MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

The organization of frontostriatal brain wiring in non-affective early psychosis compared with healthy subjects using a novel diffusion imaging fiber cluster analysis.

BACKGROUND: Alterations in brain connectivity may underlie neuropsychiatric conditions such as schizophrenia. We here assessed the degree of convergence of frontostriatal fiber projections in 56 young adult healthy controls (HCs) and 108 matched Early Psychosis-Non-Affective patients (EP-NAs) using our novel fiber cluster analysis of whole brain diffusion magnetic resonance imaging tractography. METHODS: Using whole brain tractography and our fiber clustering methodology on harmonized diffusion magnetic resonance imaging data from the Human Connectome Project for Early Psychosis we identified 17 white matter fiber clusters that connect frontal cortex (FCtx) and caudate (Cd) per hemisphere in each group. To quantify the degree of convergence and, hence, topographical relationship of these fiber clusters, we measured the inter-cluster mean distances between the endpoints of the fiber clusters at the level of the FCtx and of the Cd, respectively. RESULTS: We found (1) in both groups, bilaterally, a non-linear relationship, yielding convex curves, between FCtx and Cd distances for FCtx-Cd connecting fiber clusters, driven by a cluster projecting from inferior frontal gyrus; however, in the right hemisphere, the convex curve was more flattened in EP-NAs; (2) that cluster pairs in the right (p = 0.03), but not left (p = 0.13), hemisphere were significantly more convergent in HCs vs EP-NAs; (3) in both groups, bilaterally, similar clusters projected significantly convergently to the Cd; and, (4) a significant group by fiber cluster pair interaction for 2 right hemisphere fiber clusters (numbers 5, 11; p = .00023; p = .00023) originating in selective PFC subregions. CONCLUSIONS: In both groups, we found the FCtx-Cd wiring pattern deviated from a strictly topographic relationship and that similar clusters projected significantly more convergently to the Cd. Interestingly, we also found a significantly more convergent pattern of connectivity in HCs in the right hemisphere and that 2 clusters from PFC subregions in the right hemisphere significantly differed in their pattern of connectivity between groups.

Promoting resilience in healthcare workers during the COVID-19 pandemic with a brief online intervention.

INTRODUCTION: The psychological wellbeing of healthcare workers has been impacted by the high levels of stress many have experienced during the Coronavirus Disease 2019 (COVID-19) pandemic. This study aimed to examine the feasibility and acceptability of a brief online course focused on introducing evidence-based skills that could increase resilience and decreases emotional distress in healthcare workers during the pandemic. MATERIALS AND METHODS: Employees of a large healthcare system completed a mental health survey at baseline, and then one month and two months after some employees participated in an online resilience-enhancement course consisting of three 12-19 min videos focused on mindfulness, mentalization, and self-compassion. RESULTS: A total of 554 participants completed the baseline survey, endorsing moderate to high levels of emotional distress. Of those who completed all three assessments and participated in the course (n = 38), significant improvements in resilience and reductions in emotional distress were found one and two months later, in comparison to those who did not participate in the course (n = 110). DISCUSSION: These findings suggest that a brief, online intervention can improve the mental health of healthcare workers during a crisis such as the COVID-19 pandemic.

Management of mucous membrane pemphigoid in a joint oral medicine-dermatology clinic.

BACKGROUND: Mucous membrane pemphigoid (MMP) comprises a group of immunobullous diseases involving the mucosa and skin. Potential sequelae include painful mucosal erosions, vision loss and laryngeal stenosis. AIM: To characterize the features of patients with MMP seen within an Oral Medicine setting, including clinical features, immunofluorescence results and response to treatment. METHODS: A retrospective case note analysis was undertaken. Treatment effect was divided into response and nonresponse using predetermined adjective terms. RESULTS: In total, 42 cases of MMP were identified (18 men, 24 women), mean age 65 years (range 36-85 years). Oral involvement was most common on the gingivae (n = 38; 90.5%) while the most common extraoral sites involved were ocular (n = 13; 31.0%) and skin (n = 12; 28.6%). Features of MMP were found in 21 of 34 (61.8%) of routine biopsies, 31 of 34 (91.2%) direct immunofluorescence samples and 8 of 25 (32.0%) indirect immunofluorescence samples. Topical corticosteroids provided effective symptom control in 9 of 42 cases (21.4%), while systemic therapy was used in 31 of 42 patients (73.8%). Dapsone was prescribed for 25 patients, of whom 18 (72.0%) responded. Mycophenolate mofetil was used in 13 cases and had a response rate of 46.2%. Overall, 27 of 42 patients (64.3%) achieved a response using a tolerable topical or systemic treatment. CONCLUSION: This series demonstrates that MMP has a female predominance and is a disease of older age, with a predilection for specific oral sites. Direct immunofluorescence has a high sensitivity in detecting features of MMP. Although some patients achieve adequate symptom control with topical corticosteroids, many require systemic therapy.

The development and implementation of a biopsy safety strategy for oral medicine.

The development and implementation of a biopsy safety strategy is described in this article. Analysis of previous adverse incidents relating to biopsies acted as a catalyst to review our biopsy pathway at Liverpool University Dental Hospital. Input from all staff involved enabled us to develop a biopsy safety strategy which was divided into five stages: preoperative assessment of patient and procedure, team briefings, biopsy surgical safety checklist, surgical removal and handling of biopsy specimens, and post-biopsy follow-up. It is hoped that other clinical teams will take the opportunity to review their own biopsy processes, in the light of our experience.

Progression from selective to general involvement of hippocampal subfields in schizophrenia.

Volume deficits of the hippocampus in schizophrenia have been consistently reported. However, the hippocampus is anatomically heterogeneous; it remains unclear whether certain portions of the hippocampus are affected more than others in schizophrenia. In this study, we aimed to determine whether volume deficits in schizophrenia are confined to specific subfields of the hippocampus and to measure the subfield volume trajectories over the course of the illness. Magnetic resonance imaging scans were obtained from Data set 1: 155 patients with schizophrenia (mean duration of illness of 7 years) and 79 healthy controls, and Data set 2: an independent cohort of 46 schizophrenia patients (mean duration of illness of 18 years) and 46 healthy controls. In addition, follow-up scans were collected for a subset of Data set 1. A novel, automated method based on an atlas constructed from ultra-high resolution, post-mortem hippocampal tissue was used to label seven hippocampal subfields. Significant cross-sectional volume deficits in the CA1, but not of the other subfields, were found in the schizophrenia patients of Data set 1. However, diffuse cross-sectional volume deficits across all subfields were found in the more chronic and ill schizophrenia patients of Data set 2. Consistent with this pattern, the longitudinal analysis of Data set 1 revealed progressive illness-related volume loss (~2-6% per year) that extended beyond CA1 to all of the other subfields. This decline in volume correlated with symptomatic worsening. Overall, these findings provide converging evidence for early atrophy of CA1 in schizophrenia, with extension to other hippocampal subfields and accompanying clinical sequelae over time.

Gallium nitrate induces fibrinogen flocculation: an explanation for its hemostatic effect?

A novel hemostatic effect of gallium nitrate has recently been discovered. Our aim was to perform a preliminary investigation into its mode of action. Thromboelastography® showed no effect on coagulation but pointed instead to changes in fibrinogen concentration. We measured functional fibrinogen in whole blood after addition of gallium nitrate and nitric acid. We found that gallium nitrate induces fibrinogen precipitation in whole blood to a significantly higher degree than solutions of nitric acid alone. This precipitate is not primarily pH driven, and appears to occur via flocculation. This behavior is in line with the generally observed ability of metals to induce fibrinogen precipitation. Further investigation is required into this novel phenomenon.

In vivo imaging of adult human hippocampal neurogenesis: progress, pitfalls and promise.

New neurons are produced within the hippocampus of the mammalian brain throughout life. Evidence from animal studies has suggested that the function of these adult-born neurons is linked to cognition and emotion. Until we are able to detect and measure levels of adult neurogenesis in living human brains-a formidable challenge for now-we cannot establish its functional importance in human health, disease and new treatment development. Current non-invasive neuroimaging modalities can provide live snapshots of the brain's structure, chemistry, activity and connectivity. This review explores whether existing macroscopic imaging methods can be used to understand the microscopic dynamics of adult hippocampal neurogenesis in living individuals. We discuss recent studies that have found correlations between neuroimaging measures of human hippocampal biology and levels of pro- or anti-neurogenic stimuli, weigh whether these correlations reflect changes in adult neurogenesis, detail the conceptual and technical limitations of these studies and elaborate on what will be needed to validate in vivo neuroimaging measures of adult neurogenesis for future investigations.

Striatal function in relation to negative symptoms in schizophrenia.

BACKGROUND: Previous studies have suggested that motivational aspects of executive functioning, which may be disrupted in schizophrenia patients with negative symptoms, are mediated in part by the striatum. Negative symptoms have been linked to impaired recruitment of both the striatum and the dorsolateral prefrontal cortex (DLPFC). Here we tested the hypothesis that negative symptoms are associated primarily with striatal dysfunction, using functional magnetic resonance imaging (fMRI). METHOD: Working-memory load-dependent activation and gray matter volumes of the striatum and DLPFC were measured using a region-of-interest (ROI) approach, in 147 schizophrenia patients and 160 healthy controls. In addition to testing for a linear relationships between striatal function and negative symptoms, we chose a second, categorical analytic strategy in which we compared three demographically and behaviorally matched subgroups: patients with a high burden of negative symptoms, patients with minimal negative symptoms, and healthy subjects. RESULTS: There were no differences in striatal response magnitudes between schizophrenia patients and healthy controls, but right DLPFC activity was higher in patients than in controls. Negative symptoms were inversely associated with striatal, but not DLPFC, activity. In addition, patients with a high burden of negative symptoms exhibited significantly lower bilateral striatal, but not DLPFC, activation than schizophrenia patients with minimal negative symptoms. Working memory performance, antipsychotic exposure and changes in gray matter volumes did not account for these differences. CONCLUSIONS: These data provide further evidence for a robust association between negative symptoms and diminished striatal activity. Future work will determine whether low striatal activity in schizophrenia patients could serve as a reliable biomarker for negative symptoms.

BDNF, relative preference, and reward circuitry responses to emotional communication.

Brain derived neurotrophic factor (BDNF) regulates neural development and synaptic transmission. We have tested the hypothesis that functional variation in the BDNF gene (Val66Met polymorphism, rs6265) affects brain reward circuitry encoding human judgment and decision-making regarding relative preference. We quantified relative preference among faces with emotional expressions (angry, fearful, sad, neutral, and happy) by a keypress procedure performed offline to measure effort traded for viewing time. Keypress-based relative preferences across the ensemble of faces were mirrored significantly by fMRI signal in the orbitofrontal cortex, amygdala, and hippocampus when passively viewing these faces. For these three brain regions, there was also a statistically significant group difference by BDNF genotype in the fMRI responses to the emotional expressions. In comparison with Val/Met heterozygotes, Val/Val individuals preferentially sought exposure to positive emotions (e.g., happy faces) and had stronger regional fMRI activation to aversive stimuli (e.g., angry, fearful, and sad faces). BDNF genotype accounted for approximately 30% of the variance in fMRI signal that mirrors keypress responses to these stimuli. This study demonstrates that functional allelic variation in BDNF modulates human brain circuits processing reward/aversion information and relative preference transactions.

Polymer Brushes Containing Sulfonated Sugar Repeat Units: Synthesis, Characterization and In Vitro Testing of Blood Coagulation Activation.

A new polymer brush chemistry containing sulfonated carbohydrate repeat units has been synthesized from silicon substrates using ATRP methods and characterized both in bulk and using surface analysis. The polymer brush was designed to act as a mimic for the naturally occurring sulfonated glycosaminoglycan, heparin, commonly used for modifying blood-contacting surfaces both in vitro and in vivo. Surface analysis showed conversion of brush saccharide precursor chemistry to the desired sulfonated polymer product. The sulfonated polymer brush surface was further analyzed using three conventional in vitro tests for blood compatibility -- plasma recalcification times, complement activation, and thrombin generation. The sulfonated polymer brush films on silicon oxide wafers exhibited better assay performance in these blood component assays than the unsulfonated sugar functionalized polymer brush in all tests performed.

A comparison of salivary gland hypofunction in primary and secondary Sjögren's syndrome.

OBJECTIVE: A commonly held view by clinicians is that the salivary gland hypofunction associated with primary Sjögren's syndrome (SS-1) is more severe than that associated with secondary Sjögren's syndrome (SS-2). This study aimed to determine if this view could be substantiated, when applied to a large sample group. METHOD: Unstimulated and paraffin wax-stimulated whole salivary flow rates were retrospectively compared for age and gender matched, patients diagnosed with SS-1 or SS-2 according to the preliminary European criteria. The patients had attended the Xerostomia Clinic, in the Oral Medicine Department, at the Liverpool University Dental Hospital. RESULTS: Sixty-seven patients with SS-1 (average age 57.1 years) were matched with 67 patients with SS-2 (average age 57.6 years), according to gender and age, within 5 years. The mean unstimulated whole salivary flow rates (+/- s.d.) for patients with SS-1 and SS-2 were 0.11 (+/- 0.15) and 0.12 (+/- 0.18) mL min-1 respectively. The mean paraffin wax stimulated, whole salivary flow rates (+/- s.d.) for patients with SS-1 and SS-22 were 0.45 (+/- 0.02) and 0.47 (+/- 0.49) mL/min-1 respectively. No significant differences, in either stimulated (P = 0.54) or unstimulated (P = 0.60) whole salivary flow rates were found between individuals with SS-1 or SS-2. CONCLUSION: The severity of salivary gland hypofunction does not appear to be related to the clinical variant of Sjögren's syndrome.

Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia.

Neurochemical and functional abnormalities of the striatum have been reported in schizophrenic brains, but the cellular substrates of these changes are not known. We hypothesized that schizophrenia may involve an abnormality in one of the key modulators of striatal output, the cholinergic interneuron. We measured the densities of cholinergic neurons in the striatum in schizophrenic and control brains in a blind analysis, using as a marker of this cell population immunoreactivity for choline acetyltransferase, the synthetic enzyme of acetylcholine. As an independent marker, we used immunoreactivity for calretinin, a protein which is co-localized with choline acetyltransferase in virtually all of the cholinergic interneurons of the striatum. A significant decrease in choline acetyltransferase-positive and calretinin-positive cell densities was found in the schizophrenic cases compared with controls in the striatum as a whole [for the choline acetyltransferase-positive cells: controls: 3.21 +/- 0.48 cells/mm2 (mean +/- S.D.), schizophrenics: 2.43 +/- 0.68 cells(mm2; P < 0.02]. The decrease was patchy in nature and most prominent in the ventral striatum (for the choline acetyltransferase-positive cells: controls: 3.47 +/- 0.59 cells/mm2, schizophrenics: 2.52 +/- 0.64 cells/ mm2; P < 0.005) which included the ventral caudate nucleus and nucleus accumbens region. Three of the schizophrenic cases with the lowest densities of cholinergic neurons had not been treated with neuroleptics for periods from more than a month to more than 20 years. A decrease in the number or function of the cholinergic interneurons of the striatum may disrupt activity in the ventral striatal-pallidal-thalamic-prefrontal cortex pathway and thereby contribute to abnormalities in function of the prefrontal cortex in schizophrenia.

Hoarseness: a potential role for the dentist in early diagnosis.

A patient who smoked heavily was under regular review by the oral medicine department because of oral keratosis. He subsequently complained of hoarseness of the voice, and was referred to the department of otorhinolaryngology. An early squamous cell carcinoma of the larynx was diagnosed, and the patient was treated with radical radiotherapy. This case highlights the importance of early diagnosis and the potential role of the dentist in the total healthcare of patients.

DNA binding alkaloids from Prosopis alba.

The known beta-phenethylamine ( 1) and the new alkaloid 2-beta-methyl-3-beta-hydroxy-6-beta-piperidinedodecanol ( 2) were isolated from the aerial parts of PROSOPIS ALBA. Both compounds showed DNA binding effects of 27 and 50%, respectively, at 0.50 mg/ml.

Neurochemical architecture of the human striatum.

The striatum of the human brain has a highly differentiated neurochemical architecture visible in stains for many of the neurotransmitter-related molecules present in the striatum. The distributions for these chemical markers have never been analyzed comprehensively. We compared the distributions of multiple neurochemical markers in a serial-section analysis of the caudate nucleus, the putamen, and the ventral striatum in normal human brains. The cholinergic system was identified with choline acetyltransferase (ChAT). The organization of the cholinergic fiber system was compared with that of striatal systems expressing immunoreactivity for calbindin D28k, met-enkephalin, substance P, tyrosine hydroxylase, and parvalbumin. Each striatal region analyzed displayed a unique neurochemical organization. In the dorsal caudate nucleus, the distribution of all markers followed the classical striosome/matrix organization as previously reported. In the dorsal putamen, ChAT-staining was less intense, and striosomes were delineated primarily by unstained fiber bundles. In the ventral caudate nucleus/nucleus accumbens region, the boundaries of ChAT-stained regions were not always visible with stains for calbindin, enkephalin, and substance P. The ventral putamen displayed a similar organization, except in its lateral part, where ChAT-poor regions were often found adjacent to, rather than in register with, regions expressing low levels of the other markers (calbindin, enkephalin, substance P, and tyrosine hydroxylase). Our findings suggest that, in addition to the classical striosome-matrix organization visible in the dorsal caudate nucleus and putamen, there is further neurochemical differentiation in a large ventral part of the caudate nucleus and putamen and in the ventral striatum-nucleus accumbens proper. The more complex relationships among the different neurochemical systems in the ventral striatum may reflect the increase in size in the primate of striatal regions associated with association and limbic cortex.

Lingual ulceration related to inhalers used for respiratory disease.

A chronic ulcer of the tongue is reported, resulting from the use of inhalers for respiratory disease. This complication was managed by the use of a spacer device.

Cholinergic innervation in the human striatum: a three-compartment model.

The mammalian striatum is divided into compartments that are anatomically and neurochemically distinct. The dorsal striatum has been described as containing two compartments, striosomes and matrix, while the ventral striatum is thought to have a more complex, multi-compartmental organization. In this study, we sought to characterize the compartmentalization of the dorsal and ventral portions of the human striatum using choline acetyltransferase as a marker. Image analysis was used to assess relative densities of immunostaining, and three distinct, choline acetyltransferase-immunostained compartments were demonstrated: intensely immunostained, moderately immunostained and weakly immunostained areas. The dorsomedial portion of the striatum was made up of moderately immunostained regions embedded within a densely immunostained background, thus manifesting the characteristic striosome/ matrix organization of the dorsal striatum. However, the ventral and lateral two-thirds of the striatum were made up of a mixture of densely immunostained, moderately immunostained and weakly immunostained areas, with the moderately immunostained region forming the bulk of the background tissue, and smaller, densely immunostained and weakly immunostained regions embedded within it. These compartments were compared to regions defined by distinct levels of acetylcholinesterase immunostaining in adjacent sections; the staining patterns produced by the two cholinergic markers were found to be identical except in some portions of the nucleus accumbens, where acetylcholinesterase immunostaining was found to be more intense than choline acetyltransferase immunostaining. The immunoreactive somata were mapped within sections stained for choline acetyltransferase taken from different rostrocaudal levels of the striatum, and the distributions and densities of immunoreactive somata within these three cholinergic compartments were determined. In general, the densities of cholinergic somata roughly correlated with immunostaining intensity of regions, e.g. the most intensely immunostained compartment also had the highest densities of cholinergic somata. However, in the rostroventral striatum, the densities of cholinergic somata in the weakly immunostained compartment roughly equalled the densities of cholinergic somata in the moderately immunostained compartment, suggesting that local axonal arborizations of cholinergic cells may differ in density or orientation between the two compartments, or, alternatively, that some of the cholinergic cells in the weakly immunostained compartment may project outside of the striatum. The large proportion of striatum displaying ventral striatal characteristics (a complex, multi-compart-mental organization) in humans relative to that observed in other mammals suggests that the role of the ventral striatum may be expanded and more highly differentiated in the human brain.

Electrophysiologic and antiarrhythmic effects of magnesium in patients with inducible ventricular tachyarrhythmia.

Intravenous magnesium is reported to be effective in the treatment of ventricular arrhythmias associated with hypomagnesemia, digitalis toxicity, or prolongation of the QT interval. In most previous reports, magnesium was added to conventional antiarrhythmic drugs that had failed. There are few data on the antiarrhythmic efficacy of magnesium as monotherapy in patients without these associated abnormalities. Ten patients with life-threatening ventricular arrhythmia and inducible ventricular tachyarrhythmia by programmed electrophysiologic testing were treated with intravenous magnesium. Following magnesium infusion, all patients still had inducible ventricular tachyarrhythmia. Moreover, magnesium therapy was not associated with significant changes in ventricular refractory period or in the morphology, cycle length, or hemodynamic response to induced ventricular tachycardia. These data suggest that intravenous magnesium has no significant electrophysiologic or antiarrhythmic effects in patients with life-threatening ventricular arrhythmia and inducible ventricular tachyarrhythmia.