Intrinsic thermalization of the honeycomb optical lattice.

Ultracold atoms confined to optical lattices provide a platform for simulation of phenomena not readily accessible in condensed matter and chemical systems. One area of growing interest is the mechanism by which isolated condensed matter systems can thermalize. The mechanism for thermalization of quantum systems has been directly linked to a transition to chaos in their classical counterpart. Here we show that the broken spatial symmetries of the honeycomb optical lattice leads to a transition to chaos in the single-particle dynamics which, in turn, causes mixing of the energy bands of the quantum honeycomb lattice. For systems with single-particle chaos, "soft" interactions between atoms can cause the system to thermalize (achieve a Fermi-Dirac distribution for fermions or a Bose-Einstein distribution for bosons).

The relationship between meniscal pathologies, cartilage loss, joint replacement and pain in knee osteoarthritis: a systematic review.

OBJECTIVE: We conducted a systematic review in order to understand the relationship between imaging-visualised meniscus pathologies, hyaline cartilage, joint replacement and pain in knee osteoarthritis (OA). DESIGN: A search of the Medline, Excerpta Medica database (EMBASE) and Cochrane library databases was performed for original publications reporting association between imaging-detected meniscal pathology (extrusion or tear/damage) and longitudinal and cross-sectional assessments of hyaline articular cartilage loss [assessed on magnetic resonance imaging (MRI)], incident joint replacement and pain (longitudinal and cross-sectional) in knee OA. Each association was qualitatively characterised by a synthesis of data from each analysis, based upon study design and quality scoring (including risk of bias assessment and adequacy of covariate adjustment using Cochrane recommended methodology). RESULTS: In total 4,878 abstracts were screened and 82 publications were included (comprising 72 longitudinal analyses and 49 cross-sectional). Using high quality, well-adjusted data, meniscal extrusion and meniscal tear/damage were associated with longitudinal progression of cartilage loss, cross-sectional cartilage loss severity and joint replacement, independently of age, sex and body mass index (BMI). Medial and lateral meniscal tears were associated with cartilage loss when they occurred in the body and posterior horns, but not the anterior horns. There was a lack of high quality, well-adjusted meniscal pathology and pain publications and no clear independent association between meniscal extrusion or tear/damage with pain severity, progression in pain or incident frequent knee symptoms. CONCLUSION: Meniscal features have strong associations with cartilage loss and joint replacement in knee OA, but weak associations with knee pain. Systematic review PROSPERO registration number: CRD 42020210910.

A comparison of the effects of clozapine and its metabolite norclozapine on metabolic dysregulation in rodent models.

RATIONALE: The second generation antipsychotic drug clozapine is a psychotherapeutic agent with superior efficacy for treatment-resistant schizophrenia. Clozapine is associated with a low likelihood of neurological side-effects, but a high propensity to induce weight gain and metabolic dysregulation. The primary metabolite of clozapine is norclozapine (N-Desmethylclozapine), which has psychoactive properties itself, but its effects on metabolic function remains unknown. The goal of the present study was to determine whether directly administered norclozapine could cause metabolic dysregulation, similar to clozapine. METHODS: Adult female rats were treated with a range of doses of clozapine and norclozapine (0.5, 2, 8 & 20 mg/kg, i.p.) and then subjected to the intraperitoneal glucose tolerance test (IGTT), where glucose levels were recorded for 2 h following a glucose challenge. In parallel, rats were tested with two doses of clozapine and norclozapine (2 & 20 mg/kg, i.p.) in the hyperinsulinemic-euglycemic clamp (HIEC), to measure whole body insulin resistance. RESULTS: In the IGTT, clozapine demonstrated dose-dependent effects on fasting glucose levels and total glucose area-under-the-curve following the glucose challenge, with the two highest doses strongly increasing glucose levels. Only the highest dose of norclozapine increased fasting glucose levels, and caused a non-significant increase in glucose levels following the challenge. By contrast, both doses of clozapine and norclozapine caused a potent and long-lasting decrease in the glucose infusion rate in the HIEC, indicating that both compounds cause whole body insulin resistance. ABSTRACT: While not as potent as its parent compound, norclozapine clearly exerts acute metabolic effects, particularly on insulin resistance. This article is part of the issue entitled 'Special Issue on Antipsychotics'.

Decreased medial entorhinal cortical thickness in olanzapine exposed female rats is not ameliorated by exercise.

Aerobic exercise has been associated with hippocampal plasticity, both in healthy adults and in psychosis patients, but its impact on cortical regions remains unclear. The entorhinal cortex serves as a critical gateway for the hippocampus, and recent studies suggest that this region may also be impacted following an exercise regime. In order to investigate the effects of antipsychotic medications and exercise on the entorhinal cortex, female rats were chronically administered either olanzapine or vehicle and were either sedentary or had access to a running wheel for 9 weeks. Olanzapine-treated rats had decreased medial entorhinal cortical thickness compared to vehicle-treated rats. A statistically significant interaction was observed for layer II of the entorhinal cortex, with exercising rats having significantly greater thickness compared to sedentary rats in the vehicle group, but not the olanzapine group. Greater total entorhinal and lateral entorhinal cortical thickness was associated with greater average activity. In exercising rats, decreasing glucose intolerance was associated with larger total entorhinal and layer II cortical thickness. Lower fasting insulin levels were associated with greater total entorhinal, lateral entorhinal, and layer II cortical thickness. The relationship between increased activity and greater entorhinal cortical thickness was mediated by reduced fasting insulin, indicating that regulation of metabolic risk factors may contribute to impact of aerobic exercise on the entorhinal cortex. Aerobic exercise may be helpful in counteracting metabolic side effects of antipsychotic medications and managing these side effects may be key to promoting entorhinal cortical plasticity in patients treated with second-generation antipsychotic drugs.

The C-Band All-Sky Survey (C-BASS): Simulated parametric fitting in single pixels in total intensity and polarization.

The cosmic microwave background (CMB) B-mode signal is potentially weaker than the diffuse Galactic foregrounds over most of the sky at any frequency. A common method of separating the CMB from these foregrounds is via pixel-based parametric-model fitting. There are not currently enough all-sky maps to fit anything more than the most simple models of the sky. By simulating the emission in seven representative pixels, we demonstrate that the inclusion of a 5 GHz data point allows for more complex models of low-frequency foregrounds to be fitted than at present. It is shown that the inclusion of the C-BASS data will significantly reduce the uncertainties in a number of key parameters in the modelling of both the galactic foregrounds and the CMB. The extra data allow estimates of the synchrotron spectral index to be constrained much more strongly than is presently possible, with corresponding improvements in the accuracy of the recovery of the CMB amplitude. However, we show that to place good limits on models of the synchrotron spectral curvature will require additional low-frequency data.

The relationship between two different measures of osteoarthritis bone pathology, bone marrow lesions and 3D bone shape: data from the Osteoarthritis Initiative.

OBJECTIVE: Bone shape and bone marrow lesions (BMLs) represent different features of Magnetic resonance imaging (MRI)-detected subchondral pathology in osteoarthritis (OA). The aim of this study was to determine how these features are related and how they change in OA progression. METHODS: 600 participants from the Osteoarthritis Initiative (OAI) FNIH Biomarkers Initiative were included, having Kellgren-Lawrence grade 1-3, at baseline and MRI data at baseline and 24 months. The associations between 3D quantitative bone shape vectors and presence of (MRI Osteoarthritis Knee Score) MOAKS semi-quantitative BMLs (total BML size ≥1) were analysed for femurs and tibias using linear regression. Responsiveness over 24 months was calculated for both features in four pre-defined progression groups and reported as standardised response means (SRMs). Multilevel models investigated the longitudinal relationship between change in BML size and change in bone shape. RESULTS: Mean age was 61.5, 59% female and mean body mass index (BMI) 30.7. Correlation between baseline femur vector and BML was r = 0.28, P < 0.001. The presence of BMLs was associated with higher bone shape vector; coefficient (95% CI) 0.75 (0.54, 0.96) and 0.57 (0.38, 0.77) for femur and tibia respectively, both P < 0.001. After covariate adjustment, only the femur remained significant [coefficient 0.49, (95% CI 0.30, 0.68)]. Longitudinally bone vector demonstrated more responsiveness to change than BMLs (SRM 0.89 vs 0.13) while multilevel models revealed that increase in BML size was related to a more positive bone shape vector (representing worsening OA). CONCLUSION: There is a relationship between bone shape and BMLs, with prevalence of BMLs associated with increasing OA bone shape. Bone shape demonstrated greater responsiveness than semi-quantitative BMLs.

Electromagnetic Interference in Measurements of Radial Stress During Split Hopkinson Pressure Bar Experiments.

Split Hopkinson pressure bar experiments on soils are often carried out using a rigid steel confining ring to provide plane strain conditions, and measurements of the circumferential strain in the ring can be used to infer the radial stress on the surface of the specimen. Previous experiments have shown evidence of irregular electromagnetic interference in measurements of radial stress, which obscures the signals and impedes analysis. The development of robust constitutive models for soils in blast and impact events relies on the accurate characterisation of this behaviour, and so it is necessary to isolate and remove the source of interference. This paper uses an induction coil to identify the source of the anomalous signals, which are found to be due to induced currents in the gauge lead wires from the movement of magnetised pressure bars (martensitic stainless steel, 440C). Comparative experiments on sand and rubber specimens are used to show that the deforming soil specimen does not make a significant contribution to this activity, and recommendations are made on reducing electromagnetic interference to provide reliable radial stress measurements.

Subclinical ultrasonographic abnormalities of the suspensory ligament branches in National Hunt racehorses.

BACKGROUND: Suspensory ligament branch (SLB) desmopathy is a common cause of lameness and an important cause of lost training in the Thoroughbred racing industry. Studies have assessed the impact of insertional injuries of the SLB on the careers of flat racehorses and established the prevalence of subclinical ultrasonographic SLB abnormalities in this population, but little work has investigated SLB injury in National Hunt (NH) racehorses. OBJECTIVES: To investigate the prevalence of subclinical ultrasonographic SLB abnormalities in NH racehorses with no clinical signs or history of SLB injury and to establish the cross-sectional area (CSA) of SLBs in this population. STUDY DESIGN: Cross-sectional study using data collected from horses on an NH yard. METHODS: Ultrasonographic examination of forelimb SLBs in 62 horses on a single NH yard was performed. Images were graded according to a previously reported system. CSA measurements were obtained from transverse images. RESULTS: Nineteen of 62 horses had at least one SLB with grade 2 ultrasonographic abnormalities. Grade 2 ultrasonographic abnormalities occurred more frequently in the medial than the lateral SLB (P = 0.05). The medial SLB insertional CSA was significantly larger (P<0.001) than that of the lateral SLB. MAIN LIMITATIONS: Length of time on the yard (and therefore available veterinary history) is variable in this population. CONCLUSIONS: One in three NH racehorses without history or clinical signs of SLB injury had at least one SLB with a grade 2 ultrasonographic abnormality. The medial branch was over-represented. The medial SLB insertional CSA is larger than the lateral and thus comparison with the corresponding branch in the contralateral limb is recommended to avoid misdiagnosis of medial SLB enlargement.

The need for an integrated approach for chronic disease research and care in Africa.

With the changing distribution of infectious diseases, and an increase in the burden of non-communicable diseases, low- and middle-income countries, including those in Africa, will need to expand their health care capacities to effectively respond to these epidemiological transitions. The interrelated risk factors for chronic infectious and non-communicable diseases and the need for long-term disease management, argue for combined strategies to understand their underlying causes and to design strategies for effective prevention and long-term care. Through multidisciplinary research and implementation partnerships, we advocate an integrated approach for research and healthcare for chronic diseases in Africa.

Exercise prevents downregulation of hippocampal presynaptic proteins following olanzapine-elicited metabolic dysregulation in rats: Distinct roles of inhibitory and excitatory terminals.

Schizophrenia patients treated with olanzapine, or other second-generation antipsychotics, frequently develop metabolic side-effects, such as glucose intolerance and increased adiposity. We previously observed that modeling these adverse effects in rodents also resulted in hippocampal shrinkage. Here, we investigated the impact of olanzapine treatment, and the beneficial influence of routine exercise, on the neurosecretion machinery of the hippocampus. Immunodensities and interactions of three soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (syntaxin-1, synaptosome-associated protein of 25kDa (SNAP-25) and vesicle-associated membrane protein (VAMP)), synaptotagmin and complexins-1/2 were quantified in the hippocampus of sedentary and exercising rats exposed over 9weeks to vehicle (n=28) or olanzapine (10mg/kg/day, n=28). In addition, brain sections from subgroups of sedentary animals (n=8) were co-immunolabeled with antibodies against vesicular GABA (VGAT) and glutamate (VGLUT1) transporters, along with syntaxin-1, and examined by confocal microscopy to detect selective olanzapine effects within inhibitory or excitatory terminals. Following olanzapine treatment, sedentary, but not exercising rats showed downregulated (33-50%) hippocampal densities of SNARE proteins and synaptotagmin, without altering complexin levels. Strikingly, these effects had no consequences on the amount of SNARE protein-protein interactions. Lower immunodensity of presynaptic proteins was associated with reduced CA1 volume and glucose intolerance. Syntaxin-1 depletion appeared more prominent in VGAT-positive terminals within the dentate gyrus, and in non-VGAT/VGLUT1-overlapping areas of CA3. The present findings suggest that chronic exposure to olanzapine may alter hippocampal connectivity, especially in inhibitory terminals within the dentate gyrus, and along the mossy fibers of CA3. Together with previous studies, we propose that exercise-based therapies might be beneficial for patients being treated with olanzapine.

Treatment of clozapine-associated weight gain: a systematic review.

PURPOSE: Clozapine is an antipsychotic drug with superior efficacy in treatment-resistant schizophrenia. Clozapine is associated with a low likelihood of extrapyramidal symptoms and other neurological side-effects but a high propensity to induce weight gain and general metabolic dysregulation. Various pharmacological and behavioral treatment approaches for reducing clozapine-associated weight gain exist in the literature; however, there are currently no clear clinical guidelines as to which method is preferred. The aim of the current review is to systematically summarize studies that have studied both pharmacological and non-pharmacological interventions to attenuate or reverse clozapine-associated weight gain. METHODS: A systematic review of EMBASE and MEDLINE databases of all articles published prior to January 2014 was conducted. Seventeen studies were identified as meeting inclusion criteria and included in the review. RESULTS: Aripiprazole, fluvoxamine, metformin, and topiramate appear to be beneficial; however, available data are limited to between one and three randomized controlled trials per intervention. Orlistat shows beneficial effects, but in males only. Behavioral and nutritional interventions also show modest effects on decreasing clozapine-associated weight gain, although only a small number of such studies exist. CONCLUSIONS: While a number of pharmacological interventions can produce modest weight loss, each may be associated with negative side effects, which should be considered before beginning treatment. Given the pressing need to improve cardiometabolic health in most clozapine-treated patients, substantially more research is needed to develop sound clinical practice guidelines for the treatment of clozapine-associated weight gain.

The relationship between clinical characteristics, radiographic osteoarthritis and 3D bone area: data from the osteoarthritis initiative.

BACKGROUND: Radiographic measures of osteoarthritis (OA) are based upon two dimensional projection images. Active appearance modelling (AAM) of knee magnetic resonance imaging (MRI) enables accurate, 3D quantification of joint structures in large cohorts. This cross-sectional study explored the relationship between clinical characteristics, radiographic measures of OA and 3D bone area (tAB). METHODS: Clinical data and baseline paired radiographic and MRI data, from the medial compartment of one knee of 2588 participants were obtained from the NIH Osteoarthritis Initiative (OAI). The medial femur (MF) and tibia (MT) tAB were calculated using AAM. 'OA-attributable' tAB (OA-tAB) was calculated using data from regression models of tAB of knees without OA. Associations between OA-tAB and radiographic measures of OA were investigated using linear regression. RESULTS: In univariable analyses, height, weight, and age in female knees without OA explained 43.1%, 32.1% and 0.1% of the MF tAB variance individually and 54.4% when included simultaneously in a multivariable model. Joint space width (JSW), osteophytes and sclerosis explained just 5.3%, 14.9% and 10.1% of the variance of MF OA-tAB individually and 17.4% when combined. Kellgren Lawrence (KL) grade explained approximately 20% of MF OA-tAB individually. Similar results were seen for MT OA-tAB. CONCLUSION: Height explained the majority of variance in tAB, confirming an allometric relationship between body and joint size. Radiographic measures of OA, derived from a single radiographic projection, accounted for only a small amount of variation in 3D knee OA-tAB. The additional structural information provided by 3D bone area may explain the lack of a substantive relationship with these radiographic OA measures.

The range and prevalence of clinical signs and conformation associated with lameness in working draught donkeys in Pakistan.

REASONS FOR PERFORMING THE STUDY: Lameness is prevalent in working donkeys and has major welfare implications; however, a detailed study of the associated clinical signs is lacking. OBJECTIVES: To describe the range and prevalence of clinical signs and conformation associated with lameness in working draught donkeys. STUDY DESIGN: Prospective, cross-sectional, observational study. METHODS: Data were collected from 102 working draught donkeys in Pakistan. A lameness assessment adapted for working donkeys was used to record clinical signs of lameness, gait, limb conformation and pain responses in the feet, limbs and spine using observation, palpation and manipulation. Lameness at the walk was scored from 0 to 10 (sound to nonweightbearing). RESULTS: Every donkey examined had gait abnormalities, with 5% having a nonweightbearing limb. Lameness was significantly more severe with older age, lower body condition score and forward-at-the-knee conformation. More severe lameness was also associated with pain responses in the hoof walls, palpation of limb joints and spinal flexion. Joint, tendon and foot pathology was highly prevalent, as well as pain responses to joint flexion and spinal manipulation. Conformational abnormalities showed lateral asymmetries. CONCLUSIONS: Over 98% of the world's 42.2 million donkeys are in low-income countries, most being used for work. The high prevalence of lameness, pain and multiple limb and spinal abnormalities in working donkeys is of great welfare concern and highlights the complexity of addressing this problem. This standardised lameness assessment can be used when implementing and monitoring interventions to reduce lameness prevalence in working donkeys.

Routine exercise ameliorates the metabolic side-effects of treatment with the atypical antipsychotic drug olanzapine in rats.

Second generation antipsychotic (SGA) drugs are effective treatments for psychosis. Common side-effects of SGAs include metabolic dysregulation and risk of cardiometabolic disorders. Metabolic side-effects, including glucose intolerance, can be accurately modelled in rodents. The benefits of interventions used for treating metabolic side-effects of SGAs are mostly unknown. In a 9 wk longitudinal study, female rats were given daily olanzapine (10 mg/kg s.c.) or vehicle. Animals were either sedentary or allowed 1 or 3 h daily access to a running wheel, with total wheel revolutions electronically quantified to reflect exercise intensity. Glucose tolerance tests were performed once weekly to measure glycemic control. Drug levels were measured at week 4. At week 9, abdominal fat and skeletal muscle levels of Glucose Transporter 4 (GLUT4) were measured. Exercise intensity progressively increased over time in all groups given access to running wheels; however, rats treated with olanzapine consistently exercised less than those given the vehicle. Olanzapine caused acute and persistent glucose intolerance throughout the study, which was markedly, though incompletely, ameliorated by exercise. Exercise did not affect glycemic regulation in vehicle-treated rats. Olanzapine-treated rats showed greater central adiposity. Levels of GLUT4 in skeletal muscle were higher in both groups of exercising than in sedentary rats, and GLUT4 values were negatively correlated with glucose intolerance. Routine exercise reduced olanzapine-induced glucose intolerance and increased skeletal muscle levels of GLUT 4, the insulin-responsive transporter that mediates glucose uptake into cells. The current animal model is suitable for evaluating physiological pathways involved with glucose intolerance.

Effects of chronic exercise and treatment with the antipsychotic drug olanzapine on hippocampal volume in adult female rats.

Numerous studies have reported that the hippocampus in schizophrenia patients is reduced in volume compared to the normal population. Antipsychotic medications have had mixed benefits in maintaining hippocampal volume or reversing volume loss. Recent evidence indicates that routine aerobic exercise represents a promising intervention for reversing hippocampal loss and cognitive deficits. In the present study, we measured the effects of chronic treatment with olanzapine and daily exercise on the hippocampal volumes of rats. Adult female rats were treated during the week with either olanzapine (10mg/kg) or vehicle for 9 consecutive weeks. Subgroups of animals were provided access to exercise running wheels for 1 or 3h per day during the same period, or were sedentary. Metabolic indices, including glucose tolerance, were measured on a weekly basis. At the conclusion of the study, brains were perfused and hippocampal sections were Nissl stained. Total hippocampal volume was measured using the Cavalieri estimator. Treatment with olanzapine caused a significant decrease in hippocampal volume in sedentary rats. However, exercise was able to reverse most of this volume loss. The hippocampal sub-regions of the dentate gyrus and CA1 were most strongly affected by olanzapine and exercise. Of interest, there was a strong and highly significant negative correlation between glucose intolerance and hippocampal volume, whereby greater glucose intolerance was associated with a smaller hippocampal volume. These findings indicate that exercise may have beneficial effects on the hippocampus when antipsychotic medication can contribute to changes in volume.

Peripheral adrenoceptors: the impetus behind glucose dysregulation and insulin resistance.

It is now accepted that several pharmacological drug treatments trigger clinical manifestations of glucose dysregulation, such as hyperglycaemia, glucose intolerance and insulin resistance, in part through poorly understood mechanisms. Persistent sympathoadrenal activation is linked to glucose dysregulation and insulin resistance, both of which significantly increase the risk of emergent endocrinological disorders, including metabolic syndrome and type 2 diabetes mellitus. Through the use of targeted mutagenesis and pharmacological methods, preclinical and clinical research has confirmed physiological glucoregulatory roles for several peripheral α- and ß-adrenoceptor subtypes. Adrenoceptor isoforms in the pancreas (α(2A) and ß(2) ), skeletal muscle (α(1A) and ß(2) ), liver (α(1A & B) and ß(2) ) and adipose tissue (α(1A) and ß(1 & 3) ) are convincing aetiological targets that account for both immediate and long-lasting alterations in blood glucose homeostasis. Because significant overlap exists between the therapeutic applications of numerous classes of drugs and their associated adverse side-effects, a better understanding of peripheral adrenoceptor-mediated glucose metabolism is thus warranted. Therefore, at the same time as providing a brief review of glucose homeostasis in the periphery, the present review addresses both functional and pathophysiological roles of the mammalian α(1) , α(2) , and ß-adrenoceptor isoforms in whole-body glucose turnover. We highlight evidence relating to the clinical use of common adrenergic drugs and their impacts on glucose metabolism.

Cognitive reserve, presynaptic proteins and dementia in the elderly.

Differences in cognitive reserve may contribute to the wide range of likelihood of dementia in people with similar amounts of age-related neuropathology. The amounts and interactions of presynaptic proteins could be molecular components of cognitive reserve, contributing resistance to the expression of pathology as cognitive impairment. We carried out a prospective study with yearly assessments of N = 253 participants without dementia at study entry. Six distinct presynaptic proteins, and the protein-protein interaction between synaptosomal-associated protein 25 (SNAP-25) and syntaxin, were measured in post-mortem brains. We assessed the contributions of Alzheimer's disease (AD) pathology, cerebral infarcts and presynaptic proteins to odds of dementia, level of cognitive function and cortical atrophy. Clinical dementia was present in N = 97 (38.3%), a pathologic diagnosis of AD in N = 142 (56.1%) and cerebral infarcts in N = 77 (30.4%). After accounting for AD pathology and infarcts, greater amounts of vesicle-associated membrane protein, complexins I and II and the SNAP-25/syntaxin interaction were associated with lower odds of dementia (odds ratio = 0.36-0.68, P < 0.001 to P = 0.03) and better cognitive function (P < 0.001 to P = 0.03). Greater cortical atrophy, a putative dementia biomarker, was not associated with AD pathology, but was associated with lower complexin-II (P = 0.01) and lower SNAP-25/syntaxin interaction (P < 0.001). In conclusion, greater amounts of specific presynaptic proteins and distinct protein-protein interactions may be structural or functional components of cognitive reserve that reduce the risk of dementia with aging.