lncRNA Biomarkers of Glioblastoma Multiforme.

Long noncoding RNAs (lncRNAs) are RNA molecules of 200 nucleotides or more in length that are not translated into proteins. Their expression is tissue-specific, with the vast majority involved in the regulation of cellular processes and functions. Many human diseases, including cancer, have been shown to be associated with deregulated lncRNAs, rendering them potential therapeutic targets and biomarkers for differential diagnosis. The expression of lncRNAs in the nervous system varies in different cell types, implicated in mechanisms of neurons and glia, with effects on the development and functioning of the brain. Reports have also shown a link between changes in lncRNA molecules and the etiopathogenesis of brain neoplasia, including glioblastoma multiforme (GBM). GBM is an aggressive variant of brain cancer with an unfavourable prognosis and a median survival of 14-16 months. It is considered a brain-specific disease with the highly invasive malignant cells spreading throughout the neural tissue, impeding the complete resection, and leading to post-surgery recurrences, which are the prime cause of mortality. The early diagnosis of GBM could improve the treatment and extend survival, with the lncRNA profiling of biological fluids promising the detection of neoplastic changes at their initial stages and more effective therapeutic interventions. This review presents a systematic overview of GBM-associated deregulation of lncRNAs with a focus on lncRNA fingerprints in patients' blood.

Biomolecules to Biomarkers? U87MG Marker Evaluation on the Path towards Glioblastoma Multiforme Pathogenesis.

The heterogeneity of the glioma subtype glioblastoma multiforme (GBM) challenges effective neuropathological treatment. The reliance on in vitro studies and xenografted animal models to simulate human GBM has proven ineffective. Currently, a dearth of knowledge exists regarding the applicability of cell line biomolecules to the realm of GBM pathogenesis. Our study's objectives were to address this preclinical issue and assess prominin-1, ICAM-1, PARTICLE and GAS5 as potential GBM diagnostic targets. The methodologies included haemoxylin and eosin staining, immunofluorescence, in situ hybridization and quantitative PCR. The findings identified that morphology correlates with malignancy in GBM patient pathology. Immunofluorescence confocal microscopy revealed prominin-1 in pseudo-palisades adjacent to necrotic foci in both animal and human GBM. Evidence is presented for an ICAM-1 association with degenerating vasculature. Significantly elevated nuclear PARTICLE expression from in situ hybridization and quantitative PCR reflected its role as a tumor activator. GAS5 identified within necrotic GBM validated this potential prognostic biomolecule with extended survival. Here we present evidence for the stem cell marker prominin-1 and the chemotherapeutic target ICAM-1 in a glioma animal model and GBM pathology sections from patients that elicited alternative responses to adjuvant chemotherapy. This foremost study introduces the long non-coding RNA PARTICLE into the context of human GBM pathogenesis while substantiating the role of GAS5 as a tumor suppressor. The validation of GBM biomarkers from cellular models contributes to the advancement towards superior detection, therapeutic responders and the ultimate attainment of promising prognoses for this currently incurable brain cancer.

MRI of cerebral oedema in ischaemic stroke and its current use in routine clinical practice.

Currently, with the knowledge of the role of collateral circulation in the development of cerebral ischaemia, traditional therapeutic windows are being prolonged, with time not being the only criterion. Instead, a more personalised approach is applied to select additional patients who might benefit from active treatment. This review briefly describes the current knowledge of the pathophysiology of the development of early ischaemic changes, the capabilities of MRI to depict such changes, and the basics of the routinely used imaging techniques broadly available for the assessment of individual phases of cerebral ischaemia, and summarises the possible clinical use of routine MR imaging, including patient selection for active treatment and assessment of the outcome on the basis of imaging.

The role of abdominal ultrasonography in patients with isoattenuating pancreatic carcinoma.

AIMS: The main objective of this study was to determine the sensitivity of abdominal ultrasonography (US) in patients with isoattenuating pancreatic carcinoma and to compare the frequency of secondary signs on abdominal US and endoscopic ultrasonography (EUS) in these tumours. METHODS: Twenty-four patients with histologically or cytologically verified isoattenuating pancreatic carcinoma who underwent abdominal US, contrast-enhanced CT and EUS of the pancreas as part of the diagnostic workup were included in this retrospective study. The sensitivity of abdominal US in detecting the isoattenuating pancreatic carcinoma was investigated and the frequency of secondary signs of isoattenuating pancreatic carcinoma on abdominal US and EUS was compared. RESULTS: In 5 of 24 patients (21%) with isoattenuating pancreatic carcinoma, a hypoechogenic pancreatic lesion was directly visualised on abdominal US. Secondary signs were present on US in 21 patients (88%). These included dilatation of the common bile duct and/or intrahepatic bile ducts in 19/24 (79%), dilatation of the pancreatic duct in 3/24 (13%), abnormal contour/inhomogeneity of the pancreas in 1/24 (4%), and atrophy of the distal parenchyma in 1/24 (4%). Pancreatic duct dilatation was observed more frequently on EUS than on abdominal US (P=0.002). For other secondary signs, there was no significant difference in their detection on abdominal US and EUS (P=0.61-1.00). CONCLUSION: Abdominal US is capable of detecting secondary signs of isoattenuating pancreatic carcinoma with high sensitivity and has the potential to directly visualise these tumours.

COMIRESTROKE-A clinical study protocol for monitoring clinical effect and molecular biological readouts of COMprehensive Intensive REhabilitation program after STROKE: A four-arm parallel-group randomized double blinded controlled trial with a longitudinal design.

Introduction: While the role of physiotherapy as part of a comprehensive inpatient rehabilitation is indisputable, clear evidence concerning the effectiveness of different rehabilitation managements [interdisciplinary implementing the International Classification of Functioning, disability and health (ICF) vs. multidisciplinary model] and physiotherapy categories (neuroproprioceptive "facilitation, inhibition" vs. motor/skill acquisitions using technologies) are still lacking. In this study, four kinds of comprehensive inpatient rehabilitation with different management and content of physical therapy will be compared. Moreover, focus will be placed on the identification of novel biological molecules reflective of effective rehabilitation. Long non-coding RNAs (lncRNAs) are transcripts (>200 bps) of limited coding potential, which have recently been recognized as key factors in neuronal signaling pathways in ischemic stroke and as such, may provide a valuable readout of patient recovery and neuroprotection during therapeutic progression. Methods and analysis: Adults after the first ischemic stroke in an early sub-acute phase with motor disability will be randomly assigned to one of four groups and undergo a 3 weeks comprehensive inpatient rehabilitation of different types: interdisciplinary team work using ICF model as a guide; multidisciplinary teamwork implementing neuroproprioceptive "facilitation and inhibition" physiotherapy; multidisciplinary teamwork implementing technology-based physiotherapy; and standard multidisciplinary teamwork. Primary (the Goal Attainment Scale, the Patient-Reported Outcomes Measurement Information System, and the World Health Organization Disability Assessment Schedule) and secondary (motor, cognitive, psychological, speech and swallowing functions, functional independence) outcomes will be measured. A blood sample will be obtained upon consent (20 mls; representing pre-rehabilitation molecular) before and after the inpatient program. Primary outcomes will be followed up again 3 and 12 months after the end of the program. The overarching aim of this study is to determine the effectiveness of various rehabilitation managements and physiotherapeutic categories implemented by patients post ischemic stroke via analysis of primary, secondary and long non-coding RNA readouts. This clinical trial will offer an innovative approach not previously tested and will provide new complex analysis along with public assessable molecular biological evidence of various rehabilitation methodology for the alleviation of the effects of ischemic stroke. Clinical trial registration: NCT05323916, https://clinicaltrials.gov/ct2/show/NCT05323916.

The Immunological Epigenetic Landscape of the Human Life Trajectory.

Adaptive immunity changes over an individual's lifetime, maturing by adulthood and diminishing with old age. Epigenetic mechanisms involving DNA and histone methylation form the molecular basis of immunological memory during lymphocyte development. Monocytes alter their function to convey immune tolerance, yet the epigenetic influences at play remain to be fully understood in the context of lifespan. This study of a healthy genetically homogenous cohort of children, adults and seniors sought to decipher the epigenetic dynamics in B-lymphocytes and monocytes. Variable global cytosine methylation within retro-transposable LINE-1 repeats was noted in monocytes compared to B-lymphocytes across age groups. The expression of the human leukocyte antigen (HLA)-DQ alpha chain gene HLA-DQA1*01 revealed significantly reduced levels in monocytes in all ages relative to B-lymphocytes, as well as between lifespan groups. High melting point analysis and bisulfite sequencing of the HLA-DQA1*01 promoter in monocytes highlighted variable cytosine methylation in children and seniors but greater stability at this locus in adults. Further epigenetic evaluation revealed higher histone lysine 27 trimethylation in monocytes from this adult group. Chromatin immunoprecipitation and RNA pulldown demonstrated association with a novel lncRNA TINA with structurally conserved similarities to the previously recognized epigenetic modifier PARTICLE. Seeking to interpret the epigenetic immunological landscape across three representative age groups, this study focused on HLA-DQA1*01 to expose cytosine and histone methylation alterations and their association with the non-coding transcriptome. Such insights unveil previously unknown complex epigenetic layers, orchestrating the strength and weakening of adaptive immunity with the progression of life.

Joint Analysis of Phenotypic and Genomic Diversity Sheds Light on the Evolution of Xenobiotic Metabolism in Humans.

Variation in genes involved in the absorption, distribution, metabolism, and excretion of drugs (ADME) can influence individual response to a therapeutic treatment. The study of ADME genetic diversity in human populations has led to evolutionary hypotheses of adaptation to distinct chemical environments. Population differentiation in measured drug metabolism phenotypes is, however, scarcely documented, often indirectly estimated via genotype-predicted phenotypes. We administered seven probe compounds devised to target six cytochrome P450 enzymes and the P-glycoprotein (P-gp) activity to assess phenotypic variation in four populations along a latitudinal transect spanning over Africa, the Middle East, and Europe (349 healthy Ethiopian, Omani, Greek, and Czech volunteers). We demonstrate significant population differentiation for all phenotypes except the one measuring CYP2D6 activity. Genome-wide association studies (GWAS) evidenced that the variability of phenotypes measuring CYP2B6, CYP2C9, CYP2C19, and CYP2D6 activity was associated with genetic variants linked to the corresponding encoding genes, and additional genes for the latter three. Instead, GWAS did not indicate any association between genetic diversity and the phenotypes measuring CYP1A2, CYP3A4, and P-gp activity. Genome scans of selection highlighted multiple candidate regions, a few of which included ADME genes, but none overlapped with the GWAS candidates. Our results suggest that different mechanisms have been shaping the evolution of these phenotypes, including phenotypic plasticity, and possibly some form of balancing selection. We discuss how these contrasting results highlight the diverse evolutionary trajectories of ADME genes and proteins, consistent with the wide spectrum of both endogenous and exogenous molecules that are their substrates.

Enhanced Extracellular Transfer of HLA-DQ Activates CD3+ Lymphocytes towards Compromised Treg Induction in Celiac Disease.

Celiac disease (CeD) manifests with autoimmune intestinal inflammation from gluten and genetic predisposition linked to human leukocyte antigen class-II (HLA-II) gene variants. Antigen-presenting cells facilitate gluten exposition through the interaction of their surface major histocompatibility complex (MHC) with the T cell receptor (TCR) on T lymphocytes. This fundamental mechanism of adaptive immunity has broadened upon recognition of extracellular exosomal MHC, raising awareness of an alternative means for antigen presentation. This study demonstrates that conditioned growth media (CGM) previously exposed to monocyte-derived dendritic cells from CeD significantly downregulates the CD3+ lineage marker of control T cells. Such increased activation was reflected in their elevated IL-2 secretion. Exosome localization motif identification and quantification within HLA-DQA1 and HLA-DQB1 transcripts highlighted their significant prevalence within HLA-DQB1 alleles associated with CeD susceptibility. Flow cytometry revealed the strong correlation between HLA-DQ and the CD63 exosomal marker in T cells exposed to CGM from MoDCs sourced from CeD patients. This resulted in lower concentrations of CD25+ CD127- T cells, suggestive of their compromised induction to T-regulatory cells associated with CeD homeostasis. This foremost comparative study deciphered the genomic basis and extracellular exosomal effects of HLA transfer on T lymphocytes in the context of CeD, offering greater insight into this auto-immune disease.

Celiac Disease Defined by Over-Sensitivity to Gliadin Activation and Superior Antigen Presentation of Dendritic Cells.

The autoimmune condition, Celiac Disease (CeD), displays broad clinical symptoms due to gluten exposure. Its genetic association with DQ variants in the human leukocyte antigen (HLA) system has been recognised. Monocyte-derived mature dendritic cells (MoDCs) present gluten peptides through HLA-DQ and co-stimulatory molecules to T lymphocytes, eliciting a cytokine-rich microenvironment. Having access to CeD associated families prevalent in the Czech Republic, this study utilised an in vitro model to investigate their differential monocyte profile. The higher monocyte yields isolated from PBMCs of CeD patients versus control individuals also reflected the greater proportion of dendritic cells derived from these sources following lipopolysaccharide (LPS)/ peptic-tryptic-gliadin (PTG) fragment stimulation. Cell surface markers of CeD monocytes and MoDCs were subsequently profiled. This foremost study identified a novel bio-profile characterised by elevated CD64 and reduced CD33 levels, unique to CD14++ monocytes of CeD patients. Normalisation to LPS stimulation revealed the increased sensitivity of CeD-MoDCs to PTG, as shown by CD86 and HLA-DQ flow cytometric readouts. Enhanced CD86 and HLA-DQ expression in CeD-MoDCs were revealed by confocal microscopy. Analysis highlighted their dominance at the CeD-MoDC membrane in comparison to controls, reflective of superior antigen presentation ability. In conclusion, this investigative study deciphered the monocytes and MoDCs of CeD patients with the identification of a novel bio-profile marker of potential diagnostic value for clinical interpretation. Herein, the characterisation of CD86 and HLA-DQ as activators to stimulants, along with robust membrane assembly reflective of efficient antigen presentation, offers CeD targeted therapeutic avenues worth further exploration.

All-Trans Retinoic Acid Fosters the Multifarious U87MG Cell Line as a Model of Glioblastoma.

Glioblastoma multiforme (GBM) is a primary brain cancer of poor prognosis, with existing treatments remaining essentially palliative. Current GBM therapy fails due to rapid reappearance of the heterogeneous neoplasm, with models suggesting that the recurrent growth is from treatment-resistant glioblastoma stem-like cells (GSCs). Whether GSCs depend on survival/proliferative cues from their surrounding microenvironmental niche, particularly surrounding the leading edge after treatment remains unknown. Simulating human GBM in the laboratory relies on representative cell lines and xenograft models for translational medicine. Due to U87MG source discrepancy and differential proliferation responses to retinoic acid treatment, this study highlights the challenges faced by laboratory scientists working with this representative GBM cell line. Investigating the response to all trans-retinoic acid (ATRA) revealed its sequestering of the prominin-1 stem cell marker. ICAM-1 universally present throughout U87MG was enhanced by ATRA, of interest for chemotherapy targeting studies. ATRA triggered diverse expression patterns of long non-coding RNAs PARTICLE and GAS5 in the leading edge and established monolayer growth zone microenvironment. Karyotyping confirmed the female origin of U87MG sourced from Europe. Passaging U87MG revealed the presence of chromosomal anomalies reflective of structural genomic alterations in this glioblastoma cell line. All evidence considered, this study exposes further phenotypic nuances of U87MG which may belie researchers seeking data contributing towards the elusive cure for GBM.

Improvement of the Diagnosis of Isoattenuating Pancreatic Carcinomas by Defining their Characteristics on Contrast Enhanced Computed Tomography and Endosonography with Fine-Needle Aspiration (EUS-FNA).

(1) Background. The aim was to define typical features of isoattenuating pancreatic carcinomas on computed tomography (CT) and endosonography and determine the yield of fine-needle aspiration endosonography (EUS-FNA) in their diagnosis. (2) Methods. One hundred and seventy-three patients with pancreatic carcinomas underwent multiphase contrast-enhanced CT followed by EUS-FNA at the time of diagnosis. Secondary signs on CT, size and location on EUS, and the yield of EUS-FNA in isoattenuating and hypoattenuating pancreatic cancer, were evaluated. (3) Results. Isoattenuating pancreatic carcinomas occurred in 12.1% of patients. Secondary signs of isoattenuating pancreatic carcinomas on CT were present in 95.2% cases and included dilatation of the pancreatic duct and/or the common bile duct (85.7%), interruption of the pancreatic duct (76.2%), abnormal pancreatic contour (33.3%), and atrophy of the distal parenchyma (9.5%) Compared to hypoattenuating pancreatic carcinomas, isoattenuating carcinomas were more often localized in the pancreatic head (100% vs. 59.2%; p < 0.001). In ROC (receiver operating characteristic) analysis, the optimal cut-off value for the size of isoattenuating carcinomas on EUS was ≤ 25 mm (AUC = 0.898). The sensitivity of EUS-FNA in confirmation of isoattenuating and hypoattenuating pancreatic cancer were 90.5% and 92.8% (p = 0.886). (4) Conclusions. Isoattenuating pancreatic head carcinoma can be revealed by indirect signs on CT and confirmed with high sensitivity by EUS-FNA.

Is endovascular treatment of aorto-iliac aneurysms with simultaneous unilateral revascularization of internal iliac artery by branched iliac stentgraft sufficient?

AIMS: The coverage / occlusion of internal iliac artery (IIA) during endovascular treatment of aorto-iliac aneurysms (AIA) can be associated with risk of ischemic complications. To reduce these complications, unilateral or bilateral iliac branch device implantation (IBDI) has been reported. This study aims at evaluating the efficacy of simultaneous unilateral IBDI in the treatment of AIAs and comparing our results with literature. MATERIALS AND METHODS: From March 2010 to December 2019, 27 patients (25 men, 2 women, range 54-84 years) were treated for aorto-iliac/isolated common iliac aneurysms with simultaneous unilateral revascularization of IIA and surgical / endovascular occlusion of contralateral IIA. 27 iliac-branched devices were implanted in 27 patients. The results including ischemic complications were evaluated and compared with literature. RESULTS: The technical success was 100% with no perioperative mortality and morbidity of 3.7%. Primary internal iliac branch patency at a median follow-up of 52 months (range 1-118 months) was 96.42%. Secondary endoleak was observed in 6 patients (Type 1a [1], Type 1b [1], Type II [4]) and inflammatory complication in 1 patient. The incidence of buttock claudication one year after the procedure was 11.1%. Except for buttock claudication no other ischemic complications occurred. CONCLUSION: Unilateral flow preservation in the IIA territory using IBDI is associated with a lesser, but a certain risk of ischemic complications. Bilateral IBDI with bilateral flow preservation of IIAs increases the complexity, procedure -/ fluoroscopy times, contrast agent volume and cost, however, may further reduce these ischemic complications.

Estimating the radiation dose to the fetus during prophylactic internal iliac occlusion in patients with abnormal placentation.

AIMS: To evaluate the estimated fetal radiation dose during prophylactic internal iliac arterial occlusion in patients with abnormal placenta and to estimate the risk of radiation induced cancer in child age. METHODS: Prophylactic occlusion of the internal iliac arteries during Caesarean section was performed in 42 patients with placenta praevia and/or placenta accreta spectrum. Fogarty embolectomy catheters were used for prophylactic occlusion of the internal iliac arteries. All procedures were performed in the hybrid operating room using Philips Allura Xper FD 20 X-ray system. Low dose X-ray fluoroscopy (7.5 frames per second) was used. The CODE (Conceptus dose estimation) Software was used to estimate the fetal dose and the risk of radiation induced carcinoma. RESULTS: Fluoroscopy times required for insertion of Fogarty catheters were 0.5-4.2 min (mean: 1.7 min, median: 1.5 min). The estimated radiation dose to the fetus was 0.26-3.36 mGy (mean: 1.49 mGy, median: 1.25 mGy). The risk of radiation induced cancer in child age was 0.01-0.04% (mean 0.02%, median 0.01%). One patient developed thrombosis of a common femoral artery. CONCLUSION: Prophylactic occlusion of the internal iliac arteries is a simple and safe procedure with minimal risk of complications and with a very low estimated radiation dose to the fetus.

Distal Aneurysms of Cerebellar Arteries-Case Series.

(1) Background: Distal aneurysms of cerebellar arteries are very rare. The authors report their case series of distal aneurysms of the cerebellar arteries solved successfully by microsurgery or by endovascular treatment (Table 1) (2) Materials and Methods: Between January 2010 and March 2020, 346 aneurysms were treated in our institution. Eleven aneurysms in seven patients were located on distal cerebellar arteries and, in three patients, the aneurysms were combined with arteriovenous malformations. There were four women and three men, ranging from 50 to 72 years of age. Five patients presented with different grades of subarachnoid hemorrhage or intraventricular bleeding, and two patients were diagnosed because of headache. Aneurysm location was the posterior inferior cerebellar artery in six cases, the superior cerebellar artery in three cases, and the anterior inferior cerebellar artery in 2 cases. One patient had three aneurysms, and two patients had two aneurysms. (3) Results: Nine aneurysms were treated by microsurgery trapping or clipping and, in two patients, the associated arteriovenous malformation (AVM) was resected. Two aneurysms were treated by endovascular coiling, and one associated AVM was successfully embolized. Clinical follow-up was a mean of 11.5 months (range, 3-45 months). (4) Conclusion: The authors present their experience with the treatment of 11 peripheral aneurysms on distal branches of the cerebellar circulation in seven patients which were excluded from circulation by microsurgery or endovascular treatment. In three patients, the associated AVM was treated (two with microsurgery, one with embolization).

Safety of the Geneva Cocktail, a Cytochrome P450 and P-Glycoprotein Phenotyping Cocktail, in Healthy Volunteers from Three Different Geographic Origins.

INTRODUCTION AND OBJECTIVE: Cytochrome P450 enzymes are the major drug-metabolizing enzymes in humans and the importance of drug transport proteins, in particular P-glycoprotein, in the variability of drug response has also been highlighted. Activity of cytochrome P450 enzymes and P-glycoprotein can vary widely between individuals and genotyping and/or phenotyping can help assess their activity. Several phenotyping cocktails have been developed. The Geneva cocktail is composed of a specific probe for six different cytochrome P450 enzymes and one for P-glycoprotein and was used in the context of a research aiming at exploring genotypes and phenotypes in distinct human populations (NCT02789527). The aim of the present study is to solely report the safety results of the Geneva cocktail in the healthy volunteers of these populations. MATERIALS AND METHODS: The Geneva cocktail is composed of caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam, and fexofenadine. The volunteers fasted and avoided drinking caffeine-containing beverages or food and grapefruit juice overnight before receiving the cocktail orally. They provided blood spots for the probes' concentrations at 2, 3, and 6 h after ingestion and were asked about adverse events. RESULTS: A total of 265 healthy adult volunteers were included from Ethiopia, Oman, and the Czech Republic. The mean plasma concentrations at the 2-h sampling time of each probe drug in the total sample were: 1663 ng/mL for caffeine, 8 ng/mL for bupropion, 789 ng/mL for flurbiprofen, 6 ng/mL for dextromethorphan, 2 ng/mL for midazolam, 35 ng/mL for fexofenadine, and 103 ng/mL for omeprazole. Four adverse events were observed representing an occurrence of 1.5%. All these events were categorized as mild to moderate, non-serious, and resolved spontaneously. A causal link with the cocktail cannot be excluded because of the temporal relationship but is at most evaluated as possible according to the World Health Organization-Uppsala Monitoring Centre causal assessment system. CONCLUSIONS: In this research, healthy volunteers from three different human populations were phenotyped with the Geneva cocktail. Four adverse events were observed, confirming the safety of this cocktail that is given at lower than clinically relevant doses and therefore results in concentrations lower than those reported to cause adverse events.

Epigenetic Regulation of Circadian Rhythm and Its Possible Role in Diabetes Mellitus.

This review aims to summarize the knowledge about the relationship between circadian rhythms and their influence on the development of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Circadian rhythms are controlled by internal molecular feedback loops that synchronize the organism with the external environment. These loops are affected by genetic and epigenetic factors. Genetic factors include polymorphisms and mutations of circadian genes. The expression of circadian genes is regulated by epigenetic mechanisms that change from prenatal development to old age. Epigenetic modifications are influenced by the external environment. Most of these modifications are affected by our own life style. Irregular circadian rhythm and low quality of sleep have been shown to increase the risk of developing T2DM and other metabolic disorders. Here, we attempt to provide a wide description of mutual relationships between epigenetic regulation, circadian rhythm, aging process and highlight new evidences that show possible therapeutic advance in the field of chrono-medicine which will be more important in the upcoming years.

Low Levels of Glycemia within the First 48 Hours after Mechanical Thrombectomy for Acute Ischemic Stroke May be Associated with Better Clinical Outcome.

INTRODUCTION: Many different factors may have an impact on clinical outcome after mechanical thrombectomy (MT) for acute ischemic stroke (AIS). We aimed to investigate levels of serum glycemia (GLY) within the first 48 hours after MT. SUBJECTS AND METHODS: Consecutive AIS patients were enrolled in the retrospective bi-center study. Neurological deficit was assessed with National Institutes of Health Stroke Scale (NIHSS) and functional outcome after 3 months with modified Rankin scale with a score 0-2 for good outcome. Presence of symptomatic intracerebral hemorrhage was assessed according to the SITS- MOST criteria. RESULTS: In total, 868 patients (442 males, mean age 69.7 ± 12.2 years) with a median of admission NIHSS 17 points were enrolled in the study and 253 (29.1%) of them were diabetics. Recanalization was reached in 758 (87.3%) patients. Patients with good outcome (412, 47.5%) had lower median of GLY (6.5 versus 7.4 mmol/L, P < .0001) within the first 48 hours after MT. Similar results were found also in diabetics (8.1 versus 9.6 mmol/L, P < .0001) and in patients with achieved recanalization (6.5 versus 7.5 mmol/L, P < .0001). Multivariate regression analysis with adjustment for potential confounders showed median of GLY (P = .0001, odds ratio: 0.830, 95% confidence interval: 0.755-0.913) as a predictor of good outcome after MT. CONCLUSION: Lower levels of GLY within the first 48 hours after MT may be associated with better functional outcome after 3 months.

Unpacking Pandora From Its Box: Deciphering the Molecular Basis of the SARS-CoV-2 Coronavirus.

An enigmatic localized pneumonia escalated into a worldwide COVID-19 pandemic from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This review aims to consolidate the extensive biological minutiae of SARS-CoV-2 which requires decipherment. Having one of the largest RNA viral genomes, the single strand contains the genes ORF1ab, S, E, M, N and ten open reading frames. Highlighting unique features such as stem-loop formation, slippery frameshifting sequences and ribosomal mimicry, SARS-CoV-2 represents a formidable cellular invader. Hijacking the hosts translational engine, it produces two polyprotein repositories (pp1a and pp1ab), armed with self-cleavage capacity for production of sixteen non-structural proteins. Novel glycosylation sites on the spike trimer reveal unique SARS-CoV-2 features for shielding and cellular internalization. Affording complexity for superior fitness and camouflage, SARS-CoV-2 challenges diagnosis and vaccine vigilance. This review serves the scientific community seeking in-depth molecular details when designing drugs to curb transmission of this biological armament.

Influence of Prenatal Methamphetamine Abuse on the Brain.

Methamphetamine (MA), a psychostimulant, has become a serious problem in recent years. It is one of the most widely abused psychostimulants in the world. In the Czech Republic, ecstasy is the most commonly used non-cannabis drug, followed by hallucinogenic fungi, LSD, MA, cocaine, and finally heroin. The prevalence of the usage of all addictive substances is highest in the age category of 15-34. Approximately 17.2% of registered drug addicts, both male and female, in the Czech Republic use MA as their first-choice drug. This group consists mostly of women who are unemployed and addicted to MA (85%). Almost half of the addicted women switched to MA from other drugs in the course of pregnancy. Psychostimulants such as amphetamine and its synthetic derivate MA induce feelings of calm and happiness by suppressing anxiety and depression. When MA is abused for longer periods, it mimics symptoms of mania and can lead to the development of psychosis. MA is often abused for its anorectic effect, its simple preparation, and compared to heroin and cocaine, its low price. There are significant differences in the susceptibility of users to the stimulant, with reactions to MA fluctuating from person to person. Molecular mechanisms related to the variable response among users might represent an explanation for increased addiction-associated bipolar disorder and psychosis. Currently, there is limited information regarding genetic mechanisms linked to these disorders and the transmission of drug addiction. As such, animal models of drug addiction represent significant sources of information and assets in the research of these issues. The aim of this review is to summarize the mechanism of action of methamphetamine and its effect on pregnant addicted women and their children, including a detailed description of the anatomical structures involved.

Epigenetic Regulation in Etiology of Type 1 Diabetes Mellitus.

Type 1 diabetes mellitus (T1DM) is caused by an autoimmune destruction of the pancreatic ß-cells, a process in which autoreactive T cells play a pivotal role, and it is characterized by islet autoantibodies. Consequent hyperglycemia is requiring lifelong insulin replacement therapy. T1DM is caused by the interaction of multiple environmental and genetic factors. The integrations of environments and genes occur via epigenetic regulations of the genome, which allow adaptation of organism to changing life conditions by alternation of gene expression. T1DM has increased several-fold over the past half century. Such a short time indicates involvement of environment factors and excludes genetic changes. This review summarizes the most current knowledge of epigenetic changes in that process leading to autoimmune diabetes mellitus.