Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease)

The neuronal ceroid lipofuscinoses are a group of lysosomal storage disorders that comprise the most common, genetically heterogeneous, fatal neurodegenerative disorders of children. They are characterised by childhood onset, visual failure, epileptic seizures, psychomotor retardation and dementia. CLN3 disease, also known as Batten disease, is caused by autosomal recessive mutations in the CLN3 gene, 80–85% of which are a ~1 kb deletion. Currently no treatments exist, and after much suffering, the disease inevitably results in premature death. The aim of this study was to generate a zebrafish model of CLN3 disease using antisense morpholino injection, and characterise the pathological and functional consequences of Cln3 deficiency, thereby providing a tool for future drug discovery. The model was shown to faithfully recapitulate the pathological signs of CLN3 disease, including reduced survival, neuronal loss, retinopathy, axonopathy, loss of motor function, lysosomal storage of subunit c of mitochondrial ATP synthase, and epileptic seizures, albeit with an earlier onset and faster progression than the human disease. Our study provides proof of principle that the advantages of the zebrafish over other model systems can be utilised to further our understanding of the pathogenesis of CLN3 disease and accelerate drug discovery

Anatomy of phreatic eruptions

This study investigates phreatic eruptions at two similar volcanoes, Kawah Ijen (Indonesia) and White Island (New Zealand). By carefully processing broadband seismic signals, we reveal seismic signatures and characteristics of these eruptions. At both volcanoes, the phreatic eruptions are initiated by a very-long-period (VLP) seismic event located at shallow depths between 700 and 900 m below the crater region, and may be triggered by excitation of gas trapped behind a ductile magma carapace. The shallow hydrothermal systems respond in different ways. At Kawah Ijen, the stress change induced by VLPs directly triggers an eigenoscillation of the hyperacidic lake. This so-called seiche is characterized by long-lasting, long-period oscillations with frequencies governed by the dimensions of the crater lake. A progressive lateral rupture of a seal below the crater lake and/or fluids migrating toward the surface is seismically recorded ∼ 15 min later as high-frequency bursts superimposed to tilt signals. At White Island, the hydrothermal system later (∼ 25 min) responds by radiating harmonic tremor at a fixed location that could be generated through eddy-shedding. These seismic signals shed light on several aspects of phreatic eruptions, their generation and timeline. They are mostly recorded at periods longer than tens of seconds further emphasizing the need to deploy broadband seismic equipment close to active volcanic activity

Evaluation of a text supported weight maintenance programme ‘Lighten Up Plus’ following a weight reduction programme: randomised controlled trial

Background Many overweight people find it difficult to maintain weight loss after attending a weight reduction programme. Self-weighing and telephone support are known to be useful methods for self-monitoring for weight loss. We examined the effectiveness of an SMS-text messaging based weight maintenance programme to encourage regular self-weighing in adults who had completed a 12 week commercial weight loss programme. Methods Randomised controlled trial of 380 obese or overweight men and women. The intervention group (n=190) received a single maintenance support phone call and SMS-text based weight maintenance messages over 12 weeks to encourage regular self-weighing after completing their weight loss programme. The primary outcome was change in weight at nine months follow up. Results Our sample (N=380) had a mean age of 47.4 years (SD 13.4), mean baseline weight and BMI of 93.1kg (16.1) and 34.4 kg/m2 (5.0) respectively, as well as majority female (87.3%) and White British (80.0%). Using intention to treat analysis both groups regained weight at nine months follow up; the intervention group regained an average of 1.36 kg while the control group regained 1.81 kg. Adjusting for covariates resulted in a mean difference of 0.45 kg (95% CI -0.78, 1.67) favouring the intervention group at nine month follow up. Conclusions We found no evidence that an SMS based weight maintenance intervention encouraging adults to weigh themselves weekly prevented weight regain at three or nine months after completing a commercial weight loss programme. <br/

Murine and related chapparvoviruses are nephro-tropic and produce novel accessory proteins in infected kidneys.

Mouse kidney parvovirus (MKPV) is a member of the provisional genus Chapparvovirus that causes renal disease in immune-compromised mice, with a disease course reminiscent of polyomavirus-associated nephropathy in immune-suppressed kidney transplant patients. Here we map four major MKPV transcripts, created by alternative splicing, to a common initiator region, and use mass spectrometry to identify "p10" and "p15" as novel chapparvovirus accessory proteins produced in MKPV-infected kidneys. p15 and the splicing-dependent putative accessory protein NS2 are conserved in all near-complete amniote chapparvovirus genomes currently available (from mammals, birds and a reptile). In contrast, p10 may be encoded only by viruses with >60% amino acid identity to MKPV. We show that MKPV is kidney-tropic and that the bat chapparvovirus DrPV-1 and a non-human primate chapparvovirus, CKPV, are also found in the kidneys of their hosts. We propose, therefore, that many mammal chapparvoviruses are likely to be nephrotropic

Stranger to Familiar: Wild Strepsirhines Manage Xenophobia by Playing

The power of play in limiting xenophobia is a well-known phenomenon in humans. Yet, the evidence in social animals remains meager. Here, we aim to determine whether play promotes social tolerance toward strangers in one of the most basal group of primates, the strepsirhines. We observed two groups of wild lemurs (Propithecus verreauxi, Verreaux's sifaka) during the mating season. Data were also collected on nine visiting, outgroup males. We compared the distribution of play, grooming, and aggressive interactions across three conditions: OUT (resident/outgroup interactions), IN (resident/resident interactions in presence of outgroups) and BL-IN (baseline of resident/resident interactions in absence of outgroups). Play frequency between males was higher in OUT than in IN and BL-IN conditions; whereas, grooming was more frequent in IN than in OUT and BL-IN conditions. Aggression rates between resident and outgroup males were significantly higher than those between residents. However, aggressions between resident and outgroup males significantly decreased after the first play session and became comparable with resident-resident aggression levels. The presence of strangers in a well-established group implies the onset of novel social circumstances, which sifaka males cope with by two different tactics: grooming with ingroup males and playing with outgroup ones. The grooming peak, concurrently with the visit of outgroups, probably represents a social shield adopted by resident males to make their pre-existing affiliation more evident to the stranger “audience”. Being mostly restricted to unfamiliar males, adult play in sifaka appears to have a role in managing new social situations more than in maintaining old relationships. In particular, our results indicate not only that play is the interface between strangers but also that it has a specific function in reducing xenophobia. In conclusion, play appears to be an ice-breaker mechanism in the critical process that “upgrades” an individual from stranger to familiar

The impact of the Calman–Hine report on the processes and outcomes of care for Yorkshire's colorectal cancer patients

The 1995 Calman–Hine plan outlined radical reform of the UK's cancer services with the aim of improving outcomes and reducing inequalities in NHS cancer care. Its main recommendation was to concentrate care into the hands of site-specialist, multi-disciplinary teams. This study aimed to determine if the implementation of Calman–Hine cancer teams was associated with improved processes and outcomes of care for colorectal cancer patients. The design included longitudinal survey of 13 colorectal cancer teams in Yorkshire and retrospective study of population-based data collected by the Northern and Yorkshire Cancer Registry and Information Service. The population was all colorectal cancer patients diagnosed and treated in Yorkshire between 1995 and 2000. The main outcome measures were: variations in the use of anterior resection and preoperative radiotherapy in rectal cancer, chemotherapy in Dukes stage C and D patients, and five-year survival. Using multilevel models, these outcomes were assessed in relation to measures of the extent of Calman–Hine implementation throughout the study period, namely: (i) each team's degree of adherence to the Manual of Cancer Service Standards (which outlines the specification of the ‘ideal’ colorectal cancer team) and (ii) the extent of site specialisation of each team's surgeons. Variation was observed in the extent to which the colorectal cancer teams in Yorkshire had conformed to the Calman–Hine recommendations. An increase in surgical site specialisation was associated with increased use of preoperative radiotherapy (OR=1.43, 95% CI=1.04–1.98, P<0.04) and anterior resection (OR=1.43, 95% CI=1.16–1.76, P<0.01) in rectal cancer patients. Increases in adherence to the Manual of Cancer Service Standards was associated with improved five-year survival after adjustment for the casemix factors of age, stage of disease, socioeconomic status and year of diagnosis, especially for colon cancer (HR=0.97, 95% CI=0.94–0.99 P<0.01). There was a similar trend of improved survival in relation to increased surgical site specialisation for rectal cancer, although the effect was not statistically significant (HR=0.93, 95% CI=0.84–1.03, P=0.15). In conclusion, the extent of implementation of the Calman–Hine report has been variable and its recommendations are associated with improvements in processes and outcomes of care for colorectal cancer patients

South Asians living in the UK and adherence to coronary heart disease medication: a mixed- method study.

Background The prevalence of coronary heart disease amongst South Asian population in the UK is higher compared to the general population. Objective This study sought to investigate beliefs and experiences of South Asian patients regarding coronary heart disease and medication taking behaviour. Setting A London Heart Attack Centre. Methods This mixed method study is part of an original pilot randomised study on 71 patients involving a pharmacy-led intervention to improve medication adherence in coronary heart disease patients. South Asian patients from the randomised study took part in qualitative semi-structured telephone interviews. Both South Asian and non-South Asian patients completed the questionnaire about adherence and beliefs regarding medicines using Morisky Scale and the Belief About Medicines Questionnaire-Specific at 2 weeks, 3 and 6 months. Outcome Patients' beliefs about coronary heart disease and medication adherence. Results Seventeen South Asian patients and 54 non-South Asian patients took part. Qualitative data from 14 South Asian patients showed that while some attributed coronary heart disease to genetic, family history for their illness, others attributed it to their dietary patterns and 'god's will' and that little could be done to prevent further episodes of coronary heart disease. On the Belief About Medicines Questionnaire-Specific in South Asian patients, beliefs about necessity of medicines outweighed concerns. South Asian patients (n = 17) showed a similar pattern of adherence compared to non-Asian patients (n = 54). Adherence decreased with time in both populations, adherence measured by Morisky Scale. Conclusion South Asian patients in this study often attributed coronary heart disease to additional causes besides the known risk factors. Future studies on their understanding of the importance of cultural context in their attitudes to prevention and lived experience of the disease is warranted

Cardiac Procedures among American Indians and Alaska Natives compared to Non-Hispanic Whites Hospitalized with Ischemic Heart Disease in California

BackgroundAmerican Indians/Alaska Natives (AIAN) experience a high burden of cardiovascular disease with rates for fatal and nonfatal heart disease approximately twofold higher than the U.S. population.ObjectiveTo determine if disparities exist in cardiac procedure rates among AIAN compared to non-Hispanic whites hospitalized in California for ischemic heart disease defined as acute myocardial infarction or unstable angina.DesignCross-sectional study. EVENTS: A total of 796 ischemic heart disease hospitalizations among AIAN and 90971 among non-Hispanic whites in 37 of 58 counties in California from 1998-2002.MeasurementsCardiac catheterization, percutaneous cardiac intervention, and coronary artery bypass graft surgery procedure rates from hospitalization administrative data.Main resultsAIAN did not have lower cardiac procedure rates for cardiac catheterization and percutaneous cardiac intervention compared to non-Hispanic whites (unadjusted OR 1.00, 95% CI 0.87-1.16 and OR 1.04, 95% CI 0.90-1.20, respectively). Adjustment for age, sex, comorbidities, and payer source did not alter the results (adjusted OR 0.95, 95% CI 0.82-1.10 and OR 0.98, 95% CI 0.85-1.14, respectively). We found higher odds (unadjusted OR 1.36, 95% CI 1.09-1.70) for receipt of coronary artery bypass graft surgery among AIAN hospitalized for ischemic heart disease compared to non-Hispanic whites which after adjustment attenuated some and was no longer statistically significant (adjusted OR 1.26, 95% CI 1.00-1.58).ConclusionAIAN were not less likely to receive cardiac procedures as non-Hispanic whites during hospitalizations for ischemic heart disease. Additional research is needed to determine whether differences in specialty referral patterns, patients' treatment preferences, or outpatient management may explain some of the health disparities due to cardiovascular disease that is found among AIAN

A One Base Pair Deletion in the Canine ATP13A2 Gene Causes Exon Skipping and Late-Onset Neuronal Ceroid Lipofuscinosis in the Tibetan Terrier

Neuronal ceroid lipofuscinosis (NCL) is a progressive neurodegenerative disease characterized by brain and retinal atrophy and the intracellular accumulation of autofluorescent lysosomal storage bodies resembling lipofuscin in neurons and other cells. Tibetan terriers show a late-onset lethal form of NCL manifesting first visible signs at 5–7 years of age. Genome-wide association analyses for 12 Tibetan-terrier-NCL-cases and 7 Tibetan-terrier controls using the 127K canine Affymetrix SNP chip and mixed model analysis mapped NCL to dog chromosome (CFA) 2 at 83.71–84.72 Mb. Multipoint linkage and association analyses in 376 Tibetan terriers confirmed this genomic region on CFA2. A mutation analysis for 14 positional candidate genes in two NCL-cases and one control revealed a strongly associated single nucleotide polymorphism (SNP) in the MAPK PM20/PM21 gene and a perfectly with NCL associated single base pair deletion (c.1620delG) within exon 16 of the ATP13A2 gene. The c.1620delG mutation in ATP13A2 causes skipping of exon 16 presumably due to a broken exonic splicing enhancer motif. As a result of this mutation, ATP13A2 lacks 69 amino acids. All known 24 NCL cases were homozygous for this deletion and all obligate 35 NCL-carriers were heterozygous. In a sample of 144 dogs from eleven other breeds, the c.1620delG mutation could not be found. Knowledge of the causative mutation for late-onset NCL in Tibetan terrier allows genetic testing of these dogs to avoid matings of carrier animals. ATP13A2 mutations have been described in familial Parkinson syndrome (PARK9). Tibetan terriers with these mutations provide a valuable model for a PARK9-linked disease and possibly for manganese toxicity in synucleinopathies