Aberrant Dopamine System Function in the Ferrous Amyloid Buthionine (FAB) Rat Model of Alzheimer's Disease.

Antipsychotics increase the risk of death in elderly patients with Alzheimer's disease (AD). Thus, there is an immediate need for novel therapies to treat comorbid psychosis in AD. Psychosis has been attributed to a dysregulation of the dopamine system and is associated with aberrant regulation by the hippocampus. Given that the hippocampus is a key site of pathology in AD, we posit that aberrant regulation of the dopamine system may contribute to comorbid psychosis in AD. A ferrous amyloid buthionine (FAB) rodent model was used to model a sporadic form of AD. FAB rats displayed functional hippocampal alterations, which were accompanied by decreases in spontaneous, low-frequency oscillations and increases in the firing rates of putative pyramidal neurons. Additionally, FAB rats exhibited increases in dopamine neuron population activity and augmented responses to the locomotor-inducing effects of MK-801, as is consistent with rodent models of psychosis-like symptomatology. Further, working memory deficits in the Y-maze, consistent with an AD-like phenotype, were observed in FAB rats. These data suggest that the aberrant hippocampal activity observed in AD may contribute to dopamine-dependent psychosis, and that the FAB model may be useful for the investigation of comorbid psychosis related to AD. Understanding the pathophysiology that leads to comorbid psychosis in AD will ultimately lead to the discovery of novel targets for the treatment of this disease.

α5-GABAA Receptor Modulation Reverses Behavioral and Neurophysiological Correlates of Psychosis in Rats with Ventral Hippocampal Alzheimer's Disease-like Pathology.

Of the 35 million people in the world suffering from Alzheimer's Disease (AD), up to half experience comorbid psychosis. Antipsychotics, used to treat psychosis, are contraindicated in elderly patients because they increase the risk of premature death. Reports indicate that the hippocampus is hyperactive in patients with psychosis and those with AD. Preclinical studies have demonstrated that the ventral hippocampus (vHipp) can regulate dopamine system function, which is thought to underlie symptoms of psychosis. A viral-mediated approach was used to express mutated human genes known to contribute to AD pathology: the Swedish (K670N, M671L), Florida (I716V), and London (V717I) mutations of amyloid precursor protein and two mutations (M146L and L286V) of presenilin 1 specifically in the vHipp, to investigate the selective contribution of AD-like pathology in this region. We observed a significant increase in dopamine neuron population activity and behavioral deficits in this AD-AAV model that mimics observations in rodent models with psychosis-like symptomatologies. Further, systemic administration of MP-III-022 (α5-GABAA receptor selective positive allosteric modulator) was able to reverse aberrant dopamine system function in AD-AAV rats. This study provides evidence for the development of drugs that target α5-GABAA receptors for patients with AD and comorbid psychosis.

Clinical and therapeutic value of the adjusted Global Antiphospholipid Syndrome Score in primary obstetric antiphospholipid syndrome.

OBJECTIVES: (1) To assess the clinical utility of the adjusted global antiphospholipid syndrome score (aGAPSS) to predict new obstetric events during follow-up in primary obstetric antiphospholipid syndrome (POAPS) patients under standard-of-care treatment (SC) based on the use of low-dose aspirin (LDA) + heparin and (2) to study the risk of a first thrombotic event and to evaluate whether stratification according to this score could help to identify POAPS patients who would benefit from long-term thromboprophylaxis. METHODS: This is a retrospective, multicentre study. 169 women with POAPS were evaluated for the presence of a new obstetric event and/or a first thrombotic event during follow-up [time period: 2008-2020, median: 7 years (6-12 years)]. The outcomes of 107 pregnancies from these POAPS patients with SC were studied to evaluate relapses. Simple and multivariable logistic regression analyses were performed. RESULTS: Regarding obstetric morbidity, only triple positivity for antiphospholipid antibodies (aPLs) [OR = 8.462 (95% CI: 2.732-26.210); p < 0.0001] was found to be a strong risk factor independently associated with treatment failure. On the other hand, triple positivity for aPLs [OR=10.44 (95% CI: 2.161-50.469), p = 0.004] and an aGAPSS ≥7 [OR = 1.621 (95% CI: 1.198-2.193), p = 0.002] were independent risk factors associated with a first thrombotic event. LDA was marginally associated with a decrease in the risk of thrombosis only in patients with aGAPSS ≥ 7 (p = 0.048). CONCLUSION: aGAPSS appears to be useful in predicting the occurrence of a first thrombotic event in POAPS patients, and these stratification of patients could be helpful in selecting patients who would benefit from thromboprophylaxis with LDA.

Anticipatory weight shift between arms when reaching from a crouched posture.

Reaching movements performed from a crouched body posture require a shift of body weight from both arms to one arm. This situation has remained unexamined despite the analogous load requirements during step initiation and the many studies of reaching from a seated or standing posture. To determine whether the body weight shift involves anticipatory or exclusively reactive control, we obtained force plate records, hand kinematics, and arm muscle activity from 11 healthy right-handed participants. They performed reaching movements with their left and right arm in two speed contexts, "comfortable" and "as fast as possible," and two postural contexts, a less stable knees-together posture and a more stable knees-apart posture. Weight-shifts involved anticipatory postural actions (APAs) by the reaching and stance arms that were opposing in the vertical axis and aligned in the side-to-side axis similar to APAs by the legs for step initiation. Weight-shift APAs were correlated in time and magnitude, present in both speed contexts, more vigorous with the knees placed together, and similar when reaching with the dominant and nondominant arm. The initial weight-shift was preceded by bursts of muscle activity in the shoulder and elbow extensors (posterior deltoid and triceps lateral) of the reach arm and shoulder flexor (pectoralis major) of the stance arm, which indicates their causal role; leg muscles may have indirectly contributed but were not recorded. The strong functional similarity of weight-shift APAs during crouched reaching to human stepping and cat reaching suggests that they are a core feature of posture-movement coordination.NEW & NOTEWORTHY This work demonstrates that reaching from a crouched posture is preceded by bimanual anticipatory postural adjustments (APAs) that shift the body weight to the stance limb. Weight-shift APAs are more robust in an unstable body posture (knees together) and involve the shoulder and elbow extensors of the reach arm and shoulder flexor of the stance arm. This pattern mirrors the forelimb coordination of cats reaching and humans initiating a step.

Orexin Modulation of VTA Dopamine Neuron Activity: Relevance to Schizophrenia.

BACKGROUND: The hippocampus is a region consistently implicated in schizophrenia and has been advanced as a therapeutic target for positive, negative, and cognitive deficits associated with the disease. Recently, we reported that the paraventricular nucleus of the thalamus (PVT) works in concert with the ventral hippocampus to regulate dopamine system function; however, the PVT has yet to be investigated as target for the treatment of the disease. Given the dense expression of orexin receptors in the thalamus, we believe these to be a possible target for pharmacological regulation of PVT activity. METHODS: Here we used the methylazoxymethanol acetate (MAM) rodent model, which displays pathological alterations consistent with schizophrenia to determine whether orexin receptor blockade can restore ventral tegmental area dopamine system function. We measured dopamine neuron population activity, using in vivo electrophysiology, following administration of the dual orexin antagonist, TCS 1102 (both intraperitoneal and intracranial into the PVT in MAM- and saline-treated rats), and orexin A and B peptides (intracranial into the PVT in naïve rats). RESULTS: Aberrant dopamine system function in MAM-treated rats was normalized by the systemic administration of TCS 1102. To investigate the potential site of action, the orexin peptides A and B were administered directly into the PVT, where they significantly increased ventral tegmental area dopamine neuron population activity in control rats. In addition, the direct administration of TCS 1102 into the PVT reproduced the beneficial effects seen with the systemic administration in MAM-treated rats. CONCLUSION: Taken together, these data suggest the orexin system may represent a novel site of therapeutic intervention for psychosis via an action in the PVT.

Reproductive biology of the swell shark Cephaloscyllium ventriosum (Carcharhiniformes: Scyliorhinidae).

The Cephaloscyllium ventriosum shark is present in the artisanal fisheries of elasmobranchs on the western coast of Baja California Sur, Mexico. The main characteristics of the sexual maturation of this species based on individuals captured from off north-west Mexico in 2013-2016 are described. The size at maturity of this species was determined for the first time (total length 82 cm for females and 76 cm for males). Most females had one egg case per one uterus, and two per one uterus was an isolated event of low incidence. From the histological analysis of females, it was possible to show sperm storage in the oviducal gland. Fully developed sperm in immature organisms were identified in the testes. The main indicator of the maturity stage of males and their mating activity is the clasper. The present study provides evidence for a reliable estimation of the sexual maturity of these organisms, demonstrating the need for the combination of macroscopic and microscopic methods.

Convergent Inputs from the Hippocampus and Thalamus to the Nucleus Accumbens Regulate Dopamine Neuron Activity.

Aberrant hippocampal activity is observed in individuals with schizophrenia and is thought to underlie the augmented dopamine system function associated with psychosis. The pathway by which the ventral hippocampus (vHipp) regulates dopamine neuron activity has been demonstrated previously and involves a glutamatergic projection to the nucleus accumbens (NAc). Recent postmortem studies have confirmed glutamatergic abnormalities in the NAc of individuals with schizophrenia. Specifically, an increase in vesicular glutamate transporter 2 (vGlut2) expression was reported. Although projections from the hippocampus do express vGlut2, inputs from the thalamus are more likely to account for this alteration; however, the role of thalamic inputs to the NAc in the regulation of dopamine neuron activity has not been elucidated. Here, using male Sprague Dawley rats, we demonstrate that a subset of NAc medium spiny neurons receive convergent inputs from the vHipp and paraventricular nucleus of the thalamus (PVT), with both regions working synergistically to regulate dopamine neuron activity. Activation of either the vHipp or PVT increases the number of spontaneously active dopamine neurons in the ventral tegmental area. Moreover, this regulation requires simultaneous activity in both regions because PVT inactivation can reverse vHipp-induced increases in dopamine neuron population activity and vHipp inactivation can reverse PVT-induced increases. This is relevant to schizophrenia because inactivation of either the vHipp or PVT is sufficient to reverse aberrant dopamine system function in two distinct rodent models. These data suggest that thalamic abnormalities may contribute to the aberrant dopamine system function observed in schizophrenia and that the PVT represents a novel site of intervention for psychosis.SIGNIFICANCE STATEMENT Current treatments for schizophrenia are far from adequate and a more complete understanding of the pathophysiology underlying this disease is warranted if we are to discover novel therapeutic targets. We have previously demonstrated that the aberrant dopamine system function observed in individuals with schizophrenia and rodent models is driven by increases in hippocampal activity. We now demonstrate that thalamic (paraventricular nucleus, PVT) and ventral hippocampal afferents converge in the nucleus accumbens to regulate dopamine system function. Such information provides a potential site for therapeutic intervention for schizophrenia. Indeed, inactivation of the PVT can effectively reverse aberrant dopamine system function in two distinct rodent models displaying circuit level alterations and corresponding behavioral deficits relevant to schizophrenia.

Comparative analysis of MBD-seq and MeDIP-seq and estimation of gene expression changes in a rodent model of schizophrenia.

We conducted a comparative study of multiplexed affinity enrichment sequence methodologies (MBD-seq and MeDIP-seq) in a rodent model of schizophrenia, induced by in utero methylazoxymethanol acetate (MAM) exposure. We also examined related gene expression changes using a pooled sample approach. MBD-seq and MeDIP-seq identified 769 and 1771 differentially methylated regions (DMRs) between F2 offspring of MAM-exposed rats and saline control rats, respectively. The assays showed good concordance, with ~56% of MBD-seq-detected DMRs being identified by or proximal to MeDIP-seq DMRs. There was no significant overlap between DMRs and differentially expressed genes, suggesting that DNA methylation regulatory effects may act upon more distal genes, or are too subtle to detect using our approach. Methylation and gene expression gene ontology enrichment analyses identified biological processes important to schizophrenia pathophysiology, including neuron differentiation, prepulse inhibition, amphetamine response, and glutamatergic synaptic transmission regulation, reinforcing the utility of the MAM rodent model for schizophrenia research.

Vagal nerve stimulation reverses aberrant dopamine system function in the methylazoxymethanol acetate rodent model of schizophrenia.

Vagal nerve stimulation (VNS) is an alternative therapy for epilepsy and treatment refractory depression. Here we examine VNS as a potential therapy for the treatment of schizophrenia in the methylozoxymethanol acetate (MAM) rodent model of the disease. We have previously demonstrated that hyperactivity within ventral regions of the hippocampus (vHipp) drives the dopamine system dysregulation in this model. Moreover, by targeting the vHipp directly, we can reverse aberrant dopamine system function and associated behaviors in the MAM model. Although the central effects of VNS have not been completely delineated, positron emission topographic measurements of cerebral blood flow in humans have consistently reported that VNS stimulation induces bilateral decreases in hippocampal activity. Based on our previous observations, we performed in vivo extracellular electrophysiological recordings in MAM- and saline-treated rats to evaluate the effect of chronic (2 week) VNS treatment on the activity of putative vHipp pyramidal neurons, as well as downstream dopamine neuron activity in the ventral tegmental area. Here we demonstrate that chronic VNS was able to reverse both vHipp hyperactivity and aberrant mesolimbic dopamine neuron function in the MAM model of schizophrenia. Additionally, VNS reversed a behavioral correlate of the positive symptoms of schizophrenia. Because current therapies for schizophrenia are far from adequate, with a large number of patients discontinuing treatment due to low efficacy or intolerable side effects, it is important to explore alternative nonpharmacological treatments. These data provide the first preclinical evidence that VNS may be a possible alternative therapeutic approach for the treatment of schizophrenia.

Knockdown of Lhx6 during embryonic development results in neurophysiological alterations and behavioral deficits analogous to schizophrenia in adult rats.

A decreased expression of specific interneuron subtypes, containing either the calcium binding protein parvalbumin (PV) or the neurotransmitter somatostatin (SST), are observed in the cortex and hippocampus of both patients with schizophrenia and rodent models used to study the disorder. Moreover, preclinical studies suggest that this loss of inhibitory function is a key pathological mechanism underlying the symptoms of schizophrenia. Interestingly, decreased expression of Lhx6, a key transcriptional regulator specific to the development and migration of PV and SST interneurons, is seen in human postmortem studies and following multiple developmental disruptions used to model schizophrenia preclinically. These results suggest that disruptions in interneuron development in utero may contribute to the pathology of the disorder. To recapitulate decreased Lhx6 expression during development, we used in utero electroporation to introduce an Lhx6 shRNA plasmid and knockdown Lhx6 expression in the brains of rats on gestational day 17. We then examined schizophrenia-like neurophysiological and behavioral alterations in the offspring once they reached adulthood. In utero Lhx6 knockdown resulted in increased ventral tegmental area (VTA) dopamine neuron population activity and a sex-specific increase in locomotor response to a psychotomimetic, consistent with positive symptomology of schizophrenia. However, Lhx6 knockdown had no effect on social interaction or spatial working memory, suggesting behaviors associated with negative and cognitive symptom domains were unaffected. These results suggest that knockdown of Lhx6 during development results in neurophysiological and behavioral alterations consistent with the positive symptom domain of schizophrenia in adult rats.

Loss of opportunities in the diagnosis and treatment of primary obstetric antiphospholipid syndrome (POAPS): from theory to reality.

OBJECTIVES: (I) To identify and measure the clinical consequences of a delayed diagnosis in patients with primary obstetric antiphospholipid syndrome (POAPS), in terms of time and events associated to antiphospholipid syndrome (APS), and (II) to evaluate the impact of their treatment status on perinatal outcomes, before and after diagnosis. METHODS: This retrospective multicentre study included 99 POAPS women who were separated in two groups of timelines based on their diagnostic status: group 1: women who met the clinical criteria for POAPS; group 2: included the same patients from group 1 since they meet the laboratory criteria for APS. In group 1, we assessed the following variables: obstetric events, thrombotic events and time (years) to diagnosis of APS. We also compared perinatal outcomes between patients in group 1 vs. group 2. Women in group 2 were treated with standard of care for POAPS. Simple and multivariable logistic regression analyses were performed. RESULTS: Regarding the impact of the delay on diagnosis, a total of 87 APS-related events were recorded: 46 miscarriages, 32 foetal losses and 9 premature deliveries before the 34th week due to preeclampsia, and one thrombosis. The estimated rate of preventable events was 20.58 per year/100 patients. The mean diagnostic delay time was 4.27 years. When we compared both groups during pregnancy, we found that patients in group 1 (no treatment) had a higher association with pregnancy losses [OR = 6.71 (95% CI: 3.59-12.55), p < 0.0001]. CONCLUSION: Our findings emphasize the negative impact of POAPS underdiagnosis on patient health and the critical importance of a timely intervention to improve pregnancy outcomes. Key Points •Our study shows the relevance of underdiagnosis on primary obstetric antiphospholipid syndrome (POAPS). •These patients presented a high risk of APS-related events with each passing year. •Shorter diagnostic delay time was observed in the reference centres.

Observational study protocol for an arrhythmia notification feature.

INTRODUCTION: Screening for atrial fibrillation (AF) in the general population may help identify individuals at risk, enabling further assessment of risk factors and institution of appropriate treatment. Algorithms deployed on wearable technologies such as smartwatches and fitness bands may be trained to screen for such arrhythmias. However, their performance needs to be assessed for safety and accuracy prior to wide-scale implementation. METHODS AND ANALYSIS: This study will assess the ability of the WHOOP strap to detect AF using its WHOOP Arrhythmia Notification Feature (WARN) algorithm in an enriched cohort with a 2:1 distribution of previously diagnosed AF (persistent and paroxysmal) and healthy controls. Recruited participants will collect data for 7 days with the WHOOP wrist-strap and BioTel ePatch (electrocardiography gold-standard). Primary outcome will be participant level sensitivity and specificity of the WARN algorithm in detecting AF in analysable windows compared with the ECG gold-standard. Similar analyses will be performed on an available epoch-level basis as well as comparison of these findings in important subgroups. ETHICS AND DISSEMINATION: The study was approved by the ethics board at the study site. Participants will be enrolled after signing an online informed consent document. Updates will be shared via clinicaltrials.gov. The data obtained from the conclusion of this study will be presented in national and international conferences with publication in clinical research journals. TRIAL REGISTRATION NUMBER: NCT05809362.

cGAS Expression is Enhanced in Systemic Sclerosis Associated Interstitial Lung Disease and Stimulates Inflammatory Myofibroblast Activation.

Objective: The lungs of patients with Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD) contain inflammatory myofibroblasts arising in association with fibrotic stimuli and perturbed innate immunity. The innate immune DNA binding receptor Cyclic GMP-AMP synthase (cGAS) is implicated in inflammation and fibrosis, but its involvement in SSc-ILD remains unknown. We examined cGAS expression, activity, and therapeutic potential in SSc-ILD using cultured fibroblasts, precision cut lung slices (PCLS), and a well-accepted animal model. Methods: Expression and localization of cGAS, cytokines, and type 1 interferons were evaluated in SSc-ILD lung tissues, bronchoalveolar lavage (BAL), and isolated lung fibroblasts. CGAS activation was assessed in a publicly available SSc-ILD single cell RNA sequencing dataset. Production of cytokines, type 1 interferons, and αSMA elicited by TGFß1 or local substrate stiffness were measured in normal human lung fibroblasts (NHLFs) via qRT-PCR, ELISA, and immunofluorescence. Small molecule cGAS inhibition was tested in cultured fibroblasts, human PCLS, and the bleomycin pulmonary fibrosis model. Results: SSc-ILD lung tissue and BAL are enriched for cGAS, cytokines, and type 1 interferons. The cGAS pathway shows constitutive activation in SSc-ILD fibroblasts and is inducible in NHLFs by TGFß1 or mechanical stimuli. In these settings, and in human PCLS, cGAS expression is paralleled by the production of cytokines, type 1 interferons, and αSMA that are mitigated by a small molecule cGAS inhibitor. These findings are recapitulated in the bleomycin mouse model. Conclusion: cGAS signaling contributes to pathogenic inflammatory myofibroblast phenotypes in SSc-ILD. Inhibiting cGAS or its downstream effectors represents a novel therapeutic approach.

Pituitary-Adrenal Axis and Peripheral Immune Cell Profile in Long COVID.

In Long COVID, dysfunction in the pituitary-adrenal axis and alterations in immune cells and inflammatory status are warned against. We performed a prospective study in a cohort of 42 patients who suffered COVID-19 at least 6 months before attending the Long COVID unit at Althaia Hospital. Based on Post-COVID Functional Status, 29 patients were diagnosed with Long COVID, while 13 were deemed as recovered. The hormones of the pituitary-adrenal axis, adrenocorticotropin stimulation test, and immune cell profiles and inflammatory markers were examined. Patients with Long COVID had significantly lower EuroQol and higher mMRC scores compared to the recovered individuals. Their symptoms included fatigue, myalgia, arthralgia, persistent coughing, a persistent sore throat, dyspnoea, a lack of concentration, and anxiety. We observed the physiological levels of cortisol and adrenocorticotropin in individuals with or without Long COVID. The results of the adrenocorticotropin stimulation test were similar between both groups. The absolute number of neutrophils was lower in the Long COVID patients compared to recovered individuals (p < 0.05). The total count of B lymphocytes remained consistent, but Long COVID patients had a higher percentage of mature B cells compared to recovered participants (p < 0.05) and exhibited a higher percentage of circulating resident memory CD8+ T cells (p < 0.05) and Treg-expressing exonucleases (p < 0.05). Our findings did not identify adrenal dysfunction related to Long COVID, nor an association between adrenal function and clinical symptoms. The data indicated a dysregulation in certain immune cells, pointing to immune activation. No overt hyperinflammation was observed in the Long COVID group.

Hippocampal deep brain stimulation reverses physiological and behavioural deficits in a rodent model of schizophrenia.

Subcortical dopamine system dysregulation has been suggested to underlie the positive symptoms of schizophrenia. Recent preclinical investigations and human imaging studies have proposed that the augmented dopamine system function observed in schizophrenia patients may be secondary to aberrant hippocampal activity. Thus, we posit that the hippocampus represents a novel therapeutic target for the treatment of schizophrenia. Here we provide evidence of the effectiveness of a unique approach aimed at decreasing hippocampal function in a rodent model of schizophrenia. Specifically, in a rodent model of schizophrenia, we demonstrate that ventral hippocampal (vHipp) deep brain stimulation (DBS) can normalize aberrant dopamine neuron activity and behaviours associated with positive symptoms. In addition, we provide evidence that this approach may also be effective in restoring deficits in cognitive function, often left unaltered by conventional antipsychotic medications. Therefore, we have provided initial preclinical evidence demonstrating the feasibility of hippocampal DBS as a potential novel approach for the treatment of schizophrenia.

Congenital blindness does not protect against a schizophrenia-related phenotype in rodents.

BACKGROUND: In 1950, Drs. Chevigny and Braverman authored a book about people's attitudes and prejudices toward the blind, noting that out of the thousands of schizophrenia patients they and others had treated, not one was blind. This led some to the intriguing hypothesis that congenital blindness may provide protection against schizophrenia. In this study, we directly examined whether congenital blindness protects against a schizophrenia-related phenotype in the methylazoxymethanol acetate (MAM) rodent model. DESIGN: Enucleation surgeries were performed on pups of MAM- or saline-treated rats on post-natal day 10. Once pups reached adulthood, male and female rats were evaluated for schizophrenia-like phenotypes using behavioral and electrophysiological measures. Consistent with previous work, MAM-treated rats display elevated dopamine neuron population activity, deficits in pre-pulse inhibition of startle, and hypersensitivity to psychomotor stimulants. RESULTS: Blindness did not protect against any of the MAM-induced phenotypes. Surprisingly, blindness in saline-treated rats caused changes in behavior and dopamine neuron activity. To examine the circadian rhythms of enucleated rats, we performed non-invasive measurements of corticosterone, a steroid hormone known to vary across the light/dark period, revealing blind rats display aberrant (non-cycling) corticosterone levels. CONCLUSIONS: Alterations in dopamine neuron activity and associated behaviors observed in blind rats are likely secondary to aberrant circadian regulation. This is the first preclinical study examining whether congenital blindness protects against a schizophrenia-like phenotype. While support of this hypothesis would have led to novel avenues of research and potential novel therapies, the results of current study suggest that blindness does not protect against schizophrenia.

Hippocampal α5-GABAA Receptors Modulate Dopamine Neuron Activity in the Rat Ventral Tegmental Area.

Background: Aberrant dopamine neuron activity is attributable to hyperactivity in hippocampal subfields driving a pathological increase in dopamine neuron activity, which is positively correlated with psychosis in humans. Evidence indicates that hippocampal hyperactivity is due to loss of intrinsic GABAergic (gamma-aminobutyric acidergic) inhibition. We have previously demonstrated that hippocampal GABAergic neurotransmission can be modulated by targeting α5-GABAA receptors, which are preferentially expressed in hippocampal regions. Positive and negative allosteric modulators of α5-GABAA receptors (α5-PAMs and α5-NAMs) elicit effects on hippocampal-dependent behaviors. We posited that the selective manipulation of hippocampal inhibition, using α5-PAMs or α5-NAMs, would modulate dopamine activity in control rats. Further, α5-PAMs would reverse aberrant dopamine neuron activity in a rodent model with schizophrenia-related pathophysiologies (methylazoxymethanol acetate [MAM] model). Methods: We performed in vivo extracellular recordings of ventral tegmental area dopamine neurons in anesthetized rats to compare the effects of two novel, selective α5-PAMs (GL-II-73, MP-III-022), a nonselective α-PAM (midazolam), and two selective α5-NAMs (L-655,708, TB 21007) in control and MAM-treated male Sprague Dawley rats (n = 5-9). Results: Systemic or intracranial administration of selective α5-GABAA receptor modulators regulated dopamine activity. Specifically, both α5-NAMs increased dopamine neuron activity in control rats, whereas GL-II-73, MP-III-022, and L-655,708 attenuated aberrant dopamine neuron activity in MAM-treated rats, an effect mediated by the ventral hippocampus. Conclusions: This study demonstrated that α5-GABAA receptor modulation can regulate dopamine neuron activity under control or abnormal activity, providing additional evidence that α5-PAMs and α5-NAMs may have therapeutic applications in psychosis and other psychiatric diseases where aberrant hippocampal activity is present.

Thrombosis and Hyperinflammation in COVID-19 Acute Phase Are Related to Anti-Phosphatidylserine and Anti-Phosphatidylinositol Antibody Positivity.

Antiphospholipid antibodies (APLA) are strongly associated with thrombosis seen in patients with antiphospholipid syndrome. In COVID-19, thrombosis has been observed as one of the main comorbidities. In patients hospitalised for COVID-19, we want to check whether APLA positivity is associated with COVID-19-related thrombosis, inflammation, severity of disease, or long COVID-19. We enrolled 92 hospitalised patients with COVID-19 between March and April 2020 who were tested for 18 different APLAs (IgG and IgM) with a single line-immunoassay test. A total of 30 healthy blood donors were used to set the cut-off for each APLA positivity. Of the 92 COVID-19 inpatients, 30 (32.61%; 95% CI [23.41-43.29]) tested positive for APLA, of whom 10 (33.3%; 95% CI [17.94-52.86]) had more than one APLA positivity. Anti-phosphatidylserine IgM positivity was described in 5.4% of inpatients (n = 5) and was associated with the occurrence of COVID-19-related thrombosis (p = 0.046). Anti-cardiolipin IgM positivity was the most prevalent among the inpatients (n = 12, 13.0%) and was associated with a recorded thrombosis in their clinical history (p = 0.044); however, its positivity was not associated with the occurrence of thrombosis during their hospitalisation for COVID-19. Anti-phosphatidylinositol IgM positivity, with a prevalence of 5.4% (n = 5), was associated with higher levels of interleukin (IL)-6 (p = 0.007) and ferritin (p = 0.034). Neither of these APLA positivities was a risk factor for COVID-19 severity or a predictive marker for long COVID-19. In conclusion, almost a third of COVID-19 inpatients tested positive for at least one APLA. Anti-phosphatidylserine positivity in IgM class was associated with thrombosis, and anti-phosphatidylinositol positivity in IgM class was associated with inflammation, as noticed by elevated levels of IL-6. Thus, testing for non-criteria APLA to assess the risk of clinical complications in hospitalised COVID-19 patients might be beneficial. However, they were not related to disease severity or long COVID-19.

Low complement levels are related to poor obstetric outcomes in women with obstetric antiphospholipid syndrome. The EUROAPS Registry Study Group.

INTRODUCTION: Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disease related to antiphospholipid antibodies (aPL) with primaryinflammatory injury followed by clot cascade activation and thrombus formation. Complement system activation and their participation in aPL-related thrombosis is unclosed. METHODS: We haveanalysed adverse pregnancy outcomes (APO) related to low complement (LC) levels in a cohort of 1048 women fulfilling classification criteria for OAPS. RESULTS: Overall, 223 (21.3%) women presented LC values, during pregnancy. The length of pregnancy was shorter in OAPS women with LC compared to those with normal complement (NC) (median: 33 weeks, interquartile range: [24-38] vs. 35 weeks [27-38]; p = 0.022). Life new-born incidence was higher in patients with NC levels than in those with LC levels (74.4% vs. 67.7%; p = 0.045). Foetal losses were more related to women with triple or double aPL positivity carrying LC than NC values (16.3% vs. 8.0% NC; p = 0.027). Finally, some placental vasculopathies were affected in OAPS patients with LC as late Foetal Growth Restriction (FGR >34 weeks) rise to 7.2% in women with LC vs. 3.2% with NC (p = 0.007). DISCUSSION: Data from our registry indicate that incidence of APO was higher in OAPS women with LC levels and some could be reverted by the correct treatment.