Case report on melatonin overdose: Cause and concern.

Melatonin, the primary hormone secreted by the pineal gland, regulates central and peripheral oscillators and adapts the internal environment to the external one through MT1 and MT2 receptors. The authors present a case of 16-year-old male intentionally overdosed on 900mg of melatonin (180 tablets) and 10 tablets of 0.5mg alprazolam. Admitted to the emergency department, he was extremely drowsy and minimally responsive with a Glasgow coma scale score of 8/15. Vital signs were stable, and no renal or liver dysfunction was noted. Elevated total leucocyte count and positive benzodiazepine urine test were observed. Gastric lavage was performed, and toxicology reports showed blood alprazolam levels at 0.15 mg/litre eight hours post-overdose. The patient regained consciousness 32 hours post-ingestion and was transferred to the psychiatry unit. This case underscores the increasing abuse of melatonin due to its easy availability and lack of regulation. Although melatonin has a low toxicity potential, side effects and interactions with other drugs can be severe. Supportive measures and vital sign control are crucial in overdose treatment.

Developmental origin of oligodendrocytes determines their function in the adult brain.

In the mouse embryonic forebrain, developmentally distinct oligodendrocyte progenitor cell populations and their progeny, oligodendrocytes, emerge from three distinct regions in a spatiotemporal gradient from ventral to dorsal. However, the functional importance of this oligodendrocyte developmental heterogeneity is unknown. Using a genetic strategy to ablate dorsally derived oligodendrocyte lineage cells (OLCs), we show here that the areas in which dorsally derived OLCs normally reside in the adult central nervous system become populated and myelinated by OLCs of ventral origin. These ectopic oligodendrocytes (eOLs) have a distinctive gene expression profile as well as subtle myelination abnormalities. The failure of eOLs to fully assume the role of the original dorsally derived cells results in locomotor and cognitive deficits in the adult animal. This study reveals the importance of developmental heterogeneity within the oligodendrocyte lineage and its importance for homeostatic brain function.

Therapeutic and pharmacological efficacy of plant-derived bioactive compounds in targeting breast cancer.

Breast cancer (BC) ranks number one among cancers affecting women globally. Serious concerns include delayed diagnosis, poor prognosis, and adverse side effects of conventional treatment, leading to residual morbidity. Therefore, an alternative treatment approach that is safe and effective has become the need of the hour. In this regard, plant-based medicines via a combination of conventional drugs are gaining increasing acceptance worldwide, playing a pivotal role in cancer management as proven by their efficacy evaluation studies. This review aims to fill the knowledge gaps by providing the preclinical evidence of cellular and molecular mechanisms of Indian phytomedicines in targeting varied pathways of breast cancer progression. A comprehensive search was performed on different platforms, followed by screening of relevant studies for review. In this article, the in-depth of various botanical drugs covering their nomenclature, dosage, toxicity, and modus operandi in BC cells have been extensively discussed. Various signaling pathways like Notch signaling, MAPK signaling, apoptosis, Wnt signaling, etc. regulated by herbal medicine treatment in BC are also highlighted to understand the drug mechanism better. This will guide the researchers to plan future strategies and generate more robust integrated evidence of plant-based drugs or botanical formulations for their potential role in the management of BC.

Impact of deep brain stimulation on gait in Parkinson disease: A kinematic study.

BACKGROUND: The effect of Deep Brain Stimulation (DBS) on gait in Parkinson's Disease (PD) is poorly understood. Kinematic studies utilizing quantitative gait outcomes such as speed, cadence, and stride length have shown mixed results and were done mostly before and after acute DBS discontinuation. OBJECTIVE: To examine longitudinal changes in kinematic gait outcomes before and after DBS surgery. METHOD: We retrospectively assessed changes in quantitative gait outcomes via motion capture in 22 PD patients before and after subthalamic (STN) or globus pallidus internus (GPi) DBS, in on medication state. Associations between gait outcomes and clinical variables were also assessed. RESULT: Gait speed reduced from 110.7 ± 21.3 cm/s before surgery to 93.6 ± 24.9 after surgery (7.7 ± 2.9 months post-surgery, duration between assessments was 15.0 ± 3.8 months). Cadence, step length, stride length, and single support time reduced, while total support time, and initial double support time increased. Despite this, there was overall improvement in the Movement Disorder Society-Unified Parkinson Disease Rating Scale-Part III score "on medication/on stimulation" score (from 19.8 ± 10.7-13.9 ± 8.6). Change of gait speed was not related to changes in levodopa dosage, disease duration, unilateral vs bilateral stimulation, or target nucleus. CONCLUSION: Quantitative gait outcomes in on medication state worsened after chronic DBS therapy despite improvement in other clinical outcomes. Whether these changes reflect the effects of DBS as opposed to ongoing disease progression is unknown.

Adhatoda vasica and Tinospora cordifolia extracts ameliorate clinical and molecular markers in mild COVID-19 patients: a randomized open-label three-armed study.

BACKGROUND: SARS-CoV-2 infections caused mild-to-moderate illness. However, a sizable portion of infected people experience a rapid progression of hyper-inflammatory and hypoxic respiratory illness that necessitates an effective and safer remedy to combat COVID-19. METHODS: A total of 150 COVID-19-positive patients with no to mild symptoms, between the age groups 19-65 years were enrolled in this randomized, open-labeled three-armed clinical trial. Among them, 136 patients completed the study with RT-PCR negative reports. The patients received herbal drugs orally (Group A (Adhatoda vasica; AV; 500 mg; n = 50); Group B (Tinospora cordifolia; TC; 500 mg; n = 43), and Group C (AV + TC; 250 mg each; n = 43)) for 14 days. Clinical symptoms, vital parameters, and viral clearance were taken as primary outcomes, and biochemical, hematological parameters, cytokines, and biomarkers were evaluated at three time points as secondary outcomes. RESULTS: We found that the mean viral clearance time was 13.92 days (95% confidence interval [CI] 12.85-14.99) in Group A, 13.44 days (95% confidence interval [CI] 12.14-14.74) in Group B, and 11.86 days (95% confidence interval [CI] 10.62-13.11) days in Group C. Over a period of 14 days, the mean temperature in Groups A, and B significantly decreased linearly. In Group A, during the trial period, eosinophils, and PT/INR increased significantly, while monocytes, SGOT, globulin, serum ferritin, and HIF-1α, a marker of hypoxia reduced significantly. On the other hand, in Group B hsCRP decreased at mid-treatment. Eosinophil levels increased in Group C during the treatment, while MCP-3 levels were significantly reduced. CONCLUSIONS: All the patients of the three-armed interventions recovered from COVID-19 and none of them reported any adverse effects from the drugs. Group C patients (AV + TC) resulted in a quicker viral clearance as compared to the other two groups. We provide the first clinical report of AV herbal extract acting as a modifier of HIF-1α in COVID-19 patients along with a reduction in levels of ferritin, VEGF, and PT/INR as the markers of hypoxia, inflammation, and thrombosis highlighting the potential use in progression stages, whereas the TC group showed immunomodulatory effects. Trial registration Clinical Trials Database -India (ICMR-NIMS), CTRI/2020/09/028043. Registered 24th September 2020, https://www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=47443&EncHid=&modid=&compid=%27,%2747443det%27.

Pregabalin Dependence and Management in a 55-Year-Old Female with Chronic Low Back Pain.

This case report explores the complexities of managing chronic pain and the subsequent development of pregabalin dependence in a 55-year-old female patient with a prior history of vertebral fracture. Over a period of 10 years, the patient relied on a combination of Aceclofenac and pregabalin to alleviate her pain. An alternative treatment approach was implemented, involving adjustments to medication dosages and gradual tapering. Throughout the treatment process, interdisciplinary collaboration played a pivotal role in addressing unexpected symptoms such as facial movements and neck swelling. This case report highlights the significance of recognizing and addressing pregabalin dependence in patients with chronic pain.

Breast cancer: miRNAs monitoring chemoresistance and systemic therapy.

With a high mortality rate that accounts for millions of cancer-related deaths each year, breast cancer is the second most common malignancy in women. Chemotherapy has significant potential in the prevention and spreading of breast cancer; however, drug resistance often hinders therapy in breast cancer patients. The identification and the use of novel molecular biomarkers, which can predict response to chemotherapy, might lead to tailoring breast cancer treatment. In this context, accumulating research has reported microRNAs (miRNAs) as potential biomarkers for early cancer detection, and are conducive to designing a more specific treatment plan by helping analyze drug resistance and sensitivity in breast cancer treatment. In this review, miRNAs are discussed in two alternative ways-as tumor suppressors to be used in miRNA replacement therapy to reduce oncogenesis and as oncomirs to lessen the translation of the target miRNA. Different miRNAs like miR-638, miR-17, miR-20b, miR-342, miR-484, miR-21, miR-24, miR-27, miR-23 and miR-200 are involved in the regulation of chemoresistance through diverse genetic targets. For instance, tumor-suppressing miRNAs like miR-342, miR-16, miR-214, and miR-128 and tumor-promoting miRNAs like miR101 and miR-106-25 cluster regulate the cell cycle, apoptosis, epithelial to mesenchymal transition and other pathways to impart breast cancer drug resistance. Hence, in this review, we have discussed the significance of miRNA biomarkers that could assist in providing novel therapeutic targets to overcome potential chemotherapy resistance to systemic therapy and further facilitate the design of tailored therapy for enhanced efficacy against breast cancer.

Neuromelanin-sensitive MRI correlates of cognitive and motor function in Parkinson's disease with freezing of gait.

Substantia nigra pars compacta (SNc) and locus coeruleus (LC) are neuromelanin-rich nuclei implicated in diverse cognitive and motor processes in normal brain function and disease. However, their roles in aging and neurodegenerative disease mechanisms have remained unclear due to a lack of tools to study them in vivo. Preclinical and post-mortem human investigations indicate that the relationship between tissue neuromelanin content and neurodegeneration is complex. Neuromelanin exhibits both neuroprotective and cytotoxic characteristics, and tissue neuromelanin content varies across the lifespan, exhibiting an inverted U-shaped relationship with age. Neuromelanin-sensitive MRI (NM-MRI) is an emerging modality that allows measurement of neuromelanin-associated contrast in SNc and LC in humans. NM-MRI robustly detects disease effects in these structures in neurodegenerative and psychiatric conditions, including Parkinson's disease (PD). Previous NM-MRI studies of PD have largely focused on detecting disease group effects, but few studies have reported NM-MRI correlations with phenotype. Because neuromelanin dynamics are complex, we hypothesize that they are best interpreted in the context of both disease stage and aging, with neuromelanin loss correlating with symptoms most clearly in advanced stages where neuromelanin loss and neurodegeneration are coupled. We tested this hypothesis using NM-MRI to measure SNc and LC volumes in healthy older adult control individuals and in PD patients with and without freezing of gait (FOG), a severe and disabling PD symptom. We assessed for group differences and correlations between NM-MRI measures and aging, cognition and motor deficits. SNc volume was significantly decreased in PD with FOG compared to controls. SNc volume correlated significantly with motor symptoms and cognitive measures in PD with FOG, but not in PD without FOG. SNc volume correlated significantly with aging in PD. When PD patients were stratified by disease duration, SNc volume correlated with aging, cognition, and motor deficits only in PD with disease duration >5 years. We conclude that in severe or advanced PD, identified by either FOG or disease duration >5 years, the observed correlations between SNc volume and aging, cognition, and motor function may reflect the coupling of neuromelanin loss with neurodegeneration and the associated emergence of a linear relationship between NM-MRI measures and phenotype.

A network-based approach to identifying correlations between phylogeny, morphological traits and occurrence of fish species in US river basins.

The complex network framework has been successfully used to model interactions between entities in Complex Systems in the Biological Sciences such as Proteomics, Genomics, Neuroscience, and Ecology. Networks of organisms at different spatial scales and in different ecosystems have provided insights into community assembly patterns and emergent properties of ecological systems. In the present work, we investigate two questions pertaining to fish species assembly rules in US river basins, a) if morphologically similar fish species also tend to be phylogenetically closer, and b) to what extent are co-occurring species that are phylogenetically close also morphologically similar? For the first question, we construct a network of Hydrologic Unit Code 8 (HUC8) regions as nodes with interaction strengths (edges) governed by the number of common species. For each of the modules of this network, which are found to be geographically separated, there is differential yet significant evidence that phylogenetic distance predicts morphological distance. For the second question, we construct and analyze nearest neighbor directed networks of species based on their morphological distances and phylogenetic distances. Through module detection on these networks and comparing the module-level mean phylogenetic distance and mean morphological distance with the number of basins of common occurrence of species in modules, we find that both phylogeny and morphology of species have significant roles in governing species co-occurrence, i.e. phylogenetically and morphologically distant species tend to co-exist more. In addition, between the two quantities (morphological distance and phylogentic distance), we find that morphological distance is a stronger determinant of species co-occurrences.

In vivo detection of substantia nigra and locus coeruleus volume loss in Parkinson's disease using neuromelanin-sensitive MRI: Replication in two cohorts.

Patients with Parkinson's disease undergo a loss of melanized neurons in substantia nigra pars compacta and locus coeruleus. Very few studies have assessed substantia nigra pars compacta and locus coeruleus pathology in Parkinson's disease simultaneously with magnetic resonance imaging (MRI). Neuromelanin-sensitive MRI measures of substantia nigra pars compacta and locus coeruleus volume based on explicit magnetization transfer contrast have been shown to have high scan-rescan reproducibility in controls, but no study has replicated detection of Parkinson's disease-associated volume loss in substantia nigra pars compacta and locus coeruleus in multiple cohorts with the same methodology. Two separate cohorts of Parkinson's disease patients and controls were recruited from the Emory Movement Disorders Clinic and scanned on two different MRI scanners. In cohort 1, imaging data from 19 controls and 22 Parkinson's disease patients were acquired with a Siemens Trio 3 Tesla scanner using a 2D gradient echo sequence with magnetization transfer preparation pulse. Cohort 2 consisted of 33 controls and 39 Parkinson's disease patients who were scanned on a Siemens Prisma 3 Tesla scanner with a similar imaging protocol. Locus coeruleus and substantia nigra pars compacta volumes were segmented in both cohorts. Substantia nigra pars compacta volume (Cohort 1: p = 0.0148; Cohort 2: p = 0.0011) and locus coeruleus volume (Cohort 1: p = 0.0412; Cohort 2: p = 0.0056) were significantly reduced in the Parkinson's disease group as compared to controls in both cohorts. This imaging approach robustly detects Parkinson's disease effects on these structures, indicating that it is a promising marker for neurodegenerative neuromelanin loss.

Deep Brain Stimulation for the Management of AIFM1-Related Disabling Tremor: A Case Series.

The AIFM1 gene encodes a mitochondrial protein that acts as a flavin adenine dinucleotide-dependent nicotinamide adenine dinucleotide oxidase and apoptosis regulator. Monoallelic pathogenic AIFM1 variants result in a spectrum of X-linked neurological disorders, including Cowchock syndrome. Common features in Cowchock syndrome include a slowly progressive movement disorder, cerebellar ataxia, progressive sensorineural hearing loss, and sensory neuropathy. We identified a novel maternally inherited hemizygous missense AIFM1 variant, c.1369C>T p.(His457Tyr), in two brothers with clinical features consistent with Cowchock syndrome using next-generation sequencing. Both individuals had a progressive complex movement disorder phenotype, including disabling tremor poorly responsive to medications. Deep brain stimulation (DBS) of the ventral intermediate thalamic nucleus ameliorated contralateral tremor and improved their quality of life; this suggests the beneficial role for DBS in treatment-resistant tremor within AIFM1-related disorders.

Wetland health, water quality, and resident perceptions of declining ecosystem services: a case study of Mount Abu, Rajasthan, India.

Ecosystem services provided by wetlands are essential for communities living near wetlands, especially in an underdeveloped semi-arid landscape. The land use land cover changes and ecosystem degradation and water quality change over the past few decades have had immense effects on declining wetland ecosystem services. With the degradation, it is exerting superfluous effects on wetland communities including loss of livelihood, and decline in other wetland services like fishing, aquaculture, fuelwood, fodder, and many more. The present study attempts to assess the changing nature of wetland health, water quality, and declining ecosystem services of Mount Abu wetlands in Rajasthan, India. For assessing the change of wetland extent, we have used the remote sensing-based data for preparation of land use land cover change from 1992 to 2020. The water samples have been collected from the wetland, and different biophysical parameters of the water have been tested in the laboratory. A questionnaire-based household survey has been conducted to understand the perception of the wetland communities on the loss of ecosystem services over three decades. Further, a correlation and cluster assessment has been conducted to understand the degradation of wetland health in the selected wetlands. The study results indicated deteriorating conditions of wetland health and declining ecosystem services in the study area over the time periods. The land use land cover change analysis indicated a decrease in the spatial extent of the wetlands in the study area. Wetland communities are being affected due to the degradation of wetland health. The study recommended executing a wetland management plan for long-term conservation and livelihood management for the Mount Abu wetlands and communities.

COVID-Related suicide during the second wave of COVID-19 pandemic in India: A tip of the iceberg of mental health problems.

The coronavirus disease (COVID-19) pandemic has influenced the entire world. There has been great surge of mental health problems after the pandemic has started. The second wave has almost exhausted the Indian Health care system. There has also been cases of suicide due to COVID-19 infection. The objective of study was to highlight various factors involved in COVID-19 related suicide (CRS) during second wave of COVID-19 pandemic in India. CRS reports on the websites of 10 popular newspapers and television news channels in North India and official government websites such as the Ministry of Health and Family Welfare were searched between February 1, 2020, and May 31, 2021. We also searched the Medline and Google Scholar databases for CRS reports from India using the terms "corona", "COVID-19", "SARS CoV 2", "India", and "suicide" in various combinations. A total of 62 articles were included for the study. Most common mode of suicide was hanging and most common site was the deceased's home. Fear of infecting family members was the most common cause of CRS during second wave of the ongoing pandemic in India. Many individuals lost their lives to suicide due to COVID-19 pandemic. The media report does not provide the exact picture of community suicide. Proper physician counselling at the time of providing treatment can help in reducing few CRS.

Neuroleptic Sensitivity in Dementia with Lewy Body and Use of Pimavanserin in an Inpatient Setting: A Case Report.

BACKGROUND Antidopaminergic medications, including antipsychotics, are known to worsen motor and neuropsychiatric symptoms, including cognition and psychosis, in patients with dementia with Lewy body (DLB). The intensity of worsened clinical symptoms may vary and can result in mortality in certain situations. There have been some reports supporting clozapine, quetiapine and pimavanserin use in psychosis control in this population. CASE REPORT We describe the case of 75-year-old man with diagnosis of DLB and the post-treatment outcome with olanzapine for psychosis during hospitalization. He experienced worsened cognitive and motor functions. Discontinuation of olanzapine resulted in resolution of the clinical worsening. Further, re-initiation of Pimavanserin helped treat his hallucinations. He returned back to his baseline during a follow-up visit in the clinic at 1 month after discharge. Further, we incorporated the use of Best Practice Alert (BPA) as a part of the electronic health record (EHR) system to help providers identify patients prone to neuroleptic sensitivity and help select appropriate medications to treat psychosis in this patient population. CONCLUSIONS Administration of antipsychotics in patients with parkinsonism, especially DLB, requires close clinical monitoring and judicious use. Awareness of morbidity and mortality associated with such use is of importance, especially during hospitalization. From our experience, we incorporated use of BPA, which can help providers make judicious choices while treating this patient population. Pimavanserin, which is FDA-approved for psychosis in Parkinson's disease, could be a potential safe and effective treatment option in this patient population.

AYURAKSHA, a prophylactic Ayurvedic immunity boosting kit reducing positivity percentage of IgG COVID-19 among frontline Indian Delhi police personnel: A non-randomized controlled intervention trial.

Objective: The world continues to face the COVID-19 crisis, and efforts are underway to integrate traditional medicine interventions for its effective management. The study aimed to determine the efficacy of the "AYURAKSHA" kit in terms of post-interventional percentage of COVID-19 IgG positivity, immunity levels, and quality of life (QoL) against COVID-19. Method: This was a non-randomized controlled, prospective intervention trial, done after the distribution of 80,000 AYURAKSHA kits (constituent of Sanshamani Vati, AYUSH Kadha, and Anu Taila) among Delhi police participants in India. Among 47,827 participants, the trial group (n = 101) was evaluated with the positivity percentage of IgG COVID-19 and Immune Status Questionnaire (ISQ) scores as a primary outcome and the WHO Quality of Life Brief Version (QOL BREF) scores along with hematological parameters as a secondary outcome in comparison to the control group (n = 71). Results: The data showed that the percentage of COVID-19 IgG positivity was significantly lower in the trial group (17.5 %) as compared to the control group (39.4 %, p = 0.003), indicating the lower risk (55.6%) of COVID-19 infection in the trial group. The decreased incidence (5.05%) and reduced mortality percentage (0.44%) of COVID-19 among Delhi police officers during peak times of the pandemic also corroborate our findings. The ISQ score and WHO-QOL BREF tool analysis showed the improved scores in the trial group when compared with the controls. Furthermore, no dysregulated blood profile and no increase in inflammation markers like C-reactive protein, erythrocyte sedimentation rate, Interleukin-6 (IL-6) were observed in the trial group. However, significantly enhanced (p = 0.027) IL-6 levels and random blood sugar levels were found in the control group (p = 0.032), compared to a trial group (p = 0.165) post-intervention. Importantly, the control group showed more significant (p = 0.0001) decline in lymphocyte subsets CD3+ (% change = 21.04), CD4+ (% change = 20.34) and CD8+ (% change = 21.54) levels than in trial group, confirming more severity of COVID-19 infection in the control group. Conclusion: The AYURAKSHA kit is associated with reduced COVID-19 positivity and with a better quality of life among the trial group. Hence, the study encourages in-depth research and future integration of traditional medicines for the prevention of the COVID-19 pandemic. Clinical trial registration: http://ctri.nic.in/, identifier: CTRI/2020/05/025171.

Case report - Asterixis Post High Frequency Focused-Ultrasound Thalamotomy.

Background: High frequency focused ultrasound is used for treatment of essential tremor. Side effects associated with the procedure may resolve over time. We report a case of negative myoclonus, which has not been reported with this procedure. Case report: A 73-year-old left-handed man underwent focused ultrasound thalamotomy for treatment of essential tremor. Immediately post procedure he was noted to have negative myoclonus in the treated limb. This side effect resolved over the course of 6 months. Discussion: Although asterixis has been associated with thalamic infarcts in the past, this has not yet been reported in the literature with MRgFUS procedure and is a novel observation. Occupational and physical therapy may be considered to address this side effect. It is important to counsel patients about the rare occurrence of this complication of therapy but also its potential for complete resolution over time.

Classifying oscillatory brain activity associated with Indian Rasas using network metrics.

Neural signatures for the western classification of emotions have been widely discussed in the literature. The ancient Indian treatise on performing arts known as Natyashastra categorizes emotions into nine classes, known as Rasas. Rasa-as opposed to a pure emotion-is defined as a superposition of certain transitory, dominant, and temperamental emotional states. Although Rasas have been widely discussed in the text, dedicated brain imaging studies have not been conducted in their research. Our study examines the neural oscillations, recorded through electroencephalography (EEG) imaging, that are elicited while experiencing emotional states corresponding to Rasas. We identify differences among them using network-based functional connectivity metrics in five different frequency bands. Further, Random Forest models are trained on the extracted network features, and we present our findings based on classifier predictions. We observe slow (delta) and fast brain waves (beta and gamma) exhibited the maximum discriminating features between Rasas, whereas alpha and theta bands showed fewer distinguishable pairs. Out of nine Rasas, Sringaram (love), Bibhatsam (odious), and Bhayanakam (terror) were distinguishable from other Rasas the most across frequency bands. On the scale of most network metrics, Raudram (rage) and Sringaram are on the extremes, which also resulted in their good classification accuracy of 95%. This is reminiscent of the circumplex model where anger and contentment/happiness are on extremes on the pleasant scale. Interestingly, our results are consistent with the previous studies which highlight the significant role of higher frequency oscillations in the classification of emotions, in contrast to the alpha band that has shows non-significant differences across emotions. This research contributes to one of the first attempts to investigate the neural correlates of Rasas. Therefore, the results of this study can potentially guide the explorations into the entrainment of brain oscillations between performers and viewers, which can further lead to better performances and viewer experience.

Development of Mechanistic Neural Mass (mNM) Models that Link Physiology to Mean-Field Dynamics.

Brain rhythms emerge from the mean-field activity of networks of neurons. There have been many efforts to build mathematical and computational embodiments in the form of discrete cell-group activities-termed neural masses-to understand in particular the origins of evoked potentials, intrinsic patterns of activities such as theta, regulation of sleep, Parkinson's disease related dynamics, and mimic seizure dynamics. As originally utilized, standard neural masses convert input through a sigmoidal function to a firing rate, and firing rate through a synaptic alpha function to other masses. Here we define a process to build mechanistic neural masses (mNMs) as mean-field models of microscopic membrane-type (Hodgkin Huxley type) models of different neuron types that duplicate the stability, firing rate, and associated bifurcations as function of relevant slow variables - such as extracellular potassium - and synaptic current; and whose output is both firing rate and impact on the slow variables - such as transmembrane potassium flux. Small networks composed of just excitatory and inhibitory mNMs demonstrate expected dynamical states including firing, runaway excitation and depolarization block, and these transitions change in biologically observed ways with changes in extracellular potassium and excitatory-inhibitory balance.

Disease-modifying therapies and progressive multifocal leukoencephalopathy in multiple sclerosis: A systematic review and meta-analysis.

Background High efficacy disease modifying therapies (DMT) in the management of Multiple Sclerosis (MS) have a favorable effect on relapse rate and disability progression; however, they can expose patients to significant risks, such as progressive multifocal leukoencephalopathy (PML). Objective The study aims to investigate prognostic factors that can determine outcome in MS-related PML patients. Methods We conducted a literature review and meta-analysis of 194 patients from 62 articles in PubMed, SCOPUS and EMBASE. Results Out of 194 patients (66.5% women, 33.5% men), 81% had progression in their EDSS score by at least 1 point from the time of PML diagnosis (EDSS-P group). The remaining patients had either stable or improved EDSS (EDSS-S group). In univariate analysis, older age at the time of PML diagnosis was associated with higher probability of disability accumulation and worsening of EDSS by at least 1 point (mean age = 44.8, p = 0.046). After adjusting for other variables, age at time of PML diagnosis remained a significant predictive variable in the multivariable logistic model (OR = 0.93, 95% CI: 0.88-0.99, p = 0.037). Natalizumab is the most commonly associated DMT linked to PML, followed by fingolimod and others including dimethyl fumarate, ocrelizumab, alemtuzumab. Among the different treatments used, no therapeutic agent was found to be superior in improving post-PML EDSS. Conclusions Younger age and lower JCV viral load at the time of PML diagnosis were associated with better outcome in MS-associate PML, while none of the PML therapies was superior over the others or associated with favorable outcome.