Consequences of daily self-weighing: a pilot study in higher-weight women with a history of breast cancer.

Self-monitoring weight is commonly recommended for higher-weight women with a history of breast cancer, despite evidence demonstrating potentially negative psychological consequences of frequent self-weighing. The extent to which higher-weight women with breast cancer experience emotional and behavioral consequences in response to daily self-weighing is unknown. In this pilot study, women (n = 51) with a history of breast cancer in a behavioral weight management program completed a weeklong daily diary protocol. Participants were asked to self-weigh every morning and report on subsequent weight-related shame and guilt, and end-of-day engagement in compensatory exercise, diet, and purging behaviors. Women reported higher levels of guilt on days when their body weight was higher than usual, and when there was more discrepancy between their current vs. goal weight. Additionally, women engaged in higher levels of compensatory diet behavior on days when they experienced more weight-related guilt than usual. Based on these preliminary findings, daily self-weighing may be associated with harmful emotional and behavioral consequences among higher-weight women with a history of breast cancer.

The molecular landscape and associated clinical experience in infant medulloblastoma: prognostic significance of second-generation subtypes.

AIMS: Biomarker-driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub-classify iMB, and proffer strategies for personalized, risk-adapted therapies. METHODS: We characterized the iMB molecular landscape, including second-generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387). RESULTS: iMBGrp3 (42%) and iMBSHH (40%) subgroups predominated. iMBGrp3 harboured second-generation subtypes II/III/IV. Subtype II strongly associated with large-cell/anaplastic pathology (LCA; 23%) and MYC amplification (19%), defining a very-high-risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies; novel approaches are urgently required. Subtype VII (predominant within iMBGrp4 ) and subtype IV tumours were standard risk (80% OS) using upfront CSI-based therapies; randomized-controlled trials of upfront radiation-sparing and/or second-line radiotherapy should be considered. Seventy-five per cent of iMBSHH showed DN/MBEN histopathology in discovery and validation cohorts (P < 0.0001); central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non-DN/MBEN pathology was associated significantly with worse outcomes within iMBSHH . iMBSHH harboured two distinct subtypes (iMBSHH-I/II ). Within the discriminated favourable-risk iMBSHH DN/MBEN patient group, iMBSHH-II had significantly better progression-free survival than iMBSHH-I , offering opportunities for risk-adapted stratification of upfront therapies. Both iMBSHH-I and iMBSHH-II showed notable rescue rates (56% combined post-relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development. CONCLUSIONS: Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup-dependent survival models highlight opportunities for biomarker-directed therapies.

Expression of p16 and p21 in the frontal association cortex of ALS/MND brains suggests neuronal cell cycle dysregulation and astrocyte senescence in early stages of the disease.

AIMS: Cellular senescence plays a role in organismal ageing and has been linked to persistent DNA damage in age-related diseases. Brain senescence has been described in astrocytes and microglia, but it is less well understood in neurones. Evidence suggests that neurones activate a senescence-like mechanism that could contribute to neurodegeneration. We aimed to determine whether a persistent DNA damage response (DDR) and senescence activation are features of motor neurone disease (amyotrophic lateral sclerosis, ALS/MND). METHODS: We examined expression of senescence (p16 and p21) and DNA damage markers (8-OHdG and γH2AX) in motor cortex (MCx), frontal association cortex (FACx) and occipital cortex (OCx) in post-mortem tissue donated by patients with ALS/MND and controls. RESULTS: Nuclear expression of p16 and p21 was detected in glial cells; double immunofluorescence for p16/p21 and glial fibrillary acidic protein (GFAP) suggested that some of these cells were GFAP+ astrocytes. p21 nuclear expression was also found in neurones. Higher levels of p16+ (glia, P = 0.028) and p21+ (glia, P = 0.003; neurones, P = 0.008) cells were found in the FACx of ALS/MND donors but not in the MCx or OCx. Expression of p16 and p21 did not correlate with 8-OHdG or γH2AX. CONCLUSIONS: Expression of p16 and p21 in glia, mainly in astrocytes, suggests senescence induction in these cells; however, neuronal p21 expression might reflect a more general mechanism of age-related cell cycle dysregulation. The significantly higher proportion of cells expressing either p16 or p21 in the FACx of ALS/MND donors could indicate senescence activation and cell cycle dysregulation in early stages of the disease.

Epidemiological pathology of Aß deposition in the ageing brain in CFAS: addition of multiple Aß-derived measures does not improve dementia assessment using logistic regression and machine learning approaches.

Aß-amyloid deposition is a key feature of Alzheimer's disease, but Consortium to Establish a Registry for Alzheimer's Disease (CERAD) assessment, based on neuritic plaque density, shows a limited relationships to dementia. Thal phase is based on a neuroanatomical hierarchy of Aß-deposition, and in combination with Braak neurofibrillary tangle staging also allows derivation of primary age-related tauopathy (PART). We sought to determine whether Thal Aß phase predicts dementia better than CERAD in a population-representative cohort (n = 186) derived from the Cognitive Function and Ageing Study (CFAS). Cerebral amyloid angiopathy (CAA) was quantitied as the number of neuroanatomical areas involved and cases meeting criteria for PART were defined to determine if they are a distinct pathological group within the ageing population. Agreement with the Thal scheme was excellent. In univariate analysis Thal phase performed less well as a predictor of dementia than CERAD, Braak or CAA. Logistic regression, decision tree and linear discriminant analysis were performed for multivariable analysis, with similar results. Thal phase did not provide a better explanation of dementia than CERAD, and there was no additional benefit to including more than one assessment of Aß in the model. Number of areas involved by CAA was highly correlated with assessment based on a severity score (p < 0.001). The presence of capillary involvement (CAA type I) was associated with higher Thal phase and Braak stage (p < 0.001). CAA was not associated with microinfarcts (p = 0.1). Cases satisfying pathological criteria for PART were present at a frequency of 10.2% but were not older and did not have a higher likelihood of dementia than a comparison group of individuals with similar Braak stage but with more Aß. They also did not have higher hippocampal-tau stage, although PART was weakly associated with increased presence of thorn-shaped astrocytes (p = 0.048), suggesting common age-related mechanisms. Thal phase is highly applicable in a population-representative setting and allows definition of pathological subgroups, such as PART. Thal phase, plaque density, and extent and type of CAA measure different aspects of Aß pathology, but addition of more than one Aß measure does not improve dementia prediction, probably because these variables are highly correlated. Machine learning predictions reveal the importance of combining neuropathological measurements for the assessment of dementia.

Combined fused in sarcoma-positive (FUS+) basophilic inclusion body disease and atypical tauopathy presenting with an amyotrophic lateral sclerosis/motor neurone disease (ALS/MND)-plus phenotype.

AIMS: Amyotrophic lateral sclerosis/motor neurone disease (ALS/MND) is characterized by the presence of inclusions containing TDP-43 within motor neurones. In rare cases, ALS/MND may be associated with inclusions containing other proteins, such as fused in sarcoma (FUS), while motor system pathology may rarely be a feature of other neurodegenerative disorders. We here have investigated the association of FUS and tau pathology. METHODS: We report a case with an ALS/MND-plus clinical syndrome which pathologically demonstrated both FUS pathology and an atypical tauopathy. RESULTS: Clinical motor involvement was predominantly present in the upper motor neurone, and was accompanied by extrapyramidal features and sensory involvement, but with only minimal cognitive impairment. The presentation was sporadic and gene mutation screening was negative. Post mortem study demonstrated inclusions positive for FUS, including basophilic inclusion bodies. This was associated with 4R-tauopathy, largely as non-fibrillary diffuse phospho-tau in neurones, with granulovacuolar degeneration in a more restricted distribution. Double-staining revealed that neurones contained both types of protein pathology. CONCLUSION: FUS-positive basophilic inclusion body disease is a rare cause of ALS/MND, but in this case was associated with an unusual atypical tauopathy. The coexistence of two such rare neuropathologies raises the question of a pathogenic interaction.

Age-associated changes in the blood-brain barrier: comparative studies in human and mouse.

AIMS: While vascular pathology is a common feature of a range of neurodegenerative diseases, we hypothesized that vascular changes occur in association with normal ageing. Therefore, we aimed to characterize age-associated changes in the blood-brain barrier (BBB) in human and mouse cohorts. METHODS: Immunohistochemistry and Evans blue assays were used to characterize BBB dysfunction (tight junction protein expression and serum plasma protein accumulation), vascular pathology (pericyte loss and vascular density) and glial pathology (astrocyte and microglial density) in ageing neurological control human prefrontal cortex (a total of 23 cases from 5 age groups representing the spectrum of young adult to old age: 20-30 years, 31-45 years, 46-60 years, 61-75 years and 75+) and C57BL/6 mice (3 months, 12 months, 18 months and 24 months, n = 5/6 per group). RESULTS: Quantification of the tight junction protein ZO-1 within the cortex and cerebellum of the mouse cohort showed a significant trend to both increased number (cortex P < 0.001, cerebellum P < 0.001) and length (cortex P < 0.001, cerebellum P < 0.001) of junctional breaks associated with increasing age. GFAP expression significantly correlated with ageing in the mice (P = 0.037). In the human cohort, assessment of human protein accumulation (albumin, fibrinogen and human IgG) demonstrated cells morphologically resembling clasmatodendritic astrocytes, indicative of BBB dysfunction. Semiquantitative assessment of astrogliosis in the cortex expression revealed an association with age (P = 0.003), while no age-associated changes in microglial pathology, microvascular density or pericyte coverage were detected. CONCLUSIONS: This study demonstrates BBB dysfunction in normal brain ageing, both in human and mouse cohorts.

Waist circumference at five common measurement sites in normal weight and overweight adults: which site is most optimal?

The aim of this study was to determine (i) if adults would measure their own waist circumference (WC), (ii) which WC site(s) are the most intuitive and easy to measure and (iii) if measurement accuracy and association between WC and blood pressure differs across five measurement sites. Participants (n = 198) measured their WC first with no instruction and then using visual instructions for the iliac crest, last rib, midpoint, minimal waist and umbilicus. Without instruction, men most commonly measured their WC at the umbilicus and iliac crest, while women measured their WC at the umbilicus and minimal WC. Both men and women reported the minimal waist and umbilicus to be moderately easier to self-measure compared to the other sites (P < 0.05). Prevalence of abdominal obesity varied significantly by gender and measurement site, especially for females (normal weight: 0-18%; overweight: 51-79%). Measurement site did not influence accuracy of WC self-measurement or the association between WC and blood pressure (P > 0.05). A universal WC landmark is needed. From these results, there does not appear to be a clear clinical advantage in terms of blood pressure or practical advantage of measuring one WC site over another. However, the umbilicus may be the most intuitive and easy to measure.

Review: Neuropathology and behavioural features of transgenic murine models of Alzheimer's disease.

Our understanding of the underlying biology of Alzheimer's disease (AD) has been steadily progressing; however, this is yet to translate into a successful treatment in humans. The use of transgenic mouse models has helped to develop our understanding of AD, not only in terms of disease pathology, but also with the associated cognitive impairments typical of AD. Plaques and neurofibrillary tangles are often among the last pathological changes in AD mouse models, after neuronal loss and gliosis. There is a general consensus that successful treatments need to be applied before the onset of these pathologies and associated cognitive symptoms. This review discusses the different types of AD mouse models in terms of the temporal progression of the disease, how well they replicate the pathological changes seen in human AD and their cognitive defects. We provide a critical assessment of the behavioural tests used with AD mice to assess cognitive changes and decline, and discuss how successfully they correlate with cognitive impairments in humans with AD. This information is an important tool for AD researchers when deciding on appropriate mouse models, and when selecting measures to assess behavioural and cognitive change.

The associations of resting metabolic rate with chronic conditions and weight loss.

The aim of this study was to examine the associations between baseline and changes in resting metabolic rate (RMR) with chronic condition(s) and weight loss (WL). Sex stratified analysis was undertaken on 393 adults from the Wharton Weight Management Clinics. The association between baseline RMR and WL was examined adjusting for age, BMI, ethnicity and treatment time. The association between changes in RMR (ΔRMR) and WL was also examined adjusting for baseline RMR and above covariates. Models were further adjusted for high glucose, triglycerides, blood pressure, low-density lipoprotein (LDL) and low high-density lipoprotein (HDL). While men (6.0 ± 8.6 kg) and women (5.6 ± 8.3 kg) had significant WL throughout the intervention, their measured decreases in RMR (-48 ± 322 kcal and -5 ± 322 kcal, respectively) were non-significant (P > 0.05). Individuals with a high blood pressure had a higher baseline RMR and women with a high LDL had a lower baseline RMR than those without the chronic condition (P < 0.05). Regardless of sex, WL was not significantly associated with baseline RMR or ΔRMR (P > 0.05) in both models. Participants with a low baseline RMR do not appear to be at a disadvantage for WL. Further, WL can occur without decreases in RMR in populations with high levels of obesity and obesity-related comorbidities.

Microinfarcts in an older population-representative brain donor cohort (MRC CFAS): Prevalence, relation to dementia and mobility, and implications for the evaluation of cerebral Small Vessel Disease.

INTRODUCTION: Microinfarcts, small ischaemic foci common in ageing brain, are associated with dementia and gait dysfunction. We determined their relationship with dementia, mobility and cerebrovascular disease in an older population-representative brain donor cohort. These data on microinfarcts were evaluated in relation to pathological assessments of clinically significant cerebral small vessel disease (SVD). METHODS: Microinfarcts were assessed in the MRC Cognitive Function and Ageing Study (n = 331). Nine brain areas were staged according to the number of areas affected. RESULTS: 36% of brains showed at least 1 microinfarct. Higher cortical microinfarct stage was associated with dementia at death (OR 1.41, 95% CI 1.02; 1.96, P = 0.038), whilst cortical and subcortical microinfarct stages were associated with impaired mobility (OR 1.36, 95% CI 1.05-1.74; P 0.018) and falls (OR 1.96, 95% CI 1.11-3.43; P = 0.02). Adding data on microinfarcts to a definition of SVD, based on white matter lesions (WMLs), lacunes and significant arteriosclerosis, were assessed by comparing area under ROC curve (AUC) with and without microinfarcts. SVD was significantly related to dementia status with or without inclusion of microinfarcts. Modelling potential pathological definitions of SVD to predict dementia or impaired mobility indicated optimal prediction using combined assessment of WMLs, lacunes and microinfarcts. CONCLUSION: Cortical (dementia) and subcortical microinfarcts (impaired mobility) are related to diverse clinical outcomes. Optimal pathological assessment of significant SVD in brain ageing is achieved based on WMLs, lacunes and microinfarcts and may not require subjective assessment of the extent and severity of arteriosclerosis.

Review: Astrocytes in Alzheimer's disease and other age-associated dementias: a supporting player with a central role.

Astrocytes have essential roles in the central nervous system and are also implicated in the pathogenesis of neurodegenerative disease. Forming non-overlapping domains, astrocytes are highly complex cells. Immunohistochemistry to a variety of proteins can be used to study astrocytes in tissue, labelling different cellular components and sub-populations, including glial fibrillary acidic protein, ALDH1L1, CD44, NDRG2 and amino acid transporters, but none of these labels the entire astrocyte population. Increasing heterogeneity is recognized in the astrocyte population, a complexity that is relevant both to their normal function and pathogenic roles. They are involved in neuronal support, as active components of the tripartite synapse and in cell interactions within the neurovascular unit (NVU), where they are essential for blood-brain barrier maintenance and neurovascular coupling. Astrocytes change with age, and their responses may modulate the cellular effects of neurodegenerative pathologies, which alone do not explain all of the variance in statistical models of neurodegenerative dementias. Astrocytes respond to both the neurofibrillary tangles and plaques of Alzheimer's disease, to hyperphosphorylated tau and Aß, eliciting an effect which may be neuroprotective or deleterious. Not only astrocyte hypertrophy, in the form of gliosis, occurs, but also astrocyte injury and atrophy. Loss of normal astrocyte functions may contribute to reduced support for neurones and dysfunction of the NVU. Understanding how astrocytes contribute to dementia requires an understanding of the underlying heterogeneity of astrocyte populations, and the complexity of their responses to pathology. Enhancing the supportive and neuroprotective components of the astrocyte response has potential translational applications in therapeutic approaches to dementia.

Expression microdissection isolation of enriched cell populations from archival brain tissue.

BACKGROUND: Laser capture microdissection (LCM) is an established technique for the procurement of enriched cell populations that can undergo further downstream analysis, although it does have limitations. Expression microdissection (xMD) is a new technique that begins to address these pitfalls, such as operator dependence and contamination. NEW METHOD: xMD utilises immunohistochemistry in conjunction with a chromogen to isolate specific cell types by extending the fundamental principles of LCM to create an operator-independent method for the procurement of specific CNS cell types. RESULTS: We report how xMD enables the isolation of specific cell populations, namely neurones and astrocytes, from rat formalin fixed-paraffin embedded (FFPE) tissue. Subsequent reverse transcriptase-polymerase chain reaction (RT-PCR) analysis confirms the enrichment of these specific populations. RIN values after xMD indicate samples are sufficient to carry out further analysis. COMPARISON WITH EXISTING METHOD: xMD offers a rapid method of isolating specific CNS cell types without the need for identification by an operator, reducing the amount of unintentional contamination caused by operator error, whilst also significantly reducing the time required by the current basic LCM technique. CONCLUSIONS: xMD is a superior method for the procurement of enriched cell populations from post-mortem tissue, which can be utilised to create transcriptome profiles, aiding our understanding of the contribution of these cells to a range of neurological diseases. xMD also addresses the issues associated with LCM, such as reliance on an operator to identify target cells, which can cause contamination, as well as addressing the time consuming nature of LCM.

Interest, views and perceived barriers to bariatric surgery in patients with morbid obesity.

The objective of the study was to assess the interest, views and patient-perceived barriers to bariatric surgery among surgery-eligible patients. Surveys were completed at a weight management clinic and local hospital in Ontario, Canada. Patients were ≥18 years of age with a body mass index (BMI) >40 kg m(-2) or BMI > 35 kg m(-2) with ≥1 comorbidity. The sample included 105 participants, 73.3% female, with a mean BMI of 46.6 ± 7.1 kg m(-2) . Only 33.3% of participants were interested in surgery; 50.5% of participants were not interested and 16.2% had mixed feelings. Participants identified risks (69.5%) and side effects (57.1%) as significant surgical barriers. Interested participants were more likely to perceive themselves as obese, were unhappy with their current weight loss method and were less likely to fear surgery (P < 0.05). The prevalence of comorbidities was not different by surgical interest (P = 0.17). Despite the effectiveness of bariatric surgery, the majority of qualified patients are not interested in surgery mainly due to the perceived risk of surgery in general and satisfaction with current non-surgical weight loss efforts. The self-perception of obesity, as opposed to medical comorbidities, may be a stronger driver of the decision to have bariatric surgery. It is unclear if patients are aware of the effectiveness of bariatric surgery to help improve comorbidities or if bariatric surgery is perceived as being more cosmetic in nature.

Differences in weight change trajectory patterns in a publicly funded adult weight management centre.

OBJECTIVE: To describe differences in weight loss (WL) trajectory patterns at a publicly funded clinical weight management centre. METHODS: Groups with differences in the attainment of a 5% total body WL and percentage WL patterns over time were identified in 7,121 patients who attended a physician lead multi-disciplinary clinical lifestyle weight management that predominantly focused on education and diet counselling. Resultant health differences were examined. RESULTS: Patients had 3.2 ± 6.3%WL with 35% of patients achieving and maintaining a 5%WL. Half of these patients achieved the 5%WL within 6 months, while the other half had a more gradual approach. Another 10% achieved 5%WL, but regained weight after 6 months. There were seven distinct WL patterns identified: LargeWL (Mean WL: 21.2 ± 8.1%; Probability of group membership (PGM): 2.4%), ModerateWL (15.1 ± 5.1%WL; 5.4%PGM), SlowWL (6.7 ± 3.2%WL; 20.1%PGM) and MinimalWL (2.4 ± 2.2%WL; 34.6%PGM), WL Regain (9.4 ± 3.5%WL; 8.2%PGM), Weight Stable (1.2 ± 3.2%WL; 28.5%PGM) and Weight Gain (18.4 ± 11.2%WG; 0.8%PGM) groups. Improvements in blood pressure, lipids and glucose were generally related to the magnitude of WL achieved more than the pattern or speed of WL. CONCLUSIONS: There are large differences in the absolute WL attained and the pattern of WL during a publicly funded weight management program. Changes in clinical health markers appear to be more strongly related with the absolute WL attained as opposed to patterns of weight change. © 2016 The Authors. Obesity Science & Practice published by John Wiley & Sons Ltd, World Obesity and The Obesity Society.

Next generation of weight management medications: implications for diabetes and CVD risk.

Since the 1980s, the prevalence of obesity has almost doubled worldwide. Treatments for obesity include lifestyle modification, medications and surgery. Newer anti-obesity medications have been shown to be effective at inducing initial weight management in addition to successful long-term weight maintenance. Historically, weight management medications have been associated with public safety concerns that have resulted in the majority being withdrawn from the market or never receiving medicinal authorization. Recently, several countries have approved some newer generation weight management medications which may be beneficial to combat obesity. These medications have varying effects on cardiometabolic parameters, both positive and potentially negative. This review will outline the mechanisms of action of these medications and their implications for both diabetes and cardiovascular risks.

Brain haemosiderin in older people: pathological evidence for an ischaemic origin of magnetic resonance imaging (MRI) microbleeds.

INTRODUCTION: Magnetic resonance imaging (MRI) cerebral microbleeds (CMB) arise from ferromagnetic haemosiderin iron assumed to derive from extravasation of erythrocytes. Light microscopy of ageing brain frequently reveals foci of haemosiderin from single crystalloids to larger, predominantly perivascular, aggregates. The pathological and radiological relationship between these findings is not resolved. METHODS: Haemosiderin deposition and vascular pathology in the putamen were quantified in 200 brains donated to the population-representative Medical Research Council Cognitive Function and Ageing Study. Molecular markers of gliosis and tissue integrity were assessed by immunohistochemistry in brains with highest (n = 20) and lowest (n = 20) levels of putamen haemosiderin. The association between haemosiderin counts and degenerative and vascular brain pathology, clinical data, and the haemochromatosis (HFE) gene H63D genotype were analysed. The frequency of MRI CMB in 10 cases with highest and lowest burden of putamen haemosiderin, was compared using post mortem 3T MRI. RESULTS: Greater putamen haemosiderin was significantly associated with putaminal indices of small vessel ischaemia (microinfarcts, P < 0.05; arteriolosclerosis, P < 0.05; perivascular attenuation, P < 0.001) and with lacunes in any brain region (P < 0.023) but not large vessel disease, or whole brain measures of neurodegenerative pathology. Higher levels of putamen haemosiderin correlated with more CMB (P < 0.003). CONCLUSIONS: The MRI-CMB concept should take account of brain iron homeostasis, and small vessel ischaemic change in later life, rather than only as a marker for minor episodes of cerebrovascular extravasation. These data are of clinical relevance, suggesting that basal ganglia MRI microbleeds may be a surrogate for ischaemic small vessel disease rather than exclusively a haemorrhagic diathesis.

Medium to long term results following single stage Snodgrass hypospadias repair.

INTRODUCTION: The Snodgrass technique for primary hypospadias repair was described in 1994 and involves dorsal incision and tubularisation of the urethral plate distal to the meatus. While the advantages of good short-term outcome and good cosmesis have been reported, there is little data on long-term results in patients who have undergone a Snodgrass repair as a primary procedure for hypospadias. Our aim is to retrospectively review our medium to long-term results of primary tubularised incised-plate urethroplasty for hypospadias repair over a two-year period with up to eight-year follow-up. PATIENTS AND METHODS: We conducted a case note review of 74 patients who had undergone single-stage Snodgrass hypospadias repair, performed by a single surgeon (AB), from April 2000 to January 2003. RESULTS: The mean documented follow up was 56 months (3-103 months). The mean age of patients at time of surgery was three and a half years. 95% (70) of patients had a distal (glanular, coronal, sub-coronal, distal shaft) meatus and 5% (4) had a proximal (mid-shaft) meatus. The overall complication rate was 7% (5). Two patients developed fistulae, which was noted and repaired at six months post-op with no further surgical intervention required. One patient underwent an EUA and meatal advancement glansplasty at 6 months for mild glanular dehiscence. Two further patients required EUA and dilatation procedures at two and three years respectively, both for mild meatal stenosis. Again, no further intervention was required. From a cosmetic perspective, two patients were noted to have some residual bulkiness of the skin around the corona and a further two patients were noted to have a small meatus, but with no functional symptoms. CONCLUSION: Our study has shown a low long-term complication rate in patients undergoing Snodgrass repair as a primary procedure for distal and midshaft hypospadias repair. This supports the results of earlier studies that have shown good functional and cosmetic outcome in the short-term for this procedure which persists into the medium/long term.

Calcium dysregulation in relation to Alzheimer-type pathology in the ageing brain.

AIMS: Calcium dyshomeostasis is implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease. However, much of the previous research has focused on changes in neuronal calcium signalling. In a recent microarray study we identified dysregulation of several key signalling pathways including the Ca(2+) signalling pathway in astrocytes as Alzheimer-type pathology developed. In this study we sought to determine the expression of calpain-10 and calcium/calmodulin-dependent kinase alpha (CamKIIα) in relation to Alzheimer-type pathology in a population-based study. METHODS: Using post mortem temporal cortex samples derived from the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS) ageing brain cohort we examined calpain-10 and CamKIIα gene and protein expression using quantitative polymerase chain reaction and immunohistochemistry. RESULTS: We demonstrate that astrocytic expression of calpain-10 is up-regulated, and CamKIIα down-regulated with increasing Braak stage. Using immunohistochemistry we confirm protein expression of calpain-10 in astrocytes throughout the temporal cortex and demonstrate that calpain-10 immunoreactivity is correlated with both local and global measures of Alzheimer-type pathology. In addition, we identify a subpopulation of calpain-10 immunoreactive interlaminar astrocytes that extend processes deep into the cortex. CamKIIα is predominantly neuronal in localization and is associated with the presence of diffuse plaques in the ageing brain. DISCUSSION: Dysregulated expression of key calcium signalling molecules occurs with progression of Alzheimer-type pathology in the ageing brain, highlighting the need for further functional studies of astrocytic calcium signalling with respect to disease progression.

Difference in weight loss based on ethnicity, age and comorbidity status in a publicly funded adult weight management centre: 1-year results.

Limited evidence is available on the effectiveness of publicly funded weight loss (WL) clinics. We examined the 1-year WL outcomes and investigated predictors of WL and discontinuation of 1566 overweight and obese adults, who attended the Wharton Medical Clinic (WMC) weight management centre for at least 6 months. Overall, 42.7% (n = 669) of the entire sample achieved a ≥5%WL over the entire follow-up period from July 2008 to February 2012. On average, patients lost 5.6 ± 7.2 kg (5.0 ± 6.3%) of initial body weight (BW), while a subsample of patients attending the clinic for at least 1 year had a mean weight reduction of 6.6 ± 7.9 kg (5.9 ± 7.2%) of BW. Older patients were more likely to achieve a greater WL in comparison with young patients while White patients and those without type 2 diabetes (T2D) lost almost twice as much weight and %BW in comparison with Asian patients and patients with T2D, respectively (P < 0.05). Discontinuing patients did not differ in terms of sex, body mass index, education and smoking status from those who continued treatment (P > 0.05). Results of this study demonstrate that the WMC provides a practical model for clinically effective lifestyle-based treatment, accessible to a wide range of demographically diverse adults.

Neuro-ophthalmological Complications of Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) can lead to prominent nerve hypertrophy, which can mimic other forms of neuropathy radiologically. Neuro-ophthalmological complications can also occur in CIDP, either at presentation or chronically in the disorder. This can also cause diagnostic difficulties. We report three cases of neuro-ophthalmological complications of CIDP: two cases of papilloedema and one case of proptosis. In all three cases cranial nerve hypertrophy was present. CIDP should be considered in neuro-ophthalmological presentations associated with cranial/spinal nerve root hypertrophy.