Comparative binding analysis of WGX50 and Alpha-M with APP family proteins APLP1 and APLP2 using structural-dynamics and free energy calculation approaches.

A.D. is a common disease among other neurodegenerative disorders primarily developing due to amyloid-ß (Aß) neurotoxicity derived from the amyloid-ß protein precursor (AßPP). The amyloid precursor-like proteins 1 and 2 (APP1 and APLP2) biochemically behave similarly in many aspects to AßPP. We, therefore, proposed to test WGX-50 and Alpha-M for their interaction mechanism with APLP1 and APLP2 because both these drug candidate compounds previously showed inhibition of Aß aggregation. We employed a comparative atomic investigation on Alpha-M and WGX-50 in complex with novel targets, i.e., APLP1 and APLP2, using biophysical and molecular simulation methods. The docking score was -6.83 kcal mol-1 for Alpha-M-APLP1, -8.41 kcal mol-1 for WGX-50-APLP1, -7.02 kcal mol-1 for Alpha-M-APLP2 and -8.25 kcal mol-1 for the WGX-50-APLP2 complex. Our results also elaborate that in the case of their interaction with both APLP1 and APLP2, the WGX-50 complex exhibits better stability than the APLP1/2-Alpha-M complexes during simulation. Furthermore, WGX50 in both APLP1 and APLP2 stabilized the internal flexibility upon binding in contrast to the Alpha-M complexes. The data showed that the BFE for Alpha-M-APLP1 was calculated to be -27.38 ± 0.93 kcal mol-1, for WGX-50-APLP1 -39.65 ± 0.95 kcal mol-1, for Alpha-M-APLP2 -24.80 ± 0.63 kcal mol-1 while for WGX-50-APLP2 the BFE was -57.16 ± 1.03 kcal mol-1 respectively. These results highlight that APLP2-WGX50 has greater binding energies in all four systems. PCA and FEL analysis further revealed variations in the dynamic behavior of these complexes. Overall, our findings demonstrate that WGX50 potentially acts as a more potent inhibitor for APLP1 and APLP2 than Alpha-M and thus shows the diverse pharmacological potential of WGX50. Due to its stable binding interaction, WGX50 might be a suitable candidate drug compound for targeting these precursors under pathological conditions.

SREBP and MDT-15 protect C. elegans from glucose-induced accelerated aging by preventing accumulation of saturated fat.

Glucose-rich diets shorten the life spans of various organisms. However, the metabolic processes involved in this phenomenon remain unknown. Here, we show that sterol regulatory element-binding protein (SREBP) and mediator-15 (MDT-15) prevent the life-shortening effects of a glucose-rich diet by regulating fat-converting processes in Caenorhabditis elegans. Up-regulation of the SREBP/MDT-15 transcription factor complex was necessary and sufficient for alleviating the life-shortening effect of a glucose-rich diet. Glucose feeding induced key enzymes that convert saturated fatty acids (SFAs) to unsaturated fatty acids (UFAs), which are regulated by SREBP and MDT-15. Furthermore, SREBP/MDT-15 reduced the levels of SFAs and moderated glucose toxicity on life span. Our study may help to develop strategies against elevated blood glucose and free fatty acids, which cause glucolipotoxicity in diabetic patients.

Extracellular vesicles improve embryo cryotolerance by maintaining the tight junction integrity during blastocoel re-expansion.

Cryopreservation is a process in which the intact living cells, tissues, or embryos are preserved at subzero temperatures for preservation. The cryopreservation process highly impacts the survival and quality of the in vitro-produced (IVP) embryos. Some studies have highlighted the use of oviduct extracellular vesicles (EVs) to improve the cryotolerance of IVP embryos but the mechanism has not been well studied. The present study unravels the role of in vitro cultured bovine oviduct epithelial cells-derived EVs in improving the re-expansion and hatching potential of thawed blastocysts (BLs). The comparison of cryotolerance between synthetic oviduct fluid (SOF) and SOF + EVs-supplemented day-7 cryopreserved BLs revealed that the embryo's ability to re-expand critically depends on the intact paracellular sealing which facilitates increased fluid accumulation during cavity expansion after shrinkage. Our results demonstrated that BLs cultured in the SOF + EVs group had remarkably higher re-expansion (67.5 ± 4.2%) and hatching rate (84.8 ± 1.4%) compared to the SOF group (53.4 ± 3.4% and 63.9 ± 0.9%, respectively). Interestingly, EVs-supplemented BLs exhibited greater influence on the expression of core genes involved in trophectoderm (TE) maintenance, formation of tight junction (TJ) assembly, H2O channel proteins (aquaporins), and Na+/K+ ATPase alpha 1. The EVs improved the fluid flux and allowed the transport of H2O into an actively re-expanded cavity in EVs-cultured cryo-survived BLs relative to control BLs. Our findings explored the function of EVs in restoring the TE integrity, improved the cell junctional contacts and H2O movement which helps the blastocoel re-expansion after thawing the cryopreserved BLs.

Bovine Oviduct Epithelial Cell-Derived Culture Media and Exosomes Improve Mitochondrial Health by Restoring Metabolic Flux during Pre-Implantation Development.

Oviduct flushing is enriched by a wide variety of nutrients that guide the 3-4 days journey of pre-implantation embryo through the oviduct as it develops into a competent blastocyst (BL). However, little is known about the specific requirement and role of these nutrients that orchestrate the early stages of embryonic development. In this study, we aimed to characterize the effect of in vitro-derived bovine oviduct epithelial cell (BOECs) secretion that mimics the in vivo oviduct micro-fluid like environment, which allows successful embryonic development. In this study, the addition of an in vitro derived BOECs-condition media (CM) and its isolated exosomes (Exo) significantly enhances the quality and development of BL, while the hatching ability of BLs was found to be high (48.8%) in the BOECs-Exo supplemented group. Surprisingly, BOECs-Exo have a dynamic effect on modulating the embryonic metabolism by restoring the pyruvate flux into TCA-cycle. Our analysis reveals that Exo treatment significantly upregulates the pyruvate dehydrogenase (PDH) and glutamate dehydrogenase (GLUD1) expression, required for metabolic fine-tuning of the TCA-cycle in the developing embryos. Exo treatment increases the influx into TCA-cycle by strongly suppressing the PDH and GLUD1 upstream inhibitors, i.e., PDK4 and SIRT4. Improvement of TCA-cycle function was further accompanied by higher metabolic activity of mitochondria in BOECs-CM and Exo in vitro embryos. Our study uncovered, for the first time, the possible mechanism of BOECs-derived secretion in re-establishing the TCA-cycle flux by the utilization of available nutrients and highlighted the importance of pyruvate in supporting bovine in vitro embryonic development.

Difference in Developmental Kinetics of Y-Specific Monoclonal Antibody Sorted Male and Female In Vitro Produced Bovine Embryos.

Sex-related growth differences between male and female embryos remain an attractive subject for reproductive biologists. This study aimed to investigate the endogenous factors that play a crucial role in the pace of early development between male and female bovine embryos. Using sex pre-selected semen by Y-specific monoclonal antibodies for the production of bovine embryos, we characterized the critical endogenous factors that are responsible for creating the development differences, especially during the pre-implantation period between male and female embryos. Our results showed that at day seven, (57.8%) Y-sperm sorted in vitro cultured embryos reached the expanded blastocyst (BL) stage, whereas the X-sperm sorted group were only 25%. Y-BLs showed higher mRNA abundance of pluripotency and developmental competency regulators, such as Oct4 and IGF1-R. Interestingly, Y-sperm sorted BLs had a homogeneous mitochondrial distribution pattern, higher mitochondrial membrane potential (∆Ñ°m), efficient OXPHOS (oxidative phosphorylation) system and well-encountered production of ROS (reactive oxygen species) level. Moreover, Y-blastocysts (BLs) showed less utilization of glucose metabolism relative to the X-BLs group. Importantly, both sexes showed differences in the timing of epigenetic events. All these factors directly or indirectly orchestrate the whole embryonic progression and may help in the faster and better quality yield of BL in the Y-sperm sorted group compared to the X counterpart group.

Decompressive Craniectomy For Acute Subdural Haematoma With Expansile Duraplasty Versus Dural-Slits.

BACKGROUND: Traumatic subdural hematoma is one of the lethal injuries to brain. Various surgical techniques are used to evacuate the acute subdural hematoma. The hematoma evacuation can either be done by opening of dura by multiple slits or by opening of dura in single large c shape and then doing the expansile duraplasty. Present study aimed to compare both these techniques. METHODS: This randomized control study was conducted in department of neurosurgery, Ayub Medical College, Abbottabad from July 2011 to July 2013. A total of 59 patients were included in this study, which were randomly allocated in two groups (i.e., group A and group B) for decompressive craniectomy. Thirty-one patients were operated by craniectomy with full dural flap opening (Group A), and 28 patients were operated by craniectomy with multidural-slits (Group B). Glasgow Outcome score (GOS) at 6 weeks after the surgery was used to determine the outcome. RESULTS: Mean age of the patients was 33.4±12.8 years. Majority were males. In group A 51.6 % (16) of the patients survived out of which a favourable outcome (GOC 3-5) was observed in 41.9% of the patients, and 9.1% of patients ended up in vegetative state. While in group B 46.4% (13) of the patients survived among which favourable outcome was seen in 39.3% of patients and 7.1% of patients ended up in vegetative state. The difference in outcome measure is insignificant. CONCLUSIONS: There was no statistically significant difference among the two groups as regards the mortality, GOS, frequency of complications and hospital. While the duration of surgery was significantly shorter in patients operated with dural slits.

CLINICAL FEATURES AND OUTCOME ANALYSIS OF INTRACRANIAL HYDATID CYSTS.

BACKGROUND: Hydatid cyst of the brain is serious zoonotic parasitic infections which have profound health consequences if left untreated. The surgical excisions of the cysts are rewarding for both the patient the neurosurgeon. METHODS: The study was conducted prospectively at Department of Neurosurgery Hayatabad Medical Complex Peshawar from January 2013 to December 2014. Patients with a diagnosis of intracranial hydatid cysts were included, clinical and radiological features recorded, intervention and postoperative outcome were analysed. RESULTS: Eleven patients with a male to female ratio of 1.7:1. Mean age was 12.4 (SD ± 6.5) years with median GCS on arrival of 10 (SD ± 2.5). Clinical features were headache (81.8%), vomiting (90.9%), seizures (36.4%), focal deficits (54.5%) and papilloedema (72.7%). The median GCS on discharge was 13 (SD ± 1.1) while GOS at 1 month follow up was 4 (SD ± 0.7). The bivariate analysis showed inverse correlation (R² = -0.68; p = 0.02) between duration of symptoms and outcome while GCS on admission was positively correlated (r(s) = 0.75; p = 0.007) with the outcome. There was no mortality. CONCLUSION: Despite its rarity the clinical features are non-specific while radiological features help in establishing diagnosis. Earlier diagnosis and prompt intervention is the key to favourable outcome.

MICROVASCULAR DECOMPRESSION FOR TRIGEMINAL NEURALGIA.

BACKGROUND: Trigeminal Neuralgia (TGN) is the most frequently diagnosed type of facial pain. In idiopathic type of TGN it is caused by the neuro-vascular conflict involving trigeminal nerve. Microvascular decompression (MVD) aims at addressing this basic pathology in the idiopathic type of TGN. This study was conducted to determine the outcome and complications of patients with idiopathic TGN undergoing MVD. METHODS: In a descriptive case series patients with idiopathic TGN undergoing MVD were included in consecutive manner. Patients were diagnosed on the basis of detailed history and clinical examination. Retromastoid approach with craniectomy was used to access cerebellopontine angle (CP-angle) and microsurgical decompression was done. Patients were followed up for 6 months. RESULTS: A total of 53 patients underwent MVD with mean age of 51.6±4.2 years and male predominance. In majority of cases (58.4%) both Maxillary and Mandibular divisions were involved. Per-operatively superior cerebellar artery (SCA) was causing the neuro-vascular conflict in 33 (62.2%) of the cases, anterior inferior cerebellar artery (AICA) in 6 (11.3%) cases, both CSA and AICA in 3 (5.6%) cases, venous compressions in only 1 (1.8%) patient and thick arachnoid adhesions were seen in 10 (18.9%) patients. Postoperatively, 33 (68%) patients were pain free, in 14 (26.45%) patients pain was significantly improved whereas in 3 (5.6%) patients there was mild improvement in symptoms. Three (5.6%) patients did not improve after the primary surgery. Cerebrospinal fluid (CSF) leak was encountered in 7 (13.2%) patients post-operatively, 4 (7.5%) patients developed wound infection and 1 (1.8%) patient developed aseptic meningitis. Three (5.6%) patients had transient VII nerve palsy while one patient developed permanent VII nerve palsy. CONCLUSION: MVD is a safe and effective surgical option for treating patients with idiopathic TGN with better surgical outcome and fewer complications.

OUTCOME OF OPEN CARPAL TUNNEL RELEASE SURGERY.

BACKGROUND: Carpel tunnel syndrome is a common compression neuropathy of the median nerve causing pain, numbness and functional dysfunction of the hand. Among the available treatments, surgical release of the nerve is the most effective and acceptable treatment option. The aim of this study was to see the outcomes of surgical release of carpel tunnel using open technique. METHODS: This descriptive case series was conducted at the Department of neurosurgery, Ayub Teaching Hospital Abbottabad from April 2013 to March 2014. One hundred consecutive patients with carpel tunnel syndrome were included who underwent open carpel tunnel release surgery. They were followed up at 1, 3 and 6 months. Residual pain, numbness and functional improvement of the hand were the main outcome measures. RESULTS: Out of 100 patients, 19 were males. The age ranged from 32 to 50 years with a mean of 39.29±3.99 years. The duration of symptoms was from 5 to 24 months. In the entire series patient functional outcome and satisfaction was 82% at 1 month, 94% at 3 months and 97% at 6 months. 18% patient had residual pain at 1 month post-operative follow-up, 6% at 3 months and 3% at 6 month follow-up. CONCLUSION: Open carpel tunnel release surgery is an effective procedure for compression neuropathy of the median nerve. It should be offered to all patients with moderate to severe pain and functional disability related to carpel tunnel syndrome.

Zinc Ortho Methyl Carbonodithioate Improved Pre and Post-Synapse Memory Impairment via SIRT1/p-JNK Pathway against Scopolamine in Adult Mice.

Alzheimer's disease (AD) is globally recognized as a prominent cause of dementia for which efficient treatment is still lacking. New candidate compounds that are biologically potent are regularly tested. We, therefore, hypothesized to study the neuroprotective potential of Zinc Ortho Methyl Carbonodithioate (thereafter called ZOMEC) against Scopolamine (SCOP) induced Alzheimer's disease (AD) model using adult albino mice. We post-administered ZOMEC (30 mg/Kg) into two group of mice for three weeks on daily basis that received either 0.9% saline or SCOP (1 mg/Kg) for initial two weeks. The other two groups of mice received 0.9% saline and SCOP (1 mg/Kg) respectively. After memory related behavioral analysis the brain homogenates were evaluated for the antioxidant potential of ZOMEC and multiple protein markers were examined through western blotting. Our results provide enough evidences that ZOMEC decrease oxidative stress by increasing catalase (CAT) and glutathione S transferase (GST) and decreasing the lipid peroxidation (LPO). The SIRT1 and pre and post synaptic marker proteins, synaptophysin (SYP) as well as post synaptic density protein (PSD-95) expression were also enhanced upon ZOMEC treatment. Furthermore, memory impairment was rescued and ZOMEC appreciably abrogated the Aß accumulation, BACE1 expression C and the p-JNK pathway. The inflammatory protein markers, NF-kß and IL-1ß in ZOMEC treated mice were also comparable with control group. The predicted interaction of ZOMEC with SIRT1 was further confirmed by molecular docking. These findings thus provide initial reports on efficacy of ZOMEC in SCOP induced AD model.

Surgical Treatment Options For Chronic Subdural Haematoma.

Subdural hematoma is an encapsulated collection of blood under the dura matter. This commonly encountered neurosurgical disorder is best managed by surgical evacuation; however, contemporary neurosurgery lacks a consensus regarding surgical technique of choice. Due to high incidence of the condition and associated complications, vast amount of literature is available on the subject; including studies comparing efficacy of various available treatment modalities. Herein, literature on surgical techniques employed for management of Chronic Subdural Hematoma (CSDH) has been reviewed to provide an evidence-based review on best surgical practices. Following conclusions can be made on basis of evidence of various levels provided in the studied literature: (1) Twist-drill craniostomy is a relatively safe technique that can be employed under local anaesthesia, thus can be considered as first line treatment in high risk surgical candidates. (2) Single and double burr-hole craniostomies have shown comparable results. (3) Intraoperative irrigation during burr-hole craniostomy doesn't affect outcome. (4) Drain insertion after hematoma evacuation lowers recurrence risk. (5) Position of drain is not significant but early drain removal is associated with higher recurrence rates. (6) Craniotomy is associated with high morbidity and mortality, hence should be reserved for recurrent and large septate hematoma cases. (7) Head elevation in postoperative period reduces recurrence. (8) Embolization of middle meningeal artery (EMMA): A novel treatment modality, is promising but requires further approval in terms of large sample sized multicenter randomized control trials. In conclusion further research is required on the subject to formulate guidelines regarding management of this common neurosurgical emergency.

Hidden allosteric sites and De-Novo drug design.

INTRODUCTION: Hidden allosteric sites are not visible in apo-crystal structures, but they may be visible in holo-structures when a certain ligand binds and maintains the ligand intended conformation. Several computational and experimental techniques have been used to investigate these hidden sites but identifying them remains a challenge. AREAS COVERED: This review provides a summary of the many theoretical approaches for predicting hidden allosteric sites in disease-related proteins. Furthermore, promising cases have been thoroughly examined to reveal the hidden allosteric site and its modulator. EXPERT OPINION: In the recent past, with the development in scientific techniques and bioinformatics tools, the number of drug targets for complex human diseases has significantly increased but unfortunately most of these targets are undruggable due to several reasons. Alternative strategies such as finding cryptic (hidden) allosteric sites are an attractive approach for exploitation of the discovery of new targets. These hidden sites are difficult to recognize compared to allosteric sites, mainly due to a lack of visibility in the crystal structure. In our opinion, after many years of development, MD simulations are finally becoming successful for obtaining a detailed molecular description of drug-target interaction.

Predictive Factors of Outcomes in Acute Subdural Hematoma Evacuation.

OBJECTIVE: This comparative cross-sectional study was conducted in the Departments of Trauma and Neurosurgery, Ayub Teaching Hospital, Abbottabad, Pakistan from September 2021 to February 2022 to study predictive factors of outcomes in acute subdural hematoma evacuation. METHODOLOGY: A total of 101 patients with confirmed diagnosis of acute subdural hematoma (ASDH) who underwent surgical evacuation by consultant neurosurgeon were included in the study. A detailed clinical proforma was designed to document all the clinical and demographic details of these patients at the time of admission. Glasgow Coma Scale outcome score (GOS) was used to assess the outcome of patients after the surgery. Sociodemographic and clinical parameters were associated with outcome of surgery in our study participants. RESULTS: Out of 101 patients, 55 (54.5%) were males and 46 (45.5%) were females. Mean age was 43.66±19.66 years with 7.39 as mean Glasgow Coma Scale (GCS) at presentation. Road traffic accident (RTA) 62 (61.4%) was most frequent mechanism of injury followed by fall from height (19.8%) and history of assault (13.9%). In our study, 59 patients had poor outcomes while 42 had good outcomes. Elder age, low GCS at presentation, and use of oral anticoagulant were associated with poor outcomes while pupillary reaction had no effect on the outcome after application of test of significance. CONCLUSION: More than half of the patients managed with surgical evacuation for acute subdural hematoma as per guidelines at our neurosurgical unit had poor outcomes according to Glasgow Coma Scale. In this study, advancing age (>60 years), low GCS score at presentation, and use of oral anticoagulation therapy emerged as significant risk factors for poor outcomes in participants. Pupillary reaction had no effect on outcomes as per this study but this needs further evaluation in future studies.

Efficacy Of Conservative Management Of Early Post Traumatic Cerebrospinal Fluid Rhinorrhoea.

Background: The incidence of Post-traumatic Cerebrospinal Fluid Rhinorrhoea (PCSFR) has been decreased due to advanced therapeutic measures. The current investigative study has been arranged to assess the efficacy of conservative management of early PCSFR. Method: This cross-sectional study was conducted at departmental of Neurosurgery, Ayub Medical Institute, Abbottabad. Patients with traumatic brain injury having Cerebrospinal fluid rhinorrhoea with either gender having age 5-50 year and presenting within seven days of traumatic brain injury were included. Moreover, those with nasal fractures, penetrating head injuries having fever and neck stiffness were also included in the study. Results: A total number of 120 patients having male dominancy, i.e., 86 (72%) were included in the study with the mean age of 27 years ± 8.741 in which 77 (92%) patients were in the age range of 2nd to 4th decades. The commonest cause was trauma due to Road Traffic Accidents (RTA) having 65 (54%) patients. Conservative treatment was effective in 62 (52%) patients predominantly in the patients of 3rd decade, i.e., 31 (50%), in which the effectiveness in male gender was revealed to be 52.32% (45) and effectiveness in RTA patients was recorded to be 54.83%. Similarly, the Chi-Square value was calculated for the PCSFR patients for four groups of patients (5-20, 21-30, 31-40, 41-50) to be 48.27 having critical value of 7.81 with the p-value of 1.87e-10, which completely rejects the Null-hypothesis for the patients of various ages. Conclusion: Based on the current investigative study, it may be concluded that PCSFR is common in middle age population with slight male dominancy. It may also be inferred that RTA is the leading cause of PCSFR in our set up and majority of the patients shows improvement after conservative management. Moreover, the effectiveness of conservative management of PCSFR could be predominantly observed in the patients of 3rd decade.

Level Of Pre-Tertiary Care Hospital Management Of Traumatic Spinal Cord Injured Patients; Where Do We Stand?

BACKGROUND: Traumatic spinal cord injury is a debilitating condition that may cause long term disabilities with tremendous socioeconomic impact on affected individuals and their families. Secondary injuries can best prevent or minimized by appropriate pre hospital management and proper referral and transfer. This study was conducted to assess the clinical profile of traumatic spinal cord injuries and level of pre-hospital care provided to patients either at the site of injury or at other healthcare facilities. METHODS: This prospective study was conducted in the Department of Neurosurgery Ayub Teaching Hospital Abbottabad, from January 2012 to January 2017. All patients with suspected spinal injury were included in the study. Age, gender, mode of injuries and the pre-tertiary care provided were recorded. RESULTS: Out of 4464 patients with suspected spinal cord injury, 3685 (82.5%) were male, 779 (17.4%) were female. Age ranged from 10-70 years. 1685 (37.8%) were diagnosed as having spinal injury. Cervical spine was the most common affected level 743 (44.09%), followed by thoracic spine 135 (8.01%). 1441 (85.5%) were incomplete while 224(14.5%) were complete spinal cord injuries. Road traffic accident was the most common mechanism of injury 884 (52.4%). Only 4 (0.23%) patients directly received in our unit were properly transported, 66 (3.91%) were brought after proper spinal immobilization, intravenous line was maintained in 584 (34.66%) patients, 410 (24.3%) patients received some fluid resuscitation, parenteral analgesia was given to 441 (26.17%) patients while urinary catheterization was done in 195 (11.75%) patients. Those received from other healthcare facilities only 4 (0.23%) were brought by properly equipped ambulance, intravenous access was maintained in 438 (25.99%),320 (18.99%) received some fluid resuscitation, urinary catheterization was done in 229(13.59%) while proper parenteral analgesia was given to 988 (58.63%) patients. CONCLUSIONS: There is a complete lack of proper transport and referral of trauma patients in our area which reflects almost non-existent emergency medical (rescue) services, deficient health care facilities.

Outcome of intramedullary spinal cord tumours: experience with 18 patients operated at Ayub Teaching Hospital, Abbottabad.

BACKGROUND: Intramedullary spinal cord tumours (IMSCT) are among the uncommon lesions at spinal cord. They can present with a vast array of symptoms and cause severe neurological deficits. With advent and frequent use of MRI more and more patients with IMSCT are picked up. By using modern microsurgical techniques better surgical outcome is achieved. The Objective was to analyse the surgical outcome of the patients with intramedullary Spinal Tumour operated at Ayub Teaching Hospital (ATH). Abbottabad. METHODS: Eighteen patients with IMSCT who presented at Neurosurgery Unit. ATH. Abbottabad during 2000-2010 were included in this study. Patients were diagnosed on the basis of MRI. They were operated using standard microsurgical techniques. Patients were followed up for a mean duration of 18 months after surgery and their preoperative and postoperative neurological status was analysed. RESULTS: Patients with age group ranging from 15-50 (37.72 +/- 8.94) years with IMSCT were operated. Sixty-one percent of the patients were male and 39% were female. The region most commonly affected was cervical (44%) followed by conus medullaris (33%), cervicothoracic and thoracic each had frequency of 11%. Gross total removal (> 95%) was possible in 72% of cases while in rest of 28% cases resection of 80-95% was possible. Histologically 38.9% of the lesions were ependymomas, 27.8% were astrocytomas and 22.2% were teratomas. Neurofibromas and Primitive Neuroectodermal Tumours (PNET) each accounted for 5.5% of the cases. Overall postoperative neurology improved in 10 (55%) of patients, remained unchanged in 5 (27%) of cases, and deteriorated in 3 (16%) patients. One patient was lost in follow-up. Surgery on tumours in cervical and thoracic region carried a relatively poor outcome as compared to the lesion of conus. There were no deaths due to surgery. CONCLUSION: Surgical removal of IMSCT is beneficial to patients with acceptable surgical risk. Better outcome is expected if the patients with good Frankel grade are diagnosed and operated early the course of disease.

Clinical and radiological findings in Arnold Chiari malformation.

BACKGROUND: The Chiari Malformation I (CMI) is a disorder of uncertain origin that has been traditionally defined as downward herniation of the cerebellar tonsils through the foramen magnum. The anomaly is a leading cause of syringomyelia and occurs inassociation with osseus abnormalities at the craniovertebral junction. In contrast to other Chiari malformations, CMI tends to present in the second or third decade of life and is sometimes referred to as the 'adult-type' Chiari malformation. The objective was to document clinical and radiological findings in Arnold Chiari Malformation-I. METHOD: This was a descriptive study carried out in Ayub Teaching Hospital Abbottabad at Neurosurgery Department during July 2008-July 2010. We examined a prospective cohort of 60 symptomatic patients. All patients underwent magnetic resonance imaging of the head and spine. RESULTS: There were 40 female and 20 male patients. The age of onset was 24.9 +/- 15.8 years. Common associated radiological problems included syringomyelia (60%), scoliosis (25%), and basilarinvagination (12%), increased cervical lordosis 5 (8.5%), and Klippel Feil syndrome 2 (3.3%). The most consistent magnetic resonance imaging findings were obliteration of the retrocerebellar cerebrospinal fluid spaces (70% patients), tonsillar herniation of at least 5 mm (100% patients), and varying degrees of post fossa anomalies. Linical manifestations were headaches, pseudotumor-like episodes, a Meniere's disease-like syndrome, lower cranial nerve signs, and spinal cord disturbances in the absence of syringomyelia. CONCLUSION: These data support accumulating evidence that CMI is a disorder of the para-axial mesoderm that is characterised by underdevelopment of the posterior cranial fossa and overcrowding of the normally developed hindbrain. Tonsillar herniation of less than 5 mm does not exclude the diagnosis. Clinical manifestations of CMI seem to be related to cerebrospinal fluid disturbances (which are responsible for headaches, pseudotumor-like episodes, endolymphatic hydrops, syringomyelia, and hydrocephalus) and direct compression of nervous tissue.

Role of Wnt Signaling During In-Vitro Bovine Blastocyst Development and Maturation in Synergism with PPARδ Signaling.

Wnt/ß-catenin signaling plays vital role in the regulation of cellular proliferation, migration, stem cells cell renewal and genetic stability. This pathway is crucial during the early developmental process; however, the distinct role of Wnt/ß-catenin signaling during pre-implantation period of bovine embryonic development is obscure. Here, we evaluated the critical role of Wnt/ß-catenin pathway in the regulation of bovine blastocyst (BL) development and hatching. 6 bromoindurbin-3'oxime (6-Bio) was used to stimulate the Wnt signaling. Treatment with 6-Bio induced the expression of peroxisome proliferator-activated receptor-delta (PPARδ). Interestingly, the PPARδ co-localized with ß-catenin and form a complex with TCF/LEF transcription factor. This complex potentiated the expression of several Wnt directed genes, which regulate early embryonic development. Inhibition of PPARδ with selective inhibitor 4-chloro-N-(2-{[5-trifluoromethyl]-2-pyridyl]sulfonyl}ethyl)benzamide (Gsk3787) severely perturbed the BL formation and hatching. The addition of Wnt agonist successfully rescued the BL formation and hatching ability. Importantly, the activation of PPARδ expression by Wnt stimulation enhanced cell proliferation and fatty acid oxidation (FAO) metabolism to improve BL development and hatching. In conclusion, our study provides the evidence that Wnt induced PPARδ expression co-localizes with ß-catenin and is a likely candidate of canonical Wnt pathway for the regulation of bovine embryonic development.

Phylogenetic Analysis and Structural Perspectives of RNA-Dependent RNA-Polymerase Inhibition from SARs-CoV-2 with Natural Products.

Most recently, an outbreak of severe pneumonia caused by the infection of SARS-CoV-2, a novel coronavirus first identified in Wuhan, China, imposes serious threats to public health. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Therefore, the role and inhibition of nsp12 are indispensable. A cryo-EM structure of RdRp from SARs-CoV-2 was used to identify novel drugs from Northern South African medicinal compounds database (NANPDB) by using computational virtual screening and molecular docking approaches. Considering Remdesivir as the control, 42 compounds were shortlisted to have docking score better than Remdesivir. The top 5 hits were validated by using molecular dynamics simulation approach and free energy calculations possess strong inhibitory properties than the Remdesivir. Thus, this study paved a way for designing novel drugs by decoding the architecture of an important enzyme and its inhibition with compounds from natural resources. This disclosing of necessary knowledge regarding the screening and the identification of top hits could help to design effective therapeutic candidates against the coronaviruses and design robust preventive measurements.

An Integrated Systems Biology and Network-Based Approaches to Identify Novel Biomarkers in Breast Cancer Cell Lines Using Gene Expression Data.

Breast cancer is the most common cause of death in women worldwide. Approximately 5%-10% of instances are attributed to mutations acquired from the parents. Therefore, it is highly recommended to design more potential drugs and drug targets to eradicate such complex diseases. Network-based gene expression profiling is a suggested tool for discovering drug targets by incorporating various factors such as disease states, intensities based on gene expression as well as protein-protein interactions. To find prospective biomarkers in breast cancer, we first identified differentially expressed genes (DEGs) statistical methods p-value and false discovery rate were initially used. Of the total 82 DEGs, 67 were upregulated while the remaining 17 were downregulated. Sub-modules and hub genes include VEGFA with the highest degree, followed by 15 CCND1 and CXCL8 with 12-degree score was found. The survival analysis revealed that all the hub genes have important role in the development and progression of breast cancer. Enrichment analysis revealed that most of these genes are involved in signaling pathways and in the extracellular spaces. We also identified transcription factors and kinases, which regulate proteins in the DEGs PPI. Finally, drugs for each hub genes were identified. These results further expanded the knowledge regarding important biomarkers in breast cancer.