Genetic predisposition to prostate cancer

Prostate cancer (PC) is a significant economic and health burden in the U.S. and Europe but its causes are largely unknown. The most significant risk factors (after gender) are age and family history of the disease. A gene with high penetrance but low frequency on chromosome 1q, HPC 1, has been suggested to cause a proportion of the familial aggregation of PC but other more common genes, conferring less risk, are also thought to contribute to disease predisposition. We have pursued a strategy to study both types of genetic risk in PC. To identify high penetrance genes, affected men from thirteen families have been genotyped for genetic linkage analysis at six microsatellite markers spanning 45 cM of 1q24-25. Both LOD score and non-parametric statistics provide no significant support for HPC1 in this genomic region, although 3 of the families did combine to produce a LOD score of 0.9. These families will be included in a genome wide search for other PC predisposition genes as part of a multinational collaboration.^ For study of common genetic factors in PC development, leukocyte DNA samples from an unselected series of 55 patients and 67 controls have been examined for genetic differences in two other candidate genes, the androgen receptor gene, hAR, at Xq11-12, and the vitamin D receptor gene, hVDR, at 12q12-14. hAR was typed for two trinucleotide repeat length polymorphisms, (CAG)$\rm\sb{n}$ and (GGC)$\rm\sb{n},$ encoding polyglutamine and polyglycine tracts, respectively, which have been implicated in PC susceptibility. These data, combined with similarly processed patients and controls from the U.K. show no consistent association of allele length with PC risk. A novel finding, however, has been a significant association between the number of GGC repeats and the length of time between diagnosis and relapse in stage T1-T4 Caucasian patients irrespective of therapy and age of the patient. Of 49 patients who relapsed out of 108 entering the study, those with 16 or fewer GGC repeats had an average relapse-free-period of 101 (+/$-$7.7) months while for those with more than 16 repeats the period averaged 48 (+/$-$2.9) months, a difference of 2.1 fold or 4.4 years.^ The second gene, hVDR, was genotyped at two polymorphisms, a synonymous C/T substitution in exon 9 identified by differential TaqI enzymatic digestion and a variable length polyA tract in the 3$\sp\prime$ UTR. Although these polymorphisms are in strong linkage disequilibrium only the polyA region showed a possible association with PC risk. Men homozygous for alleles with fewer than 18 A's had an increased risk (OR = 3.0, p = 0.0578) compared to controls. This result is opposite to the findings of others and may either indicate off-setting random errors which together balance out to no significant overall effect or reflect more complex genetic and/or environmental associations.^ Overall, this research suggests that single gene familial predisposition may be less prominent in PC than in other cancers and that the characteristics of PC pathology may be useful in identifying the effects of common genetic factors. ^

NGS Nominated CELA1, HSPG2, and KCNK5 as Candidate Genes for Predisposition to Balkan Endemic Nephropathy

Balkan endemic nephropathy (BEN) is a familial chronic tubulointerstitial disease with insidious onset and slow progression leading to terminal renal failure. The results of molecular biological investigations propose that BEN is a multifactorial disease with genetic predisposition to environmental risk agents. Exome sequencing of 22 000 genes with Illumina Nextera Exome Enrichment Kit was performed on 22 DNA samples (11 Bulgarian patients and 11 Serbian patients). Software analysis was performed via NextGene, Provean, and PolyPhen. The frequency of all annotated genetic variants with deleterious/damaging effect was compared with those of European populations. Then we focused on nonannotated variants (with no data available about them and not found in healthy Bulgarian controls). There is no statistically significant difference between annotated variants in BEN patients and European populations. From nonannotated variants with more than 40% frequency in both patients' groups, we nominated 3 genes with possible deleterious/damaging variants-CELA1, HSPG2, and KCNK5. Mutant genes (CELA1, HSPG2, and KCNK5) in BEN patients encode proteins involved in basement membrane/extracellular matrix and vascular tone, tightly connected to process of angiogenesis. We suggest that an abnormal process of angiogenesis plays a key role in the molecular pathogenesis of BEN.

Persisting abdominal symptoms after travelers' diarrhea: Is there a genetic predisposition?

Functional gastrointestinal disorders (FGIDs) are defined as ailments of the mid or lower gastrointestinal tract which are not attributable to any discernable anatomic or biochemical defects.1 FGIDs include functional bowel disorders, also known as persisting abdominal symptoms (PAS). Irritable bowel syndrome (IBS) is one of the most common illnesses classified under PAS.2,3 This is the first prospective study that looks at the etiology and pathogenesis of post-infectious PAS in the context of environmental exposure and genetic susceptibility in a cohort of US travelers to Mexico. Our objective was to identify infectious, genetic and environmental factors that predispose to post infectious PAS. ^ Methods. This is a secondary data analysis of a prospective study on a cohort of 704 healthy North American tourists to Cuernavaca, Morelos and Guadalajara, Jalisco in Mexico. The subjects at risk for Travelers' diarrhea were assessed for chronic abdominal symptoms on enrollment and six months after the return to the US. ^ Outcomes. PAS was defined as disturbances of mid and lower gastrointestinal system without any known pathological or radiological abnormalities, or infectious, or metabolic causes. It refers to functional bowel disease, category C of functional gastrointestinal diseases as defined by the Rome II criterion. PAS was sub classified into Irritable bowel syndrome (IBS) and functional abdominal disease (FAD). ^ IBS is defined as recurrent abdominal pain or discomfort present at least 25% and associated with improvement with defecation, change in frequency and form of stool. FAD encompasses other abdominal symptoms of chronic nature that do not meet the criteria for IBS. It includes functional diarrhea, functional constipation, functional bloating: and unspecified bowel symptoms. ^ Results. Among the 704 travelers studied, there were 202 cases of PAS. The PAS cases included 175 cases of FAD and 27 cases of IBS. PAS was more frequent among subjects who developed traveler's diarrhea in Mexico compared to travelers who remained healthy during the short term visit to Mexico (52 vs. 38; OR = 1.8; CI, 1.3–2.5, P < 0.001). A statistically significant difference was noted in the mean age of subjects with PAS compared to healthy controls (28 vs. 34 yrs; OR = 0.97, CI, 0.95–0.98; P < 0.001). Travelers who experienced multiple episodes, a later onset of diarrhea in Mexico and passed greater numbers of unformed stools were more likely to be identified in PAS group at six months. Participants who developed TD caused by enterotoxigenic E.coli in Mexico showed a 2.6 times higher risk of developing FAD (P = 0.003). Infection with Providencia ssp. also demonstrated a greater risk to developing PAS. Subjects who sought treatment for diarrhea while in Mexico also displayed a significantly lower frequency of IBS at six months follow up (OR = 0.30; CI, 0.10–0.80; P = 0.02). ^ Forty six SNPs belonging to 14 genes were studied. Seven SNPs were associated with PAS at 6 months. These included four SNPs from the Caspase Recruitment Domain-Containing Protein 15 gene (CARD15), two SNPs from Surfactant Pulmonary-Associated Protein D gene (SFTPD) and one from Decay-Accelerating Factor For Complement gene (CD55). A genetic risk score (GRS) was composed based on the 7 SNPs that showed significant association with PAS. A 20% greater risk for PAS was noted for every unit increase in GRS. The risk increased by 30% for IBS. The mean GRS was high for IBS (2.2) and PAS (1.1) compared to healthy controls (0.51). These data suggests a role for these genetic polymorphisms in defining the susceptibility to PAS. ^ Conclusions. The study allows us to identify individuals at risk for developing post infectious IBS (PI-IBS) and persisting abdominal symptoms after an episode of TD. The observations in this study will be of use in developing measures to prevent and treat post-infectious irritable bowel syndrome among travelers including pre-travel counseling, the use of vaccines, antibiotic prophylaxis or the initiation of early antimicrobial therapy. This study also provides insights into the pathogenesis of post infectious PAS and IBS. (Abstract shortened by UMI.)^

Early-life exposure to endotoxin alters hypothalamic–pituitary–adrenal function and predisposition to inflammation

We have investigated whether exposure to Gram-negative bacterial endotoxin in early neonatal life can alter neuroendocrine and immune regulation in adult animals. Exposure of neonatal rats to a low dose of endotoxin resulted in long-term changes in hypothalamic–pituitary–adrenal (HPA) axis activity, with elevated mean plasma corticosterone concentrations that resulted from increased corticosterone pulse frequency and pulse amplitude. In addition to this marked effect on the development of the HPA axis, neonatal endotoxin exposure had long-lasting effects on immune regulation, including increased sensitivity of lymphocytes to stress-induced suppression of proliferation and a remarkable protection from adjuvant-induced arthritis. These findings demonstrate a potent and long-term effect of neonatal exposure to inflammatory stimuli that can program major changes in the development of both neuroendocrine and immunological regulatory mechanisms.

Transferring an inborn auditory perceptual predisposition with interspecies brain transplants

Inborn species' perceptual preferences are thought to serve as important guides for neonatal learning in most species of higher vertebrates. Although much work has been carried out on experiential contributions to the expression of such preferences, their neural and developmental correlates remain largely unexplored. Here we use embryonic neural transplants between two bird species, the Japanese quail and the domestic chicken, to demonstrate that an inborn auditory perceptual predisposition is transferable between species. The transfer of the perceptual preference was dissociated from changes to the vocalizations of the resulting animals (called chimeras), suggesting that experiential differences in auditory self-stimulation cannot explain the perceptual change. A preliminary localization of the effective brain region for the behavioral transfer by using a naturally occurring species-cell marker revealed that it is not contained within the major avian auditory pathways. To our knowledge, this is the first demonstration that abstract aspects of auditory perception can be transferred between species with transplants of the central nervous system.

Immune response of HLA-DQ8 transgenic mice to peptides from the third hypervariable region of HLA-DRB1 correlates with predisposition to rheumatoid arthritis.

The major histocompatibility complex class II genes play an important role in the genetic predisposition to many autoimmune diseases. In the case of rheumatoid arthritis (RA), the human leukocyte antigen (HLA)-DRB1 locus has been implicated in the disease predisposition. The "shared epitope" hypothesis predicts that similar motifs within the third hypervariable (HV3) regions of some HLA-DRB1 alleles are responsible for the class II-associated predisposition to RA. Using a line of transgenic mice expressing the DQB1*0302/DQA1*0301 (DQ8) genes in the absence of endogenous mouse class II molecules, we have analyzed the antigenicity of peptides covering the HV3 regions of RA-associated and nonassociated DRB1 molecules. Our results show that a correlation exists between proliferative response to peptides derived from the HV3 regions of DRB1 chains and nonassociation of the corresponding alleles with RA predisposition. While HV3 peptides derived from nonassociated DRB1 molecules are highly immunogenic in DQ8 transgenic mice, all the HV3 peptides derived from RA-associated DRB1 alleles fail to induce a DQ8-restricted T-cell response. These data suggest that the role of the "shared epitope" in RA predisposition may be through the shaping of the T-cell repertoire.

Chloroplast gene sequence data suggest a single origin of the predisposition for symbiotic nitrogen fixation in angiosperms.

Of the approximately 380 families of angiosperms, representatives of only 10 are known to form symbiotic associations with nitrogen-fixing bacteria in root nodules. The morphologically based classification schemes proposed by taxonomists suggest that many of these 10 families of plants are only distantly related, engendering the hypothesis that the capacity to fix nitrogen evolved independently several, if not many, times. This has in turn influenced attitudes toward the likelihood of transferring genes responsible for symbiotic nitrogen fixation to crop species lacking this ability. Phylogenetic analysis of DNA sequences for the chloroplast gene rbcL indicates, however, that representatives of all 10 families with nitrogen-fixing symbioses occur together, with several families lacking this association, in a single clade. This study therefore indicates that only one lineage of closely related taxa achieved the underlying genetic architecture necessary for symbiotic nitrogen fixation in root nodules.

On the diseases and derangements of the nervous system : in their primary forms and in their modifications by age, sex, constitution, hereditary predisposition, excesses, general disorder, and organic disease /

Mode of access: Internet.

Dissociable brain structural changes associated with predisposition, resilience, and disease expression in bipolar disorder

Genetic factors are important in the etiology of bipolar disorder (BD). However, first-degree relatives of BD patients are at risk for a number of psychiatric conditions, most commonly major depressive disorder (MDD), although the majority remain well. The purpose of the present study was to identify potential brain structural correlates for risk and resilience to mood disorders in patients with BD, type I (BD-I) and their relatives. Structural magnetic resonance imaging scans were acquired from 30 patients with BD-I, 50 of their firstdegree relatives (28 had no Axis I disorder, while 14 had MDD) and 52 controls. We used voxel-based morphometry, implemented in SPM5 to identify group differences in regional gray matter volume. From the identified clusters, potential differences were further examined based on diagnostic status (BD-I patients, MDD relatives, healthy relatives, controls). Whole-brain voxel-based analysis identified group differences in the left hemisphere in the insula, cerebellum, and substantia nigra. Increased left insula volume was associated with genetic preposition to BD-I independent of clinical phenotype. In contrast, increased left substantia nigra volume was observed in those with the clinical phenotype of BD-I. Changes uniquely associated with the absence of a clinical diagnosis in BD relatives were observed in the left cerebellum. Our data suggest that in BD, genetic and phenotype-related influences on brain structure are dissociable; if replicated, these findings may help with early identification of high-risk individuals who are more likely to transition to syndromal states. Copyright © 2009 Society for Neuroscience.

Effect of reading sport chronicles on the perception of justice and the predisposition to protest actions in soccer

In this study three chronicles from national newspapers (one generalist and two sport press) were analyzed. The chronicles belong to Spain’s soccer final of the King’s Cup in 2014. The aim of the study was to know if there was any influence on the readers’ perception of justice and consequently if this influence could cause a particular predisposition to participate in acts of protest. 462 university students participated. The results showed that different chronicles caused differences in the perception of justice depending on the chronicle read. However, a clear influence on the willingness to participate in acts of protest was not obtained. These results should make us think about the impact of sport press and its influence, and to be aware of the indirect responsibility of every sector on the antisocial behaviors generated by soccer in our country.

Antioxidant and detoxify genes polymorphisms in colorectal cancer predisposition

Colorectal cancer (CRC) results from histologic and gene alterations can lead to a massive cellular proliferation. Most of the authors assume multifactorial causes to CRC genesis. Low physical activity, a fat diet poor in fibers and smoking habits seems to have an important role in CRC. However, there are also genetic causes associated with CRC risk. It has been described that oxidative stress levels could influence CRC development. Thus, cellular balance reactive species and defense enzymes involved in oxidative stress are crucial to maintain a good tissue function and avoid neoplasic process. Therefore, genome variations on these defense enzymes, such as MNSOD, SOD3, GSTP1, GSTT1 and GSTM1, could be important biomarkers to colorectal adenocarcinomas. We intend to determine frequencies distribution of most common polymorphisms involved on oxidative stress regulation (MNSOD, SOD3, GSTP1, GSTT1 and GSTM1) in patients with sporadic colorectal adenocarcinoma (SCA) and in healthy controls, evaluation their possible correlation with SCA risk. Samples common polymorphisms of antioxidant and detoxify genes (MNSOD T175C, SOD3 R213G, GSTP1 A105G, GSTP1 C114T, GSTT1del and GSTM1del) analysis was done by PCR-SSP techniques. In this study we found a higher prevalence of MNSOD 175CC (55% vs 2%; p<0.0001; OR: 58.5; CI 13.3 to 256.7), SOD3 213GG (31% vs 2%; p<0.0001; OR: 21.89; CI 4.93 to 97.29), GSTP1 105GG (46% vs 12%; p<0.0001; OR: 6.14; CI 2.85 to 13.26), GSTP1 114TT (38% vs 0%; p<0.0001; OR: Infinity) and GSTT1 null (75% vs 28%; p<0.0001; OR: 7.71; CI 3.83 to 15.56) mutated genotypes among SCA patients, while the normal genotypes were associated with SCA absence. Furthermore, we found GSTP1 114TT mutated genotype (52% vs 27%; p=0.003; OR: 2.88; CI: 1.41 to 5.89) and GSTT1 null genotype (87% vs 65%; p=0.003; OR: 3.66; CI 1.51 to 8.84) associated with colon samples. These findings suggest a positive association between most of common polymorphisms involved on oxidative stress regulation and SCA prevalence. Dysregulation of MNSOD, SOD3, GSTP1, GSTT1 and GSTM1 genes could be associated with an increase of ROS in colon and rectum tissue and p53 pathway deregulation, induced by oxidative stress on colonic and rectal cells. The present study also provides preliminary evidence that MNSOD 175C, SOD3 213G, GSTP1 105G, GSTP1 114T and GSTT1 null polymorphisms, may be involved in SCA risk and could be useful to clarify this multifactorial disorder.

Epilepsies Associated With Hippocampal Sclerosis.

Hippocampal sclerosis (HS) is considered the most frequent neuropathological finding in patients with mesial temporal lobe epilepsy (MTLE). Hippocampal specimens of pharmacoresistant MTLE patients that underwent epilepsy surgery for seizure control reveal the characteristic pattern of segmental neuronal cell loss and concomitant astrogliosis. However, classification issues of hippocampal lesion patterns have been a matter of intense debate. International consensus classification has only recently provided significant progress for comparisons of neurosurgical and clinic-pathological series between different centers. The respective four-tiered classification system of the International League Against Epilepsy subdivides HS into three types and includes a term of gliosis only, no-HS. Future studies will be necessary to investigate whether each of these subtypes of HS may be related to different etiological factors or with postoperative memory and seizure outcome. Molecular studies have provided potential deeper insights into the pathogenesis of HS and MTLE on the basis of epilepsy-surgical hippocampal specimens and corresponding animal models. These include channelopathies, activation of NMDA receptors, and other conditions related to Ca(2+) influx into neurons, the imbalance of Ca(2+)-binding proteins, acquired channelopathies that increase neuronal excitability, paraneoplastic and non-paraneoplastic inflammatory events, and epigenetic regulation promoting or facilitating hippocampal epileptogenesis. Genetic predisposition for HS is clearly suggested by the high incidence of family history in patients with HS, and by familial MTLE with HS. So far, it is clear that HS is multifactorial and there is no individual pathogenic factor either necessary or sufficient to generate this intriguing histopathological condition. The obvious variety of pathogenetic combinations underlying HS may explain the multitude of clinical presentations, different responses to clinical and surgical treatment. We believe that the stratification of neuropathological patterns can help to characterize specific clinic-pathological entities and predict the postsurgical seizure control in an improved fashion.

Key Issues In Inhibitor Management In Patients With Haemophilia.

12 Suppl 1

Oral findings and dental care in a patient with myelomeningocele: case report of a 3-year-old child

Myelomeningocele (MMC) is a congenital malformation of the neural tube that occurs in the first weeks of pregnancy. This malformation refers to the caudal non-closure of the neural tube and neural tissue exposure, which lead to neurological problems, such as hydrocephalus, motor disability, genitourinary tract and skeletal abnormalities and mental retardation. Patients with MMC have an acknowledged predisposition to latex allergy and are usually at a high caries risk and activity due to poor oral hygiene, fermentable carbon hydrate-rich diet and prolonged use of sugar-containing medications. This paper addresses the common oral findings in pediatric patients with MMC, discusses the strategies and precautions to deal with these individuals and reports the dental care to a young child diagnosed with this condition.

Alterações bucais e cuidados orais no paciente transplantado de medula óssea

Os cuidados gerais relativos ao paciente submetido ao transplante de medula óssea (TMO) incluem avaliações odontológicas rotineiras, as quais devem estar inseridas em um contexto multiprofissional. A cavidade oral constitui um sítio propício a infecções com grande potencial de desenvolvimento de bacteremia, sendo que lesões infecciosas devem ser previamente tratadas e controladas pelo cirurgião-dentista. O objetivo desta revisão é discutir questões em destaque na literatura nacional e internacional referentes aos quadros inflamatórios e infecciosos orais de importância para o paciente transplantado de medula óssea, tanto os predisponentes a complicações durante o transplante, quanto os que ocorrem durante e após a terapia mielossupressora. Destaca-se na literatura a doença periodontal avançada, a qual constitui um quadro infeccioso crônico que deve ser evitado ou controlado durante o TMO, principalmente devido à presença de S. viridans. Os fatores de risco para mucosite oral (OM), doença do enxerto contra o hospedeiro (DECH) e xerostomia ainda não estão definidos, principalmente para OM e DECH. São citadas na literatura alternativas promissoras de tratamento para OM, tais como crioterapia, administração de fatores de crescimento e laserterapia. O risco aumentado de cárie é controverso e, dentre as lesões fúngicas e virais, destacam-se as infecções orais e de orofaringe por Candida e pela família de herpesvírus, de importância clínica considerável. Em pacientes pediátricos são relevantes as alterações craniofaciais e dentárias, decorrentes principalmente da radioterapia.