An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Skin manifestations of pancreatic diseases

Although symptoms of pancreatic diseases such as pancreatitis, acute and chronic and, carcinoma of the pancreas are mainly gastrointestinal in nature, the extra-pancreatic symptoms are also important. These include skin symptoms, such as pancreatic panniculitis, acanthosis nigricans, livedo reticularis, necrolytic migratory erythema, cutaneous signs of hemorrhage, as in persons with severe acute pancreatitis, or the finding of cutaneous metastases of pancreatic carcinoma, which may be a sign of advanced disease. The pancreas is therefore one of those organs for which diagnosis and therapy are often multidisciplinary. In this review article, we summarize current knowledge of the possible skin manifestations of pancreatic disorders

Comparative analysis of clinicopathological correlations of cyclooxygenase-2 expression in resectable pancreatic cancer

AIM: To perform a comparative analysis of clinicopathological correlations of cyclooxygenase-2 (COX-2) expression in pancreatic cancer, examined by monoclonal and polyclonal antibodies

A Prokinetic Agent with a Dual Effect – Itopride – In the Treatment of Dysmotility

A wide range of dyspeptic symptoms in clinical practice reflect the high prevalence of functional disorders of the gastrointestinal (GI) tract. Prokinetic agents are the current mainstay in the therapy of functional dyspepsia. One of these drugs is itopride. We evaluated therapeutic efficacy of itopride according to the literature review. The therapeutic potential of itopride is connected with a dual effect: influencing of enzyme acetylcholinesterase activity and blocking dopamine D2 receptors. After the itopride administration, the contractility of smooth muscle in the upper GI tract increases. Itopride is a drug with rapid absorption from the small bowel; its peak serum concentration occurs 35 minutes after oral administration. Itopride does not pass the blood-brain barrier and does not affect the heart rate by influencing the QT segment. Itopride is a safe prokinetic agent with positive influence on the symptoms of functional dyspepsia such as postprandial fullness, bloating, and gastric emptying. Itopride could also be used for the therapy of the mild form of gastro-oesophageal reflux

Autoimmune Diseases of Digestive Organs—A Multidisciplinary Challenge: A Focus on Hepatopancreatobiliary Manifestation

It is well known that some pathological conditions, especially of autoimmune etiology, are associated with the HLA (human leukocyte antigen) phenotype. Among these diseases, we include celiac disease, inflammatory bowel disease, autoimmune enteropathy, autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cholangitis. Immunoglobulin G4-related diseases (IgG4-related diseases) constitute a second group of autoimmune gastrointestinal, hepatobiliary and pancreatic illnesses. IgG4-related diseases are systemic and rare autoimmune illnesses. They often are connected with chronic inflammation and fibrotic reaction that can occur in any organ of the body. The most typical feature of these diseases is a mononuclear infiltrate with IgG4-positive plasma cells and self-sustaining inflammatory response. In this review, we focus especially upon the hepatopancreatobiliary system, autoimmune pancreatitis and IgG4-related sclerosing cholangitis. The cooperation of the gastroenterologist, radiologist, surgeon and histopathologist is crucial for establishing correct diagnoses and appropriate treatment, especially in IgG4 hepatopancreatobiliary diseases

Decreasing Seroprevalence of Measles Antibodies after Vaccination - Possible Gap in Measles Protection in Adults in the Czech Republic.

In recent years, Europe has recorded an increase in the number of measles outbreaks despite the implementation of vaccination into the National Immunization Programs. The Czech Republic introduced vaccination against measles into National Immunization Program in 1969. The aim of this study was to determine seroprevalence of IgG antibodies against measles in adults.Our study was designed as a prospective, multicenter cohort study. Samples of blood were taken from adults aged 18 years and over. Specific IgG antibodies were determined by ELISA method.A number of 1911 sera samples were obtained. The total seropositivity reached 83.3%, 14.3% of the results were negative and 2.4% were borderline. When comparing the individual age groups, the highest antibody seropositivity (> 96%) was detected in persons aged 50 years and over who were naturally infected in pre-vaccine era. The lowest seropositivity was recorded in the age groups 30-39 years (61.5%), 40-49 years (77.5%) and 18-29 years (81.1%).A long term high rate of seropositivity persists after natural measles infection. By contrast, it decreases over time after vaccination. Similarly, the concentrations of antibodies in persons with measles history persist for a longer time at a higher level than in vaccinated persons. Our results indicate possible gap in measles protection in adults born after implementation of vaccination into the National Immunization Programs. There are two probable reasons, decrease of measles antibody seropositivity in time after vaccination in setting of limited natural booster and one-dose vaccination schedule used in the first years after implementation

Prevalence of hepatitis C virus in adult population in the Czech Republic - time for birth cohort screening.

Chronic hepatitis C is curable disease. Low detection rate could be one of the reasons of poor treatment uptake. It is important to identify HCV prevalence and anti-hepatitis C virus (HCV) positive patients in population by effective screening strategy such as risk-based or birth cohort screening programs. There are no national population-based estimates of the HCV prevalence in the Czech Republic (CZ). The most recent seroprevalence survey determined a prevalence of positive anti-HCV antibodies of 0.2% (in 2001). The aim of the study was to determine the seroprevalence of HCV, HCV viraemia and HCV genotype in the CZ adult population. We also estimated the number of persons living with chronic hepatitis C in CZ. The examined group included 3000 adults, 18-90 years of age enrolled in 2015. All serum samples were examined to determined anti-HCV antibodies positivity, HCV-RNA positivity and genotypes. Of the 3000 samples, 50 were found to be anti-HCV-positive, for a seroprevalence of 1.67% (2.39% in males, 0.98% in females). The overall prevalence of positive HCV RNA was 0.93%: 1.5% in males, 0.39% in females. HCV genotype (GT) 1a was determined in 25%, GT 1b in 25% and GT 3a in 46%. Since 2001, the HCV seroprevalence has increased 8-fold. The highest HCV seroprevalence occurred in males aged 30-44 years. We can estimate that there are more than 140,000 people with HCV antibodies and more than 80,000 people with chronic hepatitis C living in the CZ. The introduction of birth cohort HCV screening could be beneficial for the country

Serological survey of mumps antibodies in adults in the Czech Republic and the need for changes to the vaccination strategy

Mumps outbreaks, especially in adolescents and young adults, have been reported in the Czech Republic. The aim of the presented study was to determine the seroprevalence of specific IgG antibodies against mumps in the adult population of the Czech Republic. The study was designed as a multicenter serological survey of adults aged 18 years and over. Specific IgG antibodies against mumps were detected in blood samples using an enzyme-linked immunosorbent assay (ELISA). A total of 1,911 serum samples were examined. The overall seropositivity reached 55.3%. In individual age groups, the highest seropositivity 63% (63.5–65.2%) was recorded in adults aged 40 years and over; the lowest seropositivity was found in adults aged 18–29 years (27.4%). The difference in seropositivity rate between the 18–29 years age group and the 40 years and over age groups was statistically significant (p < 0.001). Only the 18–29 years age group included both vaccinated and unvaccinated (born in the pre-vaccine era) individuals. In vaccinated individuals, seropositivity was reported in only 19.1% of persons; in unvaccinated individuals, seropositivity reached 48.2%. Our results demonstrate the long-term persistence of antibodies following natural infection and the decrease in seropositivity that occurs after vaccination over time. This immunity waning may account for the higher susceptibility of adolescents and young adults to mumps. Therefore, the current vaccination program in the Czech Republic could be considered as less effective. It will be modified with the shifting of the second dose of vaccine from two years of age to the preschool age