Diabetes mellitus, microalbuminuria, and subclinical cardiac disease: Identification and monitoring of individuals at risk of heart failure

Background-Patients with type 2 diabetes mellitus and elevated urinary albumin:creatinine ratio (ACR) have increased risk of heart failure. We hypothesized this was because of cardiac tissue changes rather than silent coronary artery disease. Methods and Results-In a case-controlled observational study 130 subjects including 50 ACR+ve diabetes mellitus patients with persistent microalbuminuria (ACR > 2.5 mg/mol in males and > 3.5 mg/mol in females, ≥2 measurements, no previous renin- angiotensin-aldosterone therapy, 50 ACR-ve diabetes mellitus patients and 30 controls underwent cardiovascular magnetic resonance for investigation of myocardial fibrosis, ischemia and infarction, and echocardiography. Thirty ACR+ve patients underwent further testing after 1-year treatment with renin-angiotensin-aldosterone blockade. Cardiac extracellular volume fraction, a measure of diffuse fibrosis, was higher in diabetes mellitus patients than controls (26.1±3.4% and 23.3±3.0% P=0.0002) and in ACR+ve than ACR-ve diabetes mellitus patients (27.2±4.1% versus 25.1±2.9%, P=0.004). ACR+ve patients also had lower E0 measured by echocardiography (8.2±1.9 cm/s versus 8.9±1.9 cm/s, P=0.04) and elevated high-sensitivity cardiac troponin T 18% versus 4% ≥14 ng/L (P=0.05). Rate of silent myocardial ischemia or infarction were not influenced by ACR status. Renin-angiotensin-aldosterone blockade was associated with increased left ventricular ejection fraction (59.3±7.8 to 61.5±8.7%, P=0.03) and decreased extracellular volume fraction (26.5±3.6 to 25.2±3.1, P=0.01) but no changes in diastolic function or high-sensitivity cardiac troponin T levels. Conclusions-Asymptomatic diabetes mellitus patients with persistent microalbuminuria have markers of diffuse cardiac fibrosis including elevated extracellular volume fraction, high-sensitivity cardiac troponin T, and diastolic dysfunction, which may in part be reversible by renin-angiotensin-aldosterone blockade. Increased risk in these patients may be mediated by subclinical changes in tissue structure and function

The antisaccade task as an index of sustained goal activation in working memory: modulation by nicotine

The antisaccade task provides a laboratory analogue of situations in which execution of the correct behavioural response requires the suppression of a more prepotent or habitual response. Errors (failures to inhibit a reflexive prosaccade towards a sudden onset target) are significantly increased in patients with damage to the dorsolateral prefrontal cortex and patients with schizophrenia. Recent models of antisaccade performance suggest that errors are more likely to occur when the intention to initiate an antisaccade is insufficiently activated within working memory. Nicotine has been shown to enhance specific working memory processes in healthy adults. MATERIALS AND METHODS: We explored the effect of nicotine on antisaccade performance in a large sample (N = 44) of young adult smokers. Minimally abstinent participants attended two test sessions and were asked to smoke one of their own cigarettes between baseline and retest during one session only. RESULTS AND CONCLUSION: Nicotine reduced antisaccade errors and correct antisaccade latencies if delivered before optimum performance levels are achieved, suggesting that nicotine supports the activation of intentions in working memory during task performance. The implications of this research for current theoretical accounts of antisaccade performance, and for interpreting the increased rate of antisaccade errors found in some psychiatric patient groups are discussed

Comparing Glioblastoma Surgery Decisions Between Teams Using Brain Maps of Tumor Locations, Biopsies, and Resections

PURPOSE: The aim of glioblastoma surgery is to maximize the extent of resection while preserving functional integrity, which depends on the location within the brain. A standard to compare these decisions is lacking. We present a volumetric voxel-wise method for direct comparison between two multidisciplinary teams of glioblastoma surgery decisions throughout the brain. METHODS: Adults undergoing first-time glioblastoma surgery from 2012 to 2013 performed by two neuro-oncologic teams were included. Patients had had a diagnostic biopsy or resection. Preoperative tumors and postoperative residues were segmented on magnetic resonance imaging in three dimensions and registered to standard brain space. Voxel-wise probability maps of tumor location, biopsy, and resection were constructed for each team to compare patient referral bias, indication variation, and treatment variation. To evaluate the quality of care, subgroups of differentially resected brain regions were analyzed for survival and functional outcome. RESULTS: One team included 101 patients, and the other included 174; 91 tumors were biopsied, and 181 were resected. Patient characteristics were largely comparable between teams. Distributions of tumor locations were dissimilar, suggesting referral bias. Distributions of biopsies were similar, suggesting absence of indication variation. Differentially resected regions were identified in the anterior limb of the right internal capsule and the right caudate nucleus, indicating treatment variation. Patients with (n = 12) and without (n = 6) surgical removal in these regions had similar overall survival and similar permanent neurologic deficits. CONCLUSION: Probability maps of tumor location, biopsy, and resection provide additional information that can inform surgical decision making across multidisciplinary teams for patients with glioblastoma

MicroRNA Expression Variability in Human Cervical Tissues

MicroRNAs (miRNAs) are short (∼22 nt) non-coding regulatory RNAs that control gene expression at the post-transcriptional level. Deregulation of miRNA expression has been discovered in a wide variety of tumours and it is now clear that they contribute to cancer development and progression. Cervical cancer is one of the most common cancers in women worldwide and there is a strong need for a non-invasive, fast and efficient method to diagnose the disease. We investigated miRNA expression profiles in cervical cancer using a microarray platform containing probes for mature miRNAs. We have evaluated miRNA expression profiles of a heterogeneous set of cervical tissues from 25 different patients. This set included 19 normal cervical tissues, 4 squamous cell carcinoma, 5 high-grade squamous intraepithelial lesion (HSIL) and 9 low-grade squamous intraepithelial lesion (LSIL) samples. We observed high variability in miRNA expression especially among normal cervical samples, which prevented us from obtaining a unique miRNA expression signature for this tumour type. However, deregulated miRNAs were identified in malignant and pre-malignant cervical tissues after tackling the high expression variability observed. We were also able to identify putative target genes of relevant candidate miRNAs. Our results show that miRNA expression shows natural variability among human samples, which complicates miRNA data profiling analysis. However, such expression noise can be filtered and does not prevent the identification of deregulated miRNAs that play a role in the malignant transformation of cervical squamous cells. Deregulated miRNAs highlight new candidate gene targets allowing for a better understanding of the molecular mechanism underlying the development of this tumour type

Inflammation Aggravates Disease Severity in Marfan Syndrome Patients

BACKGROUND: Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-beta signaling. However, the contribution of tissue inflammation is not addressed so far. METHODOLOGY/PRINCIPAL FINDINGS: Here we showed that both TGF-beta and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-beta and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-beta were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8x10(-6), 95% CI: 70-159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients. CONCLUSION/SIGNIFICANCE: In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients

Studies of Metabolic Phenotypic Correlates of 15 Obesity Associated Gene Variants

Genome-wide association studies have identified novel BMI/obesity associated susceptibility loci. The purpose of this study is to determine associations with overweight, obesity, morbid obesity and/or general adiposity in a Danish population. Moreover, we want to investigate if these loci associate with type 2 diabetes and to elucidate potential underlying metabolic mechanisms.15 gene variants in 14 loci including TMEM18 (rs7561317), SH2B1 (rs7498665), KCTD15 (rs29941), NEGR1 (rs2568958), ETV5 (rs7647305), BDNF (rs4923461, rs925946), SEC16B (rs10913469), FAIM2 (rs7138803), GNPDA2 (rs10938397), MTCH2 (rs10838738), BAT2 (rs2260000), NPC1 (rs1805081), MAF (rs1424233), and PTER (rs10508503) were genotyped in 18,014 middle-aged Danes.Five of the 15 gene variants associated with overweight, obesity and/or morbid obesity. Per allele ORs ranged from 1.15-1.20 for overweight, 1.10-1.25 for obesity, and 1.41-1.46 for morbid obesity. Five of the 15 variants moreover associated with increased measures of adiposity. BDNF rs4923461 displayed a borderline BMI-dependent protective effect on type 2 diabetes (0.87 (0.78-0.96, p = 0.008)), whereas SH2B1 rs7498665 associated with nominally BMI-independent increased risk of type 2 diabetes (1.16 (1.07-1.27, p = 7.8×10(-4))).Associations with overweight and/or obesity and measures of obesity were confirmed for seven out of the 15 gene variants. The obesity risk allele of BDNF rs4923461 protected against type 2 diabetes, which could suggest neuronal and peripheral distinctive ways of actions for the protein. SH2B1 rs7498665 associated with type 2 diabetes independently of BMI

Prevalence of Mistreatment or Belittlement among Medical Students – A Cross Sectional Survey at a Private Medical School in Karachi, Pakistan

Background: Mistreatment or belittlement of medical students either by faculty or fellow students has often been reported. Perception of mistreatment has also been associated with increased degree of psychological morbidity. There is a lack of such studies being conducted amongst the medical students of Pakistan. The aim of this study was to determine the prevalence and forms of perceived mistreatment and presence of mental health morbidity in a private medical school in Pakistan. Also, any association between mental health morbidity and mistreatment was to be identified. Methods: A cross sectional study was carried out on medical students from Aga Khan University Hospital, Karachi, Pakistan during the period of June-September 2007. A self administered questionnaire, adapted from Frank et al and Baldwin et al was distributed to a total of 350 students. The questionnaire consisted of three parts: the first dealing with the demographics of the population, the second concerning the various forms of mistreatment, while the third assessed the mental health of students using the General Health Questionnaire 12(GHQ12). Descriptive statistics were performed. The Chi-square test and Fisher\u27s exact tests were applied. Results: A total of 350 students were approached out of which 232 completed the questionnaire giving a response rate of 66.2%. Mistreatment was reported by 62.5% (145/232) of the respondents. Of these, 69.7% (83/145) were males and 54.9% (62/145) were females. There was a significant relationship between gender, year division, stress at medical school and possible use of drugs/alcohol and reported mistreatment but no statistical relationship was seen with psychiatric morbidity. The overall prevalence of psychological morbidity was 34.8% (77/221). Conclusion: This study suggests high prevalence of perceived mistreatment and psychological morbidity among Pakistani medical students. However, no association was found between these two aspects of medical student education. There is a need to bring about changes to make the medical education environment conducive to learning. Increased student feedback, support systems and guidance about progress throughout the year and the provision of adequate learning resources may provide help with resolving both of these issues

Enhanced prediction of breast cancer prognosis by evaluating expression of p53 and prostate-specific antigen in combination

p53 gene mutation is the most common genetic alteration in neoplastic diseases, including breast cancer, for which p53 alteration may indicate poor prognosis. Recent clinical evidence suggests that prostate-specific antigen (PSA) expression may identify breast cancer patients with favourable outcome. Assessment of p53 and PSA in combination, potentially offering improved prediction, has not yet been performed. Extracts from 952 primary breast carcinomas were assayed for PSA and p53 by quantitative enzyme-linked immunosorbent assays (ELISAs) developed by the authors. Concentrations of each marker were classified as negative or positive on the basis of median and 30th percentile cut-off points for p53 and PSA respectively. Patients followed for a median of 6 years having different combinations of negative or positive status for PSA and p53 were compared with respect to the relative risks (RRs) for relapse and death by Cox proportional hazards regression analysis, in which an interaction term was also evaluated, and with respect to disease-free survival (DFS) and overall survival (OS) probabilities by Kaplan–Meier plots and log-rank tests. Multivariate models were adjusted for oestrogen and progesterone receptor status, nodal status, patient age, tumour size, DNA ploidy, S phase fraction and receipt of chemotherapy. Interactions were not found between the status of PSA and p53 in the Cox models, in which PSA-negativity (RR = 1.47, P = 0.020 for DFS, and RR = 1.49, P = 0.023 for OS) and p53-positivity (RR = 1.46, P = 0.017 for DFS, and RR = 1.41, P = 0.033 for OS) were individually associated with prognosis. Evaluation of a combined three-level variable revealed that PSA(–)/p53(+) patients had significantly higher risks for relapse (RR = 2.13, P < 0.001) and death (RR = 2.08, P = 0.001) than PSA(+)/p53(–) patients, and that patients positive or negative for both markers had intermediate risks for the outcome events in the same multivariate analysis (RR = 1.45 for both DFS and OS). The results of our study demonstrate that the assessment of combined PSA and p53 expression status by ELISAs, easily applicable to breast tumour extracts prepared for steroid hormone receptor analyses, may stratify breast cancer patients into groups differing by relapse and death risks of greater magnitude than offered by the assessment of either p53 or PSA alone. © 1999 Cancer Research Campaig