Incidence of acute kidney injury and assessment of its associated risk factors in patients undergoing transarterial chemoembolisation for hepatocellular carcinoma.

OBJECTIVE: To determine the incidence of acute kidney injury in intermediate stage hepatocellular carcinoma patients undergoing trans-arterial chemoembolisation, and to analyse various causative factors. METHODS: The retrospective study was conducted at the Shaukat Khanum Cancer Memorial Hospital, Lahore, Pakistan,, and comprised data from January 2012 to December 2015 of adult patients of either gender with intermediate stage hepatocellular carcinoma and undergoing trans-arterial chemoembolisation with Child-Pugh score A. Outcomes were measured in the form of development of acute kidney injury, and its causative factors. Data was analysed using SPSS 20. RESULTS: Of the 133 patients, 90(67.6%) were male. The overall mean age of the sample was 59±8.4 years (range: 26-86 years). Of these, 19(14%) developed acute kidney injury. Higher alpha-fetoprotein levels and lower albumin levels were found to be the significant causative factors (p<0.05). CONCLUSIONS: The incidence of trans-arterial chemoembolisation-related acute kidney injury was 14%. Higher baseline alpha-fetoprotein and lower baseline albumin levels were found to be the significant risk factors.

Demographic variables of Vestibular schwannoma's patients presented in Radio Surgical out- patient department of Cyberknife Robotic Radiosurgery, JPMC Karachi.

OBJECTIVE: To determine the age, gender and sites of vestibular schwannoma cases using contrast-enhanced magnetic resonance imaging. METHOD: The retrospective descriptive study was conducted at the Department of Cyberknife Robotic Radiosurgery, Jinnah Postgraduate Medical Centre, Karachi, and comprised data of patients with vestibular schwannomas from January 2016 to September 2018. Some of them were histologically proven and rest were radiologically proven. Cases were reviewed on contrast-enhanced magnetic resonance imaging of the brain. Statistical Package for the Social Sciences version 20 (SPSS) was applied. RESULTS: Of the 500 cases of vestibular schwannomas identified with 515 tumours, 300(60%) were males and 200(40%) were female. The overall mean age was 42.7±14.4 years (range: 17-85 years). Out of 515 tumours, the commonest site was the right cerebellopontine angle in 340(66%) cases. There were 15(3%) cases of radiologically-proven neurofibromatosis type 2. Overall, 490(98%) patients had main clinical complaint of progressive unilateral hearing loss, 5(1%) had vertigo and 5(1%) had facial palsy. CONCLUSIONS: Vestibular schwannomas were found to be more common among adults, with male preponderance and right cerebellopontine angle being the common site.

Comparison of Dialysis Unit and Home Blood Pressures: An Observational Cohort Study.

RATIONALE & OBJECTIVE: Prior studies of patients receiving maintenance hemodialysis have shown that, on average, blood pressure (BP) measured predialysis is higher than BP measured at home. We hypothesized that a subset of hemodialysis patients has BP that is higher when measured at home than when measured predialysis and this subgroup of patients has a higher prevalence of left ventricular hypertrophy. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 97 hypertensive hemodialysis patients enrolled in the Blood Pressure in Dialysis Study (BID), a randomized trial of comparing target predialysis BP ≤140/90 to 155-165/90 mm Hg. EXPOSURE: Differences between predialysis and next-day home systolic BP measured ≥6 times over 1 year. OUTCOME: Left ventricular mass index (LVMI) by cardiac magnetic resonance imaging. ANALYTICAL APPROACH: A hierarchical clustering analysis divided patients into 3 clusters based on the average and variability of differences in systolic predialysis and home BP. Clusters were compared with respect to clinical factors and LVMI. RESULTS: Mean differences between predialysis and home systolic BP were 19.1 (95% CI, 17.0 to 21.1) mm Hg for cluster 1 ("home lower"), 3.7 (95% CI, 1.6 to 5.8) mm Hg for cluster 2 ("home and predialysis similar"), and -9.7 (95% CI, -12.0 to -7.4) mm Hg for cluster 3 ("home higher"). Systolic BP declined during dialysis in clusters 1 and 2 but increased in cluster 3. Interdialytic weight gains did not differ. After adjusting for sex and treatment arm, LVMI was higher in cluster 3 than in clusters 1 and 2: differences in means of 10.6 ± 4.96 (SE) g/m2 (P = 0.04) and 12.0 ± 5.08 g/m2 (P = 0.02), respectively. LIMITATIONS: Limited statistical power. CONCLUSIONS: Nearly one-third of participants had home BPs higher than predialysis BPs. These patients had LVMI higher than those with similar or lower BPs at home, indicating that their BP may have been undertreated.

High performance implementation of the hierarchical likelihood for generalized linear mixed models: an application to estimate the potassium reference range in massive electronic health records datasets.

BACKGROUND: Converting electronic health record (EHR) entries to useful clinical inferences requires one to address the poor scalability of existing implementations of Generalized Linear Mixed Models (GLMM) for repeated measures. The major computational bottleneck concerns the numerical evaluation of multivariable integrals, which even for the simplest EHR analyses may involve millions of dimensions (one for each patient). The hierarchical likelihood (h-lik) approach to GLMMs is a methodologically rigorous framework for the estimation of GLMMs that is based on the Laplace Approximation (LA), which replaces integration with numerical optimization, and thus scales very well with dimensionality. METHODS: We present a high-performance, direct implementation of the h-lik for GLMMs in the R package TMB. Using this approach, we examined the relation of repeated serum potassium measurements and survival in the Cerner Real World Data (CRWD) EHR database. Analyzing this data requires the evaluation of an integral in over 3 million dimensions, putting this problem beyond the reach of conventional approaches. We also assessed the scalability and accuracy of LA in smaller samples of 1 and 10% size of the full dataset that were analyzed via the a) original, interconnected Generalized Linear Models (iGLM), approach to h-lik, b) Adaptive Gaussian Hermite (AGH) and c) the gold standard for multivariate integration Markov Chain Monte Carlo (MCMC). RESULTS: Random effects estimates generated by the LA were within 10% of the values obtained by the iGLMs, AGH and MCMC techniques. The H-lik approach was 4-30 times faster than AGH and nearly 800 times faster than MCMC. The major clinical inferences in this problem are the establishment of the non-linear relationship between the potassium level and the risk of mortality, as well as estimates of the individual and health care facility sources of variations for mortality risk in CRWD. CONCLUSIONS: We found that the direct implementation of the h-lik offers a computationally efficient, numerically accurate approach for the analysis of extremely large, real world repeated measures data via the h-lik approach to GLMMs. The clinical inference from our analysis may guide choices of treatment thresholds for treating potassium disorders in the clinic.

Glycine, the smallest amino acid, confers neuroprotection against D-galactose-induced neurodegeneration and memory impairment by regulating c-Jun N-terminal kinase in the mouse brain.

BACKGROUND: Glycine is the smallest nonessential amino acid and has previously unrecognized neurotherapeutic effects. In this study, we examined the mechanism underlying the neuroprotective effect of glycine (Gly) against neuroapoptosis, neuroinflammation, synaptic dysfunction, and memory impairment resulting from D-galactose-induced elevation of reactive oxygen species (ROS) during the onset of neurodegeneration in the brains of C57BL/6N mice. METHODS: After in vivo administration of D-galactose (D-gal; 100 mg/kg/day; intraperitoneally (i/p); for 60 days) alone or in combination with glycine (1 g/kg/day in saline solution; subcutaneously; for 60 days), all of the mice were sacrificed for further biochemical (ROS/lipid peroxidation (LPO) assay, Western blotting, and immunohistochemistry) after behavioral analyses. An in vitro study, in which mouse hippocampal neuronal HT22 cells were treated with or without a JNK-specific inhibitor (SP600125), and molecular docking analysis were used to confirm the underlying molecular mechanism and explore the related signaling pathway prior to molecular and histological analyses. RESULTS: Our findings indicated that glycine (an amino acid) inhibited D-gal-induced oxidative stress and significantly upregulated the expression and immunoreactivity of antioxidant proteins (Nrf2 and HO-1) that had been suppressed in the mouse brain. Both the in vitro and in vivo results indicated that D-gal induced oxidative stress-mediated neurodegeneration primarily by upregulating phospho-c-Jun N-terminal kinase (p-JNK) levels. However, D-gal + Gly cotreatment reversed the neurotoxic effects of D-gal by downregulating p-JNK levels, which had been elevated by D-gal. We also found that Gly reversed D-gal-induced neuroapoptosis by significantly reducing the protein expression levels of proapoptotic markers (Bax, cytochrome c, cleaved caspase-3, and cleaved PARP-1) and increasing the protein expression level of the antiapoptotic protein Bcl-2. Both the molecular docking approach and the in vitro study (in which the neuronal HT22 cells were treated with or without a p-JNK-specific inhibitor (SP600125)) further verified our in vivo findings that Gly bound to the p-JNK protein and inhibited its function and the JNK-mediated apoptotic pathway in the mouse brain and HT22 cells. Moreover, the addition of Gly alleviated D-gal-mediated neuroinflammation by inhibiting gliosis via attenuation of astrocytosis (GFAP) and microgliosis (Iba-1) in addition to reducing the protein expression levels of various inflammatory cytokines (IL-1ßeta and TNFα). Finally, the addition of Gly reversed D-gal-induced synaptic dysfunction by upregulating the expression of memory-related presynaptic protein markers (synaptophysin (SYP), syntaxin (Syn), and a postsynaptic density protein (PSD95)) and markedly improved behavioral measures of cognitive deficits in D-gal-treated mice. CONCLUSION: Our findings demonstrate that Gly-mediated deactivation of the JNK signaling pathway underlies the neuroprotective effect of Gly, which reverses D-gal-induced oxidative stress, apoptotic neurodegeneration, neuroinflammation, synaptic dysfunction, and memory impairment. Therefore, we suggest that Gly (an amino acid) is a safe and promising neurotherapeutic candidate that might be used for age-related neurodegenerative diseases.

Vanillic Acid, a Bioactive Phenolic Compound, Counteracts LPS-Induced Neurotoxicity by Regulating c-Jun N-Terminal Kinase in Mouse Brain.

The receptor for advanced glycation end products (RAGE), a pattern recognition receptor signaling event, has been associated with several human illnesses, including neurodegenerative diseases, particularly in Alzheimer's disease (AD). Vanillic acid (V.A), a flavoring agent, is a benzoic acid derivative having a broad range of biological activities, including antioxidant, anti-inflammatory, and neuroprotective effects. However, the underlying molecular mechanisms of V.A in exerting neuroprotection are not well investigated. The present study aims to explore the neuroprotective effects of V.A against lipopolysaccharides (LPS)-induced neuroinflammation, amyloidogenesis, synaptic/memory dysfunction, and neurodegeneration in mice brain. Behavioral tests and biochemical and immunofluorescence assays were applied. Our results indicated increased expression of RAGE and its downstream phospho-c-Jun n-terminal kinase (p-JNK) in the LPS-alone treated group, which was significantly reduced in the V.A + LPS co-treated group. We also found that systemic administration of LPS-injection induced glial cells (microglia and astrocytes) activation and significantly increased expression level of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB) and secretion of proinflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin-1 ß (IL1-ß), and cyclooxygenase (COX-2). However, V.A + LPS co-treatment significantly inhibited the LPS-induced activation of glial cells and neuroinflammatory mediators. Moreover, we also noted that V.A treatment significantly attenuated LPS-induced increases in the expression of AD markers, such as ß-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) and amyloid-ß (Aß). Furthermore, V.A treatment significantly reversed LPS-induced synaptic loss via enhancing the expression level of pre- and post-synaptic markers (PSD-95 and SYP), and improved memory performance in LPS-alone treated group. Taken together; we suggest that neuroprotective effects of V.A against LPS-induced neurotoxicity might be via inhibition of LPS/RAGE mediated JNK signaling pathway; and encourage future studies that V.A would be a potential neuroprotective and neurotherapeutic candidate in various neurological disorders.

Cognitive assessment in a predominantly Hispanic and Native American population in New Mexico and its association with kidney transplant wait-listing.

The association between cognitive function and the likelihood of kidney transplant (KT) wait-listing, especially in minority populations, has not been clearly delineated. We performed a retrospective review of our pre-KT patients, who consist mainly of Hispanics and Native Americans, over a 16-month period. We collected data on baseline demographics and the Montreal Cognitive Assessment (MoCA) score, at the initial KT evaluation. We defined cognitive impairment as MoCA scores of <24. We constructed linear regression models to identify associations between baseline characteristics with MoCA scores and used Cox proportional hazards models to assess associations between MoCA score and KT wait-listing. During the study period, 154 patients completed the MoCA during their initial evaluation. Mean (standard deviation) MoCA scores were 23.9 (4.6), with 58 (38%) participants scoring <24. Advanced age, lower education and being on dialysis were associated with lower MoCA scores. For every one-point increase in MoCA, the likelihood of being wait-listed increased 1.10-fold (95% CI 1.01-1.19, P = .022). Being Native American and having kidney disease due to diabetes or hypertension were associated with longer time to wait-listing. Cognitive impairment was common in our pre-KT patients and was associated with a lower likelihood of KT wait-listing.

Role of MicroRNAs in Renal Parenchymal Diseases-A New Dimension.

Since their discovery in 1993, numerous microRNAs (miRNAs) have been identified in humans and other eukaryotic organisms, and their role as key regulators of gene expression is still being elucidated. It is now known that miRNAs not only play a central role in the processes that ensure normal development and physiology, but they are often dysregulated in various diseases. In this review, we present an overview of the role of miRNAs in normal renal development and physiology, in maladaptive renal repair after injury, and in the pathogenesis of renal parenchymal diseases. In addition, we describe methods used for their detection and their potential as therapeutic targets. Continued research on renal miRNAs will undoubtedly improve our understanding of diseases affecting the kidneys and may also lead to new therapeutic agents.

Arthroscopic Grading of Injuries of the Inferior Tibiofibular Syndesmosis.

The objective of this study was to describe the technical details of performing a newly developed arthroscopic grading of inferior tibiofibular syndesmosis injuries. Arthroscopy is emerging as the gold standard for evaluating painful, unstable ankles. The inferior tibiofibular syndesmosis contributes substantially to disorders of the ankle. However, no structured grading system exists that would help surgeons evaluate injuries of the syndesmosis. Seventy-eight patients with pain or instability symptoms in the ankle were arthroscopically evaluated for syndesmosis injury. The lesions were graded according to the prospectively developed protocol. More than 61% of the patients had syndesmosis disruptions of various grades affecting the anterior/posterior ligaments or both ligaments. Fourteen patients had anterior ligament disruptions whereas 4 patients had posterior lesions; another 7 patients had both ligaments asymmetrically injured. Eighteen of the 78 patients had symmetric grade 1 lesions, and 5 had grade 2 lesions. More than half of chronic ankle pain cases have syndesmotic lesions. Symmetrical lesions of the anterior and posterior ligaments predominate, followed by isolated anterior ligament disruptions. The proposed grading system for inferior tibiofibular syndesmosis disruptions serves as a guide to systematic documentation of injuries of the syndesmosis.

Experience of CyberKnife Robotic Radiosurgery in treating intra and extra-cranial tumours: A review of outcomes.

OBJECTIVE: To determine the success rate and complication of CyberKnife Robotic Radiosurgery for treating intracranial and extra cranial tumours. METHODS: The cross-sectional observational study was carried out at the Department of CyberKnife Robotic Radiosurgery at the Jinnah Postgraduate Medical Centre, Karachi, and reviewed data related to a year from December 2012 to December 2013. Patients referred from different hospitals within and outside Pakistan for stereotactic radiosurgery were included. The patients had benign tumours less than 7cm size, post-operative residual tumour and recurrent tumour with post-radiotherapy. Patients were followed up every three months with contrast magnetic resonance imaging. Radiosurgery was considered successful if patients improved clinically with radiologically stable disease or if there was interval reduction in the size of tumour. SPSS 17 was used for data analysis. RESULTS: Initially, 260 patients were selected, but 9(3.5%) were lost, and the final sample size was 251(96.5%). Clinically successful outcome results were seen in 225(90%) patients, while 8(3%) showed no change in symptoms and 18(7%) patients' follow-up is awaited. Radiological improvement was noted in 218(87%); stable disease in 138(55%) and 80(32%) cases showed more than 30% reduction in size after 6-12 months of follow-up. Only 5(2%) cases showed subtle increase in size within 3-month interval due to post-radiation oedema. Acute transient post-radiation changes were seen in 25(10%) patients, sub-acute changes in 4(1.59%) and 1(0.3%) patient showed radionecrosis after 9-month interval. CONCLUSIONS: Cyberknife was an effective, safe and successful treatment alternative to surgery in benign and malignant tumours with low risk of post-radiotherapy complication compared to conventional radiation.

Capacity building for pediatric neuro-oncology in Pakistan- a project by my child matters program of Foundation S.

Introduction: Initiated in June 2019, this collaborative effort involved 15 public and private sector hospitals in Pakistan. The primary objective was to enhance the capacity for pediatric neuro-oncology (PNO) care, supported by a My Child Matters/Foundation S grant. Methods: We aimed to establish and operate Multidisciplinary Tumor Boards (MTBs) on a national scale, covering 76% of the population (185.7 million people). In response to the COVID-19 pandemic, MTBs transitioned to videoconferencing. Fifteen hospitals with essential infrastructure participated, holding monthly sessions addressing diagnostic and treatment challenges. Patient cases were anonymized for confidentiality. Educational initiatives, originally planned as in-person events, shifted to a virtual format, enabling continued implementation and collaboration despite pandemic constraints. Results: A total of 124 meetings were conducted, addressing 545 cases. To augment knowledge, awareness, and expertise, over 40 longitudinal lectures were organized for healthcare professionals engaged in PNO care. Additionally, two symposia with international collaborators and keynote speakers were also held to raise national awareness. The project achieved significant milestones, including the development of standardized national treatment protocols for low-grade glioma, medulloblastoma, and high-grade glioma. Further protocols are currently under development. Notably, Pakistan's first pediatric neuro-oncology fellowship program was launched, producing two graduates and increasing the number of trained pediatric neuro-oncologists in the country to three. Discussion: The initiative exemplifies the potential for capacity building in PNO within low-middle income countries. Success is attributed to intra-national twinning programs, emphasizing collaborative efforts. Efforts are underway to establish a national case registry for PNO, ensuring a comprehensive and organized approach to monitoring and managing cases. This collaborative initiative, supported by the My Child Matters/Foundation S grant, showcases the success of capacity building in pediatric neuro-oncology in low-middle income countries. The establishment of treatment protocols, fellowship programs, and regional tumor boards highlights the potential for sustainable improvements in PNO care.

The Use of Thiazide Diuretics for the Treatment of Hypertension in Patients With Advanced Chronic Kidney Disease.

The use of thiazide diuretics for the treatment of hypertension in patients with advance chronic kidney disease. Thiazides have been recommended as the first-line for the treatment of hypertension, yet their use has been discouraged in advanced chronic kidney disease (CKD), as they are suggested to be ineffective in advanced CKD. Recent data suggest that thiazide diuretics may be beneficial blood pressure control in addition to natriuresis in existing CKD. This review discusses the commercially available thiazides with a focus on thiazide pharmacology, most common adverse effects, clinical uses of thiazide diuretic, and the evidence for efficacy of thiazide use in advanced CKD.

Idiopathic transient osteoporosis of the talus: a cause for unexplained foot and ankle pain.

A 53-year-old woman was investigated for several neoplastic, inflammatory, and infective conditions for her left foot, and ankle pain associated with swelling, which she developed unexpectedly without history of trauma or infection. Gross osteopenia in the talus raised the possibilities of several differential diagnoses, but a magnetic resonance imaging scan showed diffuse bone marrow edema in the talus. With negative infective and inflammatory markers, the condition was ultimately labeled as "transient osteoporosis." She was reassured and followed up regularly. At the end of 12 months, she was completely asymptomatic, and her radiograph and magnetic resonance images showed significant improvement, with a normal-appearing talus and ankle joint, and there was complete resolution of bone marrow edema. Although "transient osteoporosis" of the foot is an uncommon condition, clinicians should be aware of this. Unexplained foot pain, with osteopenic bone and diffuse bone marrow edema on magnetic resonance imaging scan, is a feature of this condition. However, the diagnosis is established once other causes are excluded. The condition is self-limiting, and watchful expectancy of a normal recovery is the mainstay of treatment.

LDHB Deficiency Promotes Mitochondrial Dysfunction Mediated Oxidative Stress and Neurodegeneration in Adult Mouse Brain.

Age-related decline in mitochondrial function and oxidative stress plays a critical role in neurodegeneration. Lactate dehydrogenase-B (LDHB) is a glycolytic enzyme that catalyzes the conversion of lactate, an important brain energy substrate, into pyruvate. It has been reported that the LDHB pattern changes in the brain during ageing. Yet very little is known about the effect of LDHB deficiency on brain pathology. Here, we have used Ldhb knockout (Ldhb-/-) mice to test the hypothesis that LDHB deficiency plays an important role in oxidative stress-mediated neuroinflammation and neurodegeneration. LDHB knockout (Ldhb-/-) mice were generated by the ablation of the Ldhb gene using the Cre/loxP-recombination system in the C57BL/6 genetic background. The Ldhb-/- mice were treated with either osmotin (15 µg/g of the body; intraperitoneally) or vehicle twice a week for 5-weeks. After behavior assessments, the mice were sacrificed, and the cortical and hippocampal brain regions were analyzed through biochemical and morphological analysis. Ldhb-/- mice displayed enhanced reactive oxygen species (ROS) and lipid peroxidation (LPO) production, and they revealed depleted stores of cellular ATP, GSH:GSSG enzyme ratio, and downregulated expression of Nrf2 and HO-1 proteins, when compared to WT littermates. Importantly, the Ldhb-/- mice showed upregulated expression of apoptosis mediators (Bax, Cytochrome C, and caspase-3), and revealed impaired p-AMPK/SIRT1/PGC-1alpha signaling. Moreover, LDHB deficiency-induced gliosis increased the production of inflammatory mediators (TNF-α, Nf-ĸB, and NOS2), and revealed cognitive deficits. Treatment with osmotin, an adipoR1 natural agonist, significantly increased cellular ATP production by increasing mitochondrial function and attenuated oxidative stress, neuroinflammation, and neuronal apoptosis, probably, by upregulating p-AMPK/SIRT1/PGC-1alpha signaling in Ldhb-/- mice. In brief, LDHB deficiency may lead to brain oxidative stress-mediated progression of neurodegeneration via regulating p-AMPK/SIRT1/PGC-1alpha signaling, while osmotin could improve mitochondrial functions, abrogate oxidative stress and alleviate neuroinflammation and neurodegeneration in adult Ldhb-/- mice.

17-ß Estradiol Rescued Immature Rat Brain against Glutamate-Induced Oxidative Stress and Neurodegeneration via Regulating Nrf2/HO-1 and MAP-Kinase Signaling Pathway.

Dysregulated glutamate signaling, leading to neuronal excitotoxicity and death, has been associated with neurodegenerative pathologies. 17ß-estradiol (E2) is a human steroid hormone having a role in reproduction, sexual maturation, brain health and biological activities. The study aimed to explain the neuroprotective role of E2 against glutamate-induced ROS production, MAP kinase-dependent neuroinflammation, synaptic dysfunction and neurodegeneration in the cortex and hippocampus of postnatal day 7 rat brain. Biochemical and immunofluorescence analyses were applied. Our results showed that a single subcutaneous injection of glutamate (10 mg/kg) induced brain oxidative stress after 4 h by disturbing the homeostasis of glutathione (GSH) and revealed an upsurge in ROS and LPO levels and downregulated the expression of Nrf2 and HO-1 antioxidant protein. The glutamate-exposed P7 pups illustrated increased phosphorylation of stress-activated c-Jun N-terminal kinase (JNK) and p38 kinase (p38) and downregulated expression of P-Erk1/2. This was accompanied by pathological neuroinflammation as revealed by enhanced gliosis with upregulated expression of GFAP and Iba-1, and the activation of proinflammatory cytokines (TNF-α) in glutamate-injected P7 pups. Moreover, exogenous glutamate also reduced the expression of synaptic markers (PSD-95, SYP) and induced apoptotic neurodegeneration in the cortical and hippocampal regions by dysregulating the expression of Bax, Bcl-2 and caspase-3 in the developing rat brain. On the contrary, co-treatment of E2 (10 mg/kg) with glutamate significantly abrogated brain neuroinflammation, neurodegeneration and synapse loss by alleviating brain oxidative stress by upregulating the Nrf2/HO-1 antioxidant pathway and by deactivating pro-apoptotic P-JNK/P-p38 and activation of pro-survival P-Erk1/2 MAP kinase pathways. In brief, the data demonstrate the neuroprotective role of E2 against glutamate excitotoxicity-induced neurodegeneration. The study also encourages future studies investigating if E2 may be a potent neuroprotective and neurotherapeutic agent in different neurodegenerative diseases.

Cyberknife Radiosurgery in Hepatocellular Carcinoma.

OBJECTIVE: To determine the outcome of Stereotactic Body Radiation Therapy (SBRT) and its prognostic factors among hepatocellular carcinoma (HCC) patients. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Radiology and Cyberknife Robotic Radiosurgery, Jinnah Postgraduate Medical Centre (JPMC), Karachi, Pakistan from 1st July 2019 to 31st August 2020. METHODOLOGY: All patients of either gender age 18 years and above presenting with pathological confirmation of HCC, ECOG performance status of ≤2 and child Pugh A or B were consecutively enrolled. Progression of >20% was defined as progressive disease (PD). SBRT was performed using the Cyberknife. Clinical outcome was measured in terms of progression free survival. Moreover, radiation induced toxicity was also observed along with other predictor variables.            Results: Of 52 patients, the median age was 58 (53-59) years. There were 42 (80.8%) males and 10 (19.2%) females. All patients were alive at 3 months, i.e. 52 (100%). However, at 6 months, 49 (94.2%) were alive, at 9 months, 38 (73.1%) patients were alive while at 1 year, 24 (46.2%) patients were alive. A significant association was observed for survival at 6 months and ECOG performance status score (p-value 0.036), survival at 9 months and AFP (p= 0.003), survival at 1 year and age (p = 0.019), survival at 1 year and HBV (p = 0.001), and survival at 1 year and previous treatment (p = 0.010). Moreover, none of the patients reported complications / radiation induced liver toxicity. CONCLUSION: A higher efficiency of SBRT was found among HCC patients attending Radiology Department. Key Words: Stereotactic body radiation therapy, Hepatocellular carcinoma, Toxicity, Survival.

17ß-Estradiol Abrogates Oxidative Stress and Neuroinflammation after Cortical Stab Wound Injury.

Disruptions in brain energy metabolism, oxidative damage, and neuroinflammation are commonly seen in traumatic brain injury (TBI). Microglial activation is the hallmark of neuroinflammation. After brain injury, microglia also act as a double-edged sword with distinctive phenotypic changes. Therefore, therapeutic applications to potentiate microglia towards pro-inflammatory response following brain injury have become the focus of attention in recent years. Here, in the current study, we investigated the hypothesis that 17ß-estradiol could rescue the mouse brain against apoptotic cell death and neurodegeneration by suppressing deleterious proinflammatory response probably by abrogating metabolic stress and oxidative damage after brain injury. Male C57BL/6N mice were used to establish a cortical stab wound injury (SWI) model. Immediately after brain injury, the mice were treated with 17ß-estradiol (10 mg/kg, once every day via i.p. injection) for one week. Immunoblotting and immunohistochemical analysis was performed to examine the cortical and hippocampal brain regions. For the evaluation of reactive oxygen species (ROS), reduced glutathione (GSH), and oxidized glutathione (GSSG), we used specific kits. Our findings revealed that 17ß-estradiol treatment significantly alleviated SWI-induced energy dyshomeostasis and oxidative stress by increasing the activity of phospho-AMPK (Thr172) and by regulating the expression of an antioxidant gene (Nrf2) and cytoprotective enzymes (HO-1 and GSH) to mitigate ROS. Importantly, 17ß-estradiol treatment downregulated gliosis and proinflammatory markers (iNOS and CD64) while significantly augmenting an anti-inflammatory response as evidenced by the robust expression of TGF-ß and IGF-1 after brain injury. The treatment with 17ß-estradiol also reduced inflammatory mediators (Tnf-α, IL-1ß, and COX-2) in the injured mouse. Moreover, 17ß-estradiol administration rescued p53-associated apoptotic cell death in the SWI model by regulating the expression of Bcl-2 family proteins (Bax and Bcl-2) and caspase-3 activation. Finally, SWI + 17ß-estradiol-treated mice illustrated reduced brain lesion volume and enhanced neurotrophic effect and the expression of synaptic proteins. These findings suggest that 17ß-estradiol is an effective therapy against the brain secondary injury-induced pathological cascade following trauma, although further studies may be conducted to explore the exact mechanisms.

Cycloastragenol, a Triterpenoid Saponin, Regulates Oxidative Stress, Neurotrophic Dysfunctions, Neuroinflammation and Apoptotic Cell Death in Neurodegenerative Conditions.

Here, we have unveiled the effects of cycloastragenol against Aß (Amyloid-beta)-induced oxidative stress, neurogenic dysfunction, activated mitogen-activated protein (MAP) kinases, and mitochondrial apoptosis in an Aß-induced mouse model of Alzheimer's disease (AD). The Aß-induced mouse model was developed by the stereotaxic injection of amyloid-beta (5 µg/mouse/intracerebroventricular), and cycloastragenol was given at a dose of 20 mg/kg/day/p.o for 6 weeks daily. For the biochemical analysis, we used immunofluorescence and Western blotting. Our findings showed that the injection of Aß elevated oxidative stress and reduced the expression of neurogenic markers, as shown by the reduced expression of brain-derived neurotrophic factor (BDNF) and the phosphorylation of its specific receptor tropomyosin receptor kinase B (p-TrKB). In addition, there was a marked reduction in the expression of NeuN (neuronal nuclear protein) in the Aß-injected mice brains (cortex and hippocampus). Interestingly, the expression of Nrf2 (nuclear factor erythroid 2-related factor 2), HO-1 (heme oxygenase-1), p-TrKB, BDNF, and NeuN was markedly enhanced in the Aß + Cycloastragenol co-treated mice brains. We have also evaluated the expressions of MAP kinases such as phospho c-Jun-N-terminal kinase (p-JNK), p-38, and phospho-extracellular signal-related kinase (ERK1/2) in the experimental groups, which suggested that the expression of p-JNK, p-P-38, and p-Erk were significantly upregulated in the Aß-injected mice brains; interestingly, these markers were downregulated in the Aß + Cycloastragenol co-treated mice brains. We also checked the expression of activated microglia and inflammatory cytokines, which showed that cycloastragenol reduced the activated microglia and inflammatory cytokines. Moreover, we evaluated the effects of cycloastragenol against mitochondrial apoptosis and memory dysfunctions in the experimental groups. The findings showed significant regulatory effects against apoptosis and memory dysfunction as revealed by the Morris water maze (MWM) test. Collectively, the findings suggested that cycloastragenol regulates oxidative stress, neurotrophic processes, neuroinflammation, apoptotic cell death, and memory impairment in the mouse model of AD.

Alpha-Linolenic Acid Impedes Cadmium-Induced Oxidative Stress, Neuroinflammation, and Neurodegeneration in Mouse Brain.

Alpha-Linolenic acid (ALA), an omega-3 polyunsaturated fatty acid, is extracted from plant sources and has been shown to be one of the anti-inflammatory and antioxidant agents. Herein, we revealed the molecular mechanism underlying the anti-inflammatory and antioxidant potential of (ALA), against cadmium in the adult mouse brain. We evaluated the neuroprotective effect of ALA (60 mg/kg per oral for 6 weeks) against CdCl2 (5 mg/kg)-induced oxidative stress, neuroinflammation, and neuronal apoptosis. According to our findings, ALA markedly reduced ROS production and nitric oxide synthase 2 (NOS2) and enhanced the expression of nuclear factor-2 erythroid-2 (Nrf-2) and heme oxygenase-1 (HO-1) in mice treated with CdCl2. Most importantly, the molecular docking study revealed that ALA allosterically decreases the overexpression of c-Jun N-terminal kinase (JNK) activity and inhibited the detrimental effect against CdCl2. Moreover, ALA suppressed CdCl2-induced glial fibrillary acidic protein (GFAP), nuclear factor-kappa b (NF-κB), and interleukin-1ß (IL-1ß) in the mouse brain. Further, we also checked the pro- and anti-apoptotic proteins markers such as Bax, Bcl-2, and caspase-3, which were regulated in the cortex of ALA co-treated mouse brain. Overall, our study suggests that oral administration of ALA can impede oxidative stress, neuroinflammation, and increase neuronal apoptosis in the cortex of Cd-injected mouse brain.