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The association between the mineral content of drinking water and urolithiasis remains elusive. The aim of this study is to investigate whether the mineral composition of tap water correlates with urinary calculus composition. Patients with calculi that underwent biochemical analysis at two urological centres in the North-West of England between November 2015 and December 2020 were included. Calculus composition was reviewed with respect to patient demographics, serum biochemical variables, and water mineral composition data obtained from the local water supply company using patient postcodes. 1711 urinary tract calculi from 1518 patients, living in 87 water supply zones were included. Water sodium concentration was an independent predictor of mixed calcium oxalate/uric acid calculi (OR 1.157, p 0.001) and a negative independent predictor of calcium oxalate monohydrate (OR 0.896, p = 0.001) and dihydrate (OR 0.742, p = 0.034) calculi. Moreover, the magnesium-to-calcium ratio of tap water was a negative independent predictor of calcium oxalate monohydrate calculi (OR 0.001, p = 0.001), while tap water magnesium concentration inversely correlated with the percentage of calcium oxalate within calculi (r

Medical education researchers are often subject to challenges that include lack of funding, collaborators, study subjects, and departmental support. The construct of a research lab provides a framework that can be employed to overcome these challenges and effectively support the work of medical education researchers; however, labs are relatively uncommon in the medical education field. Using case examples, the authors describe the organization and mission of medical education research labs contrasted with those of larger research team configurations, such as research centers, collaboratives, and networks. They discuss several key elements of education research labs: the importance of lab identity, the signaling effect of a lab designation, required infrastructure, and the training mission of a lab. The need for medical education researchers to be visionary and strategic when designing their labs is emphasized, start-up considerations and the likelihood of support for medical education labs is considered, and the degree to which department leaders should support such labs is questioned.

Background: International guidelines state that any post-surgical tumour margin wider than tumour on ink following breast conserving surgery (BCS) for early invasive breast cancer is acceptable, based on analyses of margin width and local recurrence(LR). The aim of this review is to determine if margin involvement is associated with distant recurrence and secondarily to determine a minimum surgical margin to minimize both LR and distant recurrence (DR). Methods: A systematic review of literature published up to January 2021 was conducted according to PRISMA guidelines (PROSPERO: CRD42021232115). Unpublished data were sought from authors. The association between pathological margin status and distant and local recurrence were considered using random effects modelling. Results: Sixty-nine studies comprising 103,806 breast cancer patients were included. Across all studies, 9.7% of patients had tumour on ink and 13.9% had tumour on ink or a close margin (2mm) (HR: 1.38, 95%CI: 1.13-1.69, p Distant recurrence models by margin statusDistant RecurrenceHazard ratio95% CIp-valuePositive versus Negative margins2.101.65-2.69 Citation Format: James R Bundred, David Dodwell, Ramsay Cuttress, Sarah Michael, Beth Stuart, Bernd Holleczek, Kerri Beckmann, Jane Dahlstrom, Nigel J Bundred. Margin involvement in invasive breast cancer leads to increased distant recurrence after breast conservation: Systematic review [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-18-07.

Involved margins after surgery for early breast cancer increase the risk of local recurrence (LR), but international guidelines suggest that’ no tumour’ on ink is sufficient margin clearance after breast conserving surgery (BCS). Data on the effect of margin clearance on distant recurrence (DR) are lacking. Our aim was to determine the association between margin involvement, recurrence (DR) and breast cancer deaths. Methods Data from breast cancer units in Greater Manchester (GM) and the UK National Cancer Registry (NCRAS) were analysed. Margin status was prospectively recorded after surgery according to National Health Service Breast Screening Pathology (NHSBSP) minimum pathology data standards All patients underwent curative surgery and received adjuvant therapy according to local guidelines. Patients not undergoing curative surgery(T4, inflammatory or metastatic cancer) were excluded .Cox-proportional hazards models investigated factors associated with LR, DR and risk of breast cancer death.NCRAS records breast cancer deaths . Results GM analysis included 3270 patients from 2010 to 2014, 2295 (70.2%) had margins (>2mm) ,302 (9.2%) close (1-2mm) margin clearance and 673 (20.6%) involved (2mm. For Breast Conservation margins1mm (67.5%) and 3,935 (9.6%) were classed as “clear margins” and 9,325 (22.8%) cancer patients had involved margins 1mm were associated with reduced DR and should be essential surgical management. Current guidelines about surgical margins need to be re-evaluated to achieve reduced DR and cancer deaths. Citation Format: Nigel James Bundred, Sarah Michael, John Broggio, Anne Armstrong, Glen Martin, Mohamed Absar, Jane Ooi. Increased distant recurrence following margin involvement in early invasive breast cancer in two large UK cohorts [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-20-01.

This paper examines the Noun Phrases (NP"s), Verb Phrases (VP"s) and some simple sentences within Edo constructions in comparism to their structures in English language through a syntactic contractive analysis of the two languages. This study aimed at helping the Edo second language (L2) speaker overcome the problems of transfer from his (first language or mother tongue) L1 and to become more competent in the use of English structures. Chomsky"s ST (Standard Theory) model was used as it accounts for phrase structure rules and transformational subcomponents. It has helped the researcher to highlight the major differences between the two languages within the phrase structure. It was discovered that the Edo structures are not as elaborate as that of English and that the Edo speaker of L2 is likely to omit the determiner and mix up his tenses because of their verb usage. The work concluded that there is a need for language teachers to draw the attention of the students to the areas of differences and spend more time to teach the students the correct usage so that the students can become more skilful in the use of the two languages., {"references":["Ayeleru, B. (2000). \"Problems of Transfer and Interference in the Learning of French","Language by Anglophone and Yorubaphone Students\". Studies in English Language.","A.O.Babajide.Ed. Ibadan: Enicrownfit. 198-203.","Asowata, L. (2001). A Contrastive Study of the Syntactic Structures of English and Oza. Unpublished BA essay University of Ibadan","Bamgbose, A. (1995). \"New English in the Nigerian Environment\" in Bamgbose, Banjo and Thomas (eds). New Englishes: A West African perspective. Ibadan. Musuro","Banjo, L.. (1969). A Contrastive Study of Aspects of the Syntactic and Lexical Rules of English and Yoruba.. Unpublished PhD thesis. University of Ibadan","] Eberhard, D., Simons, G., and Fennig, C. (eds.). (2019) Ethnologue: Languages of the World,. URL http://www.ethnologue.com","Filani, I. (2013). A contrastive analysis of three semantic fields of English and Ugboko\" in W. Adegbite, A. Ogunsiji and O. Taiwo (Eds.), Linguistics and the Glocalisation of African languages for sustainable development (pp529-541). Ibadan: Universal Akada Books Nigeria Limited."]}

Introduction: Non-visible haematuria (NVH) is associated with a small risk of upper-tract urothelial carcinoma (UTUC), though there is little consensus on its investigation, particularly with regard to upper-tract imaging. This study aimed to determine whether the presentation of UTUC can guide investigation of NVH in patients under 60 years old. Methods: All patients investigated at our one-stop haematuria clinics under a cancer pathway were reviewed during a 5-year period, with all patients undergoing cystoscopy and upper-tract imaging. Retrospective analysis of all UTUC cases from our urological cancer multidisciplinary team meeting database over a 10-year period was also undertaken. Results: 2,129 patients with a median age of 67 years underwent urgent investigation for haematuria between March 2015 and February 2020. 449 cases presented with NVH, of whom 124 (27.6%) were under 60. Out of 21 cases of UTUC, only 2 presented with NVH; both were over the age of 60 years. Factors that independently predicted diagnosis with urinary-tract malignancy were age ≥60 (OR 3.70, p < 0.001), visible haematuria (OR 2.50, p = 0.006), and suspicious cystoscopic findings (OR 58.06, p < 0.001). Review of all 119 UTUC cases over 10 years found 6 cases (5.0%) presenting with NVH, with one (0.8%) also presenting under 60 years. Conclusion: Diagnosis with UTUC is rare in patients presenting with NVH under the age of 60 years. Routine use of CTU in this low-risk group is best avoided, with ultrasonography constituting a safer first-line upper-tract imaging modality. Guidelines that risk-stratify NVH patients may be effective in reducing unnecessary investigations.

Background No consensus exists regarding adequacy of margins after mastectomy. To determine if pathological margin proximity is associated with local (LR) or distant recurrence after mastectomy for early invasive breast cancer or ductal carcinoma in situ. Methods A systematic review of literature published from 1980 to 2019 and meta-analysis was conducted. Unpublished data were sought from authors (PROSPERO (CRD42019127541)). Thirty-four studies comprising 34,833 breast cancer patients were included in the quantitative synthesis. Eligible studies reported on patients undergoing curative mastectomy for cancer allowing estimation of outcomes in relation to margin status/width. The association between pathological margin status and local (LR) and distant recurrence was considered using random effects modelling. PRISMA guidelines were followed. Results Positive margins were associated with increased LR on multivariable analyses (HR, 2·64, (95%CI 2·01–3·46)) and LR was higher regardless of the distance of tumour from the margin defined as positive. After skin-sparing mastectomy, positive margins were associated with increased LR (HR 3·40, (95%CI 1·9–6·2)). In the 4 studies reporting distant recurrence, patients with involved margins had a higher risk (HR 1·53, (95%CI 1·03–2·25)). Conclusions Failure to achieve clear margins after mastectomy may increase the risks of local and distant recurrence. Adequate margin clearance should be recommended to minimize recurrence after mastectomy in National and International Guidelines.

Background: Leaving involved margins after mastectomy for breast cancer has been associated with an increased risk of local recurrence. Current guidelines endorse a policy that negative margins of no ink on tumour represent sufficient margin for local control and that the routine practice of obtaining a more widely negative margin is not indicated. We performed a systematic review of the literature and meta-analysis of studies analysing the impact of margin involvement after mastectomy on subsequent local recurrence. Methods: A systematic review was carried out searching MedLine, EmBase and ProQuest databases using the terms ‘mastectomy’, ‘resection margin’, ‘deep margin’, ‘margin status’ ‘fascia’ and ‘muscle invasion or infiltration’ from 1980 - 2019. In total 2,199 papers were screened and 33 studies were included in the quantitative synthesis. Statistical Methods: Meta-analysis was conducted using random effects modelling, pooling hazard ratios (HR), and odds ratios (OR) from binary outcome data. The associations between positive margins and local recurrence were stratified by positive margin distance and analysed according to use of adjuvant radiotherapy and follow up duration. Results: In total 37,738 patients, with a median age of 54.5 years, were included in the quantitative synthesis. Positive margins were associated with increased local recurrence on univariable analyses (HR 2.99, 95%CI: 2.99, 2.15 - 4.15), multivariable adjusted analyses (HR, 2.61, (95%CI 2.03-3.35) (which included Molecular Phenotype, Stage and Node status) as well as binary outcome data (OR, 95%CI: 2.75, 1.94-3.88). Positive margins were consistently associated with increased local recurrence, regardless of the distance of the tumour from the margin defined as positive (HR, 95%CI, tumour at ink: 2.39, 1.53-3.72; margin 5 years compared to 5 years OR 3.50, 2.13 - 5.75). Data were available from five studies for patients not receiving radiotherapy. In this subgroup positive margins were associated with a 3-fold risk of local recurrence (OR: 3.01, 1.96-4.61). Conclusions: On meta-analysis the risk of local recurrence after mastectomy is associated with margin proximity. Most data on margin status has related to breast conserving surgery. Adequate surgical margin clearance greater than 2mm margin after mastectomy is required to prevent local recurrence and International guidelines should reflect this finding. Citation Format: James Bundred, Sarah Michael, Sarah Bowers, Nicola Barnes, David Dodwell, Yasmin Jauhari, Nigel Bundred. Do surgical margins matter after mastectomy? A meta-analysis of 37,738 breast cancer patients in 33 studies [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-20-07.

Background: Leaving involved margins after surgery for early breast cancer is associated with an increased risk of local recurrence but the effect on distant recurrence is controversial. ASCO and ASTRO endorsed a policy that negative margins of no ink on tumour represented sufficient margin for local control and that the routine practice of obtaining a more widely negative margin was not indicated. We aimed to assess margin status (2mm) on local and distant control of breast cancer in a consecutive UK patient audit of Breast Cancer Units. Methods: Patients (n = 2795) undergoing surgery for early breast cancer (Tis, T1-3) in 3 Greater Manchester Breast Units had margin status prospectively recorded (reported by micrometer according to NHSBSP pathology guidelines) and local and distant recurrence recorded. All patients received adjuvant therapy according to local guidelines. Statistical analysis using cox proportional hazard regression was used to identify clinicopathological factors predicting recurrence in the multivariate analysis. Results: Overall 575 women (19.3%) had involved (≤1mm clearance) and 235 (8.5%) close (≤2mm clearance) and 1895 clear surgical margins. 1652 patients underwent breast conserving surgery and 1143 mastectomy. Median follow-up is 63.7 months. Overall local recurrence rate was 3.8% and distant recurrence 4.9% by a median of 5 years follow-up. Local and distant recurrence was higher after mastectomy at 7% and 7.8%, respectively. Margin 2mm. In multivariate analysis, two factors: molecular phenotype (other phenotypes versus Luminal A HR 1.79) and close / involved margins less than 2mm clearance (versus clear >2mm) [HR 1.76 (95% confidence intervals 1.06 - 2.92)], predicted local recurrence and the same factors together with mastectomy (compared to breast conservation), T and N stage predicted distant recurrence (see table 1). Table 1. Multivariate analysis of factors predicting cancer recurrenceLocal Recurrence (HR)Distant Recurrence (HR)Margin categorical 2mm1.84 (1.05 - 3.22, p=0.031)1.82 (1.1 – 3.02, p= 0.019)Margin 2mm)1.76 (1.06-2.92, p=0.027)1.86 (1.16-2.27, p=0.009)T Stage 2 vs 11.55 (0.88 – 2.73, p=0.129)4.35 (2.07 – 9.14, p Conclusion: Clearing surgical margins improves recurrence free survival (both local and distant). Leaving margins ≤2mm increases distant cancer recurrence and clearance of margins should be essential surgical management, particularly in oestrogen receptor (ER) negative breast cancer. Current guidelines accepting margins ≤1mm will increase distant recurrence and deaths from breast cancer. Citation Format: Sarah Michael, Sarah Bowers, Jane Ooi, Mo Absar, James Bundred, Nigel Bundred. Surgical margin involvement (

ObjectiveTo determine if margin involvement is associated with distant recurrence and to determine the required margin to minimise both local recurrence and distant recurrence in early stage invasive breast cancer.DesignProspectively registered systematic review and meta-analysis of literature.Data sourcesMedline (PubMed), Embase, and Proquest online databases. Unpublished data were sought from study authors.Eligibility criteriaEligible studies reported on patients undergoing breast conserving surgery (for stages I-III breast cancer), allowed an estimation of outcomes in relation to margin status, and followed up patients for a minimum of 60 months. Patients with ductal carcinoma in situ only or treated with neoadjuvant chemotherapy or by mastectomy were excluded. Where applicable, margins were categorised as tumour on ink (involved), close margins (no tumour on ink but Results68 studies from 1 January 1980 to 31 December 2021, comprising 112 140 patients with breast cancer, were included. Across all studies, 9.4% (95% confidence interval 6.8% to 12.8%) of patients had involved (tumour on ink) margins and 17.8% (13.0% to 23.9%) had tumour on ink or a close margin. The rate of distant recurrence was 25.4% (14.5% to 40.6%) in patients with tumour on ink, 8.4% (4.4% to 15.5%) in patients with tumour on ink or close, and 7.4% (3.9% to 13.6%) in patients with negative margins. Compared with negative margins, tumour on ink margins were associated with increased distant recurrence (hazard ratio 2.10, 95% confidence interval 1.65 to 2.69, PConclusionsInvolved or close pathological margins after breast conserving surgery for early stage, invasive breast cancer are associated with increased distant recurrence and local recurrence. Surgeons should aim to achieve a minimum clear margin of at least 1 mm. On the basis of current evidence, international guidelines should be revised.Systematic review registrationCRD42021232115.

Objective: To identify variables that correlate with sexual satisfaction and sexual distress among adult cancer survivors, and how these differ, providing a basis from which approaches to intervention may be identified. This study examined four key variables: body image disruption, self-compassion, relationship satisfaction and sexual pain previously, all linked to sexual quality of life. Methods: A cross-sectional survey was conducted online, with participants (n = 113) recruited via cancer charities, support groups, and sexual counsellors’ networks. A multivariate multiple regression analysis was conducted to analyse relationships among variables. Results: In a regression adjusted for age and sex and time since diagnosis, higher sexual distress was significantly associated with higher body image disruption (β =0.23; p = .042), lower self-compassion (β = 0.29; p = .009), and higher sexual pain (β = 0.39; p < .001); but not relationship satisfaction (β =-0.08; p = .433). Higher sexual satisfaction was significantly associated with higher relationship satisfaction (β = 0.35; p = .002) and lower sexual pain (β = -0.29; p = .004), but not body image disruption (β = -0.19; p = .089), or self-compassion (β = 0.06; p = .614). Sexual pain had a significantly stronger association with sexual distress than sexual satisfaction; F (1, 87) = 18.29, p < .001. Conclusions: Sexual distress and sexual satisfaction are associated with different psycho-social correlates even though both are used as indicators of sexual health. Research should seek to further understand the differences in these two critical markers of sexual health, with these differences likely to highlight the need to match interventions to the nature of the sexual difficulties experienced following cancer treatment. Refereed/Peer-reviewed

The 11th Symposium on Polar Science/Ordinary sessions: [OB] Polar Biology, Poster presentations, Mon. 16 Nov. - Fri. 18 Dec.

ObjectivesCardiovascular disease is the leading cause of premature death in patients with mental illness. Metabolic syndrome is a cluster of co-occurring cardiovascular risk factors, seen in high frequency in severe mental illness. Despite ease of diagnosis, monitoring is often poor across psychiatric populations. This report details a quality improvement initiative undertaken on an inpatient psychiatric ward to improve rates of metabolic monitoring.MethodsFour key interventions were developed: (1) A nurse-led intervention, where nurses were upskilled in performing metabolic monitoring, (2) Education was provided to all staff, (3) Introduction of a suite of interventions to improve metabolic risk and (4) Ongoing consumer involvement. A pre–post intervention study design was used to measure effectiveness, with an audit of metabolic monitoring rates performed 12 months after the intervention began.ResultsRates of weight and height monitoring both increased from 46.0% to 69.5% (p=0.0185) and body mass index (BMI) recordings increased from 33% to 63% (p=0.0031). Rates of waist circumference monitoring increased from 44.2% to 65.2% (p=0.0498). Blood pressure (BP) measurements increased from 88.5% to 100% (p=0.0188). Lipid monitoring rates improved from 23% to 69.5% (p=0.001). Rates of glucose monitoring increased from 74% to 82.5% (p=0.8256), although this was not statistically significant.ConclusionsWe found that metabolic monitoring improved following these simple interventions, with a statistically significant increase in measurement rates of weight, BP, height, lipids, BMI and waist circumference (p

Questions remain as to the practicality of lifting the cap on medical school places from the current 9500 in the UK.12 Even before covid-19, most medical schools required students to travel to distant district general hospitals and general practices to provide adequate learning opportunities to large cohorts. The unfolding of the covid-19 pandemic has changed medical school beyond recognition, with …

Background Integrating exercise professionals into mental health settings is a key strategy in addressing the physical health inequalities of people living with mental illness. Workforce culture surrounding physical health may impact the utilisation of exercise professionals across inpatient settings. Aims To evaluate clinician perspectives regarding the implementation of an exercise professional at the mental health service in a large, urban hospital in Sydney, Australia. Methods A qualitative study using semi-structured interviews with a purposive sample of mental health staff was conducted. Data were analysed using thematic analysis. Results Fourteen mental health clinicians (approximately 35% of all eligible staff) participated in interviews. Three themes emerged regarding the role of the exercise professional; i) drivers and facilitators; ii) support from leadership; and iii) directions for future practice. Conclusions An exercise professional within a mental health service was identified as an effective strategy in improving consumer health outcomes while increasing the knowledge and confidence of mental health clinicians regarding the provision of physical health care. Exercise professionals should be recognised as important members of the standard multidisciplinary mental health team for in patients being treated for mental illness.

Mental health providers experience inappropriate sexual behavior from patients. It is unclear if training programs adequately prepare trainees to respond to such behaviors. Additionally, trainees may not seek support and guidance from supervisors after an incident. This is an exploratory study to document the prevalence of and assess the preparedness of trainees to deal with inappropriate sexual behavior. A survey was administered to 58 psychiatry residents and 14 psychology interns at the NYU School of Medicine. A total of 22 questions were asked regarding participants’ experiences with inappropriate sexual behavior, including prevalence of, and preparedness during, and support received after the behavior. Of those who completed the survey, 89% of respondents had experienced inappropriate sexual behavior. Seventy percent said they had no training in responding to inappropriate sexual behavior, and 95% wanted more training. A minority of respondents consistently sought support after these events, and of those who did, only 60% of trainees did so with a supervisor. Experiences involving inappropriate sexual behavior are prevalent among the mental health trainees surveyed, but most trainees did not feel that they received adequate training in preparation for or supervision after their experiences. Creating training or establishing protocols to respond to inappropriate sexual behavior may help trainees feel more capable and safer. Further studies are needed to understand inappropriate sexual behavior’s impact on trainees and patient care, as well as to assess the efficacy of training and protocols developed to manage inappropriate sexual behavior.

Parkinson's disease and dementia with Lewy bodies are neurodegenerative disorders characterized by accumulation of α-synuclein (α-syn). Recently, single-chain fragment variables (scFVs) have been developed against individual conformational species of α-syn. Unlike more traditional monoclonal antibodies, these scFVs will not activate or be endocytosed by Fc receptors. For this study, we investigated an scFV directed against oligomeric α-syn fused to the LDL receptor-binding domain from apolipoprotein B (apoB). The modified scFV showed enhanced brain penetration and was imported into neuronal cells through the endosomal sorting complex required for transport (ESCRT) pathway, leading to lysosomal degradation of α-syn aggregates. Further analysis showed that the scFV was effective at ameliorating neurodegenerative pathology and behavioral deficits observed in the mouse model of dementia with Lewy bodies/Parkinson's disease. Thus, the apoB modification had the effect of both increasing accumulation of the scFV in the brain and directing scFV/α-syn complexes for degradation through the ESCRT pathway, leading to improved therapeutic potential of immunotherapy.

Many neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are characterized by abnormal accumulations of aggregated proteins. Brains in these diseases also show accumulation of autophagic vesicles in the neuronal cytoplasm, suggesting impairment of the autophagic process. As autophagy involves de novo membrane production and vesicle fusion, extensive changes in lipid molecules are necessary. However, the involvement of signaling lipid-modifying enzymes in autophagy and their roles in neurodegenerative diseases are not clear. Using specific inhibitor, we show that loss of phospholipase D1 (PLD1) activity resulted in an accumulation of microtubule-associated protein light chain 3 (LC3), p62, and polyubiquitinated proteins, signs representing malfunction in autophagic flux. Fluorescence and electron microscopic analyses demonstrated impaired fusion of autophagosomes with lysosomes, resulting in accumulation of autophagosomes. Within the cells with impaired autophagic flux, α-synuclein aggregates accumulated in autophagosomes. Knockdown of PLD1 expression using small interfering RNA also resulted in impaired autophagic flux and accumulation of α-synuclein aggregates in autophagosomes. Neuronal toxicity caused by α-synuclein accumulation was rescued by overexpression of PLD1; however, expression of activity-deficient mutant, PLD1-KRM, showed reduced rescue effects. Finally, we demonstrated that both PLD activity and expression levels were reduced in brain tissues of dementia with Lewy bodies (DLB) patients, whereas the amounts of α-synuclein and p62 were increased in the same tissue samples. Collectively, these results suggest that insufficient PLD activity, and therefore, the changes in phospholipid compositions within membranes, might be an important contributor to impaired autophagic process and protein accumulation in Lewy body diseases.

Since the discovery and isolation of α-synuclein (α-syn) from human brains, it has been widely accepted that it exists as an intrinsically disordered monomeric protein. Two recent studies suggested that α-syn produced in Escherichia coli or isolated from mammalian cells and red blood cells exists predominantly as a tetramer that is rich in α-helical structure (Bartels, T., Choi, J. G., and Selkoe, D. J. (2011) Nature 477, 107-110; Wang, W., Perovic, I., Chittuluru, J., Kaganovich, A., Nguyen, L. T. T., Liao, J., Auclair, J. R., Johnson, D., Landeru, A., Simorellis, A. K., Ju, S., Cookson, M. R., Asturias, F. J., Agar, J. N., Webb, B. N., Kang, C., Ringe, D., Petsko, G. A., Pochapsky, T. C., and Hoang, Q. Q. (2011) Proc. Natl. Acad. Sci. 108, 17797-17802). However, it remains unknown whether or not this putative tetramer is the main physiological form of α-syn in the brain. In this study, we investigated the oligomeric state of α-syn in mouse, rat, and human brains. To assess the conformational and oligomeric state of native α-syn in complex mixtures, we generated α-syn standards of known quaternary structure and conformational properties and compared the behavior of endogenously expressed α-syn to these standards using native and denaturing gel electrophoresis techniques, size-exclusion chromatography, and an oligomer-specific ELISA. Our findings demonstrate that both human and rodent α-syn expressed in the central nervous system exist predominantly as an unfolded monomer. Similar results were observed when human α-syn was expressed in mouse and rat brains as well as mammalian cell lines (HEK293, HeLa, and SH-SY5Y). Furthermore, we show that α-syn expressed in E. coli and purified under denaturing or nondenaturing conditions, whether as a free protein or as a fusion construct with GST, is monomeric and adopts a disordered conformation after GST removal. These results do not rule out the possibility that α-syn becomes structured upon interaction with other proteins and/or biological membranes.

Background Studies at the behavioral and synaptic level show that effects of ethanol on the central nervous system can involve the opioid signaling system. These interactions may alter the function of a common downstream target. In this study, we examined Ca2+ channel function as a potential downstream target of interactions between ethanol and mu or kappa opioid receptor signaling.

DNA methylation is a major epigenetic modification that regulates gene expression. Dnmt1, the maintenance DNA methylation enzyme, is abundantly expressed in the adult brain and is mainly located in the nuclear compartment, where it has access to chromatin. Hypomethylation of CpG islands at intron 1 of the SNCA gene has recently been reported to result in overexpression of α-synuclein in Parkinson disease (PD) and related disorders. We therefore investigated the mechanisms underlying altered DNA methylation in PD and dementia with Lewy bodies (DLB). We present evidence of reduction of nuclear Dnmt1 levels in human postmortem brain samples from PD and DLB patients as well as in the brains of α-synuclein transgenic mice models. Furthermore, sequestration of Dnmt1 in the cytoplasm results in global DNA hypomethylation in human and mouse brains, involving CpG islands upstream of SNCA, SEPW1, and PRKAR2A genes. We report that association of Dnmt1 and α-synuclein might mediate aberrant subcellular localization of Dnmt1. Nuclear Dnmt1 levels were partially rescued by overexpression of Dnmt1 in neuronal cell cultures and in α-synuclein transgenic mice brains. Our results underscore a novel mechanism for epigenetic dysregulation in Lewy body diseases, which might underlie the decrease in DNA methylation reported for PD and DLB.

Introduction Methods for improving patient safety are predicated on cooperation between healthcare groups, but are the views of health professionals involved in promoting safety shared by other healthcare workforce staff and managers? Aim To compare patient-safety suggestions from health workforce managerial and staff groups with those of patient-safety specialists. Method Samples of managers (424) and staff (1214) in the South Australian state health system and 131 Australian patient-safety specialists were asked to write suggestions for improving patient safety. Group responses were content analysed and compared. Results Patient-safety specialists (83.2%) were more likely to make suggestions than were workforce managers (57.8%) or staff (44.1%). Workforce members from clinical professions were more likely than non-clinicians to tender suggestions. No relationship existed between the importance specialists and managers (ρ=−0.062, p=0.880) and specialists and staff (ρ=−0.046, p=0.912) attached to nine categories of suggestions. There was a high correlation between the importance that managers and non-managers attached to safety strategies (ρ=0.817, p=0.011). Among those who made suggestions, specialists were more likely to suggest implementing reviews and guidelines, and incident reporting. Workforce groups were more likely to recommend increased and improved staffing and staffing conditions, and better equipment and infrastructure. There were no significant differences in the proportions of group members recommending: improving management and leadership; increasing staff safety education and supervision; communication and teamwork; improved patient focus; or tackling specific safety projects. Implications Differences between safety specialists' and workforce groups' beliefs about how to improve patient safety may impede the successful implementation of patient-safety programmes.

It is a dilemma that every researcher undertaking interviews faces: what questions should I ask and how should I ask them? Setting out to interview the directors of 60 local NGOs in three African c...

In this analysis of the global workforce, the Joint Learning Initiative-a consortium of more than 100 health leaders-proposes that mobilisation and strengthening of human resources for health, neglected yet critical, is central to combating health crises in some of the world's poorest countries and for building sustainable health systems in all countries. Nearly all countries are challenged by worker shortage, skill mix imbalance, maldistribution, negative work environment, and weak knowledge base. Especially in the poorest countries, the workforce is under assault by HIV/AIDS, out-migration, and inadequate investment. Effective country strategies should be backed by international reinforcement. Ultimately, the crisis in human resources is a shared problem requiring shared responsibility for cooperative action. Alliances for action are recommended to strengthen the performance of all existing actors while expanding space and energy for fresh actors.

Alzheimer's disease (AD) is associated with the formation of toxic amyloid-β (Aβ)42 oligomers, and recent evidence supports a role for Aβ dimers as building blocks for oligomers. Molecular dynamics simulation studies have identified clans for the dominant conformations of Aβ42 forming dimers; however, it is unclear if a larger spectrum of dimers is involved and which set(s) of dimers might evolve to oligomers verse fibrils. Therefore, for this study we generated multiple structural conformations of Aβ42, using explicit all-atom molecular dynamics, and then clustering the different structures based on key conformational similarities. Those matching a selection threshold were then used to model a process of oligomerization. Remarkably, we showed a greater diversity in Aβ dimers than previously described. Depending on the clan family, different types of Aβ dimers were obtained. While some had the tendency to evolve into oligomeric rings, others formed fibrils of diverse characteristics. Then we selected the dimers that would evolve to membranephilic annular oligomers. Nearly one third of the 28 evaluated annular oligomers had the dimer interfaces between the neighboring Aβ42 monomers with possible salt bridges between the residue K28 from one side and either residue E22 or D23 on the other. Based on these results, key amino acids were identified for point mutations that either enhanced or suppressed the formation and toxicity of oligomer rings. Our studies suggest a greater diversity of Aβ dimers. Understanding the structure of Aβ dimers might be important for the rationale design of small molecules that block formation of toxic oligomers.

Synaptic loss is the cardinal feature linking neuropathology to cognitive decline in Alzheimer’s disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here, using FRET-based glutamate sensor imaging, we show that amyloid-β peptide (Aβ) engages α7 nicotinic acetylcholine receptors to induce release of astrocytic glutamate, which in turn activates extrasynaptic NMDA receptors (eNMDARs) on neurons. In hippocampal autapses, this eNMDAR activity is followed by reduction in evoked and miniature excitatory postsynaptic currents (mEPSCs). Decreased mEPSC frequency may reflect early synaptic injury because of concurrent eNMDAR-mediated NO production, tau phosphorylation, and caspase-3 activation, each of which is implicated in spine loss. In hippocampal slices, oligomeric Aβ induces eNMDAR-mediated synaptic depression. In AD-transgenic mice compared with wild type, whole-cell recordings revealed excessive tonic eNMDAR activity accompanied by eNMDAR-sensitive loss of mEPSCs. Importantly, the improved NMDAR antagonist NitroMemantine, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from Aβ-induced damage both in vitro and in vivo.

Abnormal aggregation of alpha-synuclein and sustained microglial activation are important contributors to the pathogenic processes of Parkinson's disease. However, the relationship between disease-associated protein aggregation and microglia-mediated neuroinflammation remains unknown. Here, using a combination of in silico, in vitro and in vivo approaches, we show that extracellular alpha-synuclein released from neuronal cells is an endogenous agonist for Toll-like receptor 2 (TLR2), which activates inflammatory responses in microglia. The TLR2 ligand activity of alpha-synuclein is conformation-sensitive; only specific types of oligomer can interact with and activate TLR2. This paracrine interaction between neuron-released oligomeric alpha-synuclein and TLR2 in microglia suggests that both of these proteins are novel therapeutic targets for modification of neuroinflammation in Parkinson's disease and related neurological diseases.

BGIN is an alternatively spliced Rac1-GAP comprising a unique C-terminal poly-ubiquitin–binding module. Poly-Ub/BGIN interactions enhance BGIN distribution to membranes to limit Rac1 activity and downstream effector function in tissue culture cells and with proteotoxic stress such as neurodegenerative APP proteotoxicity., Spatial control of RhoGTPase-inactivating GAP components remains largely enigmatic. We describe a brain-specific RhoGAP splice variant, BARGIN (BGIN), which comprises a combination of BAR, GAP, and partial CIN phosphatase domains spliced from adjacent SH3BP1 and CIN gene loci. Excision of BGIN exon 2 results in recoding of a 42–amino acid N-terminal stretch. The partial CIN domain is a poly-ubiquitin (poly-Ub)–binding module that facilitates BGIN distribution to membranous and detergent-insoluble fractions. Poly-Ub/BGIN interactions support BGIN-mediated inactivation of a membranous Rac1 population, which consequently inactivates membrane-localized Rac1 effector systems such as reactive oxygen species (ROS) generation by the Nox1 complex. Given that Ub aggregate pathology and proteotoxicity are central themes in various neurodegenerative disorders, we investigated whether BGIN/Rac1 signaling could be involved in neurodegenerative proteotoxicity. BGIN/Ub interactions are observed through colocalization in tangle aggregates in the Alzheimer’s disease (AD) brain. Moreover, enhanced BGIN membrane distribution correlates with reduced Rac1 activity in AD brain tissue. Finally, BGIN contributes to Rac1 inhibition and ROS generation in an amyloid precursor protein (APP) proteotoxicity model. These results suggest that BGIN/poly-Ub interactions enhance BGIN membrane distribution and relay poly-Ub signals to enact Rac1 inactivation, and attenuation of Rac1 signaling is partially dependent on BGIN in a proteotoxic APP context.

Neurosin is a predominant serine protease in the central nervous system (CNS) and has been shown to play a role in the clearance of α-synuclein (α-syn) which is centrally involved in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Although it has been previously shown that neurosin and α-syn colocalize and that neurosin degrades α-syn aggregates in vitro, it is not clear if neurosin is dysregulated in the brains of patients with PD/DLB and to what extent delivery of neurosin into the CNS might ameliorate the deficits associated with α-syn accumulation in vivo. We analyzed the levels of neurosin in the brains of patients with PD/DLB and in α-syn transgenic (tg) models. With increased accumulation of α-syn, we observed decreased neurosin expression. Lentiviral vector (LV) driven expression of neurosin in neuronal cell cultures reduced the accumulation of wild type but not A53T α-syn and prevented α-syn associated toxicity. Neuropathological analysis following delivery of LV-Neurosin to α-syn tg mice resulted in reduced accumulation of α-syn and reversal of neurodegenerative alterations in wild type but not A53T α-syn tg mice. Therefore, viral vector driven expression of neurosin may warrant further investigation as a potential therapeutic tool for DLB.