Cardiac telomere attrition following changes in the expression of shelterin genes in pulmonary hypertensive chickens.

1. The alterations of relative telomere length and expression of shelterin genes (TRF1, TRF2, RAP1, POT1, and TPP1) were evaluated from the chickens' right heart ventricle in the early and last stages of cold-induced pulmonary hypertension (PHS) at 21 and 42 d of age.2. The relative telomere length in the right ventricular tissues was significantly shorter in the PHS group of broilers than in the control group at 42 d, but did not statistically change at 21 d of age. There was a significant negative correlation between relative telomere length and RV:TV ratio in the broilers at 42 d of age.3. The relative expression of POT1, RAP1 and TPP1 genes in the right ventricular tissues was significantly lower in the PHS group than in the control group at 21 d. The relative expression of the TRF2 gene was only higher in the PHS group of broilers than control at 42 d. The mRNA level of the TRF2 gene exhibited a significant positive correlation with RV:TV ratio at 42 d.4. It was concluded that most shelterin genes are dysregulated in the early stage of PHS (right ventricular hypertrophy) while telomere attrition occurs only at the last stage (heart dilation/failure).

The impact of interactions on invasion and colonization resistance in microbial communities.

In human microbiota, the prevention or promotion of invasions can be crucial to human health. Invasion outcomes, in turn, are impacted by the composition of resident communities and interactions of resident members with the invader. Here we study how interactions influence invasion outcomes in microbial communities, when interactions are primarily mediated by chemicals that are released into or consumed from the environment. We use a previously developed dynamic model which explicitly includes species abundances and the concentrations of chemicals that mediate species interaction. Using this model, we assessed how species interactions impact invasion by simulating a new species being introduced into an existing resident community. We classified invasion outcomes as resistance, augmentation, displacement, or disruption depending on whether the richness of the resident community was maintained or decreased and whether the invader was maintained in the community or went extinct. We found that as the number of invaders introduced into the resident community increased, disruption rather than augmentation became more prevalent. With more facilitation of the invader by the resident community, resistance outcomes were replaced by displacement and augmentation. By contrast, with more facilitation among residents, displacement outcomes shifted to resistance. When facilitation of the resident community by the invader was eliminated, the majority of augmentation outcomes turned into displacement, while when inhibition of residents by invaders was eliminated, invasion outcomes were largely unaffected. Our results suggest that a better understanding of interactions within resident communities and between residents and invaders is crucial to predicting the success of invasions into microbial communities.

The higher prevalence of multiple sclerosis among Iranian Georgians; new clues to the role of genetic factors.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) with varied prevalence rates among populations with different ethnic backgrounds. Therefore, studies done on minorities have shed more light on the risk factors. OBJECTIVE: Comparing MS prevalence in Georgian-based population immigrated to Iran and other Iranians. METHODS: All records of MS patients enrolled in the two biggest registry systems were investigated. All of the patients born in Fereydunshahr and Buin va Miandasht (2 biggest cities with Georgian immigrants) were interviewed and their baseline characteristics were obtained. Patients' ethnic background information were obtained from the Iran National organization for civil registration. RESULTS: Forty-one patients from Fereydunshahr and Buin va Miandasht were identified. The population of the two cities combined and the estimated number of Georgian-based patients in both cities were reported 59817 and 12000, respectively. The estimated ethnicity-adjusted prevalence among the Georgian-based individuals was 2.3 times higher than the non-Georgian ones. Baseline characteristics were also compared. CONCLUSION: There was a higher prevalence of multiple sclerosis among the Georgian minority of Isfahan. Due to the ethnic background of the Georgian minority, genetic risk factors should be considered more as a risk factor.

FTO Gene Affects Obesity and Breast Cancer Through Similar Mechanisms: A New Insight into the Molecular Therapeutic Targets.

OBJECTIVES: This review focused on the possible mediatory role of the FTO in the association between obesity and breast cancer. METHOD: All articles published in English from June 1990 to January 2017 were studied. The search terms used were FTO gene, FTO polymorphism, breast cancer, and obesity. Inclusion criteria consisted of assessment of the relationship between FTO polymorphisms and/or FTO expression level with obesity and/or breast cancer as a primary outcome. RESULTS: The FTO gene may have a role in the cellular sensing of macronutrients. Over expression of the FTO gene increases the levels of mammalian target of rapamycin (mTOR) signaling that is a key regulator of cell growth. Moreover, some SNPs in intron locations of the FTO gene exert their effects on body mass index, body composition and breast cancer risk through change of the homeobox transcription factor iriquois 3 (IRX3) gene expression level. CONCLUSION: The FTO gene may has a critical role in obesity and breast cancer. Similar molecular mechanisms may play a role in the development of breast cancer and obesity. If this result is correct then, it will be interesting to examine the FTO gene as a molecular therapeutics target.

Association between interleukin 4 (IL-4) VNTR, gene polymorphism, and breast cancer susceptibility in Iranian population: experimental and web base analysis.

BACKGROUND: Breast cancer (BC) is one of the most common types of cancer and the second leading cause of cancer death among women. Epidemiological studies showed that BC is linked to genetic and environmental factors, and inheritance plays a key role in the pathobiology of this disease. Interleukin 4 (IL-4) is a key differentiation cytokine and is produced by Th2 and activates Th2 development. Hence the current study aimed to assess the possible association between interleukin 4 (IL-4) VNTR polymorphism, and BC susceptibility in a sample of Iranian population. MATERIAL AND METHODS: IL-4 VNTR polymorphism was evaluated in 150 women with BC and 150 age-matched healthy women by polymerase chain reaction method. RESULT: Among 3 possible alleles for IL-4 gene, we only observed 2 alleles. Current findings indicate that RP2/RP2 genotypes can be regarded as potent protective factors against breast cancer (OR = 0.929 [95%CI, 0.929-0.995]). CONCLUSION: Our result showed that the RP2/RP2 genotype of the IL-4 VNTR polymorphism could be a protective factor for BC susceptibility (Tab. 2, Fig. 1, Ref. 46).

Lack of adherence to SHEA-IDSA treatment guidelines for Clostridium difficile infection is associated with increased mortality.

OBJECTIVES: The objective of this study was to determine our institution's compliance with 2010 Society for Healthcare Epidemiology of America and IDSA Clostridium difficile infection (CDI) treatment guidelines and their respective outcomes. METHODS: We collected clinical parameters, laboratory values, antibiotic therapy and clinical outcomes from the electronic medical records for all patients hospitalized at our institution with a diagnosis of CDI from December 2012 to November 2013. We specifically evaluated whether SHEA-IDSA treatment guidelines were followed and evaluated the associations between guideline adherence and severe outcomes including mortality. RESULTS: We identified 230 patients with CDI meeting inclusion criteria during the study period. Of these, 124 (54%) were appropriately treated, 46 (20%) were under-treated and 60 (26%) were over-treated. All-cause 90 day mortality was 17.4% overall; 43.5% in the under-treated group versus 12.9% in those appropriately treated (P < 0.0001) and 10.9% in those appropriately treated plus over-treated (P < 0.0001). Similarly, 90 day mortality attributed to CDI was 21.7% in those under-treated versus 8.9% in those appropriately treated (P = 0.03) and 8.2% in those either appropriately treated or over-treated (P = 0.015). Severe-complicated CDI occurred in 46 patients. In this subgroup, there was a non-significant trend towards increased mortality in under-treated patients (56.7%) compared with appropriately treated patients (37.5%, P = 0.35). Under-treatment was also associated with a higher rate of CDI-related ICU transfer (17.4% versus 4.8% in those appropriately treated, P = 0.023). CONCLUSIONS: Adherence to CDI treatment guidelines is associated with improved outcomes especially in those with severe disease. Increased emphasis on provision of appropriate, guideline-based CDI treatment appears warranted.

Improved diagnostic yield of neuromuscular disorders applying clinical exome sequencing in patients arising from a consanguineous population.

Neuromuscular diseases (NMDs) include a broad range of disorders affecting muscles, nerves and neuromuscular junctions. Their overlapping phenotypes and heterogeneous genetic nature have created challenges in diagnosis which calls for the implementation of massive parallel sequencing as a candidate strategy to increase the diagnostic yield. In this study, total of 45 patients, mostly offspring of consanguineous marriages were examined using whole exome sequencing. Data analysis was performed to identify the most probable pathogenic rare variants in known NMD genes which led to identification of causal variants for 33 out of 45 patients (73.3%) in the following known genes: CAPN3, Col6A1, Col6A3, DMD, DYSF, FHL1, GJB1, ISPD, LAMA2, LMNA, PLEC1, RYR1, SGCA, SGCB, SYNE1, TNNT1 and 22 novel pathogenic variants were detected. Today, the advantage of whole exome sequencing in clinical diagnostic strategies of heterogeneous disorders is clear. In this cohort, a diagnostic yield of 73.3% was achieved which is quite high compared to the overall reported diagnostic yield of 25% to 50%. This could be explained by the consanguineous background of these patients and is another strong advantage of offering clinical exome sequencing in diagnostic laboratories, especially in populations with high rate of consanguinity.

Temporary skin grafts based on hybrid graphene oxide-natural biopolymer nanofibers as effective wound healing substitutes: pre-clinical and pathological studies in animal models.

In recent years, temporary skin grafts (TSG) based on natural biopolymers modified with carbon nanostructures have received considerable attention for wound healing. Developments are required to improve physico-mechanical properties of these materials to match to natural skins. Additionally, in-deep pre-clinical examinations are necessary to ensure biological performance and toxicity effect in vivo. In the present work, we show superior acute-wound healing effect of graphene oxide nanosheets embedded in ultrafine biopolymer fibers (60 nm) on adult male rats. Nano-fibrous chitosan-based skin grafts crosslinked by Genepin with physico-mechanical properties close to natural skins were prepared by electrospinning of highly concentrated chitosan- polyvinylpyrrolidone solutions containing graphene oxide (GO) nanosheets. No surfactants and organic solvents were utilized to ensure high biocompatibility of the fibrous structure. In vitro evaluations by human skin fibroblast cells including live and dead assay and MTT results show that GO promote cell viability of porous nanofibrous membrane while providing enhanced bactericidal capacity. In vivo studies on rat's skin determine accelerated healing effect, i.e. a large open wound (1.5 × 1.5 cm2) is fully regenerated after 14-day of post operation while healing is observed for sterile gauze sponge (as the control). Pathological studies support thick dermis formation and complete epithelialization in the presence of 1.5 wt% GO nanosheets. Over 99% wound healing occurs after 21 days for the injury covered with TSG containing 1.5 wt% GO while this would takes weeks for the control. Therefore, the developed materials have a high potential to be used as TSG as pre-clinical testing has shown.

Prevalence of founder mutations in the BRCA1 and BRCA2 genes among unaffected women from the Bahamas.

Population-based testing for BRCA1/2 mutations detects a high proportion of carriers not identified by cancer family history-based testing. We sought to determine whether population-based testing is an effective approach to genetic testing in the Bahamas, where 23% of women with breast cancer carry one of seven founder mutations in the BRCA1 or BRCA2 gene. We determined the prevalence of founder BRCA mutations in 1847 Bahamian women without a personal history of breast or ovarian cancer, unselected for age or family history. We found that 2.8% (20/705) of unaffected women with a family history of breast/ovarian cancer and 0.09% (1/1089) of unaffected women without a family history carry a BRCA mutation. A total of 38% of unaffected women with a known mutation in the family were found to carry the familial mutation. We previously suggested that all Bahamian women with breast or ovarian cancer be offered genetic testing. These current data suggest that additionally all unaffected Bahamian women with a family history of breast/ovarian cancer should be offered genetic testing for the founder BRCA mutations.

Factors associated with self-rated health status in Southwestern Iran: a population-based study.

OBJECTIVE: This study aimed to reveal the relationship between self-rated health (SRH) and objective health status in the general population in the Southwest of Iran. STUDY DESIGN: A cross-sectional study. METHODS: Data were collected by face-to-face interview with 3554 residents, aged ≥18 years, who were selected by multistage sampling procedure. Collected data included sociodemographic, SRH status, and medical conditions; chronic diseases and mental symptoms. SRH was indicated by a single question in five scales of very good, good, fair, poor and very poor. An ordinal logistic regression analysis was used. Independent variables were organized into four blocks: block 1, age, gender, marital status, education level, employment status, size of household and monthly household income; block 2, chronic or long-term illness (coronary heart disease, hypertension and diabetes mellitus); block 3, psychological disorders (anxiety, impatience and sleep disorders); and block 4 (visual, skin, hearing and oral disorders). RESULTS: SRH status in most subjects reported to be positive, indicating 47.3% as very good, 30.8% good, 16.2% fair, 3.3% bad and 2.4% very bad. In studied subjects, poorer SRH was significantly related to older age (odds ratio [OR], 1.01), low-education level (OR, 1.09), single status (OR, 1.25), monthly household income (OR, 1.21), more chronic or long-term illness (OR, 1.61), greater psychological health disorders (OR, 1.69), more dermatologic disorders (OR, 1.30), and hearing problems (OR, 1.47). CONCLUSION: Results of this study revealed that subjects with worse SRH were older with low-education level, lower household monthly income, more chronic illness, greater psychological health disorders, and more visual, skin, hearing and oral disorders. So, SRH, as indicated globally, can be used as a population screening tool to identify subjects who are most in need of public health services.

A rare case of cerebral hydatidosis caused by a G1 genotype of Echinococcus granulosus in a cow from Iran.

Hydatidosis is a medically and veterinary important parasitic disease that is endemic in many parts of the world. Unilocular hydatid cysts may develop in almost any part of the body. Up to 70% of hydatid cysts are located in the liver, followed by 25% in the lungs. Cerebral hydatidosis is an uncommon manifestation of the disease, occurring in less than 1/1000 infected hosts, yet diagnosis does pose a problem. We have reported an exceptionally rare case of cerebral hydatidosis in cattle. This is the first report to describe the characteristic pathological features of the cerebral hydatidosis in cattle caused by the G1 genotype of Echinococcus granulosus. Genotypic analysis was performed on a hydatid cyst from a cow originating from southern Iran, based on the sequence analysis of the cox1 mitochondrial gene.

Phenytoin accelerates tendon healing in a rat model of Achilles tendon rupture.

INTRODUCTION: Tendons are vulnerable to various types of acute or chronic injures. Different methods have been investigated to achieve better healing. Phenytoin is a drug which could stimulate fibroblasts to produce collagen. This experimental study was performed to assess the effect of phenytoin on tendon healing in a rat model of tendon rupture. METHODS: Thirty healthy rats were divided into 3 groups, 1) Sham group; 2) Tendon rupture; 3) Tendon rupture+phenytoin (100 mg/kg intraperitoneally) for 21 days. On 21st day after tendon injury, the rats were anesthetized and tendon tissue was sampled for studying by light and electron microscopy. RESULTS: Qualitative and quantitative microscopic comparisons of the repair tissues of both groups were made on the 21st day. The results obtained from light and electron microscopy studies showed that tendon tissue healing was significantly better in phenytoin group compared to the control group (p < 0.05). CONCLUSIONS: Systemic administration of phenytoin may have a positive effect on tendon healing by increasing fibroblast quantity, fibrillar collagen synthesis, vascularity, and suppressing inflammation (Tab. 2, Ref. 25).

Factors associated with genetic counseling and BRCA testing in a population-based sample of young Black women with breast cancer.

Concerns about the potential for genomic advances to increase health disparities have been raised. Thus, it is important to assess referral and uptake of genetic counseling (GC) and testing in minority populations at high risk for hereditary breast and ovarian cancer (HBOC). Black women diagnosed with invasive breast cancer ≤age 50 in 2009-2012 were recruited through the Florida State Cancer Registry 6-18 months following diagnosis and completed a baseline questionnaire. Summary statistics, Chi-square tests, and path modeling were conducted to examine which demographic and clinical variables were associated with referral and access to genetic services. Of the 440 participants, all met national criteria for GC, yet only 224 (51 %) were referred for or received GC and/or HBOC testing. Variables most strongly associated with healthcare provider referral for GC included having a college education (OR 2.1), diagnosis at or below age 45 (OR 2.0), and triple negative tumor receptor status (OR 1.7). The strongest association with receipt of GC and/or HBOC testing was healthcare provider referral (OR 7.9), followed by private health insurance at diagnosis (OR 2.8), and household income greater than $35,000 in the year prior to diagnosis (OR 2.0). Study findings suggest efforts are needed to improve genetic services access among a population-based sample of high-risk Black women. These results indicate that socioeconomic factors and physician referral patterns contribute to disparities in access to genetic services within this underserved minority population.

Prevalence of PALB2 mutations in the Creighton University Breast Cancer Family Registry.

The purpose of this study is to determine the prevalence of PALB2 mutations among breast cancer families from the United States. The PALB2 gene was screened for mutations in 90 familial breast cancer patients from the Creighton University Breast Cancer Family Registry. These patients had previously tested negative for mutations in BRCA1 and BRCA2. Two of 90 breast cancer patients (2.2 %) were found to carry a truncating mutation in PALB2 (c.2411_2412delCT and c.2053delC). Both probands were diagnosed with breast cancer before age 35 and each had three relatives with breast cancer. Mutations in PALB2 are less common than BRCA1 and BRCA2 in familial breast cancer patients. However, testing for PALB2 mutations is a useful adjunct for patients undergoing testing for BRCA1 and BRCA2.

Genetic testing for RAD51C mutations: in the clinic and community.

Much of the observed familial clustering of breast and ovarian cancer cannot be explained by mutations in BRCA1 and BRCA2. Several other cancer susceptibility genes have been identified, but their value in routine clinical genetic testing is still unclear. Germline mutations in RAD51C have been identified in about 1% of hereditary breast and ovarian cancer families. RAD51C mutations are predominantly found in families with a history of ovarian cancer and are rare in families with a history of breast cancer alone. RAD51C is primarily an ovarian cancer susceptibility gene. A mutation is present in approximately 1% of unselected ovarian cancers. Among mutation carriers, the lifetime risk of ovarian cancer is approximately 9%. The average age at onset is approximately 60 years; this suggests that preventive oophorectomy can be delayed until after natural menopause. Under current guidelines, genetic testing for RAD51C is expected to have a limited impact on ovarian cancer incidence at a population level. This is because the penetrance is 9% to age 80; the great majority of families with mutations would be represented by a single case of ovarian cancer, these are potentially preventable through population screening but not through screening of established ovarian cancer families.

Strategies for recruitment of relatives of BRCA mutation carriers to a genetic testing program in the Bahamas.

The prevalence of BRCA1 and BRCA2 mutations among unselected breast cancer patients in the Bahamas is 23%. It is beneficial to advise relatives of mutation carriers that they are candidates for genetic testing. Women who test positive are then eligible for preventive interventions, such as oophorectomy. It is not clear how often relatives of women with a mutation in the Bahamas wish to undergo genetic testing for the family mutation. Furthermore, it is not clear how best to communicate this sensitive information to relatives in order to maximize patient compliance. We offered genetic testing to 202 first-degree relatives of 58 mutation carriers. Of 159 women who were contacted by the proband or other family member, only 14 made an appointment for genetic testing (9%). In contrast, among 32 relatives who were contacted directly by the genetic counselor, 27 came for an appointment (84%). This study suggests that for recruitment of relatives in the Bahamas, direct contact by counselor is preferable to using the proband as an intermediary.

Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland.

A number of genes other than BRCA1 and BRCA2 have been associated with breast cancer predisposition, and extended genetic testing panels have been proposed. It is of interest to establish the full spectrum of deleterious mutations in women with familial breast cancer.We performed whole-exome sequencing of 144 women with familial breast cancer and negative for 11 Polish founder mutations in BRCA1, CHEK2 and NBS1, and we evaluated the sequences of 12 known breast cancer susceptibility genes. A truncating mutation in a breast cancer gene was detected in 24 of 144 women (17%) with familial breast cancer. A BRCA2 mutation was detected in 12 cases, a (non-founder) BRCA1 mutation was detected in 5 cases, a PALB2 mutation was detected in 4 cases and an ATM mutation was detected in 2 cases. Polish women with familial breast cancer who are negative for founder mutations in BRCA1, CHEK2 and NBS1 should be fully screened for mutations in BRCA1, BRCA2 and PALB2. The PALB2 founder mutation c.509_519delGA should be included in the panel of Polish founder mutations.

Recurrent mutations of BRCA1 and BRCA2 in Poland: an update.

Three founder alleles of BRCA1 (C61G, 4153delA, 5382insC) were reported in Poland in 2000, and these three mutations have comprised the standard testing panel used throughout the country. However, since 2000, other recurrent mutations of BRCA1 and BRCA2 have been reported. To establish if the inclusion of one or more of these mutations will increase the sensitivity of the standard test panel, we studied 1164 Polish women with unselected breast cancer diagnosed at age of 50 or below. All women were genotyped for 12 recurrent mutations of BRCA1 and BRCA2. We identified a mutation in 83 of 1164 patients (7.1%) including 61 women with one of the original three mutations (C61G, 4153delA, 5382insC) and 22 women with a different mutation (1.9%). Three new mutations (3819del5, 185delAG and 5370C>T) were seen in multiple families. By including these three mutations in the extended panel, the mutant frequency increased from 5.2 to 6.7%. Polish women with breast cancer diagnosed at age of 50 or below should be screened with a panel of six founder mutations of BRCA1 (C61G, 4153delA, 5382insC, 3819del5, 185delAG and 5370C>T).

Survival in women with ovarian cancer with and without microsatellite instability.

PURPOSE OF INVESTIGATION: Microsatellite instability (MSI) is a hallmark of defective mismatch repair and is present in approximately 20% of ovarian cancers. It is not known if the presence of MSI predicts survival in women with epithelial ovarian cancer. MATERIALS AND METHODS: Cases of epithelial ovarian cancer were ascertained from a population-based study in Ontario and tumour samples were tested for MSI, using five MSI markers. Patients were divided into MSI-high and MSI-low/normal, according to National Cancer Institute criteria. The authors compared the prevalence of specific prognostic factors in the two subgroups, including age, grade, stage, and histology. They estimated the hazard ratio for death from ovarian cancer associated with MSI-high and with other prognostic factors using a multi-variate analysis. RESULTS: A total of 418 ovarian cancer patients were included. One hundred and twenty-seven (19.7%) cancers were MSI- high. Subgroup analyses did not reveal any statistically significant differences for pathologic features associated with MSI status. No survival difference was seen according to MSI status. CONCLUSIONS: The presence of MSI in ovarian cancer is not associated with survival.

The use of cell-free fetal DNA in maternal plasma for noninvasive prenatal linkage analysis in beta globin gene cluster.

OBJECTIVES: To use the PCR-RFLP-based linkage analysis for non-invasive prenatal diagnosis of ß-thalassemia. BACKGROUNDS: Thalassemia is a prevalent genetic disorder occurring throughout the world. Cell-free fetal DNA (cffDNA) in the maternal plasma during pregnancy has been used to develop non-invasive prenatal screening and diagnostic tests. METHODS: PCR-RFLP for six SNPs in the ß-globin gene was executed on paternal and maternal DNA as well as DNA extracted from CVS of the fetuses in seven ß-thalassemic families. Based on the results, two families in which the paternal inherited SNPs in specific loci were different from the maternal one were selected and PCR-RFLP was performed on cffDNA extracted from the maternal plasma. RESULTS: Paternal SNPs in cffDNA were distinguished and the inheritance of paternally normal or mutant ß globin allele was predicted by linkage analysis. CONCLUSION: The use of PCR-RFLP on cffDNA as a simple and inexpensive method was capable to provide similar results achieved by studying CVS of the fetuses. However, there is a limiting factor in this approach, namely that there is the little amount of cffDNA in maternal plasma. The PCR yield was improved either by adding BSA to PCR reaction or increasing the PCR cycles (Tab. 2, Fig. 2, Ref. 18).