Correction: Ashraf et al. Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches. Molecules 2022, 27, 4652.

The updated affiliation information can be seen in the affiliation part of this correction [...].

Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches.

Microtubule affinity regulating kinase 4 (MARK4) regulates the mechanism of microtubules by its ability to phosphorylate the microtubule-associated proteins (MAP's). MARK4 is known for its major role in tau phosphorylation via phosphorylating Ser262 residue in the KXGS motif, which results in the detachment of tau from microtubule. In lieu of this vital role in tau pathology, a hallmark of Alzheimer's disease (AD), MARK4 is a druggable target to treat AD and other neurodegenerative disorders (NDs). There is growing evidence that NDs and diabetes are connected with many pieces of literature demonstrating a high risk of developing AD in diabetic patients. Metformin (Mtf) has been a drug in use against type 2 diabetes mellitus (T2DM) for a long time; however, recent studies have established its therapeutic effect in neurodegenerative diseases (NDs), namely AD, Parkinson's disease (PD) and amnestic mild cognitive impairment. In this study, we have explored the MARK4 inhibitory potential of Mtf, employing in silico and in vitro approaches. Molecular docking demonstrated that Mtf binds to MARK4 with a significant affinity of -6.9 kcal/mol forming interactions with binding pocket's critical residues. Additionally, molecular dynamics (MD) simulation provided an atomistic insight into the binding of Mtf with MARK4. ATPase assay of MARK4 in the presence of Mtf shows that it inhibits MARK4 with an IC50 = 7.05 µM. The results of the fluorescence binding assay demonstrated significant binding of MARK4 with a binding constant of 0.6 × 106 M-1. The present study provides an additional axis towards the utilization of Mtf as MARK4 inhibitor targeting diabetes with NDs.

Consanguinity in patients with mesial temporal lobe epilepsy due to hippocampal sclerosis in a Saudi population.

OBJECTIVE: To investigate if there is an association between consanguinity and hippocampal sclerosis (HS) in the Saudi population. METHODS: A retrospective case-control study was conducted by assessing the prevalence of consanguinity in patients with pathologically proven HS, who underwent epilepsy surgery at King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia, between January 2004 and December 2015. We reviewed the medical records to extract data, which included; age, gender, duration of epilepsy, history of febrile seizure, family history of epilepsy in a first or second-degree relative, and pathology reports. RESULTS: A total of 120 patients, out of which 40 patients (65% male) having mesial temporal lobe epilepsy due to HS, and 80 controls (56% male) with cryptogenic epilepsy, were identified. Twenty-two patients (53.5%) in the HS group had a history of consanguinity. In the control group, 30 patients (37.5%) had a history of consanguinity. The odds ratio was 2.04 (95% confidence interval = 0.94 - 4.4, p=0.052). A family history of epilepsy was found in 28% of the patients with HS and 32.5% cryptogenic epilepsy. Only 8 patients (19.5%) with HS reported a history of febrile seizure. CONCLUSION: Our retrospective case-control study suggests that consanguinity might increase the likelihood of developing HS.

Infratentorial immature teratoma of congenital origin can be associated with a 20-year survival outcome: a case report and review of literature.

BACKGROUND: Congenital intracranial tumors are very rare and account for less than 2% of all childhood brain tumors. Teratomas constitute about one third to one half of these, predominantly located midline in the supratentorial region. Posterior fossa location rarely occurs and, based on the cases reported in the literature, commonly has a poor prognosis. CASE PRESENTATION: A newborn female, diagnosed prenatally with hydrocephalus, is presented at birth with increasing head circumference and Parinaud's syndrome. Magnetic resonance imaging scans demonstrated a huge posterior fossa tumor with obstructive hydrocephalus. At surgery, through a suboccipital craniotomy, complete excision was achieved of a histological-proven immature teratoma. The infant received adjuvant chemotherapy for 1 year. She had normal neurological development and remained tumor-free through her 20-year follow-up. CONCLUSION: The authors report this rare case of congenital posterior fossa teratoma with long-term outcome, and the literature is reviewed.

Intracranial Dystrophic Calcification of Ventriculoperitoneal Shunt: A Case Report.

Ventriculoperitoneal (VP) shunting is one of the most common simple neurosurgical procedures. VP shunt catheters are made of silicone-coated Silastic tubes, which are made to be inert and hardly induce any reaction in normal tissue. We report a rare case of an extensive intracranial calcification of a VP shunt. This is a very rare case of a documented extensive calcification around the ventricular catheter of a VP shunt. We review the previously reported cases in the literature and present our management of the case. We discuss the possible mechanisms for such a dystrophic calcification around a VP shunt.

Physician awareness of decompressive hemicraniectomy for malignant middle cerebral artery infarction in Saudi Arabia and the Gulf countries.

OBJECTIVE: To explore the perspective on Decompressive craniectomy (DH) of each of these specialties to establish common grounds for improved clinical practice. METHODS: An electronic survey was distributed via email and social media groups to members of these specialties in Kingdom of Saudi Arabia and the Gulf countries. Local practices, common triggers for referral for DH, perceived outcomes of these procedures, individual impression of what constitutes good clinical outcomes were explored. RESULTS: There are 89 physicians participated: 41 (46.1%) neurologists, 34 (38.2%) neurosurgeons, and 14 (15.7%) intensivests. Participants are mostly practicing in intermediate volume centers or high volume centers. Half of the neurosurgeons preferred to be consulted immediately on candidates with large middle cerebral artery (MCA) strokes. The most important referral trigger for DH was clinical changes. The modified Rankin Scale (mRS) cutoff for good clinical outcome was 3 for 73.6% of respondents. There was agreement that DH only improves survival (64.4%). A third of the neurologists considered it to improve functional outcome compared to 15.4% of intensivests and 14.8% of neurosurgeons. There was agreement (66.7%) that patients older than 60 years with involvement of more than one territory should be excluded from DH. Only 7.7% of neurosurgeons excluded patients with dominant hemispheric strokes. CONCLUSION: Our physicians` views are variable in what`s called acceptable outcome, and further studies are needed to to test the characteristics that helps in decision making such as hemisphere dominancy, time onset of stroke and vital radiological signs. This is seen despite the literature being full of data that supports the DC over medical management in malignant MCA infarction. Better multidisciplinary education initiatives are needed to unify the understanding and help improve the practices in this challenging subset of patients.

Public awareness of central nervous system tumors in the Kingdom of Saudi Arabia.

OBJECTIVE: To investigate individuals` knowledge about central nervous system tumors (CNST) signs and symptoms and risk factors, as well as their readiness to seek medical advice. The signs and symptoms associated with CNSTs are often vague, and failure to recognize them could lead to delays in seeking help and possibly fatal results. METHODS: This was a cross-sectional survey that utilized 2 delivery methods. A total of 1,500 personally delivered and 1,500 online self-administered questionnaires were completed in parallel between June 2015 and June 2016 for the occupants of the Kingdom of Saudi Arabia. RESULTS: Significant differences were observed for the sociodemographic characteristics of participants recruited via the 2 methods. The most recognized symptom was "Headaches" (45.2%), and the most recognized risk factor was "Radioactive location/occupation" (84.1%). Overall knowledge scores were low, significantly predicted by employment and cancer contact (p<0.05), while the scores significantly higher for participants who were willing to see their doctors within a week (p<0.005). The most recognized barrier to seeking help was "Worry about what the doctor might find" (74.0%). CONCLUSION: The level of awareness of CNSTs was low. Using a questionnaire delivered in 2 different ways enabled the recruitment of sample pools with different sociodemographic characteristics.

Comprehensive molecular biomarker identification in breast cancer brain metastases.

BACKGROUND: Breast cancer brain metastases (BCBM) develop in about 20-30% of breast cancer (BC) patients. BCBM are associated with dismal prognosis not at least due to lack of valuable molecular therapeutic targets. The aim of the study was to identify new molecular biomarkers and targets in BCBM by using complementary state-of-the-art techniques. METHODS: We compared array expression profiles of three BCBM with 16 non-brain metastatic BC and 16 primary brain tumors (prBT) using a false discovery rate (FDR) p < 0.05 and fold change (FC) > 2. Biofunctional analysis was conducted on the differentially expressed probe sets. High-density arrays were employed to detect copy number variations (CNVs) and whole exome sequencing (WES) with paired-end reads of 150 bp was utilized to detect gene mutations in the three BCBM. RESULTS: The top 370 probe sets that were differentially expressed between BCBM and both BC and prBT were in the majority comparably overexpressed in BCBM and included, e.g. the coding genes BCL3, BNIP3, BNIP3P1, BRIP1, CASP14, CDC25A, DMBT1, IDH2, E2F1, MYCN, RAD51, RAD54L, and VDR. A number of small nucleolar RNAs (snoRNAs) were comparably overexpressed in BCBM and included SNORA1, SNORA2A, SNORA9, SNORA10, SNORA22, SNORA24, SNORA30, SNORA37, SNORA38, SNORA52, SNORA71A, SNORA71B, SNORA71C, SNORD13P2, SNORD15A, SNORD34, SNORD35A, SNORD41, SNORD53, and SCARNA22. The top canonical pathway was entitled, role of BRCA1 in DNA damage response. Network analysis revealed key nodes as Akt, ERK1/2, NFkB, and Ras in a predicted activation stage. Downregulated genes in a data set that was shared between BCBM and prBT comprised, e.g. BC cell line invasion markers JUN, MMP3, TFF1, and HAS2. Important cancer genes affected by CNVs included TP53, BRCA1, BRCA2, ERBB2, IDH1, and IDH2. WES detected numerous mutations, some of which affecting BC associated genes as CDH1, HEPACAM, and LOXHD1. CONCLUSIONS: Using complementary molecular genetic techniques, this study identified shared and unshared molecular events in three highly aberrant BCBM emphasizing the challenge to detect new molecular biomarkers and targets with translational implications. Among new findings with the capacity to gain clinical relevance is the detection of overexpressed snoRNAs known to regulate some critical cellular functions as ribosome biogenesis.

Decompressive hemicraniectomy for malignant middle cerebral artery infarction. Experience from the Western Province of Saudi Arabia.

OBJECTIVE: To describe our experience implementing decompressive hemicraniectomy (DH) for eligible patients with malignant middle cerebral artery (MCA) infarcts. METHODS: We retrospectively collected data of malignant MCA infarction patients requiring DH at King Abdulaziz University Hospital & King Faisal Specialist Hospital & Research Center, Jeddah, Kingdom of Saudi Arabia between October 2010 and July 2015. Clinical outcome was assessed immediately postoperatively using Glasgow Coma Score (GCS), and at 12 months using the modified Rankin scale (mRS) and Barthel index. Survival was evaluated at thirty-days and one year after surgery. RESULTS: Six out of 10 patients diagnosed with malignant MCA infarction underwent DH. Among the surgically treated patients (n=6), 4 were males (66%), and the median age was 22.5 years. The median time from admission to surgery was 35.5 hours. The median post-operative GCS was 6.5. Three patients (50%) died within 30 days of DH. In those who survived, the median mRS was 4.5 and BI was 7.5. CONCLUSION: Decompressive hemicraniectomy saves life and has the potential of improving survival functional outcome when done fast and in carefully selected patients. We call for national awareness of the management of such cases and early intervention.

Publications pattern of clinical epilepsy research in Saudi Arabia.

OBJECTIVE: To assess the progress in the field clinical epilepsy in Saudi Arabia, by analyzing in depth the research output productivity and publication pattern, and to identify the current situation of epilepsy research and offer solutions. METHODS: Literature search strategy was designed to retrieve accessible articles that are related to epilepsy utilizing PubMed, Google Scholar, and Embase. The retrieved articles were analyzed with several parameters, then evaluated using Oxford Center of Evidence Based Medicine level of evidence scale. RESULTS: Of all identified articles, 90 were conducted in Kingdom of Saudi Arabia and therefore were included. The included articles had a frequency of only 3.5 publications per year, and growth of 24.4% between the periods of 1990-2003 and 2004-2016. Only 13.3% of the articles were related to surgical epilepsy but the majority (86.7%) were related to medical epilepsy. Many articles (53.3%) were level III studies. The most common study design was retrospective studies in 35.6%, and the citations number ranged from 1-289 (Mean=7). CONCLUSION: Pattern of publications in clinical epilepsy researches revealed a slow growth rate in the frequency and a lower significance in the quality throughout the past 26 years. Active institutional and national promotion of clinical research is needed to help assess and therefore improve the quality of the provided epilepsy services.

De novo glioblastoma in the territory of a recent middle cerebral artery infarction and a residual meningioma: pathogenesis revisited.

BACKGROUND: The pathogenesis of glioblastoma is complex, and the implicated molecular mechanisms are yet to be understood. There are scattered reports describing a possible relationship between meningioma and glioblastoma and more rarely a relationship between infarction and glioblastoma. CASE PRESENTATION: We are reporting a 32-year-old male who developed left middle cerebral artery (MCA) infarction as a surgical complication for sphenoid meningioma. He developed recurrent symptoms 4 months later due to development of a glioblastoma adjacent to both the territory of the prior MCA infarct and the residual meningioma. CONCLUSIONS: This case adds further contribution to the literature of the possible pathological association between glioblastoma and brain infarction on a background of meningioma.

Essentials of research methods in neurosurgery and allied sciences for research, appraisal and application of scientific information to patient care (Part I).

Every neurosurgeon ought to be acquainted with the basics of research methods to enhance the comprehension of the research process and critical appraisal procedures of a scientific write-up. This in turn will ensure the appropriate application of scientific knowledge to patient care. Recent publications reveal that a significant proportion of articles published in neurosurgery are mislabeled with dire consequences on the sorting and indexing of evidence. Furthermore, many clinicians report that they feel unqualified to read the medical literature critically hence, it is for this reason that we conducted this review. Herein, we present a simple algorithm to facilitate the comprehension of research methods, as well as elucidate on the anatomy of common study designs in neurosurgery. Illustrative examples are provided when necessary. Understanding research methods and the critical analysis of published reports of clinical investigation is a fundamental skill of the physician to enable the incorporation of new clinical knowledge to practice.

Evidence-based neurosurgery. Basic concepts for the appraisal and application of scientific information to patient care (Part II).

Medical evidence is obtainable from approaches, which might be descriptive, analytic and integrative and ranked into levels of evidence, graded according to quality and summarized into strengths of recommendation. Sources of evidence range from expert opinions through well-randomized control trials to meta-analyses. The conscientious, explicit, and judicious use of current best evidence in making decisions related to the care of individual patients defines the concept of evidence-based neurosurgery (EBN). We reviewed reference books of clinical epidemiology, evidence-based practice and other previously related articles addressing principles of evidence-based practice in neurosurgery. Based on existing theories and models and our cumulative years of experience and expertise conducting research and promoting EBN, we have synthesized and presented a holistic overview of the concept of EBN. We have also underscored the importance of clinical research and its relationship to EBN. Useful electronic resources are provided. The concept of critical appraisal is introduced.

Outcome of intracranial arterial stenting of symptomatic atherosclerotic disease: A single center experience from Saudi Arabia.

OBJECTIVE: To present our local experience with intracranial angioplasty and stenting used for the treatment of symptomatic intracranial stenosis to assess its safety, efficacy, and outcome. METHODS: This is a retrospective review of all the patients with symptomatic intracranial atherosclerotic disease who underwent endovascular treatment in King Faisal Specialist Hospital and research center, Jeddah, Kingdom of Saudi Arabia from January 2003 to December 2014. Clinical, procedural, and outcome variables were gathered. RESULTS: We identified 22 patients who were referred for stenting of symptomatic intracranial atherosclerotic stenosis. In all but 3, the stents were deployed successfully (86% procedural success rate). The procedure was carried out under conscious sedation in 32%. Excellent flow was restored immediately in all successfully-stented cases. Post procedural strokes occurred in 4 patients (17.4%). One non-neurological death was identified in a patient who suffered a major post procedural stroke (4.3%). CONCLUSION: Intracranial atherosclerotic disease is not uncommon in our population. Angioplasty and stenting might be a valid option for the treatment of patients with recurrent symptoms despite optimal medical treatment.

De Novo intracerebral aneurysm in a child with acquired immunodeficiency syndrome.

Human immunodeficiency virus (HIV) infection associated aneurysmal vasculopathy is a rare complication of HIV infection affecting the pediatric and adult population. We present a case of a 7-year-old male child known to have a congenitally acquired HIV infection presenting with a ruptured left distal internal carotid artery fusiform aneurysm that was diagnosed on MRI scans 6 months prior to his presentation. He underwent craniotomy and successful aneurysm reconstruction. He had uncomplicated postoperative course and experienced a good recovery. This case is among the few reported pediatric cases of HIV-associated cerebral arteriopathy to undergo surgery. We also reviewed the relevant literature of this rare condition.

Acute paraplegia caused by Schistosoma mansoni.

Schistosomiasis affects over 200 million people worldwide. Involvement of the CNS is a rare occurrence. We report 2 young males who presented with rapidly progressing paraparesis associated with urinary incontinence. In both cases, MRI of the spine demonstrated a diffusely enhancing mass at the conus medullaris with extensive spinal cord edema. Laboratory investigations revealed mild peripheral eosinophilia and abnormal, but non-specific, CSF analysis. In one patient, the diagnosis was made based on a rising schistosomal titer with a positive rectal biopsy. In the other patient, spinal cord biopsy revealed a granuloma. Both cases were caused by Schistosoma mansoni and patients were treated with praziquantel and steroid therapy. They both made a remarkable neurological recovery. We emphasize that a high index of suspicion should be raised in the differential diagnosis of transverse myelitis in endemic areas.

Subependymal Giant Cell Astrocytoma Apoplexy: A Case Report and Systematic Review.

Subependymal giant cell astrocytoma (SEGA) is the most common intracranial tumor in tuberous sclerosis (TS) patients. The tumor generally localizes in the proximity of Monro's foramen; as it grows, it subsequently causes hydrocephalus and increases intracranial pressure (ICP). However, acute symptoms of increased ICP due to intratumoral bleeding rarely manifest in SEGA patients. We present a 27-year-old male with TS who presented due to hemorrhagic complications of SEGA with intratumoral bleeding and vitreous orbital hemorrhage. We then conducted a systematic review with four databases (PubMed, Web of Science, Google Scholar, and Cochrane) to identify similar cases using the following keywords: "Subependymal giant cell astrocytoma," "Hemorrhage," "Haemorrhage," and "Bleeding." Our review identified 12 articles reporting 14 cases of hemorrhagic complications of SEGA in addition to our case report. The median age of diagnosis was 21 (range 5-79) years with unequal gender distribution (M:F ratio, 11:4). Headache was the most presented symptom, followed by hemiparesis, seizure, altered mental status, visual deterioration, and headache accompanied by seizure. TS was seen in most of the cases (80%). Gross total resection (GTR) was achieved in 53.5% of the patients. Regarding the clinical outcome, 66.7% had a good outcome, 20% died, and 13.3% had no report of their outcomes. No tumor recurrence was seen in the cases with a reported duration of follow-up. Catastrophic presentation of SEGA apoplexy is a rare occurrence. We present a case report with a systematic review and discuss SEGA apoplexy's possible pathophysiology and outcome.

Programmable Versus Differential Pressure Ventriculoperitoneal Shunts for Pediatric Hydrocephalus: A 20-Year Single-Center Experience From Saudi Arabia.

Background Shunt malfunction is the most common complication after ventriculoperitoneal shunt (VPS) insertion for pediatric hydrocephalus. The incidence of shunt malfunction and the need for VPS revision may be related to the type of valve used in the shunt. Therefore, we aimed to compare the outcome of VPS in the pediatric age group stratified by differential pressure valves (DPV) and programmable shunt valves (PSV). Materials and methods This ethics-approved retrospective study was conducted at a tertiary care hospital in Saudi Arabia. We included 175 children with congenital hydrocephalus who underwent a shunt insertion or revision between 2003 and 2018 and followed them up to December 2022. The VPS complication and revision rates were compared with the patient's demographics and shunt valve types. The Kaplan-Meier method, log-rank test, and univariate and multivariate Cox proportional hazards regression were used to analyze several variables and subsequent shunt revisions. Results Females represented 52% of the study participants, and the mean age of the patients was 21.7 ± 38.4 months. The main indication for VPS was congenital hydrocephalus due to aqueductal stenosis (40%). The differential shunt valve was used in 78.9% and the PSV in 21.1% of the patients. Surgical complications occurred in 33.7% of the patients. Shunt malfunction and infection occurred in 16% and 11.4% of the patients, respectively. The VPS revision rate was significantly lower when PSV was used (odds ratio = 0.39, P < 0.05). Conclusion Overall, one-third of the studied pediatric cohort required shunt revision at some point during the 15-year follow-up. However, children with PSV had fewer revision rate-related complications compared to children with DPV during the first five years of follow-up.

Desmodin and isopongachromene as potential inhibitors of cyclin-dependent kinase 5: phytoconstituents targeting anticancer and neurological therapy.

Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine-threonine protein kinase vital for neuronal cell cycle arrest and differentiation. It activates by binding with p35 and p39 and is important for the functioning of the nervous system. A growing body of evidence suggests that CDK5 contributes to the onset and progression of neurodegeneration and tumorigenesis and represents itself as a potential therapeutic target. Our research illustrates virtual screening of phytochemicals from the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) library to search for potential inhibitors of CDK5. Initially, the compounds from the parent library were filtered out via their physicochemical properties following the Lipinski rule of five. Then sequentially, molecular docking-based virtual screening, PAINS filter, ADMET, PASS analysis, and molecular dynamics (MD) simulation were done using various computational tools to rule out adversities that can cause hindrances in the identification of potential inhibitors of CDK5. Finally, two compounds were selected via the extensive screening showing significant binding with CDK5 ATP-binding pocket and ultimately were selected as potent ATP-competitive inhibitors of CDK5. Finally, we propose that the elucidated compounds Desmodin and Isopongachromene can be used further in the drug discovery process and act as therapeutics in the medical industry to treat certain complex diseases, including cancer and neurodegeneration.Communicated by Ramaswamy H. Sarma.

Remote cerebellar hemorrhage in neurosurgery.

Remote cerebellar hemorrhage (RCH) is a rare complication in neurosurgery that remains enigmatic both in underlying mechanism and clinical behavior. The range of procedures associated with RCH is diverse and includes both supratentorial and spinal procedures that entail significant CSF loss or lesion resection. The risk factors identified in the literature are not sufficient in predicting the patients at risk of developing RCH. It thereby remains an unpredictable hazard that requires better understanding of its pathophysiology. This study is a comprehensive review of the available literature to provide an understanding of where it stands so far, and to explain an observation in the literature that may have implications for better understanding the disease. Areas of future research are also identified.