Pan-striatal reduction in the expression of the astrocytic dopamine transporter precedes the development of dorsolateral striatum dopamine-dependent incentive heroin seeking habits.

The emergence of compulsive drug-seeking habits, a hallmark feature of substance use disorder, has been shown to be predicated on the engagement of dorsolateral striatal control over behaviour. This process involves the dopamine-dependent functional coupling of the anterior dorsolateral striatum (aDLS) with the nucleus accumbens core, but the mechanisms by which this coupling occurs have not been fully elucidated. The striatum is tiled by a syncytium of astrocytes that express the dopamine transporter (DAT), the level of which is altered in individuals with heroin use disorder. Astrocytes are therefore uniquely placed functionally to bridge dopamine-dependent mechanisms across the striatum. Here we tested the hypothesis that exposure to heroin influences the expression of DAT in striatal astrocytes across the striatum before the development of DLS-dependent incentive heroin seeking habits. Using Western-blot, qPCR, and RNAscope™, we measured DAT protein and mRNA levels in whole tissue, culture and in situ astrocytes from striatal territories of rats with a well-established cue-controlled heroin seeking habit and rats trained to respond for heroin or food under continuous reinforcement. Incentive heroin seeking habits were associated with a reduction in DAT protein levels in the anterior aDLS that was preceded by a heroin-induced reduction in DAT mRNA and protein in astrocytes across the striatum. Striatal astrocytes were also shown to be susceptible to direct dopamine- and opioid-induced downregulation of DAT expression. These results suggest that astrocytes may critically regulate the striatal dopaminergic adaptations that lead to the development of incentive heroin seeking habits.

An observational study to monitor and report radiation-related adverse events by a clinical pharmacist to achieve a better therapeutic outcome and suggest preventive measures in a tertiary care teaching hospital.

Objectives: This study was conducted to investigate the potential role of clinical pharmacists in monitoring and developing a reporting system of radiation-related adverse events (RRAEs) in cancer patients and provided suggestive measures to prevent RRAEs to achieve a better therapeutic outcome for improving patient health-related quality of life. Methodology: This study was a prospective observational study conducted for a period of 2 years at a private academic oncology teaching care hospital. Patients on radiation therapy or chemoradiation therapy were enrolled and followed by clinical pharmacists on daily basis to identify adverse event(s) if any. Upon identification, adverse events were discussed with concerned radiation oncologists for authentication and graded as defined by the radiation therapy oncology group. Enrolled patients were also followed to ensure if they were provided adequate supportive care for RRAEs. Results: A total of 715 patients were followed during the study period. A total of 422 RRAEs were identified in patients who were on radiation therapy or chemoradiation therapy. The most common reported events were fatigue (n = 64, 15.16%), followed by mucositis (n = 55, 13.03%), diarrhea (n = 37, 8.76%), vomiting (n = 31, 7.34%), gastritis (n = 29, 6.87%), and dryness of the mouth (n = 22, 5.21%). Among the study patients who developed RRAEs, majority (n = 253, 60%) of them received a combination of chemotherapy and radiation therapy and 169 (40%) of 442 patients received radiotherapy alone. Cisplatin weekly monotherapy or cisplatin-based chemotherapy was commonly used pharmacological treatment in patients on chemoradiation therapy. Clinical pharmacists intervened to initiate adequate supportive care for nearly 20% (n = 84) patients. Conclusions: Clinical pharmacists may be contributing to monitoring and development of reporting systems for radiation-related toxicities/RRAEs in cancer patients. Teamwork of clinical pharmacists with radiation oncologists can improve the safety reporting of radiation and can ensure required medical and supportive care to manage RRAEs.

Knowledge, attitude, and practice of generic medicines among physicians at multispecialty hospital: An observational study.

Background: Nowadays, brand-name drugs are becoming an out-of-pocket expense which comprises 80% of total health-care expenditures. However, generic drugs are less expensive than brand-name drugs with the same therapeutic effect, but many doctors hold negative views of generics and resist prescribing. This study was designed to assess the knowledge, attitude, and practice of doctors toward generic medicines. Methods: This was a questionnaire-based cross-sectional study conducted in a multispecialty private hospital. The study participants were doctors who were practising in a hospital during the study period (January 2017 to July 2017). The questionnaire comprises 35 questions related to demographics, knowledge, attitude, and practice evaluation of generic medicines. Descriptive statistics was applied to represent participant characteristics and response rates. Results: A total of 86 questionnaires were distributed to the doctors and the response rate was 37%. The majority of doctors who participated in this survey perceived that generic medicine is effective, safe, and has same active component, dose, and bioequivalent as the brand medicines. Majority of the doctors (72%) believe that generic drugs were manufactured by poor techniques. However, more than three-quarter of doctors (78%) routinely prescribed generic drugs. Conclusion: Most of the doctors had an honest angle about the efficacy and safety of generic medicine. However, a high proportion of physicians believe that the generic drugs are of poorer quality. To have a better understanding of the generic drug, the doctor must be well informed about the generics products during their academic career that will significantly impact health-care budgets.

Poroid hidradenocarcinoma and atypical hidradenoma papilliferum of the vulva - Two cases.

Benign and malignant tumours may arise from eccrine and apocrine sweat glands. Hidradenocarcinoma is a rare malignant eccrine sweat gland tumour representing <0.01% of all skin cancers. There are 6 case reports in the literature of hidradenocarcinoma arising on the vulva, none of which are classified as poroid hidradenocarcinoma. Hidradenocarcinoma is thought to be an aggressive tumour with poor prognosis and high levels of local recurrence and systemic metastases. Conversely, hidradenoma papilliferum is a common benign apocrine sweat gland tumour found on the vulva. The prevalence and significance of atypical changes, however, is unknown. Distinguishing between these tumour types can be difficult. The authors present two cases, a poroid hidradenocarcinoma and an atypical hidradenoma papilliferum with necrosis and increased mitotic activity, to illustrate the diagnostic challenges associated with rare tumours of the vulva in the absence of an established histopathological classification system.

Knock-in models related to Alzheimer's disease: synaptic transmission, plaques and the role of microglia.

BACKGROUND: Microglia are active modulators of Alzheimer's disease but their role in relation to amyloid plaques and synaptic changes due to rising amyloid beta is unclear. We add novel findings concerning these relationships and investigate which of our previously reported results from transgenic mice can be validated in knock-in mice, in which overexpression and other artefacts of transgenic technology are avoided. METHODS: AppNL-F and AppNL-G-F knock-in mice expressing humanised amyloid beta with mutations in App that cause familial Alzheimer's disease were compared to wild type mice throughout life. In vitro approaches were used to understand microglial alterations at the genetic and protein levels and synaptic function and plasticity in CA1 hippocampal neurones, each in relationship to both age and stage of amyloid beta pathology. The contribution of microglia to neuronal function was further investigated by ablating microglia with CSF1R inhibitor PLX5622. RESULTS: Both App knock-in lines showed increased glutamate release probability prior to detection of plaques. Consistent with results in transgenic mice, this persisted throughout life in AppNL-F mice but was not evident in AppNL-G-F with sparse plaques. Unlike transgenic mice, loss of spontaneous excitatory activity only occurred at the latest stages, while no change could be detected in spontaneous inhibitory synaptic transmission or magnitude of long-term potentiation. Also, in contrast to transgenic mice, the microglial response in both App knock-in lines was delayed until a moderate plaque load developed. Surviving PLX5266-depleted microglia tended to be CD68-positive. Partial microglial ablation led to aged but not young wild type animals mimicking the increased glutamate release probability in App knock-ins and exacerbated the App knock-in phenotype. Complete ablation was less effective in altering synaptic function, while neither treatment altered plaque load. CONCLUSIONS: Increased glutamate release probability is similar across knock-in and transgenic mouse models of Alzheimer's disease, likely reflecting acute physiological effects of soluble amyloid beta. Microglia respond later to increased amyloid beta levels by proliferating and upregulating Cd68 and Trem2. Partial depletion of microglia suggests that, in wild type mice, alteration of surviving phagocytic microglia, rather than microglial loss, drives age-dependent effects on glutamate release that become exacerbated in Alzheimer's disease.

The anterior insular cortex in the rat exerts an inhibitory influence over the loss of control of heroin intake and subsequent propensity to relapse.

The anterior insular cortex (AIC) has been implicated in addictive behaviour, including the loss of control over drug intake, craving and the propensity to relapse. Evidence suggests that the influence of the AIC on drug-related behaviours is complex as in rats exposed to extended access to cocaine self-administration, the AIC was shown to exert a state-dependent, bidirectional influence on the development and expression of loss of control over drug intake, facilitating the latter but impairing the former. However, it is unclear whether this influence of the AIC is confined to stimulant drugs that have marked peripheral sympathomimetic and anxiogenic effects or whether it extends to other addictive drugs, such as opiates, that lack overt acute aversive peripheral effects. We investigated in outbred rats the effects of bilateral excitotoxic lesions of AIC induced both prior to or after long-term exposure to extended access heroin self-administration, on the development and maintenance of escalated heroin intake and the subsequent vulnerability to relapse following abstinence. Compared to sham surgeries, pre-exposure AIC lesions had no effect on the development of loss of control over heroin intake, but lesions made after a history of escalated heroin intake potentiated escalation and also enhanced responding at relapse. These data show that the AIC inhibits or limits the loss of control over heroin intake and propensity to relapse, in marked contrast to its influence on the loss of control over cocaine intake.

Brainstem stroke caused by left atrial cardiac papillary fibroelastoma: an increasingly recognized rare cause of stroke.

Cardiac papillary fibroelastoma is a rare but increasingly recognized cause of embolic stroke that is prevalent in the older population and requires prompt surgical management. We report an unusual case of left atrial appendage cardiac fibroelastoma in a 76-year-old gentleman who presented with left internuclear ophthalmoplegia and ataxia, with corresponding diffusion-weighted imaging on magnetic resonance imaging of the brain. This case illustrates the importance of echocardiographic imaging in the workup of cardioembolic stroke in the older adult population in the acute setting.

Bacillus sp. strain DJ-1, potent arsenic hypertolerant bacterium isolated from the industrial effluent of India.

Arsenic hypertolerant bacterial cells were isolated from the common industrial effluent treatment plant, Vapi, India. Strain DJ-1 sustaining 400 mM, As (V) out of 16 bacterial strains was identified as Bacillus sp. strain DJ-1 through 16S rRNA ribotyping. The maximum arsenic accumulation of 9.8+/-0.5 mg g(-1) (dry weight) was observed during stationary phase of growth. Intracellular compartmentalization has shown 80% of arsenic accumulation in cytoplasm. The lack of arsC gene and arsenate reductase activity indicated that Bacillus sp. strain DJ-1 may lack classical ars operon and detoxification may be mediated through some novel mechanism. The arsenite binding protein was purified by affinity chromatography and characterized as DNA protection during starvation (DPS) protein by electrospray ionization mass spectrometry. The induction of DPS showed the adaptation of bacteria in arsenic stress condition and/or in detoxification mechanism, relies on its ability to bind with arsenic. These results indicate the hypertolerance with higher intracellular accumulation of arsenic by Bacillus sp. strain DJ-1, which could be mediated by DPS protein thus signifying this organism is a potential candidate for the removal of arsenic from industrial wastewater, which needs further study.