Extreme cause-specific mortality in a cohort of adult prisoners--1988 to 2002: a data-linkage study

OBJECTIVES: Describe the standardized mortality ratio (SMR) and its trend in adults who have served time in prison. Design: A retrospective cohort study of 85,203 adults imprisoned in New South Wales (NSW), Australia, between 1 January 1988 and 31 December 2002. METHODS: We obtained information on deaths by record linkage with the Australian National Death Index (NDI). Mortality rates were estimated using the person-time method. SMRs were calculated using sex, age, and calendar-specific death rates from the NSW population. Time trends in SMRs were assessed using the test for linear trends. RESULTS: The median overall follow-up of the cohort was 7.7 years. We identified 5137 deaths (4714 men, 423 women) among the cohort of which the vast majority (4834, 94%) occurred following release from custody. All-cause SMR was 3.7 (95% CI: 3.6-3.8) in men and 7.8 (95% CI: 7.1-8.5) in women. SMRs were substantially raised for deaths due to mental and behavioural disorders (men: 13.2, 95% CI: 12.3-14.0; women: 62.8, 95% CI: 52.7-74.9) and drug-related deaths (men: 12.8, 95% CI: 12.2-13.5; women: 50.3, 95% CI: 43.7-57.8). The SMR for death by homicide was 10.2 (95% CI: 8.9-11.7) in men and 26.3 (95% CI: 17.8-39.0) in women. Aboriginal men were 4.8 times, and Aboriginal women 12.6 times, more likely to die than the general NSW population. Over the study period on average all-cause SMR decreased significantly in men (p = 0.003) and women (p = 0.05) largely due to the decline in SMRs for drug-related deaths and suicide. CONCLUSION: In the largest study so far reported, mortality of male and female offenders was far greater than expected for all major causes, especially deaths caused by drug overdose. Despite some indication of a reduction in excess mortality in recent years, there remains an overwhelming need for enhanced responses to mental health and drug problems for people who have been in prison.     

Potential mechanisms of retinal ganglion cell type-specific vulnerability in glaucoma

Glaucoma is a neurodegenerative disease characterised by progressive damage to the retinal ganglion cells (RGCs), the output neurons of the retina. RGCs are a heterogenous class of retinal neurons which can be classified into multiple types based on morphological, functional and genetic characteristics. This review examines the body of evidence supporting type-specific vulnerability of RGCs in glaucoma and explores potential mechanisms by which this might come about. Studies of donor tissue from glaucoma patients have generally noted greater vulnerability of larger RGC types. Models of glaucoma induced in primates, cats and mice also show selective effects on RGC types – particularly OFF RGCs. Several mechanisms may contribute to type-specific vulnerability, including differences in the expression of calcium-permeable receptors (for example pannexin-1, P2X7, AMPA and transient receptor potential vanilloid receptors), the relative proximity of RGCs and their dendrites to blood supply in the inner plexiform layer, as well as differing metabolic requirements of RGC types. Such differences may make certain RGCs more sensitive to intraocular pressure elevation and its associated biomechanical and vascular stress. A greater understanding of selective RGC vulnerability and its underlying causes will likely reveal a rich area of investigation for potential treatment targets.     

Fronto‐cerebellar dysfunction and dysconnectivity underlying cognition in friedreich ataxia: The IMAGE‐FRDA study

Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder defined by pathology within the cerebellum and spinal tracts. Although FRDA is most readily linked to motor and sensory dysfunctions, reported impairments in working memory and executive functions indicate that abnormalities may also extend to associations regions of the cerebral cortex and/or cerebello‐cerebral interactions. To test this hypothesis, 29 individuals with genetically confirmed FRDA and 34 healthy controls performed a verbal n‐back working memory task while undergoing functional magnetic resonance imaging. No significant group differences were evident in task performance. However, individuals with FRDA had deficits in brain activations both in the lateral cerebellar hemispheres, principally encompassing lobule VI, and the prefrontal cortex, including regions of the anterior insular and rostrolateral prefrontal cortices. Functional connectivity between these brain regions was also impaired, supporting a putative link between primary cerebellar dysfunction and subsequent cerebral abnormalities. Disease severity and genetic markers of disease liability were correlated specifically with cerebellar dysfunction, while correlations between behavioural performance and both cerebral activations and cerebello‐cerebral connectivity were observed in controls, but not in the FRDA cohort. Taken together, these findings support a diaschisis model of brain dysfunction, whereby primary disease effects in the cerebellum result in functional changes in downstream fronto‐cerebellar networks. These fronto‐cerebellar disturbances provide a putative biological basis for the nonmotor symptoms observed in FRDA, and reflect the consequence of localized cerebellar pathology to distributed brain function underlying higher‐order cognition. Hum Brain Mapp 37:338–350, 2016. © 2015 Wiley Periodicals, Inc.     

Reconstructive surgery for lower pole ureteropelvic junction obstruction associated with incomplete ureteral duplication

IntroductionThe lower moiety of duplex kidney can be associated with ureteropelvic junction obstruction (UPJO). Surgical correction can be challenging in cases of incomplete duplication where the junction of the lower and upper pole ureters is proximal. We review our experience with this unusual entity with an emphasis on surgical techniques employed in reconstruction.MethodsWe retrospectively reviewed the charts of eight patients with lower pole UPJO who underwent surgery in 2002–2008. The surgical approach, specifically the utilization of the non-obstructed upper pole ureter, used in the reconstruction was noted.ResultsFour of eight patients were symptomatic at presentation with either infection or pain. UPJO was at least in part secondary to lower pole crossing vessels in four patients and was treated with dismembered pyeloplasty. Lower pole to upper pole pyeloureterostomy was necessary in four patients due to short ureteral length between the UPJ and junction of lower and upper pole ureters. No complications or obstruction of either moiety developed during 1 year of follow up.ConclusionsLower pole UPJO in incomplete renal duplication mandates individualized surgical treatment dependent upon anatomy encountered. We have found that pyeloureterostomy is a safe alternative to drainage of the obstructed lower pole.     

STAT3 mediates bone marrow mesenchymal stem cell VEGF production

The mechanisms by which mesenchymal stem cells (MSCs) may protect native tissue are incompletely understood. Understanding the mechanisms by which these cells release factors such as vascular endothelial growth factor (VEGF), may lead to enhanced protection. We hypothesized that stress, in the form of hypoxia or TNF, activates MSCs to release VEGF by STAT3 and p38 MAPK dependent mechanisms. Mouse MSCs from wild type (WT) and STAT3 knockout mice (STAT3KO) were harvested and purified by a single-step method using adhesion. The release of VEGF was analyzed by using MSC conditioned media under hypoxia or TNF stimulation with or without p38 MAPK inhibition. Activation of STAT3 and p38 MAPK was determined by analysis of cell lysates. MSCs released VEGF under normoxia, which was associated with constitutive STAT3 activity. STAT3 deficiency resulted in decreased MSC production of VEGF. In response to hypoxia or TNF, MSCs produced more VEGF, which was correlated with hypoxia or TNF activated p38 MAPK and STAT3. The p38 MAPK inhibitor significantly decreased hypoxia-induced or TNF-stimulated VEGF production in WT. Additionally, STAT3 ablation neutralized hypoxia-induced MSC release of VEGF. No effect of p38 MAPK inhibitor alone was observed on MSC release of VEGF in WT. However, inhibition of p38 MAPK blocked release of VEGF in STAT3KO MSCs. MSCs are a potent source of VEGF, the production of which is mediated by STAT3 under normoxia partly; however, following hypoxia or TNF exposure, MSC release of VEGF is mediated by both STAT3 and p38 MAPK.     

Gender differences in injury induced mesenchymal stem cell apoptosis and VEGF, TNF, IL-6 expression: role of the 55 kDa TNF receptor (TNFR1)

Concomitant pro- and anti-inflammatory properties of bone marrow stem cells (BMSC) may be an important aspect of their ability to heal injured tissue. However, very few studies have examined whether gender differences exist in BMSC function. Indeed, it remains unknown whether gender differences exist in BMSC function and ability to resist apoptosis, and if so, whether TNF receptor 1 (TNFR1) plays a role in these differences. We hypothesized that TNFR1 ablation equalizes gender differences in bone marrow mesenchymal stem cell (MSC) apoptosis, as well as expression of vascular endothelial growth factor (VEGF), TNF and interleukin (IL)-6. Mouse MSCs from male wild type (WT), female WT, male TNFR1 knockouts (TNFR1KO) and female TNFR1KO were stressed by endotoxin 200 ng/ml or 1 h hypoxia. MSC activation was determined by measuring VEGF, TNF and IL-6 production (ELISA). Differences considered significant if p<0.05. LPS and hypoxia resulted in significant activation in all experimental groups compared to controls. Male WT demonstrated significantly greater TNF and IL-6 and significantly less VEGF release than female WT MSCs. However, release of TNF, IL-6 and VEGF in male TNFR1 knockouts differed from male WT, but was not different from female WT MSCs. Similarly apoptosis in hypoxic male TNFRIKO differed from male WT, but it was not different from apoptosis from WT female. Female WT did not differ in TNF, IL-6 and VEGF release compared to female TNFR1KO. Gender differences exist in injury induced BMSC VEGF, TNF and IL-6 expression. TNFR1 may autoregulate VEGF, TNF and IL-6 expression in males more than females. MSCs are novel therapeutic agents for organ protection, but further study of the disparate expression of VEGF, TNF and IL-6 in males and females as well as the role of TNFR1 in these gender differences is necessary to maximize this protection.     

Clinical features of Friedreich ataxia

Friedreich ataxia, the most common hereditary ataxia, affects approximately 1 per 29,000 white individuals. In about 98% of these individuals, it is due to homozygosity for a GAA trinucleotide repeat expansion in intron 1 of FXN; in the other 2%, it is due to compound heterozygosity for a GAA expansion and point mutation or deletion. The condition affects multiple sites in the central and peripheral nervous system as well as a number of other organ systems, resulting in multiple signs and symptoms. Onset of this autosomal recessive condition is usually in the first 2 decades of life. Major clinical features include progressive ataxia, absent lower limb reflexes, upgoing plantar responses, and peripheral sensory neuropathy. The main nonneurological sites of morbidity are the heart, resulting in cardiomyopathy, and the pancreas, resulting in diabetes mellitus. In this review, we provide an overview of the clinical features of Friedreich ataxia and discuss differential diagnoses.