Molecular Mechanisms of Ischemic Stroke: A Review Integrating Clinical Imaging and Therapeutic Perspectives.

Ischemic stroke poses a significant global health challenge, necessitating ongoing exploration of its pathophysiology and treatment strategies. This comprehensive review integrates various aspects of ischemic stroke research, emphasizing crucial mechanisms, therapeutic approaches, and the role of clinical imaging in disease management. It discusses the multifaceted role of Netrin-1, highlighting its potential in promoting neurovascular repair and mitigating post-stroke neurological decline. It also examines the impact of blood-brain barrier permeability on stroke outcomes and explores alternative therapeutic targets such as statins and sphingosine-1-phosphate signaling. Neurocardiology investigations underscore the contribution of cardiac factors to post-stroke mortality, emphasizing the importance of understanding the brain-heart axis for targeted interventions. Additionally, the review advocates for early reperfusion and neuroprotective agents to counter-time-dependent excitotoxicity and inflammation, aiming to preserve tissue viability. Advanced imaging techniques, including DWI, PI, and MR angiography, are discussed for their role in evaluating ischemic penumbra evolution and guiding therapeutic decisions. By integrating molecular insights with imaging modalities, this interdisciplinary approach enhances our understanding of ischemic stroke and offers promising avenues for future research and clinical interventions to improve patient outcomes.

Amelioration by Withania somnifera of neurobehavioural and immunological markers in time dependent sensitization induced post traumatic stress disorder in rats.

AIMS AND OBJECTIVES: Posttraumatic stress disorder (PTSD) is a complex neuropsychiatric pathophysiology with an unmet need for safe, effective, and sustainable therapeutic modalities. Thus, the present study evaluated the effects of Withaniasomnifera (WS, Ashwagandha) on an experimental model of PTSD in rats. MATERIALS AND METHODS: Wistar rats (200-250 g) were used and time-dependent sensitization (TDS) was used as the experimental model of PTSD. Standardized WS root extract (100 and 300 mg/kg, p.o. for 15 days) was administered with TDS and their effects were observed on neurobehavioral (anxiety) and brain cytokines, corticosterone, and oxidative stress markers. RESULTS: Exposure to TDS resulted in anxiogenic behavior in the elevated plus maze (EPM) test, i.e., reductions in open arm entries and open arm time, as compared to the control group. Pretreatment with WS extract (100 and 300 mg/kg × 14 days) attenuated the TDS-induced anxiogenic activity in a dose-related manner, and these WS effects were comparable to those seen after the comparator drug fluoxetine (10 mg/kg). Assay of brain homogenates showed that TDS also resulted in elevations in brain interleukin-6 and reduction in corticosterone levels in both the hippocampus and prefrontal cortex (PFC), which were reversed after WS pretreatments. Further, WS pretreatment also reversed the TDS-induced changes in brain oxidative stress markers, namely elevated malondialdehyde and reduced glutathione levels in both the hippocampus and PFC. CONCLUSION: These results suggest that WS could have potential as a therapeutic agent for treating PTSD by attenuating anxiogenesis, neuroimmune axis activation, and oxidative stress.

Modulation by Withania somnifera of stress-induced anxiogenesis and airway inflammation in rats.

OBJECTIVES: Stress is an aversive stimulus which disrupts the biological milieu of the organism and a variety of emotional and environmental stressors are known to influence allergic and immunological disorders like bronchial asthma but the pharmacological basis of such interactions is not clearly defined. Withania somnifera (ashwagandha) is a potent anti-stress agent used widely in Indian traditional medicine and the present experimental study evaluated the effects of W. somnifera extract (WSE) on chronic stress-induced neurobehavioral and immunological responses in an experimental model of allergic asthma in rats. METHODS: Wistar rats (200-250 g) were immunized and challenged with ovalbumin (OVA) and exposed to restraint stress (RS) and WSE treatments for 15 days. Following this, anxiety behavior was assessed by the elevated plus maze (EPM) test, and blood and BAL fluid samples were collected for measuring of inflammatory/immune markers by ELISA and biochemical assay. The data of the various treatment groups were analyzed by ANOVA and Tukey's test. RESULTS: Restraint stress (RS) induced anxiogenic behavior in the (EPM) test in OVA immunized rats, and this was attenuated by WSE (200 and 400 mg/kg), in a dose related manner. Examination of blood and BAL fluid in these RS exposed rats also resulted in elevations in IgE, TNF-α and IL-4 levels, which were also attenuated by WSE pretreatments. Further, WSE pretreatment neutralized the such RS induced changes in oxidative stress markers viz. elevated MDA and reduced GSH levels. CONCLUSIONS: The data pharmacologically validates role of stress in asthma and suggests that adaptogens like WSE could be a potential complementary agent for reducing anxiety as well as airway inflammation by a multi-targeted and holistic approach. The study also highlights the significance of integration of traditional and modern medical concepts in such chronic disorders.

Biopsychosocial Factors Associated With Pain and Pain-Related Outcomes in Adults and Children With Sickle Cell Disease: A Multivariable Analysis of the GRNDaD Multicenter Registry.

Pain is the primary symptomatic manifestation of sickle cell disease (SCD), an inherited hemoglobinopathy. The characteristics that influence pain experiences and outcomes in SCD are not fully understood. The primary objective of this study was to use multivariable modeling to examine associations of biopsychosocial variables with a disease-specific measure of pain interference known as pain impact. We conducted a secondary analysis of data from the Global Research Network for Data and Discovery national SCD registry. A total of 657 children and adults with SCD were included in the analysis. This sample was 60% female with a median age of 34 (interquartile range 26-42 years) and a chronic pain prevalence of 64%. The model accounted for 58% of the variance in pain impact. Low social (P < .001) and emotional (P < .001) functioning, increasing age (P = .004), low income (P < .001), and high acute painful episodes (P = .007) were most strongly associated with high pain impact in our multivariable model. Additionally, multivariable modeling of pain severity and physical function in 2 comparable samples of registry participants revealed that increasing age and low social functioning were also strongly associated with higher pain severity and low physical functioning. Overall, the results suggest that social and emotional functioning are more strongly associated with pain impact in individuals with SCD than previously studied biological modifiers such as SCD genotype, hemoglobin, and percentage fetal hemoglobin. Future research using longitudinally collected data is needed to confirm these findings. PERSPECTIVE: This study reveals that psychosocial (ie, social and emotional functioning) and demographic (ie, age) variables may play an important role in predicting pain and pain-related outcomes in SCD. Our findings can inform future multicenter prospective longitudinal studies aimed at identifying modifiable psychosocial predictors of adverse pain outcomes in SCD.

Assessment of the Prevalence of Infections in Pediatric Patients With Acute Lymphoblastic Leukemia.

Infections cause notable treatment-related morbidity during pediatric acute lymphoblastic leukemia/lymphoma (ALL/LLy) therapy. Infections are the most critical cause of morbidity and mortality in children undergoing treatment for acute lymphoblastic leukemia (ALL). Children with ALL, who are frequently underweight, are at increased risk of community-acquired pathogens, nosocomial multidrug-resistant pathogens, and opportunistic microorganisms. A weakened immune system from ALL itself and chemotherapy's side effects further worsen the prognosis. PubMed and Google Scholar articles were curated in a Google document with shared access. Discussion and development of the paper were achieved over Zoom meetings. This narrative review aims to analyze and summarize various pathogens responsible for infections in children receiving treatment for ALL and their treatment regimen and prophylaxis. The incidence of viral infection is higher in ALL patients, followed by bacterial and fungal infections. Prevention via prophylaxis and timely initiation of treatment is essential for positive outcomes.

Spatial differences influence nitrogen uptake, grain yield, and land-use advantage of wheat/soybean relay intercropping systems.

Cereal/legume intercropping is becoming a popular production strategy for higher crop yields and net profits with reduced inputs and environmental impact. However, the effects of different spatial arrangements on the growth, grain yield, nitrogen uptake, and land-use advantage of wheat/soybean relay intercropping are still unclear, particularly under arid irrigated conditions. Therefore, in a three-year field study from 2018 to 2021, soybean was relay intercropped with wheat in different crop configurations (0.9 m, narrow strips; 1.8 m, medium strips; and 2.7 m, wide strips), and the results of intercropping systems were compared with their sole systems. Results revealed that intercrops with wide strips outperformed the narrow and medium strips, when the objective was to obtain higher total leaf area, dry matter, nitrogen uptake, and grain yield on a given land area due to reduced interspecific competition between intercrops. Specifically, at maturity, wide strips increased the dry matter accumulation (37% and 58%) and its distribution in roots (37% and 55%), straw (40% and 61%), and grains (30% and 46%) of wheat and soybean, respectively, compared to narrow strips. This enhanced dry matter in wide strips improved the soybean's competitive ability (by 17%) but reduced the wheat's competitive ability (by 12%) compared with narrow strips. Noticeably, all intercropping systems accumulated a significantly higher amount of nitrogen than sole systems, revealing that wheat/soybean relay intercropping requires fewer anthropogenic inputs (nitrogen) and exerts less pressure on the ecosystem than sole systems. Overall, in wide strips, intercropped wheat and soybean achieved 62% and 71% of sole wheat and soybean yield, respectively, which increased the greater total system yield (by 19%), total land equivalent ratio (by 24%), and net profit (by 34%) of wide strips compared to narrow strips. Our study, therefore, implies that the growth parameters, grain yields, nutrient accumulation, and land-use advantage of intercrop species could be improved with the proper spatial arrangement in cereal/legume intercropping systems.

Efficacy and Safety of RET-Specific Kinase Inhibitors in RET-Altered Cancers: A Systematic Review.

RET proto-oncogene encodes receptor tyrosine kinase. Selpercatinib and pralsetinib are the only RET-specific tyrosine kinase inhibitors approved by FDA in RET-altered tumors. We searched PubMed, Embase, Cochrane, WOS, and Clinicaltrials.gov. Objective-response, complete-response, and partial-response were 60-89%, 0-11%, and 55-89%, respectively, with the use of RET-specific drugs. ≥Grade 3 adverse events were seen in 28-53% of the patients, with hypertension, change in ALT, QT prolongation, neutropenia, and pneumonitis among the common side effects. Hence, selpercatinib and pralsetinib were effective and well tolerated by most of the patients with RET-altered tumors.

Assessment of Bacterial Infections and Antibiotic Regimens in Intravenous Drug Users.

Bacterial infections in people who inject drugs (PWID) are a significant cause of hospitalizations and increased morbidity in this group. In this review, we evaluated bacterial trends in the most common infections and appropriate empiric antibiotic coverage. Articles from PubMed and Google Scholar were curated in a Google document with shared access. Discussion and development of the paper were achieved over Zoom meetings. The common infections in PWID were skin and soft tissue infections (SSTIs), infective endocarditis, septic arthritis, osteomyelitis, and bloodstream infections (BSIs). The presence of comorbidities increased susceptibility to bacterial infections. Staphylococcus aureus was the predominant species in all the infections and included methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA). The current standard of antibiotic use for Staphylococcus species was found to be sufficient. The gram-negative bacillus Serratia marcescens was prevalent in PWID as a causative agent of septic arthritis, osteomyelitis, and infective endocarditis. Its treatment required a combination of ß-lactam and either a fluoroquinolone or an aminoglycoside for a prolonged duration. Streptococci were commonly implicated in SSTIs and BSIs. The appropriate response was seen with ß-lactam antibiotics. In PWID, Enterococcus and Pseudomonas were implicated in infective endocarditis of native and prosthetic valves. The former being difficult to treat, a new strategy of using dual ß-lactam antibiotics was found to be supported by clinical data. Anti-pseudomonal antibiotics can be avoided in other infections seen in this group, as their prevalence was low. PWID, especially those with comorbidities, have an increased risk of acquiring infections with difficult-to-treat microbes. Therefore, empiric antibiotic treatment should be relevant to the infection, for which bacterial trends and antibiotic susceptibility must be reassessed periodically.

Comparison of Pharmacological Therapies in Relapse Rates in Patients With Relapsing-Remitting Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune neurological disorder that significantly impacts the central nervous system (CNS), which includes the brain and spinal cord. Approximately 2.8 million individuals are believed to be living with MS worldwide. The management of MS has evolved considerably over the years, offering a multitude of guidelines, diverse treatment options, and different approaches to signs and symptoms. The present systematic literature review serves as a comprehensive analysis of the current therapeutic options for MS. It provides a thorough literature review of Food and Drug Administration (FDA)-approved drugs comparing their various clinical end points while concurrently assessing their risk-benefit ratio. It also provides an extensive review of current guidelines and offers an in-depth examination of the different approaches to MS. Through this multifaceted approach, this paper facilitates easy access to available treatment options and aims to aid healthcare providers in decision-making as well as providing a foundation for future research aimed at enhancing treatment options for MS.

Struvite separation from wastewater and its use with sulfur-oxidizing bacteria improves phosphorus utilization in alkaline soil.

A major portion of phosphatic fertilizer comes from the limiting natural resource, rock phosphate, which demands a timely alternative. Struvite, a crystalline mineral of low solubility, is a worthwhile alternative. Evaluation of the local wastewater streams for their ability to precipitate struvite and its capability as phosphatic fertilizer under an alkaline soil environment was studied. Two stirring speeds, a pH range of 8.0-11.0, and a constant molar ratio were used to optimize local wastewater streams for struvite precipitation. Struvite was used in five different combinations to assess the release of phosphorus (P), including control (no P source), single superphosphate, struvite, struvite + sulfur, and rock phosphate with or without inoculation of sulfur-oxidizing bacteria (SOB). For struvite precipitation, low stirring speeds are ideal because the precipitates readily sink to the bottom once they form. Furthermore, the amalgamation of SOB with sulfur significantly improved P use efficiency under alkaline soils through increased phosphorus sources solubility and enabled optimum wheat production due to its low solubility in an alkaline soil condition. Due to its capacity to recycle phosphorus from wastewater, struvite is poised to emerge as a sustainable fertilizer and had an opportunity to capture a share of this expanding market.

Modulation of Immunological, Biochemical, and Histopathological Changes of Airway Remodeling by Withania somnifera in an Experimental Model of Allergic Asthma in Rats.

Objectives: Airway remodeling in asthma involves chronic inflammation associated with structural changes, which result in severe airflow limitation and very few therapeutic options. Thus, the present study was designed to experimentally evaluate the ameliorative effects of Withania somnifera (WS) root extract against Ovalbumin (OVA)-induced airway remodeling in a rat model of asthma. Methods: Wistar rats were immunized (i.p) and challenged (aerosol) with ovalbumin (OVA), and the effects of WS extract were investigated on the development and progress of airway remodeling by assessing immunological, biochemical, and histological changes in these rats. Results: OVA-immunization and challenge in rats resulted in significant increases in the levels of IL-13, 8-OhdG, TGF-ß, hydroxyproline, and periostin in bronchoalveolar lavage fluid (BALF) and serum/lung homogenate compared to normal control (saline only) rats, and these changes were attenuated after WS extract (200 and 400 mg/kg), as well as dexamethasone (DEX, 1 mg/kg) pretreatments. Further, WS extract attenuated histopathological changes and maintained lung integrity. In herb-drug interactions, sub-threshold doses of WS extract and DEX showed synergistic effects on all parameters studied as compared to either form of monotherapy. Conclusion: These results indicated that WS exerted significant protective effects against airway remodeling in the experimental model by modulating inflammatory and fibrotic cytokines, and could have the potential for developing a therapeutic alternative/adjunct for the treatment of airway remodeling of bronchial asthma.

Unrevealing the potential of microbes in decomposition of organic matter and release of carbon in the ecosystem.

Organic matter decomposition is a biochemical process with consequences affecting climate change and ecosystem productivity. Once decomposition begins, C is lost as CO2 or sequestered into more recalcitrant carbon difficult to further degradation. As microbial respiration releases carbon dioxide into the atmosphere, microbes act as gatekeepers in the whole process. Microbial activities were found to be the second largest CO2 emission source in the environment after human activities (industrialization), and research investigations suggest that this may have affected climate change over the past few decades. It is crucial to note that microbes are major contributors in the whole C cycle (decomposition, transformation, and stabilization). Therefore, imbalances in the C cycle might be causing changes in the entire carbon content of the ecosystem. The significance of microbes, especially soil bacteria in the terrestrial carbon cycle requires more attention. This review focuses on the factors that affect microorganism behavior during the breakdown of organic materials. The key factors affecting the microbial degradation processes are the quality of the input material, nitrogen, temperature, and moisture content. In this review, we suggest that to address global climate change and its effects on agricultural systems and vice versa, there is a need to double-up on efforts and conduct new research studies to further evaluate the potential of microbial communities to reduce their contribution to terrestrial carbon emission.

Efficacy and toxicity of surufatinib in neuroendocrine tumors: A systematic review and meta-analysis.

The incidence and prevalence of neuroendocrine neoplasms (NENs) has increased in the US in recent decades. These are well-vascularized tumors, but no antiangiogenic drug has been approved for treatment of extra-pancreatic NENs. The aim is to assess efficacy and safety of surufatinib in pancreatic and extra-pancreatic NETs. We searched PubMed, Embase, Cochrane Library, Web of Science and Clinicaltrials.gov. Clinical trials and observational studies that provided safety and efficacy data in clinical terms were included. Characteristics of the study, baseline characteristics of participants, treatment drugs, measures of efficacy, and toxicity (≥grade 3 adverse effects) were extracted. The meta-analysis was performed using the "R" programming language. Risk ratio (RR) of objective response (OR)/partial response (PR) was 8.55 (95% CI: 1.68-43.66, I2  = 0) in favor of surufatinib. The hazard ratio (HR) of progression-free survival (PFS) was 0.48 (95% CI: 0.25-0.92, I2  = 77%) in favor of surufatinib. The risk of ≥grade 3 adverse effects: diarrhea, hypertension, hypertriglyceridemia, proteinuria, and vomiting were high with the use of surufatinib. Quality of life (QoL) was similar in surufatinib and placebo groups except for the diarrhea that was high with surufatinib. Lack of randomized clinical trials in non-Chinese population. Surufatinib is well tolerated and is more effective than placebo in both pancreatic and extra-pancreatic NETs. More multicenter randomized, double-blinded clinical trials are needed to confirm these results.

Periostin: A Potential Biomarker and Therapeutic Target in Pulmonary Diseases.

Periostin is a matricellular, nonstructural protein belonging to the fasciclin family and is encoded by the POSTN gene in humans. Periostin plays an important role in maintaining a normal tissue matrix in the lungs. Despite the vital role as a structural mediator in tissue growth and repair, periostin is involved in the pathogenic mechanism during tissue remodeling and fibrosis. Periostin is a chemoattractant mediator, promotes eosinophil recruitment and adhesion on the airways sub-epithelial membrane of asthmatic patients. POSTN gene was identified as one of the highly expressed genes induced by interleukins IL-13, IL-5 and IL-4 - the key cytokines of Th2 immune responses in the bronchial tissues of asthmatic patients. This review highlights the potential role of periostin as a validated biomarker in respiratory disease progression and its candidacy to predict the response to treatments targeting Th-2 cytokines in bronchial asthma. In addition, its potential role in COPD, IPF, lung cancer and lung infection, is also speculated.   Keywords Periostin, Asthma, Pneumonia, COPD, Idiopathic pulmonary fibrosis, Biomarker.

Current Status of Monoclonal Antibodies-Based Therapies in Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis of Clinical Trials.

Background Multiple patients with prostate cancer become resistant to castration therapies, which is termed castration-resistant prostate cancer (CRPC). Purpose The purpose of this review is to assess the status of efficacy (≥50% decline in prostate-specific antigen (PSA), progression-free survival (PFS), and overall survival (OS)) and safety (grade 3-4 adverse effects) of monoclonal antibodies in CRPC. Data source We searched databases including PubMed, Embase, Cochrane, Web of Science, and ClinicalTrials.gov. Results Hazard ratios of PFS and OS were 0.77 (95% CI = 0.69-0.87, I2 = 53%) and 0.98 (95% CI = 0.86-1.11, I2 = 40%), respectively, in the favor of monoclonal antibodies as compared to placebo. Risk ratio (RR) of >50% decline in PSA was 1.99 (95% CI = 0.97-4.08, I2 = 53%) in favor of monoclonal antibodies. Pooled incidence of >50% decline in PSA levels was 15% (95% CI = 0.1-0.23, I2 = 83%), 29% (95% CI = 0.14-0.51, I2 = 93%), 63% (95% CI = 0.49-0.76, I2 = 77%), and 88% (95% CI = 0.81-0.93, I2 = 0%) in single, two, three, and four-drug regimens, respectively. Conclusion Monoclonal antibodies are well tolerated and showed better PFS as compared to placebo. However, OS was only improved with ipilimumab. Denosumab delayed skeletal-related adverse events as compared to zoledronic acid. More multicenter double-blind clinical trials may be needed to confirm these results.

Cerebral Salt-Wasting Syndrome in a Patient With Active Pulmonary Tuberculosis.

A 37-year-old female with a medical history of recently diagnosed active pulmonary tuberculosis and a new intracranial lesion presented with altered mental status, nausea, and vomiting for two days. An initial physical examination revealed that the patient was euvolemic. Laboratory findings revealed a serum sodium concentration of 105 mEq/L. During her admission, she was initially managed with lactated ringer solution in the emergency department, followed by 3% normal saline in the intensive care unit, and, eventually, on oral sodium chloride and fluid restriction on discharge. Once she was stabilized, she had episodes of dizziness, and concerns were raised about the salt-wasting syndrome.

Imaging Spectrum of Infections in the Setting of Immunotherapy and Molecular Targeted Therapy.

Advances in genomics and immunology are revolutionizing our understanding and treatment of cancer with improved treatment outcomes and patient quality of life. With the increasing use of immunotherapy and molecular targeted therapy, a variety of unusual and/or opportunistic infections are also observed. A variety of factors including use of immunosuppression for immune-mediated adverse effects play an important role for increasing the likelihood of these infections and form the basis of this case-based review. Imaging features of infections arising in patients undergoing immunotherapy regimens have not been previously highlighted. Prompt recognition of the spectrum of mycobacterial, bacterial, invasive fungal and viral pathogens can potentially lead to reduction in the high morbidity and mortality in this patient population.

SHORT-COMMUNICATION-Lesson learnt during COVID-19 pandemic in Pakistan.

The outbreak of novel coronavirus (COVID-19) is a major health crisis affecting the several nations. In particular, the high ratio of COVID-19 pandemic in Pakistan is significantly deteriorating human mental as well as physical health. The huge mental and physical loss has taught several lessons, which have been retrieved from already existing literature. The latest researches were consulted to identify the challenges and solution to combat COVID-19. First of all, the pharmacy communities in Pakistan are not sufficient to handle the burden of COVID-19 due to economic issues. However, the Government should provide interest-free loans to students and researchers for conducting scholarly work for manufacturing advance medication to combat against COVID-19. Secondly, the drugs that have been used to control the spread of COVID-19, found to be associated with the development of a neuropsychiatric complication. Therefore, there is a dire need to develop more mental health services to control the medication side effects. Thirdly as the traditional mental health services are not sufficient to provide effective and advanced mental health services, therefore, transformative changes through community psychology are mandatory to implement. Lastly, as communicable disease limit the geographical access to avail mental health services. Therefore, the e-CBT approaches must be provided to mitigate the pre and post-pandemic effects. The findings of the study would provide the direction for preparing to combat communicable diseases in the future.

Dark Tetrad Personality during COVID-19: An Overview of Psycho-somatic Therapies for Managing Mental Health Response.

The recent empirical data represented the unprecedented opportunity to understand how threatful situations affect people adaptive and mal-adaptive behaviour and diverse ways to cope with the situation. In particular, the people with existing mental health issues such as dark tetrad personality found to be higher in forming an unhealthy relationship on cyber as well as real life during COVID-19. The current paper provides an interesting but alarming picture of how people with dark tetrad personality trait formed relationships with others during COVID-19. Also, the current paper highlights the significance of psycho-somatic therapies in managing their mental health response during COVID-19.