Glioma-Induced Alterations in Excitatory Neurons are Reversed by mTOR Inhibition.

Gliomas are highly aggressive brain tumors characterized by poor prognosis and composed of diffusely infiltrating tumor cells that intermingle with non-neoplastic cells in the tumor microenvironment, including neurons. Neurons are increasingly appreciated as important reactive components of the glioma microenvironment, due to their role in causing hallmark glioma symptoms, such as cognitive deficits and seizures, as well as their potential ability to drive glioma progression. Separately, mTOR signaling has been shown to have pleiotropic effects in the brain tumor microenvironment, including regulation of neuronal hyperexcitability. However, the local cellular-level effects of mTOR inhibition on glioma-induced neuronal alterations are not well understood. Here we employed neuron-specific profiling of ribosome-bound mRNA via 'RiboTag,' morphometric analysis of dendritic spines, and in vivo calcium imaging, along with pharmacological mTOR inhibition to investigate the impact of glioma burden and mTOR inhibition on these neuronal alterations. The RiboTag analysis of tumor-associated excitatory neurons showed a downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development, and an upregulation of transcripts encoding cytoskeletal proteins involved in dendritic spine turnover. Light and electron microscopy of tumor-associated excitatory neurons demonstrated marked decreases in dendritic spine density. In vivo two-photon calcium imaging in tumor-associated excitatory neurons revealed progressive alterations in neuronal activity, both at the population and single-neuron level, throughout tumor growth. This in vivo calcium imaging also revealed altered stimulus-evoked somatic calcium events, with changes in event rate, size, and temporal alignment to stimulus, which was most pronounced in neurons with high-tumor burden. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed the glioma-induced alterations on the excitatory neurons, including the alterations in ribosome-bound transcripts, dendritic spine density, and stimulus evoked responses seen by calcium imaging. These results point to mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma - manifested by alterations in ribosome-bound mRNA, dendritic spine density, and stimulus-evoked neuronal activity. Collectively, our work identifies the pathological changes that tumor-associated excitatory neurons experience as both hyperlocal and reversible under the influence of mTOR inhibition, providing a foundation for developing therapies targeting neuronal signaling in glioma.

Reward Functioning in General and Specific Psychopathology in Children and Adults.

OBJECTIVE: Problems with reward processing have been implicated in multiple psychiatric disorders, but psychiatric comorbidities are common and their specificity to individual psychopathologies is unknown. Here, we evaluate the association between reward functioning and general or specific psychopathologies. METHOD: 1,213 adults and their1,531 children (ages 6-12) completed various measures of the Positive Valence System domain from the Research Domain Criteria (RDoC). Psychopathology was assessed using the Child Behavior Checklist for children and the Adult Self Report for parents. RESULTS: One general factor identified via principal factors factor analysis explained most variance in psychopathology in both groups. Measures of reward were associated with the general factor and most specific psychopathologies. Certain reward constructs were associated solely with specific psychopathologies but not general psychopathology. However, some prior associations between reward and psychopathology did not hold following removal of comorbidity. CONCLUSION: Reward dysfunction is significantly associated with both general and specific psychopathologies.

Research Landscape on Student Suicide: A Bibliometric and Visual Analysis of 62 Years (1959-2021).

Background: To guide and provide orientation to research on student suicide, this study aimed to analyze the research status on student suicide with the help of bibliometric analysis. Utilising bibliometric methodology, this study complements existing literature by giving a comprehensive, reliable thematic representation of this topic. Method: A Scopus search was done and all published research papers were reviewed. A total of 187 papers published between 1959 and 2021 were analyzed. We identified the most influential journals in this field, the most prolific nations and institutions, as well as the years with the most publications, the most cited papers, notable authors, and most researched areas, It was followed by use of the VOSviewer software (version 1.6.18) to construct and visualize the bibliometric networks like co-authorship network map, inter-country co-authorship network map, and keywords co-occurrences network maps. Results: The analysis reveals the current research trend where the number of publications on 'student suicide' reflects an overall upward trend over the years, suggesting that research on student suicidology is fast evolving but the pace is slow. The maximum publications were in the year 2020. The United States made the largest contribution (n = 85). The most productive institution was the University of Rochester, New York (n = 10). Allan J Schwartz was the most prolific author, with nine research papers. Journal of College Student Psychotherapy (n = 13) was the journal and Medicine (n = 118) was the discipline with the highest number of publications. Conclusion: The study potentially has important implications for designing more comprehensive screening and assessment tools for suicide risk. Future work should pay more attention to developing effective intervention programs for students. The results also highlight the need for more research work on student suicidology. More research in this area is needed to create awareness among students. Consequently, this study can be a big critique and torch bearer at the same time.

Putting the Patient in Patient Safety Investigations: Barriers and Strategies for Involvement.

OBJECTIVES: In an adverse event investigation, the patients have the potential to add a unique perspective because they can identify contributing factors that providers may miss. However, patients are rarely included in patient safety investigations. We aimed to identify the barriers to patient involvement in patient safety investigations and propose strategies to overcome them. METHODS: We reviewed literature on active participation by patients in safety investigations to construct a framework for healthcare institutions to use in approaching patients about a potential role in investigating an error in their care. We searched 3 electronic databases (PubMed, PSNet, Web of Science) for the years 1990 to 2018, without restrictions to language. Search terms included: "patient empowerment, "patient involvement," "patient participation," "patient safety investigation," "root cause analysis," "error analysis." We also examined reference lists of relevant studies to identify additional articles. RESULTS: Our electronic search produced 10,624 records with 30 potentially eligible articles. However, we identified only 6 relevant published articles. We used these as the basis for a proposed framework that is predicated on the thoughtful disclosure of adverse events and has 3 main levels (i.e., patient, clinician, and institutional level). For each level, we identify barriers to patient participation and potential strategies to overcome them. CONCLUSIONS: The proposed framework can be used as a starting point to promote patient involvement in error investigations. Involving patients in patient safety investigations could increase patient centeredness, patient autonomy, and transparency and make analyses more effective by adding unique and potentially actionable information.

Helicobacter pylori: Perturbation and restoration of gut microbiome.

Alternate remedies with natural products provides unlimited opportunities for new drug development. These can be either as pure compounds or as standardized set of compounds. The phytochemicals and secondary metabolites are in great demand for screening bioactive compounds and plays an important role towards drug development. Natural products have many advantages over to synthetic chemical drugs. Helicobacter pylori (H. pylori) a Gram-negative bacteria has been classified as Class I carcinogen by World Health Organization in 1994. Current treatment regimens for H. pylori is 'triple therapy' administrated for two weeks which includes a combination of two antibiotics like Amoxicillin and Clarithromycin and a proton pump inhibitor (PPI) like Lansoprazole, and for 'quadruple therapy' in addition to antibiotics and a PPI, Bismuth is used. Antibiotic resistance can be named as the main factor for failure of treatment of H. pylori infection. The need of the hour is to develop a herbal remedy that could combat the growth of H. pylori. Probiotics can also be used as 'feasible' tool for H. pylori infection management. Present review is an attempt to briefly discuss about the pathogenicity, genetic predisposition, perturbation of gut microbiota due to antibiotic treatment and restoration of healthy gut microbiota with phytochemicals and probiotics.

Low thigh muscle mass is associated with coronary artery stenosis among HIV-infected and HIV-uninfected men: The Multicenter AIDS Cohort Study (MACS).

BACKGROUND: HIV-infected individuals are at increased risk for both sarcopenia and cardiovascular disease. Whether an association between low muscle mass and subclinical coronary artery disease (CAD) exists, and if it is modified by HIV serostatus, are unknown. METHODS: We performed cross-sectional analysis of 513 male MACS participants (72% HIV-infected) who underwent mid-thigh computed tomography (CT) and non-contrast cardiac CT for coronary artery calcium (CAC) during 2010-2013. Of these, 379 also underwent coronary CT angiography for non-calcified coronary plaque (NCP) and obstructive coronary stenosis ≥50%. Multivariable-adjusted Poisson regression was used to estimate prevalence risk ratios of associations between low muscle mass (<20th percentile of the HIV-uninfected individuals in the sample) and CAC, NCP and obstructive stenosis. RESULTS: The prevalence of low thigh muscle mass was similar by HIV serostatus (20%). There was no association of low muscle mass with CAC or NCP. However, low thigh muscle mass was significantly associated with a 2.5-fold higher prevalence of obstructive coronary stenosis, after adjustment for demographics and traditional CAD risk factors [PR 2.46 (95% CI 1.51, 4.01)]. This association remained significant after adjustment for adiposity, inflammation, and physical activity. There was no significant interaction by HIV serostatus (p-interaction = 0.90). CONCLUSIONS: In this exploratory analysis, low thigh muscle mass was significantly associated with subclinical obstructive coronary stenosis. Additional studies involving larger sample sizes and prospective analyses are needed to confirm the potential utility of measuring mid-thigh muscle mass for identifying individuals at increased risk for obstructive CAD who might benefit from more aggressive risk factor management.

Education Research: Difficult conversations in neurology: Lessons learned from medical students.

OBJECTIVE: To characterize features of medical student exposure to difficult conversations during a neurology core clerkship. METHODS: This was a cross-sectional concurrent nested mixed methods study, and all students rotating through a required neurology clerkship between 2014 and 2015 were enrolled. Data collection included an electronic communication tracker, baseline and end-of-clerkship surveys, and 4 facilitated focus groups. Students were asked to log exposure to patient-clinician conversations about (1) new disability, (2) poor prognosis, (3) prognostic uncertainty (4), terminal diagnosis, and (5) end-of-life care. RESULTS: A total of 159 students were enrolled and 276 conversations were tracked. Most (70%) students observed at least 1 difficult conversation, and conversations about poor prognosis, new disability, and prognostic uncertainty were most commonly logged. At clerkship end, most students (87%) desired additional bedside training in communication skills. Exposure to one of the predefined conversation types did not improve student perceived preparedness to lead difficult conversations in the future. In focus groups, students noted that the educational value of observation of a difficult conversation could be optimized with preconversation planning and postconversation debriefing. CONCLUSIONS: Difficult conversations are common in neurology, and represent a valuable opportunity to provide communication skills training on the wards. Future curricula should consider ways to leverage these existing opportunities to enhance communication skills training.

Quantitative determination of multi markers in five varieties of Withania somnifera using ultra-high performance liquid chromatography with hybrid triple quadrupole linear ion trap mass spectrometer combined with multivariate analysis: Application to pharmaceutical dosage forms.

An ultra-high performance liquid chromatography electrospray ionization tandem mass spectrometry method has been developed and validated for simultaneous quantification of six major bioactive compounds in five varieties of Withania somnifera in various plant parts (leaf, stem and root). The analysis was accomplished on Waters ACQUITY UPLC BEH C18 column with linear gradient elution of water/formic acid (0.1%) and acetonitrile at a flow rate of 0.3mLmin(-1). The proposed method was validated with acceptable linearity (r(2), 0.9989-0.9998), precision (RSD, 0.16-2.01%), stability (RSD, 1.04-1.62%) and recovery (RSD ≤2.45%), under optimum conditions. The method was also successfully applied for the simultaneous determination of six marker compounds in twenty-six marketed formulations. Hierarchical cluster analysis and principal component analysis were applied to discriminate these twenty-six batches based on characteristics of the bioactive compounds. The results indicated that this method is advance, rapid, sensitive and suitable to reveal the quality of Withania somnifera and also capable of performing quality evaluation of polyherbal formulations having similar markers/raw herbs.

Lack of genotoxic potential of pesticides, spinosad, imidacloprid and neem oil in mice (Mus musculus).

Pesticides, spinosad, imidacloprid and neem oil are widely used both in residential and agricultural environments because of its broad spectrum insecticidal activity and effectiveness. The present study was undertaken to estimate genotoxicity of formulations of some pesticides in mice. Three pesticides of diverse group studied were spinosad (45% w/v), imidacloprid (17.8%, w/v) and neem oil. Animals were exposed 37, 4.5 and 50 mg kg⁻¹ b.wt. for spinosad, imidacloprid and neem oil, respectively, through oral gavage for 5 consecutive days. A vehicle control group and one positive control (cyclophosphamide; 20 mg kg⁻¹ b. wt.) were also selected. The results showed that cyclophosphamide produced 1.12% micronuclei in mice, as against 0.18 in vehicle control, 0.30 in spinosad, 0.28 in imidacloprid and 0.22% in neem oil, respectively. The gross percentage of chromosomal aberration in mice were 28.5% in cyclophosphamide against 6.5% in vehicle control, 8.0% in spinosad, 9.5% in imidacloprid and 7.0% in neem oil, respectively. The overall findings of the present study revealed that all the three pesticide formulations, imidacloprid, spinosad and neem oil at tested dose did not show any genotoxic effect in mice.

Formulation and evaluation of mucoadhesive buccal patch of acyclovir utilizing inclusion phenomenon

Mucoadhesive buccal patch releasing drug in the oral cavity at a predetermined rate may present distinct advantages over traditional dosage forms, such as tablets, gels and solutions. A buccal patch for systemic administration of acyclovir in the oral cavity was developed using polymers hydroxy propyl methyl cellulose (K4M), hydroxy propyl methyl cellulose (K15M), sodium carboxy methyl cellulose and poly vinyl pyrolidone (K30), plasticizer poly ethylene glycol (400) and a backing membrane of Eudragit (RL100). The films were evaluated in terms of swelling, residence time, mucoadhesion, release, and organoleptic properties. The optimized films showed lower release as compared to controlled drug delivery systems. Hence, an inclusion complex of acyclovir was prepared with hydrophilic polymer hydroxylpropyl beta-cyclodextrin in the molar ratio of 1:1. The inclusion complex was characterized by optical microscopy, FAB mass spectroscopy, and FTIR spectroscopy. Patches formulated with the acyclovir inclusion complex were evaluated along the same lines as those containing acyclovir alone. The in vitro release data revealed a substantial increase from 64.35 percent to 88.15 percent in the case of PS I and PS II batches, respectively, confirming the successful use of inclusion complexes for the formulation of buccal patch of acyclovir.

Mucoadesivos bucais liberadores de fármacos para a cavidade oral com taxa de liberação pré-determinada podem apresentar distintas vantagens em relação às formas farmacêuticas convencionais como comprimidos, géis e soluções. Neste trabalho, um adesivo bucal para administração sistêmica de aciclovir através da cavidade oral foi desenvolvido empregando-se os polímeros hidroxipropilmetil celulose (K4M), hidroxipropilmetil celulose (K15M), carboximetil celulose sódica e polivinil pirrolidona (K30), polietilenoglicol plastificado (400) e uma membrana suporte de Eudragit (RL100). Os filmes obtidos foram avaliados em termos de intumescimento, tempo de residência, mucoadesão, liberação e propriedades organolépticas. Os filmes otimizados apresentaram liberação mais lenta em comparação a outros sistemas de liberação controlada. Desta maneira, um complexo de inclusão de aciclovir foi preparado com o polímero hidrofílico hidroxipropil beta-ciclodextrina em proporções molares 1:1. O complexo de inclusão foi caracterizado por microscopia ótica, espectrometria de massas FAB e espectroscopia FTIR. Os adesivos formulados com o complexo de inclusão de aciclovir foram avaliados em paralelo com adesivos contendo aciclovir isolado. Os dados de liberação in vitro revelaram um aumento substancial, de 64,34 por cento para 88,15 por cento, nos lotes PS I e PS II, respectivamente, confirmando o sucesso do uso de complexos de inclusão para a formulação de adesivos bucais de aciclovir.