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Genetic Variants of the α-Synuclein Gene SNCA Are Associated with Multiple System Atrophy  [PDF]
Ammar Al-Chalabi, Alexandra Dürr, Nicholas W. Wood, Michael H. Parkinson, Agnes Camuzat, Jean-Sébastien Hulot, Karen E. Morrison, Alan Renton, Sigurd D. Sussmuth, Bernhard G. Landwehrmeyer, Albert Ludolph, Yves Agid, Alexis Brice, P. Nigel Leigh, Gilbert Bensimon, for the NNIPPS Genetic Study Group
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0007114
Abstract: Background Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of α-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the α-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson's disease has identified association of a SNP in SNCA with MSA. Methodology/Findings We evaluated 32 SNPs in the SNCA gene in a European population of 239 cases and 617 controls recruited as part of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) study. We used 161 independently collected samples for replication. Two SNCA SNPs showed association with MSA: rs3822086 (P = 0.0044), and rs3775444 (P = 0.012), although only the first survived correction for multiple testing. In the MSA-C subgroup the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153, (95% CI 1.3–3.6); rs3775444 P = 0.0017, OR 4.386 (95% CI 1.6–11.7). A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7×10?4). The association with rs3822086 was replicated in the independent samples (P = 0.035). Conclusions/Significance We report a genetic association between MSA and α-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA. Trial Registration ClinicalTrials.gov NCT00211224. [NCT00211224]
Behavioural induced severe hypernatremia without neurological manifestations  [cached]
Hassan Hossam,Al Aseri Zohair,Suriya Owais
Saudi Journal of Kidney Diseases and Transplantation , 2010,
Abstract: Hypernatremia is a relatively common entity and is more prevalent among the elderly and critically ill. A number of medical conditions are commonly associated with hypernatremia, and these differ substantially among children and adults. Severe hypernatremia is usually associated with central nervous system manifestations and carries a high mortality rate. We report a case of a female patient who presented to the emergency department of the King Khalid University Hospital, Riyadh, Saudi Arabia with severe hypernatremia and without any associated co-morbid conditions or neurological manifestations. We did not find any etiological background despite extensive eva-luation other than under hydration due to decreased fluid intake, which was secondary to beha-vioural causes.
Variants on the promoter region of PTEN affect breast cancer progression and patient survival
Tuomas Heikkinen, Dario Greco, Liisa M Pelttari, Johanna Tommiska, Pia Vahteristo, P?ivi Heikkil?, Carl Blomqvist, Kristiina Aittom?ki, Heli Nevanlinna
Breast Cancer Research , 2011, DOI: 10.1186/bcr3076
Abstract: We screened the promoter region of the PTEN gene for germline variation in 330 familial breast cancer cases and further determined the genotypes of three detected PTEN promoter polymorphisms -903GA, -975GC, and -1026CA in a total of 2,412 breast cancer patients to evaluate the effects of the variants on tumor characteristics and disease outcome. We compared the gene expression profiles in breast cancers of 10 variant carriers and 10 matched non-carriers and performed further survival analyses based on the differentially expressed genes.All three promoter variants associated with worse prognosis. The Cox's regression hazard ratio for 10-year breast cancer specific survival in multivariate analysis was 2.01 (95% CI 1.17 to 3.46) P = 0.0119, and for 5-year breast cancer death or distant metastasis free survival 1.79 (95% CI 1.03 to 3.11) P = 0.0381 for the variant carriers, indicating PTEN promoter variants as an independent prognostic factor. The breast tumors from the promoter variant carriers exhibited a similar gene expression signature of 160 differentially expressed genes compared to matched non-carrier tumors. The signature further stratified patients into two groups with different recurrence free survival in independent breast cancer gene expression data sets.Inherited variation in the PTEN promoter region affects the tumor progression and gene expression profile in breast cancer. Further studies are warranted to establish PTEN promoter variants as clinical markers for prognosis in breast cancer.Hereditary predisposition to breast cancer is caused by variation in multiple genes affecting the cancer risk with varying penetrance. Mutations in the main high penetrance genes BRCA1 and BRCA2 are mostly found in families with multiple breast cancer cases particularly with early onset and with ovarian cancer [1,2], and may also affect breast cancer survival among the mutation carriers [3,4]. Strong familial breast cancer predisposition is also present in rare cancer s
M. Ghaffarpour,A. Khoshroo,M. H. Harirchian,H. Sikaroodi
Acta Medica Iranica , 2007,
Abstract: Brucellosis is an endemic disease in our country. Neurobrucellosis occurs in 5 to 10% of cases, and can present at any stage of of the disease. This study was undertaken to evaluate clinical, epidemiological and paraclinical aspects of brucellosis with and without neurological manifestations. Data of 30 patients, 15 cases with nervous system involvement (neurobrucellosis) and 15 cases without neurological complication (brucellosis) were collected and analyzed. Constitutional manifestations of the disease were detected with nearly the same frequencies in both groups. Exceptions were headache which was more common in patients with neurobrucellosis (73% vs. 33%) and arthralgia which was detected more frequently in cases with brucellosis than neurobrucellosis (53% vs. 13%). Signs and symptoms of meningeal irritation and disturbances of consciousness were the most common manifestations in cases with neurobrullosis, which had been detected in 60% and 46.7% of cases, respectively. Less common neurological presentations, in decreasing order of frequency were ophthalmoplegia, papilledema and seizures, spastic weakness of limbs, hearing loss and spinal epidural abscess. In two patients with negative serum and CSF agglutinin test, diagnosis of neurobrucellosis was made by blood and CSF cultures. In patients with neurobrucellosis, MRI of brain and spinal cord showed abnormalities in 5/15(33.3%) of cases, including decreased lateral ventricular volume due to brain swelling (2/15), hydrocephalus with periventricular edema and meningeal enhancement in posterior fossa (1/15), multiple hypodense periventricular lesions, ischemic or demyelinating in nature (1/15) and spinal epidural abscess (1/15). Brucellosis should be kept in mind in patients with neurological presentations.
Long Time to Diagnosis of Medulloblastoma in Children Is Not Associated with Decreased Survival or with Worse Neurological Outcome  [PDF]
Jean-Francois Brasme, Jacques Grill, Francois Doz, Brigitte Lacour, Dominique Valteau-Couanet, Stephan Gaillard, Olivier Delalande, Nozar Aghakhani, Stéphanie Puget, Martin Chalumeau
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033415
Abstract: Background The long time to diagnosis of medulloblastoma, one of the most frequent brain tumors in children, is the source of painful remorse and sometimes lawsuits. We analyzed its consequences for tumor stage, survival, and sequelae. Patients and Methods This retrospective population-based cohort study included all cases of pediatric medulloblastoma from a region of France between 1990 and 2005. We collected the demographic, clinical, and tumor data and analyzed the relations between the interval from symptom onset until diagnosis, initial disease stage, survival, and neuropsychological and neurological outcome. Results The median interval from symptom onset until diagnosis for the 166 cases was 65 days (interquartile range 31–121, range 3–457). A long interval (defined as longer than the median) was associated with a lower frequency of metastasis in the univariate and multivariate analyses and with a larger tumor volume, desmoplastic histology, and longer survival in the univariate analysis, but not after adjustment for confounding factors. The time to diagnosis was significantly associated with IQ score among survivors. No significant relation was found between the time to diagnosis and neurological disability. In the 62 patients with metastases, a long prediagnosis interval was associated with a higher T stage, infiltration of the fourth ventricle floor, and incomplete surgical resection; it nonetheless did not influence survival significantly in this subgroup. Conclusions We found complex and often inverse relations between time to diagnosis of medulloblastoma in children and initial severity factors, survival, and neuropsychological and neurological outcome. This interval appears due more to the nature of the tumor and its progression than to parental or medical factors. These conclusions should be taken into account in the information provided to parents and in expert assessments produced for malpractice claims.
Influence of Genetic Variants in Type I Interferon Genes on Melanoma Survival and Therapy  [PDF]
Romina Elizabeth Lenci, Melanie Bevier, Andreas Brandt, Justo Lorenzo Bermejo, Antje Sucker, Iris Moll, Dolores Planelles, Celia Requena, Eduardo Nagore, Kari Hemminki, Dirk Schadendorf, Rajiv Kumar
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050692
Abstract: Melanoma is an immunogenic tumor; however, the efficacy of immune-therapy shows large inter-individual variation with possible influence of background genetic variation. In this study we report the influence of genetic polymorphisms in the type I interferon gene cluster on chromosome 9p22 on melanoma survival. We genotyped 625 melanoma patients recruited in an oncology center in Germany for 44 polymorphisms located on chromosome 9p22 that were informative for 299 polymorphisms and spanned 15 type I interferon genes. Our results showed associations between time to metastasis/survival and two linked (r2 = 0.76) polymorphisms, rs10964859 (C>G) and rs10964862 (C>A). The rs10964859 polymorphism was located at 3′UTR and rs10964862 was 9.40 Kb towards 5′UTR of IFNW1 gene. The carriers of the variant alleles of the rs10964859 and rs10964862 polymorphisms were associated with a reduced disease-free survival. The validation of data in an independent group of 710 patients from Spain showed that the direction of the effect was similar. Stratification based on therapy showed that the adverse effect on metastasis development was statistically significant in the patients from Spain who did not receive any treatment and were homozygous for variant allele of rs10964862 (HR = 2.52, 95% CI 1.07–5.90; P = 0.03). Patients homozygous for rs10964859 (HR = 2.01, 95% CI 1.17–3.44; P = 0.01) and rs10964862 (HR 1.84, 95%CI 1.03–3.27, P = 0.04) were associated to increased risk of death following metastasis. GTCGACAA haplotype, found in 8.8% of the patients, was associated with an increased risk of death (HR 1.94, 95%CI 1.16–3.26, P = 0.01). In conclusion, our results identified genetic variants in interferon genes that influence melanoma progression and survival with modulation of effect due to treatment status.
HE4 Transcription- and Splice Variants-Specific Expression in Endometrial Cancer and Correlation with Patient Survival  [PDF]
Shi-Wen Jiang,Haibin Chen,Sean Dowdy,Alex Fu,John Attewell,Eleftheria Kalogera,Ronny Drapkin,Karl Podratz,Russell Broaddus,Jinping Li
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms141122655
Abstract: We investigated the HE4 variant-specific expression patterns in various normal tissues as well as in normal and malignant endometrial tissues. The relationships between mRNA variants and age, body weight, or survival are analyzed. ICAT-labeled normal and endometrial cancer (EC) tissues were analyzed with multidimensional liquid chromatography followed by tandem mass spectrometry. Levels of HE4 mRNA variants were measured by real-time PCR. Mean mRNA levels were compared among 16 normal endometrial samples, 14 grade 1 and 14 grade 3 endometrioid EC, 15 papillary serous EC, and 14 normal human tissue samples. The relationship between levels of HE4 variants and EC patient characteristics was analyzed with the use of Pearson correlation test. We found that, although all five HE4 mRNA variants are detectable in normal tissue samples, their expression is highly tissue-specific, with epididymis, trachea, breast and endometrium containing the highest levels. HE4-V0, -V1, and -V3 are the most abundant variants in both normal and malignant tissues. All variants are significantly increased in both endometrioid and papillary serous EC, with higher levels observed in grade 3 endometrioid EC. In the EC group, HE4-V1, -V3, and -V4 levels inversely correlate with EC patient survival, whereas HE4-V0 levels positively correlate with age. HE4 variants exhibit tissue-specific expression, suggesting that each variant may exert distinct functions in normal and malignant cells. HE4 levels appear to correlate with EC patient survival in a variant-specific manner. When using HE4 as a biomarker for EC management, the effects of age should be considered.
The 3′ UTR Variants in the GRP78 Are Not Associated with Overall Survival in Resectable Hepatocellular Carcinoma  [PDF]
Xiao Zhu,Fang Wang,Marie C. M. Lin,Linwei Tian,Wenguo Fan,Samuel S. Ng,Minjuan Liu,Jianqing Huang,Zhenhua Xu,Dongpei Li,Hsiangfu Kung
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017783
Abstract: Elevated glucose-regulated protein 78 (GRP78) levels in tissues have been known to be related with poor prognosis in hepatocellular carcinoma (HCC) patients. Though the variants in the 3′ untranslated region (UTR) of GRP78 gene were not associated with HCC risk, we wonder whether these polymorphisms affect survival of HCC patients.
Associations of Common Variants at APLN and Hypertension in Chinese Subjects with and without Diabetes  [PDF]
Rong Zhang,Jingyi Lu,Cheng Hu,Congrong Wang,Weihui Yu,Feng Jiang,Shanshan Tang,Yuqian Bao,Kunsan Xiang,Weiping Jia
Journal of Diabetes Research , 2012, DOI: 10.1155/2012/917496
Abstract: Background. Apelin, the endogenous ligand for the APJ receptor, has a potent hypotensive effect via a nitric oxide-dependent mechanism in vivo. The aim of the study was to investigate the association between the common variants of apelin gene (APLN) and hypertension, which was reported recently in a Chinese Han population with and without diabetes. Methods. Three single nucleotide polymorphisms (SNPs) on APLN were genotyped in 3156 diabetic patients and 3736 nondiabetic individuals. For non-diabetic subjects, 1779 were enrolled in stage 1 and 1757 were recruited for validation. A meta-analysis combining the two stages was carried out to obtain the overall effect. Results. In diabetic patients, no significant associations of the three SNPs with hypertension were observed. In contrast, we found that rs2235306 was associated with hypertension in non-diabetic males after adjusting for covariates ( , ) while rs2235307 and rs3115759 displayed no evidence of association in both genders. One haplotype, C-C-A, also showed an association with hypertension ( , ) only in men. However, analysis in stage 2 and meta-analysis did not support these findings. Conclusions. We conclude that common variants on APLN are not associated with the prevalence of hypertension in the Chinese. 1. Introduction Essential hypertension is a major risk factor for many common causes of morbidity and mortality including stroke, myocardial infarction, heart failure, and end-stage renal disease [1–3]. Approximately, 30–50% of blood pressure variation in the general population is determined by genetic factors [4, 5] and a variety of gene variants have been shown to be associated with essential hypertension [6, 7]. Apelin, the endogenous ligand for the APJ receptor (an orphan G-protein-coupled receptor), is a bioactive peptide that is expressed in a wide variety of tissues [8–11]. The apelin gene (APLN) in humans is located on chromosome Xq25–26.1, which encodes a 77-amino acid prepropeptide that is cleaved into isoforms of varying lengths [8–13]. During the recent years, there is a mounting evidence that apelin has pleiotropic effects on lipid and glucose metabolisms [14–16] and therefore is correlated with metabolic disorders including diabetes. On the other side, since the apelin/APJ system has high sequence homology to the angiotensin II/angiotensin receptor (AII/AT) system [17], it has gained much research interest regarding its role in blood pressure control. By binding to APJ, apelin exerts a potent hypotensive effect via a nitric oxide-dependent mechanism in vivo [12, 18, 19]. In
Expression of Androgen Receptor Splice Variants in Prostate Cancer Bone Metastases is Associated with Castration-Resistance and Short Survival  [PDF]
Emma H?rnberg,Erik Bovinder Ylitalo,Sead Crnalic,Henrik Antti,P?r Stattin,Anders Widmark,Anders Bergh,Pernilla Wikstr?m
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019059
Abstract: Constitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN) and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival.
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