Talar neck and body fracture outcomes: a multicentre retrospective review.

PURPOSE: Talar neck and body fractures are uncommon injuries that are challenging to manage with high reported complication rates, including post-traumatic arthritis, avascular necrosis, and poor functional outcomes. The aim of this study was to assess the complication rates for patients with talus fractures across three major trauma centres (MTCs) in England. METHODS: A retrospective analysis was performed of prospectively collected trauma databases. Data were collected from three English MTCs. Patients with talar neck and/or body fractures sustained between August 2015 and August 2019 were identified and their clinical course reviewed radiologically and clinically. Isolated process fractures, osteochondral defects and paediatric patients were excluded. Patients were analysed by fracture type and for definitive treatment method with separation into non-operative and operative management groups. Procedure type was identified in the operative group. Superficial infection, deep infection, non-union, avascular necrosis, post-traumatic arthritis and removal of metalwork rates were analysed. RESULTS: Eighty-five patients with talar neck and/or body fractures were included. Seventy-five patients received operative management, 10 non-operative. The overall AVN rate was 5.9% (five patients), overall post-traumatic arthritis rate was 18.8% (16 patients), deep infection rate 1.2% (one patient), non-union rate 4.7% (four patients). Removal of metalwork rate was 9.4% (eight patients). CONCLUSION: Our reported outcomes and complication rates are generally lower than those previously described. This may be a result of improved techniques, a higher frequency of open reduction with direct visualisation or by surgery occurring in centralised specialist centres.

Association of ACTN3 R577X but not ACE I/D gene variants with elite rugby union player status and playing position.

We aimed to quantify the ACE I/D and ACTN3 R577X (rs1815739) genetic variants in elite rugby athletes (rugby union and league) and compare genotype frequencies to controls and between playing positions. The rugby athlete cohort consisted of 507 Caucasian men, including 431 rugby union athletes that for some analyses were divided into backs and forwards and into specific positional groups: front five, back row, half backs, centers, and back three. Controls were 710 Caucasian men and women. Real-time PCR of genomic DNA was used to determine genotypes using TaqMan probes and groups were compared using χ(2) and odds ratio (OR) statistics. Correction of P values for multiple comparisons was according to Benjamini-Hochberg. There was no difference in ACE I/D genotype between groups. ACTN3 XX genotype tended to be underrepresented in rugby union backs (15.7%) compared with forwards (24.8%, P = 0.06). Interestingly, the 69 back three players (wings and full backs) in rugby union included only six XX genotype individuals (8.7%), with the R allele more common in the back three (68.8%) than controls (58.0%; χ(2) = 6.672, P = 0.04; OR = 1.60) and forwards (47.5%; χ(2) = 11.768, P = 0.01; OR = 2.00). Association of ACTN3 R577X with playing position in elite rugby union athletes suggests inherited fatigue resistance is more prevalent in forwards, while inherited sprint ability is more prevalent in backs, especially wings and full backs. These results also demonstrate the advantage of focusing genetic studies on a large cohort within a single sport, especially when intrasport positional differences exist, instead of combining several sports with varied demands and athlete characteristics.

The problem of over-medicalisation: How AOD disease models perpetuate inequity for young people with multiple disadvantage.

Young people who experience multiple disadvantage have been identified as some of the most marginalised and under-serviced people in the alcohol and other drug (AOD) system. In this paper, we draw on a range of research evidence to argue that one of the challenges in responding appropriately to the needs of these young people are models of care which seek to ameliorate 'illness' rather than promote wellness. While disease approaches have some important benefits, overly-medicalised AOD treatment responses also have negative impacts. We argue that disease models rest on understandings of substance use as an individual enterprise and thereby pay insufficient attention to the material disadvantage that shape young people's substance use, creating feelings of shame, failure and a reluctance to return to care if they continue to use. Additionally we draw on literature that shows how disease models construe young people's substance use as compulsive, perpetuating deficit views of them as irrational and failing to account for the specific meanings that young people themselves give to their substance use. By focusing on clinical solutions rather than material and relational ones, medicalised treatment responses perpetuate inequity: they benefit young people whose resources and normative values align with the treatments offered by disease models, but are much less helpful to those who are under-resourced,. We suggest that alternative approaches can be found in First Nations models of care and youth programs that attend to social, cultural, and material wellbeing, making living well the focus of treatment rather than illness amelioration.

Community pharmacists' views on providing a reproductive health service to women receiving opioid substitution treatment: A qualitative study using the TDF and COM-B.

BACKGROUND: The absence of menstruation is common in women who use drugs. This can give a belief that conception is unlikely. When stabilised on Opioid Substitution Treatment (OST), fertility often returns, initially without realisation as ovulation precedes menstruation. This leaves women vulnerable to unplanned pregnancies. Community pharmacists (CPs) are frequently in contact with this patient group through the Supervised Consumption of OST service. This provides a timely opportunity to provide reproductive health (RH) advice. The aim of this study was to investigate pharmacists' views on providing a RH service to women receiving OST. METHODS: Twenty semi-structured interviews based on the Capability-Opportunity-Motivation to Behaviour (COM-B) model and the Theoretical Domains Framework (TDF) were conducted between 2016 and 2017. Data analysis involved deductive coding using the TDF domains. The TDF domains were mapped onto the elements of the COM-B and used in the second step to create the framework and chart the data. The third step involved re-reading and clustering the codes, and inductive themes were generated to explain the data in depth. RESULTS: Nine of the 14 TDF domains, mapped into five elements of the COM-B, were identified. Five inductive themes were generated: 1) The pharmacists' experience and knowledge of reproductive health (RH) needs of women receiving OST, 2) The pharmacists' approach to providing advice, 3) The pharmacists' perception of the relationship with women receiving OST, 4) Social influences, and 5) Environmental factors. Community pharmacists feared causing offense to women receiving OST and described requiring cues as to when the service was needed. Pharmacists' highlighted a power imbalance in the relationship with women receiving OST. This could influence how receptive this patient group would be to pharmacy RH interventions. CONCLUSIONS: CPs' concerns of providing RH service could hinder a proactive service provision. Supporting good rapport and providing a structured consultation would increase the accessibility of such a service.

Fructose Metabolism and Cardiac Metabolic Stress.

Cardiovascular disease is one of the leading causes of mortality in diabetes. High fructose consumption has been linked with the development of diabetes and cardiovascular disease. Serum and cardiac tissue fructose levels are elevated in diabetic patients, and cardiac production of fructose via the intracellular polyol pathway is upregulated. The question of whether direct myocardial fructose exposure and upregulated fructose metabolism have potential to induce cardiac fructose toxicity in metabolic stress settings arises. Unlike tightly-regulated glucose metabolism, fructose bypasses the rate-limiting glycolytic enzyme, phosphofructokinase, and proceeds through glycolysis in an unregulated manner. In vivo rodent studies have shown that high dietary fructose induces cardiac metabolic stress and functional disturbance. In vitro, studies have demonstrated that cardiomyocytes cultured in high fructose exhibit lipid accumulation, inflammation, hypertrophy and low viability. Intracellular fructose mediates post-translational modification of proteins, and this activity provides an important mechanistic pathway for fructose-related cardiomyocyte signaling and functional effect. Additionally, fructose has been shown to provide a fuel source for the stressed myocardium. Elucidating the mechanisms of fructose toxicity in the heart may have important implications for understanding cardiac pathology in metabolic stress settings.

Regenerative neurogenic response from glia requires insulin-driven neuron-glia communication.

Understanding how injury to the central nervous system induces de novo neurogenesis in animals would help promote regeneration in humans. Regenerative neurogenesis could originate from glia and glial neuron-glia antigen-2 (NG2) may sense injury-induced neuronal signals, but these are unknown. Here, we used Drosophila to search for genes functionally related to the NG2 homologue kon-tiki (kon), and identified Islet Antigen-2 (Ia-2), required in neurons for insulin secretion. Both loss and over-expression of ia-2 induced neural stem cell gene expression, injury increased ia-2 expression and induced ectopic neural stem cells. Using genetic analysis and lineage tracing, we demonstrate that Ia-2 and Kon regulate Drosophila insulin-like peptide 6 (Dilp-6) to induce glial proliferation and neural stem cells from glia. Ectopic neural stem cells can divide, and limited de novo neurogenesis could be traced back to glial cells. Altogether, Ia-2 and Dilp-6 drive a neuron-glia relay that restores glia and reprogrammes glia into neural stem cells for regeneration.

Physical activity and the prevention, reduction, and treatment of alcohol and other drug use across the lifespan (The PHASE review): A systematic review.

The aim of this review is to systematically describe and quantify the effects of PA interventions on alcohol and other drug use outcomes, and to identify any apparent effect of PA dose and type, possible mechanisms of effect, and any other aspect of intervention delivery (e.g. key behaviour change processes), within a framework to inform the design and evaluation of future interventions. Systematic searches were designed to identify published and grey literature on the role of PA for reducing the risk of progression to alcohol and other drug use (PREVENTION), supporting individuals to reduce alcohol and other drug use for harm reduction (REDUCTION), and promote abstinence and relapse prevention during and after treatment of alcohol and other drug use (TREATMENT). Searches identified 49,518 records, with 49,342 excluded on title and abstract. We screened 176 full text articles from which we included 32 studies in 32 papers with quantitative results of relevance to this review. Meta-analysis of two studies showed a significant effect of PA on prevention of alcohol initiation (risk ratio [RR]: 0.72, 95%CI: 0.61 to 0.85). Meta-analysis of four studies showed no clear evidence for an effect of PA on alcohol consumption (Standardised Mean Difference [SMD]: 0.19, 95%, Confidence Interval -0.57 to 0.18). We were unable to quantitatively examine the effects of PA interventions on other drug use alone, or in combination with alcohol use, for prevention, reduction or treatment. Among the 19 treatment studies with an alcohol and other drug use outcome, there was a trend for promising short-term effect but with limited information about intervention fidelity and exercise dose, there was a moderate to high risk of bias. We identified no studies reporting the cost-effectiveness of interventions. More rigorous and well-designed research is needed. Our novel approach to the review provides a clearer guide to achieve this in future research questions addressed to inform policy and practice for different populations and settings.

An alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in C. elegans.

In the nematode C. elegans, insulin signaling regulates development and aging in response to the secretion of numerous insulin peptides. Here, we describe a novel, non-signaling isoform of the nematode insulin receptor (IR), DAF-2B, that modulates insulin signaling by sequestration of insulin peptides. DAF-2B arises via alternative splicing and retains the extracellular ligand binding domain but lacks the intracellular signaling domain. A daf-2b splicing reporter revealed active regulation of this transcript through development, particularly in the dauer larva, a diapause stage associated with longevity. CRISPR knock-in of mScarlet into the daf-2b genomic locus confirmed that DAF-2B is expressed in vivo and is likely secreted. Genetic studies indicate that DAF-2B influences dauer entry, dauer recovery and adult lifespan by altering insulin sensitivity according to the prevailing insulin milieu. Thus, in C. elegans alternative splicing at the daf-2 locus generates a truncated IR that fine-tunes insulin signaling in response to the environment.

Choline acetyltransferase activity of spinal cord cell cultures increased by co-culture with muscle and by muscle-conditioned medium.

Activity of the enzyme choline acetyltransferase (CAT), which mediates the synthesis of the neurotransmitter, acetylcholine, was increased up to 20- fold in spinal cord (SC) cells grown in culture with muscle cells for 2 wk. This increase was directly related to the duration of co-culture as well as to the cell density of both the SC and muscle involved and was not affected by the presence of the acetylcholine receptor blocking agent, alpha-bungarotoxin. Glutamic acid decarboxylase (GAD) activity was often markedly decreased in SC-muscle cultures while the activities of acetylcholinesterase and several other enzymes were little changed. Increased CAT activity was also observed when SC cultures were maintained in medium which had been conditioned by muscle cells or by undifferentiated cells from embryonic muscle. Muscle-conditioned medium (CM) did not affect the activities of SC cell GAD or acetylcholinesterase. Dilution or concentration of the CM directly affected its ability to increase SC CAT activity , as did the duration and timing of exposure of the SC cells to the CM. The medium could be conditioned by muscle cells in the presence or absence of serum, and remained effective after dialysis or heating to 58 degrees C. Membrane filtration data were consistent with the conclusion that the active material(s) in CM had a molecular weight in excess of 50,000 daltons. We conclude that large molecular weight material that is released by muscle cells is capable of producing a specific increase in CAT activity of SC cells.

Radioautography of the optic tectum of the goldfish after intraocular injection of ( 3 H)proline.

Radioautography of the optic tectum of the goldfish, performed after injection of [(3)H]proline into the contralateral eye, effectively resolves several distinct layers of retinal synapses. Silver grains are found unilaterally over nerve tracts containing efferent fibers from the tectum, a result that suggests intercellular migration of labeled molecules. The low background and high specific grain density obtained with [(3)H]proline radioautography indicate the usefulness of this technique for the elucidation of neuroanatomical connections in the visual system.

Camptothecin blocks memory of conditioned avoidance in the goldfish.

Intracranial injection of 10 to 75 micrograms of camptothecin, a plant alkaloid that blocks RNA synthesis in eucaryotic cells, blocks incorporation of tritiated uridine into RNA in the goldfish brain. Injection of 10 to 50 micrograms of the drug within 1.5 hours of training results in greatly diminished memory, tested 1 week later. Injection of the drug 5 or 24 hours after training produces no measurable effect on retention of the learned response.

Enkephalin-containing neurons visualized in spinal cord cell cultures.

Neuronal cells, axons, and terminals containing immunoreactive enkephalin have been visualized in cultures of dissociated fetal spinal cord. These cultures may provide a valuable system in which to explore the effects of chronic drug treatment on the physiology of enkephalin-containing cells and their interactions with other cells.

Opiate peptide modulation of amino acid responses suggests novel form of neuronal communication.

Mouse spinal neurons grown in tissue culture were used to study the electrophysiological pharmacology of the opiate peptide leucine-enkephalin. Enkephalin depressed glutamate-evoked responses in a noncompetitive manner independent of any other effects on membrane properties. The results demonstrate a neuromodulatory action of opiate peptide functionally distinct from the conventional neurotransmitter class of operation.

Role of human CYP1A1 and NAT2 in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced mutagenicity and DNA adducts.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is carcinogenic in multiple organs and numerous species. Bioactivation of PhIP is initiated by PhIP N(2)-hydroxylation catalysed by cytochrome P450s. Following N-hydroxylation, O-acetylation catalysed by N-acetyltransferase 2 (NAT2) is considered a further possible activation pathway. Genetic polymorphisms in NAT2 may modify cancer risk following exposure. Nucleotide excision repair-deficient Chinese hamster ovary (CHO) cells stably transfected with human cytochrome P4501A1 (CYP1A1) and a single copy of either NAT2*4 (rapid acetylator) or NAT2*5B (slow acetylator) alleles were used to test the effect of CYP1A1 and NAT2 polymorphism on PhIP genotoxicity. Cells transfected with NAT2*4 had significantly higher levels of N-hydroxy-PhIP O-acetyltransferase (p = 0.0150) activity than cells transfected with NAT2*5B. Following PhIP treatment, CHO cell lines transfected with CYP1A1, CYP1A1/NAT2*4 and CYP1A1/NAT2*5B each showed concentration-dependent cytotoxicity and hypoxanthine phosphoribosyl transferase (hprt) mutagenesis not observed in untransfected CHO cells. dG-C8-PhIP was the primary DNA adduct formed and levels were dose dependent in transfected CHO cells in the order: CYP1A1 < CYP1A1 and NAT2*5B < CYP1A1 and NAT2*4, although levels did not differ significantly (p > 0.05) following one-way analysis of variance. These results strongly support activation of PhIP by CYP1A1 with little effect of human NAT2 genetic polymorphism on mutagenesis and DNA damage.

Variation in preparation for gastroscopy: lessons towards safer and better outcomes.

OBJECTIVE: To identify the methods employed within the UK practice prior to diagnostic gastroscopy and compare with published guidelines for patients undergoing general anaesthesia. DESIGN: National Health Service (NHS) endoscopy units were invited to take part in a structured telephone survey to determine the length of time patients are kept nil-by-mouth (NBM) for food and fluids prior to gastroscopy, and whether a preprocedure mucolytic drink was used. METHODS: 212 NHS Trusts providing endoscopy services were identified from the Joint Advisory Group on GI Endoscopy. Trusts were excluded if they were children's hospitals (n=5). RESULTS: 207 NHS Trusts were telephoned. 193 completed the survey (93%), 11 Trusts declined and there was no response from 3 Trusts. 13 separate policies regarding NBM timings were identified. 51 Trusts (21%) used the timings ratified by Surgical and Anaesthetic Societies (6 h NBM for food, 2 h for clear fluid). 135 Trusts (70%) used a policy which starved patients in excess of the standard surgical guidelines. No Trust used a mucolytic drink prior to gastroscopy. CONCLUSIONS: The survey revealed large variation in NHS Trust's policies regarding the times patients were starved prior to gastroscopy. Results of surgical studies demonstrate increased risk of significant pulmonary aspiration with increased fluid-starvation periods, 68% of NHS endoscopy policy would be deemed excessive by surgical practice. There is no routine use of a mucolytic drink to improve mucosal visualisation in the UK practice.

Contaminant loads and hematological correlates in the harbor seal (Phoca vitulina) of San Francisco Bay, California.

An expanding body of research indicates that exposure to contaminants may impact marine mammal health, thus possibly contributing to population declines. The harbor seal population of the San Francisco Bay (SFB), California, has suffered habitat loss and degradation, including decades of environmental contamination. To explore the possibility of contaminant-induced health alterations in this population, blood levels of polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (DDE), and polybrominated diphenyl ethers (PBDEs) were quantified in free-ranging seals; relationships between contaminant exposure and several key hematological parameters were examined; and PCB levels in the present study were compared with levels determined in SFB seals a decade earlier. PCB residues in harbor seal blood decreased during the past decade, but remained at levels great enough that adverse reproductive and immunological effects might be expected. Main results included a positive association between leukocyte counts and PBDEs, PCBs, and DDE in seals, and an inverse relationship between red blood cell count and PBDEs. Although not necessarily pathologic, these responses may serve as sentinel indications of contaminant-induced alterations in harbor seals of SFB, which, in individuals with relatively high contaminant burdens, might include increased rates of infection and anemia.

The neuropsychological signature of schizophrenia: generalized or differential deficit?

OBJECTIVE: The aim of this study was to provide a comprehensive assessment of neuropsychological functioning in schizophrenia so as to evaluate hypotheses of lateralized or differential cognitive impairment in this disorder. Furthermore, the study sought to address the potentially confounding factors of medication side effects and relevant demographic variables such as age, education, gender, and handedness. METHOD: The neuropsychological functioning of 28 schizophrenic patients whose medication had been withdrawn for research purposes and 15 demographically matched normal subjects was evaluated. A comprehensive battery of tasks was used to determine whether performance patterns of schizophrenic patients were consistent with models of lateralized or localized neuropsychological impairment in schizophrenia. To facilitate comparison with results of other studies, several analytic strategies were used, including comparisons of group performance on individual tests, composite function scores, and evaluation of performance based on "clinical" criteria of impairment. RESULTS: In contrast to the normal subjects, the schizophrenic patients displayed impairment across measures of motor, sensory, and perceptual functioning, verbal and nonverbal memory, and indexes of frontal lobe functioning. This pattern of generalized dysfunction was evident regardless of the method of analysis used to assess performance. CONCLUSIONS: These findings fail to support conjectures regarding differential neurocognitive deficits in schizophrenia. However, the psychometric limitations of currently available neuropsychological measures may obscure the finding of differential impairment and must be considered in interpreting the results of this study as well as those of any investigation using such instruments.

Two forms of the GABAA receptor distinguished by anion-exchange chromatography.

The GABAA receptor complex was solubilized from rat brain membranes in Triton X-100, enriched by 1012-S affinity chromatography, and subjected to DEAE anion-exchange chromatography. Two forms were distinguished by their differential elution during this HPLC with a KCl gradient. They displayed similar [3H]muscimol- and [3H]flunitrazepam-binding characteristics, as well as [3H]flunitrazepam-binding inhibition by CL 218872. Rechromatography of these distinct ionic forms indicated that they were not in dynamic equilibrium during chromatography. Resolution of these two pharmacologically similar populations of GABAA receptor by anion-exchange HPLC suggests that they differ in charge densities, a condition which may reflect differing glycosylation or phosphorylation states of the complex.

N-acetylaspartylglutamate immunoreactivity in neurons of the monkey's visual pathway.

The acidic dipeptide N-acetylaspartylglutamate (NAAG) was identified immunohistochemically within neurons of the visual pathways of two adult macaque monkeys which had undergone midsagittal sectioning of the optic chiasm 6 or 9 years earlier. In both temporal and nasal retinae, amacrine cells, including some displaced amacrine cells, expressed NAAG immunoreactivity. In temporal but not nasal retina, retinal ganglion cells were stained, as were their dendrites in the inner plexiform layer, and their axons in the optic nerve fiber layer. In nasal retina, the ganglion cells had degenerated because they were axotomized by the optic chiasm section. In the target regions of the retinal ganglion cells, the superior colliculus and the lateral geniculate nucleus (LGN), both neuropil and cell bodies were stained. In LGN, staining was confined to layers 2, 3, and 5, that is, to the layers innervated by the intact ipsilateral pathway. Immunoreactivity was also seen in the cells of layers 2, 3A, 4B, 5, and 6 of area 17 and layers 3 and 5 of area 18. The neuropil was stained in all layers of area 17, but more heavily in layers 1, 2, 4B, the bottom of 4C beta, 5B, and 6B. Within 4C the staining was patchy; in tangential sections there were alternating bands of light and dark label which matched the ocular dominance bands demonstrated by cytochrome oxidase histochemistry in adjacent sections. This banding pattern is consistent with the presence of NAAG in geniculocortical terminals of the intact ipsilateral pathway and the absence of such terminals for the contralateral pathway, which had undergone transneuronal degeneration due to the optic chiasm sectioning. Overall, our results for monkey are very similar to those in cat and suggest that NAAG or a structurally related molecule may have a prominent role in the communication of visual signals at retinal, thalamic, and cortical levels.