers that produces a blue-grey colour on a wild-type feather pattern background. It has been previously demonstrated by intergeneric hybridization that the lavender mutation in quail is homologous to the same phenotype in chicken, which is caused by a single base-pair change in exon 1 of MLPH. RESULTS: In this study, we have shown that a mutation of MLPH is also associated with feather colour dilution in quail, but that the mutational event is extremely different. In this species, the lavender phenotype is associated with a non-lethal complex mutation involving three consecutive overlapping chromosomal changes (two inversions and one deletion) that have consequences on the genomic organization of four genes (MLPH and the neighbouring PRLH, RAB17 and LRRFIP1). The deletion of PRLH has no effect on the level of circulating prolactin. Lavender birds have lighter body weight, lower body temperature and increased feed consumption and residual feed intake than wild-type plumage quail, indicating that this complex mutation is affecting the metabolism and the regulation of homeothermy. CONCLUSIONS: An extensive overlapping chromosome rearrangement was associated with a non-pathological Mendelian trait and minor, non deleterious effects in the lavender Japanese quail which is a natural knockout for PRLH.     

Adult Mortality Attributable to Preventable Risk Factors for Non-Communicable Diseases and Injuries in Japan: A Comparative Risk Assessment

Background

The population of Japan has achieved the longest life expectancy in the world. To further improve population health, consistent and comparative evidence on mortality attributable to preventable risk factors is necessary for setting priorities for health policies and programs. Although several past studies have quantified the impact of individual risk factors in Japan, to our knowledge no study has assessed and compared the effects of multiple modifiable risk factors for non-communicable diseases and injuries using a standard framework. We estimated the effects of 16 risk factors on cause-specific deaths and life expectancy in Japan.

Methods and Findings

We obtained data on risk factor exposures from the National Health and Nutrition Survey and epidemiological studies, data on the number of cause-specific deaths from vital records adjusted for ill-defined codes, and data on relative risks from epidemiological studies and meta-analyses. We applied a comparative risk assessment framework to estimate effects of excess risks on deaths and life expectancy at age 40 y. In 2007, tobacco smoking and high blood pressure accounted for 129,000 deaths (95% CI: 115,000–154,000) and 104,000 deaths (95% CI: 86,000–119,000), respectively, followed by physical inactivity (52,000 deaths, 95% CI: 47,000–58,000), high blood glucose (34,000 deaths, 95% CI: 26,000–43,000), high dietary salt intake (34,000 deaths, 95% CI: 27,000–39,000), and alcohol use (31,000 deaths, 95% CI: 28,000–35,000). In recent decades, cancer mortality attributable to tobacco smoking has increased in the elderly, while stroke mortality attributable to high blood pressure has declined. Life expectancy at age 40 y in 2007 would have been extended by 1.4 y for both sexes (men, 95% CI: 1.3–1.6; women, 95% CI: 1.2–1.7) if exposures to multiple cardiovascular risk factors had been reduced to their optimal levels as determined by a theoretical-minimum-risk exposure distribution.

Conclusions

Tobacco smoking and high blood pressure are the two major risk factors for adult mortality from non-communicable diseases and injuries in Japan. There is a large potential population health gain if multiple risk factors are jointly controlled. Please see later in the article for the Editors'' Summary     

Synthesis and SAR study of 4,5-diaryl-1H-imidazole-2(3H)-thione derivatives,as potent 15-lipoxygenase inhibitors

A series of 4,5-diaryl-1H-imidazole-2(3H)-thione was synthesized and their inhibitory potency against soybean 15-lipoxygenase and free radical scavenging activities were determined. Compound 11 showed the best IC₅₀ for 15-LOX inhibition (IC₅₀ = 4.7 μM) and free radical scavenging activity (IC₅₀ = 14 μM). Methylation of SH at C₂ position of imidazole has dramatically decreased the 15-LOX inhibition and radical scavenging activity as it can be observed in the inactive compound 14 (IC₅₀ >250 μM). Structure activity similarity (SAS) showed that the most important chemical modification in this series was methylation of SH group and Docking studies revealed a proper orientation for SH group towards Fe core of the 15-LOX active site. Therefore it was concluded that iron chelating could be a possible mechanism for enzyme inhibition in this series of compounds.     

Future Impact of Various Interventions on the Burden of COPD in Canada: A Dynamic Population Model

Background

Chronic obstructive pulmonary disease (COPD) is a growing economic burden worldwide. Smoking cessation is thought to be the single most effective way of reducing the economic burden of COPD. The impact of other strategies such as interventions that predict risk of disease, reduce progression of disease, or reduce exacerbations has not been systematically studied.

Objectives

We estimated the economic and clinical burden of COPD over the next 25 years in Canada and the impact of three potential interventions (screening test for predisposition to COPD, new drugs to avoid progression into more severe disease stages, and predictive test for exacerbations) on COPD burden.

Methods

Using a dynamic simulation model, we projected the total burden of COPD (cost, morbidity, and mortality) from 2011 to 2035 using the population of Canada as a case study. The model stratified population based on sex, age, smoking status, respiratory symptoms, and their COPD stage. The cost and quality adjusted life years (QALYs) associated with each intervention were estimated.

Results

The model indicates that annual societal cost of COPD is $4.52 billion (B) Canadian dollars in 2011 and will reach $3.61B ($7.33B undiscounted) per year in 2035. Over the next 25 years, COPD will be responsible for approximately $101.4B in societal costs ($147.5B undiscounted) and 12.9 million QALYs lost (19.0 million undiscounted). Our results suggested that the best strategy to reduce the financial burden of COPD is by reducing exacerbations. Smoking cessation, while it is the cornerstone of COPD prevention, has only a modest effect in attenuating the financial burden of COPD over the next 25 years in Western countries such as Canada.

Conclusion

Our data suggest that any intervention that can reduce the number of exacerbations has a substantial impact on morbidity and costs of COPD and should be considered in conjunction with the ongoing efforts to reduce smoking rates.     

Cadmium-induced oxidative stress and DNA damage in kidney of pregnant female rats

In the present study, we have investigated the influence of sub-acute treatment with cadmium (Cd) on some parameters indicative of oxidative stress and DNA damage in tissues of pregnant female rats. Pregnant female rats (n=6) were injected subcutaneously, daily with a dose of cadmium chloride of 3 mg/kg body weight (b.w.) from day 6 to day 19 of pregnancy, and they were allowed to deliver normally. MDA level and GPx, CAT and SOD activities were used as markers of oxidative stress in liver and kidney. The 8-oxo-dG level was measured by the HPLC-EC system. Cd treatment increased MDA (+116%, p<0.01) in kidney. Moreover, Cd treatment also decreased CuZn-SOD (-11%, p<0.05) and GSH level (-52%, p<0.05) in kidney. Treated rats displayed an increase of the liver metallothionein (MT) level. Induction of MT in liver was probably implicated in the detoxification of Cd. The high level of Cd (3 mg/kg) used in the present study is partially neutralized by MT in liver, whereas the free fraction could be implicated in the oxidative stress and DNA oxidation observed in kidney. Cd treatment failed to alter 8-oxodGuo, indicating the absence of DNA oxidation in liver; by contrast, the same treatment increased the 8-oxodGuo level (+51%, p<0.05) in the kidney of pregnant female rats, indicating an oxidative stress associated with DNA damage only in kidney.     

Identification and characterization of "rd22" dehydration responsive gene in grapevine (Vitis vinifera L.)

To identify and isolate genes related to abiotic stresses (salinity and drought) tolerance in grapevine, a candidate gene approach was developed and allowed isolating a full-length cDNA of rd22 gene from the Cabernet Sauvignon variety. The latter, named Vvrd22, is a dehydration-responsive gene that is usually induced by the application of exogenous ABA. Details of the physicochemical parameters and structural properties (molecular mass, secondary structure, conserved domains and motives, putative post-translational modification sites...) of the encoded protein have also been elucidated. The expression study of Vvrd22 was carried out at the berry growth stages and at the level of plant organs and tissues as well as under both drought and salt stresses. The results showed that Vvrd22 is constitutively expressed at a low level in all analyzed tissues. Moreover, salt stress induced Vvrd22 expression, particularly for the tolerant variety (Razegui), contrary to the sensitive one (Syrah), which did not display any expression variation during the stress, which means that Vvrd22 is involved in salt stress response and that its expression level depends on regulatory mechanisms that are efficient only for the tolerant variety. On the other hand, under drought stress, Vvrd22 is induced in an identical manner for both tolerant and sensitive varieties. In addition, stress signal molecules such as ABA (lonely applied or in combination with sucrose) induced Vvrd22 expression, even at a low level. A minimal knowledge about the role and the functionality of this gene is necessary and constitutes a prerequisite condition before starting and including Vvrd22 in any program of improvement of grapevine's abiotic stress tolerance.