Atorvastatin modulates drug transporters and ameliorates nicotine-induced testicular toxicity.

We studied the changes in mRNA expressions of influx and efflux transporters, blood-testis-barrier proteins (BTB) and key apoptotic genes in the testis of rats coadministered with nicotine and atorvastatin. Rats were divided into four groups: (i) control, (ii) atorvastatin (10 mg/kg b.wt), (iii) nicotine (0.6 mg/kg b.wt) and (iv) atorvastatin (10 mg/kg b.wt) + nicotine (0.6 mg/kg b.wt). Atorvastatin was given by oral intubation and nicotine by intraperitoneal injection. After 60 days of treatment, expressions of key apoptotic genes involved in both intrinsic and extrinsic pathways; solute carrier influx transporters SLCOB1, SLC22A1 and efflux transporter ABCB1 associated with transport of atorvastatin and nicotine, and proteins of BTB were assayed. Nicotine administration activated apoptosis and downregulated SLCOB1, which transport atorvastatin. Atorvastatin administration suppressed apoptotic pathway and downregulated SLC22A1, transporter of nicotine. Coadministration of atorvastatin with nicotine downregulated expressions of apoptotic genes. The combined administration of atorvastatin and nicotine reduced the influx of both atorvastatin and nicotine and enhanced the efflux of these drugs thereby altering the microenvironment of testis and improving testicular function. We conclude that atorvastatin-mediated alterations of BTB and drug transporters might have played a significant role in ameliorating nicotine-induced testicular toxicity.

Impact of COVID-19 on Guillain-Barre Syndrome in India: A Multicenter Ambispective Cohort Study.

Introduction/Aims: Studies conducted during the coronavirus disease 2019 (COVID-19) pandemic have reported varied data regarding the incidence of Guillain-Barre syndrome (GBS). The present study investigated demographic and clinical features, management, and outcomes of patients with GBS during a specified period of the COVID-19 pandemic, and compared these features to those of GBS in the previous year. Methods: A multicenter, ambispective cohort study including 26 centers across India was conducted. Data from a pre-COVID-19 period (March 1 to August 31, 2019) were collected retrospectively and collected ambispectively for a specified COVID-19 period (March 1 to August 31, 2020). The study was registered with the Clinical Trial Registry India (CTRI/2020/11/029143). Results: Data from 555 patients were included for analysis: pre-COVID-19 (n = 334) and COVID-19 (n = 221). Males were more commonly affected during both periods (male:female, 2:1). Gastroenteritis was the most frequent antecedent event in 2019 (17.4%), whereas fever was the most common event in 2020 (10.7%). Paraparesis (21.3% versus [vs.] 9.3%, P = 0.001) and sensory involvement (51.1% vs. 41.3%; P = 0.023) were more common during COVID-19 in 2020, whereas back pain (26.3% vs. 18.4%; P = 0.032) and bowel symptoms (20.7% vs. 13.7%; P = 0.024) were more frequent in the pre-COVID period. There was no difference in clinical outcomes between the two groups in terms of GBS disability score at discharge and 3 months after discharge. Independent predictors of disability in the pre-COVID period included areflexia/hyporeflexia, the requirementfor intubation, and time to bulbar weakness; in the COVID-19 period, independent predictors included time from onset to admission, intubation, and intubation requirement. The mortality rate was 2.3% during the entire study period (13/555 cases). Discussion: Results of this study revealed an overall reduction in the frequency of GBS during the pandemic. The lockdown likely reduced the risk for antecedent infections due to social distancing and improved hygiene, which may have resulted in the reduction of the frequency of GBS.

Lurasidone-Induced Manic Switch in an Adolescent with Bipolar I Disorder: a Case Report.

Lurasidone is used for treatment of bipolar depression in adults and adolescents. Lurasidone-associated manic switch has been reported in adults but not yet in adolescents. We report a case of lurasidone-induced manic switch in a male adolescent treated for bipolar I depression. Five days after adding lurasidone to his regimen (sodium valproate and olanzapine), our patient became manic with psychotic features. After discontinuation of lurasidone, he was stabilised with electroconvulsive therapy, and the medication was switched to a lithium-quetiapine combination. This case highlights the potential risk of lurasidone-induced manic switch in adolescents with bipolar depression.

Relationship between leadership support and operational excellence in health care sector: A study of Indian health care managers.

BACKGROUND AND OBJECTIVE: Leadership communicates purpose and innovative ways to thrive for performance. Leadership support influences and impacts operational excellence in the health sector as a patient-centered operation, with effective management, excellence framework, challenges and constraints, teamwork and value stream mapping. It is hypothesized that: (1) perceived leadership support will positively correlate with perceived operational excellence (Patient-centered Operations, Effective Resource Management, Excellence framework, Eliminating Challenges or Constraints, Team Work, Value Stream Mapping) and (2) the correlation would be highest with Patient-centered Operations. The aim of this study was to examine the relationship between leadership support and operational excellence in the health care sector among a selected group of healthcare managers. MATERIALS AND METHOD: A correlation study between leadership support and operational excellence was designed for a group of health care managers (n=80) from eight hospitals in Kerala, South India. The selection of executives was from NABH accredited hospitals from districts with a minimum of four NABH accredited hospital. A survey was sent to a selected study sample. The respondents were cooperative and provided responses on perceived leadership support for operational excellence. RESULTS: Factors of leadership support correlated to operational excellence. CONCLUSION: In the health care sector, leadership support for patient-centered operations helps achieve operational excellence.

Computational model of extracellular glutamate in the nucleus accumbens incorporates neuroadaptations by chronic cocaine.

Chronic cocaine administration causes instability in extracellular glutamate in the nucleus accumbens that is thought to contribute to the vulnerability to relapse. A computational framework was developed to model glutamate in the extracellular space, including synaptic and nonsynaptic glutamate release, glutamate elimination by glutamate transporters and diffusion, and negative feedback on synaptic release via metabotropic glutamate receptors (mGluR2/3). This framework was used to optimize the geometry of the glial sheath surrounding excitatory synapses, and by inserting physiological values, accounted for known stable extracellular, extrasynaptic concentrations of glutamate measured by microdialysis and glutamatergic tone on mGluR2/3. By using experimental values for cocaine-induced reductions in cystine-glutamate exchange and mGluR2/3 signaling, and by predicting the down-regulation of glutamate transporters, the computational model successfully represented the experimentally observed increase in glutamate that is seen in rats during cocaine-seeking. This model provides a mathematical framework for describing how pharmacological or pathological conditions influence glutamate transmission measured by microdialysis.

Stereotactic body radiation therapy for early-stage primary lung cancer, is an active breath coordinator necessary? An audit from a tertiary cancer care center.

CONTEXT: The hypofractionated stereotactic body radiation therapy (SBRT) has emerged as a safe and effective treatment modality for early-stage nonsmall cell lung carcinoma. AIMS: An audit SBRT in primary lung cancer treated in our center with and without an active breath coordinator (ABC) was undertaken to evaluate its impact on target volumes and clinical outcomes. SETTINGS AND DESIGN: This was an observational study. MATERIALS AND METHODS: Nine patients with lung carcinoma were treated from January 2014 to August 2016. Five patients were simulated using ABC and four patients with free breathing. Volumetric modulated arc therapy plans were generated using Monaco treatment planning software. Three patients were treated with a dose of 54 Gy in three fractions and six patients with a dose of 48 Gy in four fractions. STATISTICAL ANALYSIS USED: The statistical analysis was performed using Kaplan-Meier survival. RESULTS: The mean planning target volumes (PTV) in ABC and free breathing groups were 42.19cc and 60.17cc, respectively. The mean volume of lung receiving 20, 10, and 5 Gy (V20, V10and V5) in ABC group were 5.37cc, 10.49cc, and 18.45cc whereas in free breathing 6.63cc, 12.74cc, and 20.64cc, respectively. At a median follow-up of 18 months, there were three local recurrences. No significant toxicity occurred in our series. CONCLUSION: Our initial results show that SBRT is well tolerated with good local control. Although the PTV volume and irradiated normal lung volume was higher in this group compared to ABC group, this did not translate to any added clinical toxicity.

Mechanisms underlying the formation of the amygdalar fear memory trace: A computational perspective.

Recent experimental and modeling studies on the lateral amygdala (LA) have implicated intrinsic excitability and competitive synaptic interactions among principal neurons (PNs) in the formation of auditory fear memories. The present modeling studies, conducted over an expanded range of intrinsic excitability in the network, revealed that only excitable PNs that received tone inputs participate in the competition. Strikingly, the number of model PNs integrated into the fear memory trace remained constant despite the much larger range considered, and model runs highlighted several conditioning-induced tone responsive characteristics of the various PN populations. Furthermore, these studies showed that although excitation was important, disynaptic inhibition among PNs is the dominant mechanism that keeps the number of plastic PNs stable despite large variations in the network's excitability. Finally, we found that the overall level of inhibition in the model network determines the number of projection cells integrated into the fear memory trace.

Virgin coconut oil supplementation ameliorates cyclophosphamide-induced systemic toxicity in mice.

Virgin coconut oil (VCO) is an unrefined kernal oil, prepared from Cocos nucifera L., having substantial nutritional and medicinal value. Experimental studies have suggested its antioxidant, anti-inflammatory, immunostimulatory and hypolipidemic effects. The present study assesses its effect on formalin-induced chronic inflammation and cyclophosphamide (CTX)-induced systemic toxicity in murine models. Oral administration of VCO effectively reduced formalin-induced paw oedema in mice with more or less similar efficacy as that of diclofenac. The CTX-induced hike in blood urea, creatinine, thiobarbituric acid reactive substances (TBARS) and liver marker enzymes in mice was marginally decreased by VCO (8 g/kg body weight) ingestion orally. The liver and kidney catalase, superoxide dismutase and glutathione peroxidase activities, together with cellular glutathione and TBARS levels, were found to be improved in these animals. Overall the study reveals the protective efficacy of VCO against secondary toxicity induced by CTX possibly through its antioxidant and anti-inflammatory properties.

Pulmonary hypertension and systemic lupus erythematosus.

A combination of systemic lupus erythematosus (SLE) and fatal pulmonary hypertension occurred in a patient who, to our knowledge, had the highest pulmonary artery pressure (120/65 mm Hg) reported without any clinical or autopsy findings of pulmonary interstitial disease or vasculitis. The gradual development of pulmonary hypertension over years is a rare complication in patients with SLE.

Stress reactions of children and adolescents in war and siege conditions.

OBJECTIVE: This was a study of posttraumatic stress symptoms in children and adolescents during siege conditions in Sarajevo. METHOD: Seven hundred ninety-one students aged 7-15 years were surveyed to assess symptoms of posttraumatic stress and level of deprivation. RESULTS: Girls reported more stress than boys. Loss of family members and deprivation of basic needs were associated with more symptoms. CONCLUSIONS: Personal experiences of siege are related to increased stress.

Relationship of personality, environmental, and DICA variables to adolescent hopelessness: a neural network sensitivity approach.

OBJECTIVE: This study identified critical factors from a set of psychiatric diagnoses, personality traits, and family and social support variables that relate to hopelessness in adolescents. METHOD: One hundred fifty adolescents were selected in a systematic sample from 1,700 high school students; they completed the Millon Adolescent Personality Inventory, the Parental Bonding Questionnaire, the Social Support Questionnaire, the Hopelessness Scale for Children and were interviewed by trained clinicians on the Diagnostic Interview for Children and Adolescents. Selected variables were chosen for a back-propagation neural network model and for subsequent sensitivity and statistical analysis. RESULTS: Sensitive adolescents and adolescents with less impulse control scored high on hopelessness. Forceful adolescents were less hopeless. CONCLUSIONS: Using the neural network models, the authors suggest that assertive training as well as group activities that increase cooperativeness may ameliorate hopelessness.

Parametric studies of human thermal mechanisms and measurements.

A systematic methodology is proposed for mathematically quantifying the effects of measurement inaccuracies due to instrument uncertainty in a human calorimetry project. Human thermal mechanisms are poorly understood at the systems level and this study investigates the importance of these mechanisms quantitatively. The proposed methodology uses sensitivity derivatives combined with sensor accuracies to quantify the effect of each heat transfer mechanism contributing to the errors in the system equations. The method is applicable to any differentiable model to be validated by experimentation. To illustrate the methodology, two example cases, a reclining nude resting subject and a reclining clothed working subject, are analyzed. The calculated expected errors clearly suggest specific modifications.

Specific modifications of phosphatidylinositol and nonesterified fatty acid fractions in cultured porcine cardiomyocytes supplemented with n-3 polyunsaturated fatty acids.

Mechanisms for the antiarrhythmic effect of n-3 polyunsaturated fatty acids (PUFA) are currently being investigated using isolated cardiac myocytes. It is still not known whether the incorporation of n-3 PUFA into membrane phospholipids is a prerequisite for its protective action or if n-3 PUFA exert antiarrhythmic effects in their nonesterified form as demonstrated by recent studies. Adult porcine cardiomyocytes were grown in media supplemented with arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). After 24 h, analysis of total lipids showed that the myocytes were enriched with the respective fatty acids compared to control cells. Large proportions of all three fatty acids supplemented (69% AA, 72% DHA, and 66% EPA) remained unesterified. Fatty acid analyses of total phospholipids (PL) revealed that the incorporation of EPA and DHA, though small, was significantly different (P<0.05) from that of the control cells. The PL fraction was further separated into phosphatidylinositol (PI), phosphatidylethanolamine, phosphatidylcholine, and phosphatidylserine to study the pattern of incorporation of the fatty acids in these fractions. It became apparent that EPA and DHA were selectively incorporated into the PI fraction. This study demonstrates that in adult porcine cardiomyocytes, the n-3 PUFA supplementation selectively modulates two important lipid fractions, nonesterified fatty acid and PI, which were implicated in the mechanisms of prevention of cardiac arrhythmias.

Indirect control of a class of nonlinear dynamic systems.

Identification and control designs are considered using neural networks for a class of nonlinear partially known dynamic systems. Real-time implementation of two designs, a neural identifier and a proposed neural controller, using an experimental system, comparisons with two other neural networks as well as conventional schemes, and an implementation architecture are reported. The proposed control design facilitates incorporation of available knowledge about the structure of the system. The study also illustrates the inherent capability of neural networks to handle nonlinearities and perform control effectively for a real world system, based on minimal system information.

Beneficial effects of garlic (Allium sativum Linn) on rats fed with diets containing cholesterol and either of the oil seeds, coconuts or groundnuts.

Feeding of 2% cholesterol diet increased lipid parameters in serum and tissues of rats during a period of one month. In addition to the above, lipid peroxidation also increased and activities of certain enzymes were significantly altered in the tissues. Similar changes were also observed to a greater extent with diets containing 40% by weight of coconut kernel or groundnut with and without 2% cholesterol. The enzymes studied were HMGCoA reductase, AST, ALT and ALP in tissues and serum as the case may be. In general the atherogenic effects were observed more with groundnut containing diets than those with coconut. Even though the oil from the former is mostly unsaturated and that from the latter is mostly saturated, these analytical criteria do not relate to their atherogenic effects. When 5% garlic was incorporated with any of the high fat diets, the lipid parameters, their peroxidation and alterations in enzyme activities were significantly decreased. These results show that garlic contains some principles that counteract the atherogenicity of the above oil seeds.

A neural network approach to identifying adolescent adjustment.

This study examined the relationship between the quality of adjustment in adolescents and a set of psychiatric diagnoses, personality traits, parental bonding, and social support variables. One hundred fifty adolescents were administered the Millon Adolescent Personality Inventory, the Parental Bonding Questionnaire, the Social Support Questionnaire, and the Diagnostic Interview for Children and Adolescents. A neural network approach was then utilized, and it was found that several of the variables (e.g., Major Depressive Disorder, Conduct Disorder, and Societal Conformity) had a significant role in classifying adolescents into three groups: maladjusted, nominally adjusted, and well-adjusted.

Comparison of some modeling and control issues for a flexible two link manipulator.

The nonlinear dynamics of a flexible two link manipulator presents a challenging modeling and control problem with its lumped actuator dynamics coupled with distributed link dynamics. Issues related to modeling uncertainty and control robustness as well as a good understanding of the experimental issues are essential for advanced modeling and control for such systems. This paper reports some of the advanced modeling, control, and experimental issues for a flexible two link manipulator, including some novel approaches developed by the authors.

Role of sensory input distribution and intrinsic connectivity in lateral amygdala during auditory fear conditioning: a computational study.

We propose a novel reduced-order neuronal network modeling framework that includes an enhanced firing rate model and a corresponding synaptic calcium-based synaptic learning rule. Specifically, we propose enhancements to the Wilson-Cowan firing-rate neuron model that permit full spike-frequency adaptation seen in biological lateral amygdala (LA) neurons, while being sufficiently general to accommodate other spike-frequency patterns. We also report a technique to incorporate calcium-dependent plasticity in the synapses of the network using a regression scheme to link firing rate to postsynaptic calcium. Together, the single-cell model and the synaptic learning scheme constitute a general framework to develop computationally efficient neuronal networks that employ biologically realistic synaptic learning. The reduced-order modeling framework was validated using a previously reported biophysical conductance-based neuronal network model of a rodent LA that modeled features of Pavlovian conditioning and extinction of auditory fear (Li et al., 2009). The framework was then used to develop a larger LA network model to investigate the roles of tone and shock distributions and of intrinsic connectivity in auditory fear learning. The model suggested combinations of tone and shock densities that would provide experimental estimates of tone responsive and conditioned cell proportions. Furthermore, it provided several insights including how intrinsic connectivity might help distribute sensory inputs to produce conditioned responses in cells that do not directly receive both tone and shock inputs, and how a balance between potentiation of excitation and inhibition prevents stimulus generalization during fear learning.

Exchange bias effect in partially oxidized amorphous Fe-Ni-B based metallic glass nanostructures.

The magnetic properties of amorphous Fe-Ni-B based metallic glass nanostructures were investigated. The nanostructures underwent a spin-glass transition at temperatures below 100 K and revealed an irreversible temperature following the linear de Almeida-Thouless dependence. When the nanostructures were cooled below 25 K in a magnetic field, they exhibited an exchange bias effect with enhanced coercivity. The observed onset of exchange bias is associated with the coexistence of the spin-glass phase along with the appearance of another spin-glass phase formed by oxidation of the structurally disordered surface layer, displaying a distinct training effect and cooling field dependence. The latter showed a maximum in exchange bias field and coercivity, which is probably due to competing multiple equivalent spin configurations at the boundary between the two spin-glass phases.