Medicine, Dentistry & Health Sciences Collected Works - Research Publications
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MUC13 overexpression in renal cell carcinoma plays a central role in tumor progression and drug resistance
Metastatic renal cell carcinoma is a largely incurable disease, and existing treatments targeting angiogenesis and tyrosine kinase receptors are only partially effective. Here we reveal that MUC13, a cell surface mucin glycoprotein, is aberrantly expressed by most renal cell carcinomas, with increasing expression positively correlating with tumor grade. Importantly, we demonstrated that high MUC13 expression was a statistically significant independent predictor of poor survival in two independent cohorts, particularly in stage 1 cancers. In cultured renal cell carcinoma cells MUC13 promoted proliferation and induced the cell cycle regulator, cyclin D1, and inhibited apoptosis by inducing the anti-apoptotic proteins, BCL-xL and survivin. Silencing of MUC13 expression inhibited migration and invasion, and sensitized renal cancer cells to killing by the multi-kinase inhibitors used clinically, sorafenib and sunitinib, and reversed acquired resistance to these drugs. Furthermore, we demonstrated that MUC13 promotion of renal cancer cell growth and survival is mediated by activation of nuclear factor κB, a transcription factor known to regulate the expression of genes that play key roles in the development and progression of cancer. These results show that MUC13 has potential as a prognostic marker for aggressive early stage renal cell cancer and is a plausible target to sensitize these tumors to therapy.
Bone turnover markers and bone mineral density in healthy mother-daughter pairs from South India
Bone turnover markers (BTMs) provide important insights into the dynamics of bone remodelling and are subjected to preanalytical and ethnic variations in addition to influence of genetic and environmental factors. AIM/OBJECTIVES: To derive ethnicity specific reference range for BTMs and to study their correlation with Bone Mineral Density (BMD) in a cohort of healthy postmenopausal women and their premenopausal daughters and to look at the impact of maternal bone mineral status on daughters bone health. MATERIAL AND METHODS: This community based cross sectional study included 300 subjects (150 mother-daughter pairs). Demographic details were collected. Fasting blood and a second void morning urine samples were obtained for measurement of BTMs (sCTX, sPTNP1, sOC and urine DPD respectively) and bone mineral parameters. BMD was measured by DXA scan. RESULTS: Osteoporosis was seen in 44·7% of the postmenopausal women. Ethnicity specific reference ranges of BTMs were derived for the study population. Significant inverse correlation was found between all BTMs (except urine DPD) and BMD(P < 0·05). Daughters of mothers with osteoporosis at spine and femoral neck had lower BMD, compared to daughters of mothers without osteoporosis(P = 0·03 & 0·05). CONCLUSION: Apart from deriving the ethnicity specific reference range for BTMs and finding a significant inverse correlation between BTM and BMD, this study found significantly lower BMD in daughters of mothers with osteoporosis at spine and femoral neck implicating the probable interplay of genetic, epigenetic and similar environmental factors.
Tropical Drosophila pandora carry Wolbachia infections causing cytoplasmic incompatibility or male killing
Wolbachia infections have been described in several Drosophila species, but relatively few have been assessed for phenotypic effects. Cytoplasmic incompatibility (CI) is the most common phenotypic effect that has been detected, while some infections cause male killing or feminization, and many Wolbachia infections have few host effects. Here, we describe two new infections in a recently described species, Drosophila pandora, one of which causes near-complete CI and near-perfect maternal transmission (the "CI" strain). The other infection is a male killer (the "MK" strain), which we confirm by observing reinitiation of male production following tetracycline treatment. No incompatibility was detected in crosses between CI strain males and MK strain females, and rare MK males do not cause CI. Molecular analyses indicate that the CI and MK infections are distantly related and the CI infection is closely related to the wRi infection of Drosophila simulans. Two population surveys indicate that all individuals are infected with Wolbachia, but the MK infection is uncommon. Given patterns of incompatibility among the strains, the infection dynamics is expected to be governed by the relative fitness of the females, suggesting that the CI infection should have a higher fitness. This was evidenced by changes in infection frequencies and sex ratios in population cages initiated at different starting frequencies of the infections.
'That red flag on your file': misinterpreting physical symptoms as mental illness.
AIMS AND OBJECTIVES: To ascertain the views and experiences of mental health consumers regarding the availability and quality of care and treatment received for their physical health needs. BACKGROUND: People diagnosed with mental illness have higher occurrence of physical health problems. Responsive health care services are crucial for prevention and management of physical health problems, and for reducing disparities in health between people diagnosed with mental illness and those who are not. There is limited research giving voice to consumer perspectives on their experiences with health care providers. DESIGN: Exploratory qualitative. METHODS: Focus group interviews with mental health consumers accessed via a consumer network group in a region of Australia (n = 31). All interview audio recordings were transcribed professionally. Interviews were thematically analysed. RESULTS: The main themes were: symptomising; failure to act and alertness to prejudice. The first two themes were consumer perceptions of the actions and behaviours of health professionals, and the third describes consumer responses to these behaviours and actions. Consumers described increased risks of illness and death because of undiagnosed physical illness despite their physical health advice-seeking as the reason for the health consultation. CONCLUSION: Health care providers' non-recognition of physical health problems presents a clear example of a significant and potentially life threatening health inequity. The service provider responses described by participants suggest that mental health consumers' physical health needs may not be taken seriously. RELEVANCE TO CLINICAL PRACTICE: Clinicians need to take seriously the physical health needs and concerns of people with mental illness. Nurses can play a crucial role in the prevention of diagnostic overshadowing as part of a broader direction of balancing biomedical perspectives with other approaches to health care.
Participative mental health consumer research for improving physical health care: An integrative review.
People with mental illness have a significantly lower life expectancy and higher rates of chronic physical illnesses than the general population. Health care system reform to improve access and quality is greatly needed to address this inequity. The inclusion of consumers of mental health services as co-investigators in research is likely to enhance service reform. In light of this, the current paper reviews mental health consumer focussed research conducted to date, addressing the neglect of physical health in mental health care and initiatives with the aim of improving physical health care. The international literature on physical healthcare in the context of mental health services was searched for articles, including mental health consumers in research roles, via Medline, CINAHL and Google Scholar, in October 2015. Four studies where mental health consumers participated as researchers were identified. Three studies involved qualitative research on barriers and facilitators to physical health care access, and a fourth study on developing technologies for more effective communication between GPs and patients. This review found that participatory mental health consumer research in physical health care reform has only become visible in the academic literature in 2015. Heightened consideration of mental health consumer participation in research is required by health care providers and researchers. Mental health nurses can provide leadership in increasing mental health consumer research on integrated care directed towards reducing the health gap between people with and without mental illness.
Gene expression profiling of reproductive meristem types in early rice inflorescences by laser microdissection
In rice, inflorescence architecture is established at early stages of reproductive development and contributes directly to grain yield potential. After induction of flowering, the complexity of branching, and therefore the number of seeds on the panicle, is determined by the activity of different meristem types and the timing of transitions between them. Although some of the genes involved in these transitions have been identified, an understanding of the network of transcriptional regulators controlling this process is lacking. To address this we used a precise laser microdissection and RNA-sequencing approach in Oryza sativa ssp. japonica cv. Nipponbare to produce quantitative data that describe the landscape of gene expression in four different meristem types: the rachis meristem, the primary branch meristem, the elongating primary branch meristem (including axillary meristems), and the spikelet meristem. A switch in expression profile between apical and axillary meristem types followed by more gradual changes during transitions in axillary meristem identity was observed, and several genes potentially involved in branching were identified. This resource will be vital for a mechanistic understanding of the link between inflorescence development and grain yield.
A randomised controlled trial comparing meat-based with human cadaveric models for teaching ultrasound-guided regional anaesthesia
The aim of this prospective, blinded, randomised controlled study was to compare novices' acquisition of the technical skills of ultrasound-guided regional anaesthesia using either a meat phantom model or fresh-frozen human cadavers. The primary outcome was the time taken to successfully perform an ultrasound-guided sciatic nerve block on a cadaver; secondary outcomes were the cumulative score of errors, and best image quality of the sciatic nerve achieved. After training, the median (IQR [range]) time taken to perform the block was 311(164-390 [68-600]) s in the meat model trained group and 210 (174-354 [85-600]) s in the fresh-frozen cadaver trained group (p = 0.24). Participants made a median (IQR [range]) of 18 (14-33 [8-55]) and 15 (12-22 [8-44]) errors in the two groups respectively (p = 0.39). The image quality score was also not different, with a median (IQR [range]) of 62.5 (59.4-65.6 [25.0-100.0])% vs 62.5 (62.5-75.0 [25.0-87.5])% respectively (p = 0.58). The training and deliberate feedback improved all participants' block performance, the median (IQR [range]) times being 310 (206-532 [110-600]) s before and 240 (174-354 [85-600]) s after training (p = 0.02). We conclude that novices taught ultrasound scanning and needle guidance skills using an inexpensive and easily constructed meat model perform similarly to those trained on a cadaveric model.
Lysine acetylation of the Mycobacterium tuberculosis HU protein modulates its DNA binding and genome organization
Nucleoid-associated protein HU, a conserved protein across eubacteria is necessary for maintaining the nucleoid organization and global regulation of gene expression. Mycobacterium tuberculosis HU (MtHU) is distinct from the other orthologues having 114 amino acid long carboxyl terminal extensions with a high degree of sequence similarity to eukaryotic histones. In this study, we demonstrate that the DNA binding property of MtHU is regulated by posttranslational modifications akin to eukaryotic histones. MtHU purified from M. tuberculosis cells is found to be acetylated on multiple lysine residues unlike the E. coli expressed recombinant protein. Using coimmunoprecipitation assay, we identified Eis as one of the acetyl transferases that interacts with MtHU and modifies it. Although Eis is known to acetylate aminoglycosides, the kinetics of acetylation showed that its protein acetylation activity on MtHU is robust. In vitro Eis modified MtHU at various lysine residues, primarily those located at the carboxyl terminal domain. Acetylation of MtHU caused reduced DNA interaction and alteration in DNA compaction ability of the NAP. Over-expression of the Eis leads to hyperacetylation of HU and decompaction of genome. These results provide first insights into the modulation of the nucleoid structure by lysine acetylation in bacteria.
Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome
Hunter syndrome or mucopolysaccharidosis type II (MPSII) is caused by pathogenic variants in the IDS gene. This is the first study that examines the mutational spectrum in 25 unrelated Mexican MPSII families. The responsible genotype was identified in 96% of the families (24/25) with 10 novel pathogenic variants: c.133G>C, c.1003C>T, c.1025A>C, c.463_464delinsCCGTATAGCTGG, c.754_767del, c.1132_1133del, c.1463del, c.508-1G>C, c.1006+1G>T and c.(-217_103del). Extensive IDS gene deletions were identified in four patients; using DNA microarray analysis two patients showed the loss of the entire AFF2 gene, and epilepsy developed in only one of them. Wide allelic heterogeneity was noted, with large gene alterations (e.g. IDS/IDSP1 gene inversions, partial to extensive IDS deletions, and one chimeric IDS-IDSP1 allele) that occurred at higher frequencies than previously reported (36% vs 18.9-29%). The frequency of carrier mothers (80%) is consistent with previous descriptions (>70%). Carrier assignment allowed molecular prenatal diagnoses. Notably, somatic and germline mosaicism was identified in one family, and two patients presented thrombocytopenic purpura and pancytopenia after idursulfase enzyme replacement treatment. Our findings suggest a wide allelic heterogeneity in Mexican MPSII patients; DNA microarray analysis contributes to further delineation of the resulting phenotype for IDS and neighboring loci deletions.
Examining the N400m in affectively negative sentences: A magnetoencephalography study
Magnetoencephalography was used to examine the effect on the N400m of reading words that create emotional violations in sentences. The beginnings of the sentences were affectively negative and were completed with either a negative congruous, positive incongruous, or neutral incongruous adjective (e.g., "My mother was killed and I felt bad/great/normal"). The task conditions were also manipulated to favor semantic over affective processing. Compared to the sentences with the congruous negative adjectives, the results of sensor space analysis showed that there was an N400m effect with the sentences with the neutral but not positive adjectives, despite both types of sentences containing an emotional violation. Source localization results showed a similar pattern where the sentences with the incongruous positive versus congruous negative adjectives showed no significant N400m effect in the temporal and frontal areas examined, but the sentences with the incongruous neutral versus incongruous positive adjectives in the temporal areas did, particularly the left middle temporal gyrus. These results suggest that (a) the N400m effect was likely to be caused by the incongruous neutral adjectives being comparatively harder to integrate into a negative emotional context than the incongruous positive ones, (b) emotional context created by the negative sentence stems caused deeper semantic processing of the incongruous positive adjectives to be bypassed, and (c) negative affective context was generated from reading the sentences even in task conditions where it has not been generated with isolated words.
Embedding a physical health nurse consultant within mental health services: Consumers' perspectives.
The life expectancy of people living with mental illness is significantly shorter than that of the rest of the population. Despite the profound impact of physical health issues on both quality of life and life expectancy, the perspectives of mental health consumers have yet to be thoroughly explored. Furthermore, research has focused far more on describing barriers than on identifying solutions. This paper reports on findings from a qualitative exploratory research study, with the aim to examine the potential role of a specialist nurse with advanced physical health-care skills. Focus groups were conducted with 31 consumers. Data were analysed thematically. The concept of a role like this was supported; however, participants stressed: (i) the importance of integration between health professionals and various components of the health-care system; and (ii) the need for culture change for nurses to work from a less medically-dominated approach. Previous research literature suggests that a nursing position dedicated to physical health care and coordination might produce positive outcomes for mental health consumers. The findings from the current research project emphasize the need for consumers to be identified as key stakeholders in a solution-focused approach to improved physical health care for mental health consumers.