Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior.

Epitranscriptomic mechanisms linking tRNA function and the brain proteome to cognition and complex behaviors are not well described. Here, we report bi-directional changes in depression-related behaviors after genetic disruption of neuronal tRNA cytosine methylation, including conditional ablation and transgene-derived overexpression of Nsun2 in the mouse prefrontal cortex (PFC). Neuronal Nsun2-deficiency was associated with a decrease in tRNA m5C levels, resulting in deficits in expression of 70% of tRNAGly isodecoders. Altogether, 1488/5820 proteins changed upon neuronal Nsun2-deficiency, in conjunction with glycine codon-specific defects in translational efficiencies. Loss of Gly-rich proteins critical for glutamatergic neurotransmission was associated with impaired synaptic signaling at PFC pyramidal neurons and defective contextual fear memory. Changes in the neuronal translatome were also associated with a 146% increase in glycine biosynthesis. These findings highlight the methylation sensitivity of glycinergic tRNAs in the adult PFC. Furthermore, they link synaptic plasticity and complex behaviors to epitranscriptomic modifications of cognate tRNAs and the proteomic homeostasis associated with specific amino acids.

Current practices of Western Australian general dentists regarding management of patients on anticoagulant/antiplatelet therapy.

PURPOSE: Currently, there are little to no published studies outlining general dentists' knowledge in the management of patients on anticoagulant/antiplatelet therapies in Australia. The aim of this study was to investigate the current practices of Western Australian (WA) general dentists with regards to dental management of patients taking anticoagulants/antiplatelets. MATERIALS AND METHODS: WA dentists were invited to undertake a survey to investigate their knowledge on the management of patients taking anticoagulant/antiplatelet. The questionnaire provided to WA general dentists consisted of pre-extraction advice on patients (direct oral anticoagulants [DOACs], antiplatelets, warfarin, dual antiplatelets and antiplatelet/anticoagulant). Results were analysed using descriptive statistics as well as chi-square tests. RESULTS: Of the 89 participants, 40.5% had <5 years of general dental experience. Most WA general dentists (64%-71%) responded with 'no change' when performing extractions on patients on DOACs, antiplatelet therapy, warfarin, dual antiplatelets and antiplatelets/anticoagulants (P = 0.00). Furthermore, dentists with 6-10 years of experience were more likely to cease antiplatelet for 24 h before extractions (P < 0.05). Dentists who extracted 10-30 teeth per month were likely to stop antiplatelets and DOACs for more than 48 h compared to other groups (P < 0.05). CONCLUSION: Most WA dentists would not cease anticoagulant/antiplatelet therapy when undergoing dental extractions.

Routine antiseptic baths and MRSA decolonization: diverse approaches across Singapore's acute-care hospitals.

To determine the variation in practices on meticillin-resistant Staphylococcus aureus (MRSA) surveillance and management of MRSA-colonized patients amongst 17 acute healthcare facilities in Singapore, the Ministry of Health convened a sharing session with Infection Prevention and Control Leads. All hospitals practised close to universal MRSA entry swabbing in keeping with national policy. There were, however, major variations in the response to both positive and negative surveillance swabs across facilities including the role of routine antiseptic bathing and MRSA decolonization. Most undertaking decolonization considered its role to be in 'bioburden reduction' rather than longer-term clearance.

Rendezvous endovascular common carotid artery stenting (RECCAS) technique for symptomatic steno-occlusive disease.

This report describes a patient who presented with acute but transient right arm weakness and altered sensation secondary to severe stenosis of the left common carotid artery (CCA) origin. Endovascular stenting of the stenosed origin was achieved utilising a novel rendezvous technique through combined retrograde common carotid artery and anterograde transfemoral approaches. This technique has numerous potential advantages over traditional transfemoral endovascular and open retrograde common carotid artery approaches. It allows increased procedural control and success in traversing the stenosis and provides a smooth transition for the stent delivery catheter. An open cutdown procedure or open surgical technique is not required. Our patient recovered well from the procedure with no complications within the three-month follow up period.

Women in interventional radiology: insights into Australia's gender gap.

AIM: To assess differences in the exposure, teaching, knowledge, appreciation, and interest in interventional radiology (IR) between male and female doctors prior to specialisation and to identify potential predisposing factors to the gender inequality in interventional radiology. MATERIALS AND METHODS: A prospective cross-sectional multicentre study was conducted using in-person and web-based distribution of a voluntary, anonymous questionnaire to junior doctors yet to commence specialisation at 11 health services across two Australian states. RESULTS: Complete responses were provided by 333 junior doctors (21.9% response rate). Women were significantly less likely than men to consider a career in IR (13.1% versus 29.7%, p < 0.001). No other statistically significant gender disparities were identified, as both men and women reported low levels of prior teaching and exposure to IR, strong belief in the importance of IR, and suboptimal knowledge of IR. CONCLUSIONS: The gender gap amongst practising Australian interventional radiologists is perpetuated by a consistent gender gap in upcoming junior doctors' desire to pursue IR. This disparity exists despite junior doctors receiving the same exposure and opportunities in interventional radiology, possibly suggesting that preconceived stereotypes or psychosocial factors deter females from pursuing this procedural, male-dominated subspecialty. Future qualitative studies are required to confirm this hypothesis, in conjunction with prospective, experimental trials to determine whether changes in education, mentorship, and advocacy can promote gender equality.

Health-Related Quality of Life in Patients Treated with Continuous Ambulatory Peritoneal Dialysis and Automated Peritoneal Dialysis in Singapore.

OBJECTIVE: This study aimed to compare the health-related quality of life (HRQOL) in patients with end-stage renal disease (ESRD) treated with continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD) in Singapore. METHODS: The data used in this study were from two cross-sectional surveys of ESRD patients. HRQOL was assessed using the Kidney Disease Quality of Life (KDQOL) instrument. Socio-demographic characteristics and clinical data were collected. The physical component summary (PCS) and mental component summary (MCS) scores, kidney disease component summary (KDCS) score and its three scales (symptoms, effects, burden), and one health utility score [EuroQol 5-dimension (EQ-5D)] were calculated and compared between CAPD and APD using multivariate linear regression. RESULTS: In total, 266 patients were included, with 145 on CAPD (mean age 60.8 years) and 121 on APD (mean age 57.4 years). After adjustment for all variables collected, APD patients had significant higher scores in PCS and KDQOL symptoms than CAPD patients, suggesting that APD was associated with better physical health and milder dialysis-related symptoms. CONCLUSION: The HRQOL of CAPD and APD patients was largely equivalent in Singapore, but APD patients seemed to experience better physical health and be less bothered by dialysis-related symptoms.

Quality of life and emotional distress in patients and burden in caregivers: a comparison between assisted peritoneal dialysis and self-care peritoneal dialysis.

PURPOSE: Assisted peritoneal dialysis (PD) involving caregivers allows more patients to get started on home-based dialysis with good clinical outcomes, but evidence on patient-reported and caregiver-reported outcomes is lacking. This study aimed to compare assisted PD versus self-care PD on quality of life (QoL) and psychosocial outcomes for patients and caregivers. The effect of PD modality [automated PD (APD); continuous ambulatory PD (CAPD)] in relation to self-care or assisted care was also examined. METHODS: A cross-sectional sample of 231 PD patients [142 self-care (57 APD/85 CAPD) and 89 assisted care PD (45 APD/44 CAPD)], 72 caregivers of assisted PD patients and 39 family members of self-care PD patients completed the Kidney Disease Quality of Life Short Form (KDQOL-SF), World Health Organisation Quality of Life Instrument-brief and the Hospital Anxiety and Depression Scale. Caregivers and family members completed the Lay Care-Giving for Adults Receiving Dialysis questionnaire and Zarit Burden Interview. RESULTS: Case-mix-adjusted comparisons indicated comparable QoL in all dimensions with the exception of physical SF-12 (p = .001) and the KDQOL effects of kidney disease in favour of self-care PD. Levels of anxiety (9.72 ± 4.90; 8.25 ± 5.22) and depression (8.63 ± 3.80; 6.35 ± 4.76) were equivalent in assisted PD and self-care PD, respectively. Assisted PD caregivers reported more task-orientated duties (p = .007), yet levels of perceived burden were equal to those reported by family members of self-care PD. CONCLUSION: Our findings of mostly comparable patient and caregiver outcomes in assisted PD and self-care PD suggest that caregiver burden and QoL should not be a barrier to using assisted PD.

Health-related quality of life of Asian patients with end-stage renal disease (ESRD) in Singapore.

BACKGROUND: This study aimed to identify factors associated with the health-related quality of life (HRQOL) of multiethnic Asian end-stage renal disease (ESRD) patients treated with dialysis. The role of dialysis modality was also explored. METHODS: Data used in this study were from two cross-sectional surveys of Singaporean ESRD patients on haemodialysis (HD) or peritoneal dialysis (PD). In both surveys, participants were assessed using the kidney disease quality of life (KDQOL) instrument and questions assessing socio-demographic characteristics. Clinical data including co-morbidity (measured by Charlson comorbidity index [CCI]), albumin level, haemoglobin level, and dialysis-related variables (e.g. dialysis vintage and dialysis adequacy) were retrieved from medical records. The 36-item KDQOL (KDQOL-36) was used to generate three summary scores (physical component summary [PCS], mental component summary [MCS] and kidney disease component summary [KDCS]) and two health utility scores (Short Form 6-dimension [SF-6D] and EuroQol 5-dimension [EQ-5D]). Linear regression analysis was performed to examine the association of factors with each of the HRQOL scale scores. RESULTS: Five hundred and two patients were included in the study (mean age 57.1 years; male 52.4 %; HD 236, PD 266). Mean [standard deviation (SD)] PCS, MCS and KDCS scores were 37.9 (9.7), 46.4 (10.8) and 57.6 (18.1), respectively. Mean (SD) health utility score was 0.66 (0.12) for SF-6D and 0.60 (0.21) for EQ-5D. In multivariate regression analysis, factors found to be significantly associated with better HRQOL included: young (<45 years) or old age (>60 years), low CCI (<5), high albumin (≥37 g/l) and high haemoglobin (≥11 g/dl) with PCS; long dialysis vintage (≥3.5 years) with MCS; old age, Malay ethnicity and PD modality with KDCS; low CCI, high albumin and high haemoglobin with EQ-5D and high albumin with SF-6D. CONCLUSIONS: Clinical characteristics are better predictors of HRQOL in ESRD patients than socio-demographics in Singapore. Dialysis modality has no impact on the health utility of those patients.

Role of (chemo)-radiotherapy in resectable gastric cancer.

The prognosis of patients with locally advanced gastric cancer remains poor, despite radical surgical resection. Adjuvant therapy has been shown to improve survival and, in Western countries, is delivered either postoperatively (chemoradiotherapy) or perioperatively (chemotherapy). Debate continues as to which of these represents the optimal strategy. High-dose gastric irradiation comes at the expense of significant toxicity, and increasing efforts have focused on attempts to reduce toxicity and normal tissue doses. The development of advancing radiotherapy technologies now allows improved target delineation and coverage. However, gastric irradiation remains technically challenging and requires an understanding of postoperative surgical anatomy, patterns of failure and lymph node drainage, as well as an appreciation of the uncertainties around organ motion and filling. Ongoing trials are examining the optimal strategy in which to incorporate (chemo)-radiotherapy, as well as the addition of targeted therapies, in gastric cancer. This overview discusses the current role and evidence for (chemo)-radiotherapy, as well as the technical challenges encountered in the radiotherapeutic management of resectable gastric cancer.

Definitive chemoradiotherapy for oesophageal cancer -- a promising start on an exciting journey.

Despite many advances in the management of oesophageal cancer, survival rates remain poor. Currently there is no clear consensus on the optimum management modality for localised disease. Surgery alone or combined with neoadjuvant chemotherapy or chemoradiotherapy and definitive chemoradiotherapy are all treatment options used for treating selected patient groups throughout the world. This overview discusses the evidence for definitive chemoradiotherapy, its role for certain patient groups and compared with other treatment options and how it has evolved with emerging technologies over recent decades. It highlights some key areas of research for future trials, including more precise treatment delivery, treatment intensification and a possible randomised controlled trial comparing radiation and surgical-based treatment.

Quality of life and emotional distress between patients on peritoneal dialysis versus community-based hemodialysis.

PURPOSE: Patient-reported outcomes are important endpoints to evaluate new models of renal delivery. This is the first study to compare Quality of Life (QOL) and emotional adjustment outcomes between patients on community-based hemodialysis (HD) and those on peritoneal dialysis (PD). METHODS: Data were collected between 2009 and 2011 from a cross-sectional sample of 232 HD patients and 201 PD patients recruited through community dialysis centers and outpatient PD clinics in Singapore. Participants completed the Hospital Anxiety and Depression Scale, World Health Organization Quality of Life Brief and the Short form for the Kidney Disease Quality of Life. Measures of ESRD severity, comorbidity and biochemistry were also collected. RESULTS: Physical and emotional QOL impairments were noted for both dialysis groups. Case-mix-adjusted comparisons indicated higher symptoms of depression (p = 0.027), and poorer physical health yet higher satisfaction with care (p = 0.001) in PD relative to community-based HD. CONCLUSIONS: Peritoneal dialysis regimes offer flexibility and autonomy under the support of PD teams. Although outcomes for most QOL domains measured were equivalent, PD patients are more satisfied with care but are at risk for emotional distress and provide poor ratings of physical health. Further research is needed to explore the expansion of standards of care to address psychosocial needs in PD populations.

Quantum-classical simulations of the electronic stopping force and charge on slow heavy channelling ions in metals.

By simulating the passage of heavy ions along open channels in a model crystalline metal using semi-classical Ehrenfest dynamics we directly investigate the nature of non-adiabatic electronic effects. Our time-dependent tight-binding approach incorporates both an explicit quantum mechanical electronic system and an explicit representation of a set of classical ions. The coupled evolution of the ions and electrons allows us to explore phenomena that lie beyond the approximations made in classical molecular dynamics simulations and in theories of electronic stopping. We report a velocity-dependent charge-localization phenomenon not predicted by previous theoretical treatments of channelling. This charge localization can be attributed to the excitation of electrons into defect states highly localized on the channelling ion. These modes of excitation only become active when the frequency at which the channelling ion moves from interstitial point to equivalent interstitial point matches the frequency corresponding to excitations from the Fermi level into the localized states. Examining the stopping force exerted on the channelling ion by the electronic system, we find broad agreement with theories of slow ion stopping (a stopping force proportional to velocity) for a low velocity channelling ion (up to about 0.5 nm fs(-1) from our calculations), and a reduction in stopping power attributable to the charge localization effect at higher velocities. By exploiting the simplicity of our electronic structure model we are able to illuminate the physics behind the excitation processes that we observe and present an intuitive picture of electronic stopping from a real-space, chemical perspective.

Impact of patterns of proteinuria on renal allograft function and survival: a prospective cohort study.

BACKGROUND: Proteinuria is an important complication in renal transplant recipients. The aim of this prospective study was to evaluate the long-term impact of transplant proteinuria patterns on allograft function and survival. METHODS: We analyzed urinary protein of a cohort of 83 renal transplants with proteinuria ≥0.5 g/d by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and radial immunogel diffusion assay. After initial stratification and analysis, the cohort was followed up for 16 yr. The graft outcome and survival were analyzed using Cox regression model to determine their association with different patterns of initial transplant proteinuria. RESULTS: Group with predominantly glomerular (middle- and high-molecular-weight with or without low-molecular-weight) proteinuria (61%) had higher serum creatinine (p < 0.001) than the group with predominantly tubular (low-molecular-weight) proteinuria (39%). The incidences of chronic graft dysfunction and graft loss had increased in the glomerular proteinuria group (p < 0.001, hazard ratio 3.6, 95% confidence interval 1.7-7.5 and p < 0.001, hazard ratio 4.9, 95% confidence interval 1.9-12.1, respectively). Patient death did not differ (p = 0.434, hazard ratio 1.5, 95% confidence interval 0.5-4.5). CONCLUSION: Proteinuria in renal transplants can be differentiated into glomerular and tubular types based on molecular weight. Glomerular proteinuria is associated with significant increase in graft dysfunction and graft loss.

The changing pattern of primary glomerulonephritis in Singapore and other countries over the past 3 decades.

This review of 2,586 renal biopsies over the past 3 decades in Singapore documents the changing pattern of glomerulonephritis (GN) from that of a third world country to that of a developed nation. In the 1st decade, mesangial proliferative glomerulonephritis was the most common form of primary GN, just as it was in the surrounding Asian countries. In the 2nd decade, the prevalence of mesangial proliferative GN decreased with a rise in membranous, GN which is also seen in China and Thailand. In the 3rd decade, there was a dramatic increase in focal sclerosing glomerulosclerosis. This increase reflects aging and obesity in keeping with more developed countries like Australia, India, Thailand and the United States of America. IgA nephritis remains the most common GN. Apart from the geographical influence, other socioeconomic factors play a significant role in the evolution of the renal biopsy pattern. Mesangial proliferative GN remains prevalent in many Asian countries, but in Singapore the prevalence is decreasing just as it is in Japan, Korea and Malaysia. Worldwide, the prevalence of focal sclerosing glomerulosclerosis continues to increase in many countries.

Beneficial effects of high-dose losartan in IgA nephritis.

AIM: Several short-term studies have reported the efficacy of high-dose ARB in reducing proteinuria in patients with diabetic nephropathy. The benefits of long-term high-dose ARB losartan in IgA nephritis have not been explored. METHOD: This was a 6-year randomized trial in 207 patients with IgA nephritis comparing high-dose ARB (losartan 200 mg/day) with normal dose ARB (losartan 100 mg/day), normal dose ACEI (20 mg/day) and low-dose ACEI (10 mg/day). Multivariate ANOVA was used to test the effect of drug treatment on both eGFR and total urinary protein (TUP). RESULTS: Comparing patients on high-dose ARB (n = 63) with those on normal dose ARB (n = 43), normal dose ACEI (n = 61) and low-dose ACEI (n = 40), patients on high Dose ARB had significantly higher eGFR (p < 0.0005) and lower proteinuria (p < 0.005) at the end of the study. The loss in eGFR was 0.7 ml/min/year for high-dose ARB compared to 3.2 - 3.5 ml/ min/year for the other 3 groups (p = 0.0005). There were more patients on high-dose ARB with improvement in eGFR compared to other 3 groups (p < 0.001). CONCLUSION: Data from this study suggest that high-dose ARB therapy is more efficacious in reducing proteinuria and preserving renal function when compared with normal dose ARB and ACEI. In Year 5, patients on high-dose ARB had a gain in eGFR suggesting that there is possibility of recovery of renal function in these patients on long-term high-dose therapy.

Resin bonding using an all-etch or self-etch adhesive to enamel after carbamide peroxide and/or CPP-ACP treatment.

BACKGROUND: Limited evidence exists regarding the effect of carbamide peroxide and casein phosphopeptide amorphous calcium phosphate (CPP-ACP) on composite-enamel bonding. Microshear bond strengths, using either a total-etch or self-etching adhesive, to enamel treated with carbamide peroxide and/or CPP-ACP were investigated. MATERIALS AND METHODS: Twenty-six extracted human third molars were sectioned into four parts, each being allocated into one of the four groups (n=26): bleach (Polanight, 16% carbamide peroxide), CPP-ACP (GC Tooth Mousse), bleach and then CPP-ACP, or untreated (control). The surfaces were bonded with a total-etch bonding system (Single Bond) or a self-etching primer system (Clearfil SE Bond) and tested using a microshear test. RESULTS: A significant difference in bond strength was found between bonding systems. SE Bond showed the highest bond strength to untreated enamel (p < 0.05). The microshear bond strength of SE Bond decreased when the enamel was treated with carbamide peroxide, CPP-ACP or both (p < 0.05). Only combined use of carbamide peroxide and CPP-ACP significantly affected microshear bond strength with Single Bond. CONCLUSION: These findings suggest the shear bond strength of resin to enamel using a self-etching priming adhesive may be affected if the enamel is treated with a bleaching agent or CPP-ACP.

Protein expression profiling of normal and neoplastic canine prostate and bladder tissue.

Prostatic carcinoma is an important cancer in both men and dogs. Dogs have been a valuable animal model for investigating prostate cancer, but their relevance is unclear as the origin of canine prostatic carcinomas is unknown. We hypothesized that a proteomic approach for diagnosis of these neoplasms might provide quantitative data useful for more complete characterization of their origin. Protein expression profiles were prepared from normal canine prostate glands and bladders. The normal protein profiles were then compared with protein expression profiles of three canine prostatic carcinomas. Two-dimensional differential in-gel electrophoresis (2-D DIGE) was used to analyse an average of approximately 1000 proteins per carcinoma. When compared with normal prostate tissue, the carcinomas exhibited greater than 2.5-fold difference in expression for an average of 230 proteins. Similar proteomic comparisons between the carcinomas and the normal bladder revealed a greater than 2.5-fold difference in expression for an average of 208 proteins. Mass spectrometry and protein database homology were used to identify nine proteins (alpha-enolase, vimentin, GRP78, endoplasmin (GRP94), albumin, keratins 7 and 8, haptoglobin, and transferrin) overexpressed by the carcinomas. Statistical testing demonstrated that keratin 7, GRP78, and endoplasmin were significantly overexpressed in the carcinomas compared with normal prostate or bladder. Principal components analysis revealed that the carcinomas formed a unique cluster distinct from either the normal prostate or normal bladder. In conclusion, proteomic analysis revealed that whereas the majority of proteins expressed by canine prostatic carcinomas are also expressed by normal and neoplastic bladder and prostate tissue, the carcinomas contained unique protein components that allowed their segregation as a distinct group separate from normal canine prostate and bladder. Additionally, several proteins uniquely expressed by canine prostatic carcinomas were also identified.

Large enhancement of the thermopower in Na(x)CoO2 at high Na doping.

Research on the oxide perovskites has uncovered electronic properties that are strikingly enhanced compared with those in conventional metals. Examples are the high critical temperatures of the cuprate superconductors and the colossal magnetoresistance in the manganites. The conducting layered cobaltate Na(x)CoO2 exhibits several interesting electronic phases as the Na content x is varied, including water-induced superconductivity and an insulating state that is destroyed by field. Initial measurements showed that, in the as-grown composition, Na(x)CoO2 has moderately large thermopower S and conductivity sigma. However, the prospects for thermoelectric cooling applications faded when the figure of merit Z was found to be small at this composition (0.60.75, S undergoes an even steeper enhancement. At the critical doping x(p) approximately 0.85, Z (at 80 K) reaches values approximately 40 times larger than in the as-grown crystals. We discuss prospects for low-temperature thermoelectric applications.