Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes.

Over the last five decades, a large body of evidence has accrued for structural and metabolic brain alterations in schizophrenia. Here we provide an overview of these findings, focusing on measures that have traditionally been thought to reflect synaptic spine density or synaptic activity and that are relevant for understanding if there is lower synaptic density in the disorder. We conducted literature searches to identify meta-analyses or other relevant studies in patients with chronic or first-episode schizophrenia, or in people at high genetic or clinical risk for psychosis. We identified 18 meta-analyses including over 50,000 subjects in total, covering: structural MRI measures of gyrification index, grey matter volume, grey matter density and cortical thickness, neurite orientation dispersion and density imaging, PET imaging of regional glucose metabolism and magnetic resonance spectroscopy measures of N-acetylaspartate. We also review preclinical evidence on the relationship between ex vivo synaptic measures and structural MRI imaging, and PET imaging of synaptic protein 2A (SV2A). These studies show that schizophrenia is associated with lower grey matter volumes and cortical thickness, accelerated grey matter loss over time, abnormal gyrification patterns, and lower regional SV2A levels and metabolic markers in comparison to controls (effect sizes from ~ -0.11 to -1.0). Key regions affected include frontal, anterior cingulate and temporal cortices and the hippocampi. We identify several limitations for the interpretation of these findings in terms of understanding synaptic alterations. Nevertheless, taken with post-mortem findings, they suggest that schizophrenia is associated with lower synaptic density in some brain regions. However, there are several gaps in evidence, in particular whether SV2A findings generalise to other cohorts.

Google search behaviour relating to perinatal mental wellbeing during the United Kingdom's first COVID-19 lockdown period: a warning for future restrictions.

Infodemiological studies derive public health information from internet activity. Here we compare Google searches of perinatal mental health-related terms during the U.K.'s first COVID-19 lockdown with the corresponding period in 2019. We report evidence of reduced pathologising/recognition of perinatal mental illness; increased perceived maternal inadequacy and estrangement from newborn baby; increased maternal domestic abuse; and increased domestic and substance abuse generally. These insights offer important population-level considerations ahead of further U.K. restrictions, and should be imminently confirmed with epidemiological work.

An unusually impressive atorvastatin-induced elevation of serum alkaline phosphatase.

A 90-year-old woman is referred six months after a transient ischaemic attack (TIA) with asymptomatic cholestatic liver function test (LFT) derangement. Following the TIA, atorvastatin and clopidogrel therapy are initiated. This is added to pre-existent once daily nifedipine for hypertension. Nifedipine (a weak inhibitor of CYP3A4 and competing substrate) and clopidogrel (a competitive inhibitor of CYP3A4) may have affected the metabolism of atorvastatin, resulting in the elevation of serum alkaline phosphatase levels to over six times the upper limit of normal. More often, statin therapy elevates serum alanine aminotransferase levels. Drug-induced liver injury (DILI) was deemed 'probable' as judged by the Roussel Uclaf Causality Assessment Method score. Statin therapy remains overwhelmingly safe, with benefits outweighing risks in the vast majority. The UK recommended LFT monitoring regime facilitates early recognition of DILI. Case reports are examined where similar drug combinations resulted in severe morbidity and mortality.

Psych Socs: student-led psychiatry societies, an untapped resource for recruitment and reducing stigma.

Medical recruitment and retention are national problems. Psychiatry has been more affected than many specialties, as a result of stigma from the public and other healthcare professionals. The Royal College of Psychiatrists has undertaken several initiatives to redress this, notably the 'Choose Psychiatry' campaign. In this editorial we argue that student-led university psychiatry societies are a wonderful but frequently untapped resource to help attract the brightest and best medical students to our profession. We describe the activities of three 'Psych Socs' across the UK and propose next steps to continue this work.

Studies on long term behavioural changes in group-housed rat models of brain and spinal cord injury using an automated home cage recording system.

BACKGROUND: Neurotrauma patients face major neurological sequelae. The failure in the preclinical-to-clinical translation of candidate therapies could be due to poor evaluation of rodent behaviours after neurotrauma. NEW METHOD: A home cage automated system was used to study the long term behaviour of individual rats with traumatic brain injury (TBI), spinal cord injury (SCI) and non-CNS injured controls, whilst group-housed in their home cages. Naïve rats were used as baseline controls. Automated locomotor activity and body temperature recordings were carried out 24 h /day for 3 days/week during 12 weeks post-injury. Behavioural patterns, including aggression, rearing, grooming, feeding and drinking were analysed from automated video recordings during week 1, 6 and 12. RESULTS: SCI animals showed a lower locomotor activity compared to TBI or control animals during light and dark phases. TBI animals showed a higher aggression during the dark phase in the first week post-injury compared to SCI or control animals. Individual grooming and rearing were reduced in SCI animals compared to TBI and control animals in the first week post-injury during the dark phase. No differences in drinking or feeding were detected between groups. Locomotor activity did not differ between naïve male and female rats, but body temperature differ between light and dark phases for both. STANDARD METHODS: Injury severity was compared to standard SCI and TBI behaviour scores (BBB and mNSS, respectively) and histological analysis. CONCLUSIONS: This study demonstrates the practical benefits of using a non-intrusive automated home cage recording system to observe long term individual behaviour of group-housed SCI and TBI rats.

Acute angle closure glaucoma - A potential blind spot in critical care.

We report a case of a 69-year-old gentleman who developed an acutely painful eye with loss of visual acuity whilst on the critical care unit. He was admitted three days previously with an infective exacerbation of chronic obstructive pulmonary disease requiring invasive mechanical ventilation. In addition, he received intravenous antibiotics, steroids, nebulised bronchodilators and intravenous aminophylline, together with noradrenaline for blood pressure support. On development of visual symptoms, an emergency ophthalmology review diagnosed acute angle closure glaucoma. Treatment with pilocarpine eye drops, intravenous acetazolamide and bilateral YAG laser iridotomies provided immediate symptom relief and he went on to make an excellent recovery. Acute angle closure glaucoma is a potentially devastating ophthalmic emergency. Critical care patients are at particular risk for the development of this condition due to the use of predisposing medications, such as sympathomimetics and beta agonists. Sedated patients also run a risk of delayed diagnosis so a high index of suspicion is required.

A threshold for concern? C-reactive protein levels following operatively managed neck of femur fractures can detect infectious complications with a simple formula.

INTRODUCTION: C-reactive protein (CRP) rises in response to multiple stimuli, including surgical procedures and infections. Deviations from the predicted CRP response to a given procedure may be an early indication of a postoperative complication. METHODS: Three hundred and fifty-four patients with an operatively managed neck of femur fracture admitted over a 1-year period to an NHS Hospital Trust were included. CRP values collected during the postoperative period were retrospectively examined, and objective evidence of postoperative complications was sought. Data analysis explored daily CRP thresholds that maximised sensitivity and specificity for the detection of patients with a postoperative complication. RESULTS: From the 5th to the 30th postoperative day, a CRP value in excess of the threshold defined by the formula 500/d (where d represents the number of postoperative days) retrospectively detected patients with a postoperative complication with a sensitivity of 0.97 and specificity of 0.82. Patients with a CRP value above the 500/d threshold during this period had a significantly increased 30-day mortality (10.0% vs. 3.9%, RR=2.74, p=0.03). CONCLUSION: Following operatively managed neck of femur fractures, a CRP value in excess of the threshold defined by the formula 500/d may indicate the presence of a postoperative complication and defines a group with increased mortality. In this context, a prompt wound review and septic screen could promote the early detection and management of infectious postoperative complications.

Rebound spiking properties of mouse medial entorhinal cortex neurons in vivo.

The medial entorhinal cortex is the gateway between the cortex and hippocampus, and plays a critical role in spatial coding as represented by grid cell activity. In the medial entorhinal cortex, inhibitory circuits are robust, and the presence of the h-current leads to rebound potentials and rebound spiking in in vitro experiments. It has been hypothesized that these properties, combined with network oscillations, may contribute to grid cell formation. To examine the properties of in vivo rebound spikes, we performed whole-cell patch-clamp recordings in medial entorhinal cortex neurons in anaesthetized mice. We injected hyperpolarizing inputs representing inhibitory synaptic inputs along with sinusoidal oscillations and found that hyperpolarizing inputs injected at specific phases of oscillation had a higher probability of inducing subsequent spikes at the peak of the oscillation in some neurons. This effect was prominent in the cells with large sag potential, which is a marker of the h-current. In addition, larger and longer hyperpolarizing current square-pulse stimulation resulted in a larger probability of eliciting rebound spikes, though we did not observe a relationship between the amplitude or duration of hyperpolarizing current pulse stimulation and the delay of rebound spikes. Overall these results suggest that rebound spikes are observed in vivo and may play a role in generating grid cell activity in medial entorhinal cortex neurons.

The effects of rearing light level and duration differences on the optic nerve, brain, and associated structures in developing zebrafish larvae: a light and transmission electron microscope study.

The ultrastructure of the optic nerve, brain, and some associated structures of larval zebrafish, grown under three different light regimens were studied. Fish grown under cyclic light (control), constant dark (CD), and constant light (CL) were studied for 4 and 8 days postfertilization (dpf). We also studied the control and CD fish at 15 dpf. The brains of the control and CL fish were larger at 4 dpf than at 8 dpf. In all 4 dpf fish, the brain occupied the entire expanse between the two retinas and the optic nerve extended the shortest distance between the retina and the brain. The 15 dpf zebrafish had the smallest brain size. Groups of skeletal muscle cells associated with the optic nerves became visible in all older larvae. In the 15 dpf larvae, bulges and dilations in the optic nerve occurred as it reached the brain and optic chiasms occurred proximal to the brain. Electron microscopy yielded information about myelinated and unmyelinated axons in the optic nerve, the dimensions of neurotubules, neurofilaments, and myofilaments, including a unique variation in actin myofilaments, and a confirmation of reported myosin myofilament changes (but with dimensions). We also describe the ultrastructure of a sheath-like structure that is confluent over the optic nerve and the brain, which has not been described before in zebrafish. Also presented are images of associated fibroblasts, epithelial cells lining the mouth, cartilage plates, blood vessels, nerve bundles, and skeletal muscle cells, most of which have not been previously described in the literature.

An unexpected enhancement in methanol electro-oxidation on an ensemble of Pt(111) nanofacets: a case of nanoscale single crystal ensemble electrocatalysis.

Pt nanoparticles having the same size ( approximately 10 nm) but different shapes (cubic or octahedral/tetrahedral), as determined by transmission electron microscopy, were synthesized via a polyol-based synthetic procedure. Their respective electrocatalytic activities for methanol oxidation were characterized by cyclic voltammetry and chronoamperometry in both sulfuric and perchloric acid electrolytes, which showed clear shape (surface orientation) dependences. Furthermore, the octahedral/tetrahedral Pt nanoparticles displayed an unexpectedly large enhancement in methanol electro-oxidation activity; about 3-fold increase in transient intrinsic activity and 10-fold increase in CO tolerance steady-state activity when compared to commercial Pt black. Gaseous and methanolic CO adsorption on the synthesized nanoparticles were also investigated by surface-enhanced IR absorption spectroscopy in perchloric acid electrolyte, which suggested that the different trends observed might be related to the electronic effects specific to a given ensemble of the nanofacets.

A light- and electron-microscope study of hepatocytes of rats fed different diets.

Ketogenic diets are used in the treatment of epilepsy in children refractory to drug therapy. This study identifies changes in liver morphology in rats fed four different diets: a normal rodent chow diet, a calorie-restricted high-fat (ketogenic) diet and each diet supplemented with clofibric acid. Hepatocytes of rats fed the ketogenic diet show many lipid droplets and these are reduced to control levels when clofibrate is present in the diet. Mitochondria are enlarged in the livers of rats fed the ketogenic diet and further enlarged if clofibrate is present. Alterations in the appearance or numbers of other organelles are also found.

Generation of islet-like hormone-producing cells in vitro from adult human pancreas.

Transplantation of pancreatic islets can provide long-lasting insulin independence for diabetic patients, but the current islet supply is limited. Here we describe a new in vitro system that utilizes adult human pancreatic islet-enriched fractions to generate hormone-producing cells over 3-4 weeks of culture. By labeling proliferating cells with a retrovirus-expressing green fluorescent protein, we show that in this system hormone-producing cells are generated de novo. These hormone-producing cells aggregate to form islet-like cell clusters. The cell clusters, when tested in vitro, release insulin in response to glucose and other secretagogues. After transplantation into immunodeficient, nondiabetic mice, the islet-like cell clusters survive and release human insulin. We propose that this system will be useful as an experimental tool for investigating mechanisms for generating new islet cells from the postnatal pancreas, and for designing strategies to generate physiologically competent pancreatic islet cells ex vivo.

A transmission electron microscope study of "New Dawn" climber rose (Rosa wichuraiana x safrano) exhibiting rose rosette disease.

The arrival of rose rosette disease (RRD) in the Washington D.C. area prompted a transmission electron microscope study of ultrathin sections of leaves from symptomatic Rosa wichuraiana x safrano plants. Virus-like particles (VLPs) or double membrane-bound particles (DMPs) resembling those associated with RRD in other types of roses, and found in several other plant diseases, were seen in the cytoplasm of parenchymal and vascular bundle cells and shown, for the first time, in guard cells and budding into the vacuoles. Contrary to previous reports, starch granules were found in chloroplasts of the infected cells. A presumably unique intramitochondrial crystal was also observed. Variations in vacuolar content were noted.

ARL1 and membrane traffic in Saccharomyces cerevisiae.

To examine the functions of the Arf-like protein, Arl1p, in Saccharomyces cerevisiae, a null allele, arl1delta::HIS3, was constructed in two strains. In one background only, loss of ARL1 resulted in temperature-sensitive (ts) growth (suppressed on high-osmolarity media). Allelic variation at the SSD1 locus accounted for differences between strains. Strains lacking ARL1 exhibited several defects in membrane traffic. First, arl1delta strains secreted less protein as measured by TCA-precipitable radioactivity found in the media of [(35)S]-labelled cells. A portion of newly synthesized carboxypeptidase Y (CPY) was secreted rather than correctly targeted to the vacuole. Uptake of the fluid-phase marker, lucifer yellow, was reduced. All these phenotypes were exacerbated in an ssd1 background. The ts phenotype of the arl1deltassd1 strain was suppressed by YPT1, the yeast Rab1a homologue, suggesting that ARL1 and YPT1 have partially overlapping functions. These findings demonstrate that ARL1 encodes a regulator of membrane traffic.

Ultrastructure of the posterior half of the intestine of the channel catfish, Ictalurus punctatus.

The posterior half of the channel catfish intestine has a similar histological organization to that of other teleost fishes. This region is organized into a muscosa, a submucosa, a double layered muscularis and a serosa. A "stratum compactum" of dense connective tissue was confirmed for the submucosa. In its histology and cytology, the midgut resembles the hindgut, except that in the hindgut the muscularis is thicker, the microvilli are shorter, there are fewer absorptive inclusions in the columnar cells and there are more goblet cells. With the exception of the serosa, the tissue layers of the intestine of the 6 cm juvenile catfish are fully developed. The most notable difference between the intestines of the juvenile and adult catfish occurs in the columnar epithelial cells. The mucosal cells of the juvenile catfish contain an abundance of large clear vacuoles while the mucosal cells of the mature catfish contain smaller dense granules. With few exceptions, the ultrastructural details of the cells in the catfish intestine are identical to those of the same cell types of the mammalian intestine.