Molecular mechanisms of GBA-linked PD

Objective: To investigate the effect of GBA heterozygote L444P (wt/L444P) mutation in human dermal fibroblasts and mouse cortical neurons models (MCN) and find if glucocerebrosidase (GCase) deficiency in these cells impair the lysosomal function and induce unfolded protein response (UPR). In addition, to investigate the consequent impairment of alpha synuclein (A-SYN) metabolism in the form of increased intracellular accumulation and extracellular release of fibrillar A-SYN following seeding MCN and differentiated SH-SY5Y neuronal cultures with preformed A-SYN fibrils (PFFs). Background: GBA heterozygous mutations are numerically the most important predisposing factor for developing PD. They contribute to the earlier age of onset and increased cognitive decline in GBA-PD. L444P mutation is proposed to induce unfolded protein response (UPR) and perturbed autophagy pathways. This consequently can lead to impairment of (A-SYN) turnover and eventually result in the loss of substantia nigra dopaminergic cells, the most vulnerable type of cells affected in PD. It is hypothesized that A-SYN pathology can spread through brain regions to reach SNpc thereby supporting the prion-like theory. Fibrillar forms of A-SYN are thought to contribute to this spread as they can induce the endogenous A-SYN to recruit, misfold, and become insoluble aggregates like that observed in Lewy bodies. Methods: Functions of ALP and UPS, protein degradation pathways, were assessed in L444P heterozygous fibroblasts and MCN models. ER stress and UPR investigated in all disease models including fibroblasts, wt/L444P MCN and differentiated SH-SY5Y neurons overexpressing (O/E) L444P GBA. Both differentiated SH-SY5Y treated with the GCase inhibitor (CBE) and wt/L444P mutant MCN were incubated with PFFs to initiate A-SYN pathology. Misfolded and aggregated A-SYN was assessed by western blotting and dot blot. Results: wt/L444P fibroblasts and MCN cellular models showed no impairment of protein quality control systems. There was ER retention of mutant enzyme in wt/ L444P fibroblast but this was not enough to induce UPR in cells. There was also subtle or no alteration in endogenous A-SYN level in wt/L444P MCN and differentiated SH-SY5Y neurons treated with CBE until the addition of another stress such as PFFs seeding. Treating cells with PFFs for 10 days enhanced the recruitment and aggregation of endogenous A-SYN that were phosphorylated at Ser129 with evidence of HMW species. Differentiated SH-SY5Y neurons O/E wildtype SNCA and preloaded with PFFs showed enhanced extracellular release of fibrillar A-SYN. In addition, differentiated cells O/E L444P GBA, but not MCN or fibroblasts, showed evidence of ER stress and UPR. Conclusions: Wt/L444P MCN and differentiated SH-SY5Y dopaminergic neurons treated with CBE showed augmented A-SYN pathology. The increased release of pathogenic A-SYN fibrils was more evident in cells with higher endogenous A-SYN levels and only differentiated SHSY5Y cells O/E L444P GBA showed evidence of UPR

Brown Tumor of the Cervical Spines: A Case Report with Literature Review

To report a rare case of axis brown tumor and to review literature of cervical spine brown tumor. Brown tumor is a rare bone lesion, incidence less than 5% in primary hyperparathyroidism. It is more common in secondary hyperparathyroidism with up to 13% of cases. Brown tumor reactive lesion forms as a result of disturbed bone remodeling due to long standing increase in parathyroid hormones. Cervical spine involvement is extremely rare, can be confused with serous spine lesions. To date, only four cases of cervical spine involvement have been reported. Three were due to secondary hyperparathyroidism. Only one was reported to involve the axis and was due to secondary hyperparathyroidism. This is the first reported case of axis brown tumor due to primary hyperparathyroidism. A case report of brown tumor is presented. A literature review was conducted by a Medline search of reported cases of brown tumor, key words: brown tumor, osteoclastoma and cervical lesions. The resulting papers were reviewed and cervical spine cases were listed then classified according to the level, cause, and management. Only four previous cases involved the cervical spine. Three were caused by secondary hyperparathyroidism and one was by primary hyperparathyroidism which involved the C6. Our case was the first case of C2 involvement of primary hyperparathyroidism and it was managed conservatively. Brown tumor, a rare spinal tumor that presents with high PTH and giant cells, requires a high level of suspicion

Epidemiology Of Cataract, Role Of Nursing, Optometrist, General Practitioner And Pharmacist In Management Strategies

A cataract is an ocular condition in which the typically transparent lens becomes opaque, hindering the transmission of light. It is a condition that progresses slowly over time and is a major contributor to blindness worldwide. This activity demonstrates the assessment and therapy of cataracts and examines the involvement of the interprofessional team in caring for people with this condition. Several symptoms may remain undetected for an extended period of time, however, timely identification could assist patients in acquiring the skills to cope with the slow decline in eyesight, thereby enabling them to keep a high standard of living for as long as feasible. While cataract surgery is generally safe, it might lead to consequences including retinal detachment. Therefore, there is a need to find cost-effective pharmaceutical alternatives for treating this eye condition. The lens possesses a highly developed network of non-enzymatic and enzymatic antioxidants that eliminate reactive oxygen species in order to protect lens proteins. The depletion or failure of the major antioxidant defense system leads to damage in lenticular molecules and their repair mechanisms, ultimately resulting in the development of cataracts. Hence, the nursing, optometrist, general practitioner, and pharmacist play a pivotal role in the implementation of cataract treatment techniques

Global prevalence of Colistin resistance in Klebsiella Pneumoniae from bloodstream infection: A systematic review and meta-analysis

Background: Among gram-negative bacteria, Klebsiella pneumoniae is one of the most common causes of healthcare-related infection. Bloodstream infections (BSIs) caused by Klebsiella pneumoniae are notorious for being difficult to treat due to resistance to commonly used antimicrobials. Klebsiella pneumoniae isolates from bloodstream infections are becoming increasingly resistant to carbapenems. In the fight against carbapenem-resistant Klebsiella pneumoniae, colistin [polymyxin E] is the antimicrobial of choice and is thus widely used.Objective: This study aimed to determine the global prevalence of colistin resistance amongst Klebsiella pneumoniae isolates from bloodstream infections. Methods: PubMed, Medline, Scopus, and the Cochrane Library were searched for published articles without restricting the search period. Studies meeting the predefined inclusion and exclusion criteria were included, and quality was assessed using Joanna Briggs Institute Checklist. We used a statistical random effect model to analyze data with substantial heterogeneity (I2 > 50%) in the meta-analysis. Results: A total of 10 studies out of 2873 search results that met the inclusion criteria were included in the final synthesis for this study. A pooled prevalence of colistin resistance was 3.1%, 95% CI (1.5–4.7%). The highest colistin resistance pooled prevalence was recorded in isolates studied in 2020 and beyond 12.90% (4/31), while Klebsiella pneumoniae isolates studied in 2015 and before and in 2016–2019 showed a pooled colistin resistance rate of 2.89% (48/1661) and 2.95% (28/948), respectively. The highest colistin resistance was found in Klebsiella pneumoniae isolates from Thailand (19.2%), while the least pooled resistance was in Klebsiella pneumoniae from South Korea (0.8%). The pooled prevalence of the multidrug-resistant (MDR) of Klebsiella pneumoniae from bloodstream infection ranged from 80.1%, 95% CI (65.0–95.2%), and the resistance prevalence of other antibiotics by Klebsiella pneumoniae from bloodstream infections were as follows; ciprofloxacin (45.3%), ertapenem (44.4%), meropenem (36.1%), imipenem (35.2%), gentamicin (33.3%), amikacin (25.4%) and tigecycline (5.1%). Klebsiella pneumoniae recovered from the intensive care unit (ICU) showed higher colistin resistance, 11.5% (9/781%), while non-ICU patients showed 3.03% (80/2604) pooled colistin resistance. Conclusion: This study showed low colistin resistance in Klebsiella pneumoniae isolates from global bloodstream infections. However, significant colistin resistance was observed in isolates collected from 2020 and beyond. Significant colistin resistance was also observed in Klebsiella pneumoniae isolates in bloodstream infections from the intensive care unit (ICU) compared to those from non-ICUs. As a result, there is a need to institute colistin administration stewardship in the ICU in clinical settings

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Laser-Assisted Endoscopic Cricotracheal Stenosis Resection (CTSR) in Paediatric Congenital Cartilaginous Subglottic Stenosis

Subglottic stenosis (SGS) in children can be a congenital condition or acquired through injury such as from prolonged intubation. Surgeons face challenges in choosing the best SGS treatment for a particular patient because of variability in the success rate of each technique. Conventional open surgical resection and reconstruction have been proven effective but, in recent years, endoscopic surgery has become more prevalent as it eliminates the incision and reduces the surgery time and subsequent hospital stay. The purpose of this retrospective case study was to report on an endoscopic technique using a CO2 laser for cricotracheal stenosis resection (CTSR) for high-grade congenital SGS. From forty-five paediatric patients who underwent endoscopic intervention as a primary modality of treatment for high-grade SGS in a tertiary referral centre, a total of eight patients who met the inclusion criteria have been included in our study. This small patient series is the first to use a CO2 laser alone as a single excision tool to eliminate complex congenital SGS and restore airway patency. The procedure’s goal was to return the airway to an early stage of postintubation injury prior to scar formation; therefore, surgical sessions at intervals of 2–3 weeks were performed to ensure natural epithelization, to remove any granulation tissue, and manage fibrosis. Successful treatment was defined as a resolution of symptoms, restoration of a normal patent airway with no stenosis, and decannulation. The success rate was 75%. Two outcomes need to be highlighted. First, the CO2 laser should be reconsidered as an excision tool for congenital SGS because of its low risk of exacerbating preexisting stenosis. It allows the surgeon to restore and augment the airway without the need for open surgery or dilatation. Second, the shorter interval between procedures is crucial for controlling the healing process and making sure that it is proceeding properly

Efficiency of diet change in irritable bowel syndrome

Background: Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by symptoms of abdominal pain, bloating, and altered bowel habit such as constipation, diarrhea, or both. Food is one of the most commonly reported triggers of IBS symptoms. we aim to assess the effect of diet change in improving IBS. Methods: This study was a cross-sectional study. A questionnaire was developed for data collection in the present study. The survey was distributed online in Arabic language. Results: A total of 1202 subjects participated in our study. Of these, 685 (57%) were female patients and 517 (43%) were male patients. The age of patients ranged from 15 to 55 years, more than one-third of them located in the age range between 15 and 25. The statistical analysis reported a significant correlations between having IBS for three successive days for 3 months regarding age and duration of IBS (P value <0.001), having depression or anxiety before, and if the depression affects IBS symptoms or not (P value = 0.013 and <0.001, respectively). Having dietary regimen, advising to increase fibers, thinking about changing diet improves IBS symptoms (P value = 0.001, 0.005, and < 0.001, respectively) and having treatment (P value = 0.006). Conclusion: According to our results, the prevalence of IBS was higher among females. Some diets, especially onions, garlic, and coffee, were reported to increase the IBS symptoms. Decreasing carbohydrate diets and increasing fiber diet would enhance the patient health where the symptoms where decreased

A Novel Blockchain-Based Encryption Model to Protect Fog Nodes from Behaviors of Malicious Nodes

The world has experienced a huge advancement in computing technology. People prefer outsourcing their confidential data for storage and processing in cloud computing because of the auspicious services provided by cloud service providers. As promising as this paradigm is, it creates issues, including everything from data security to time latency with data computation and delivery to end-users. In response to these challenges, the fog computing paradigm was proposed as an extension of cloud computing to overcome the time latency and communication overhead and to bring computing and storage resources close to both the ground and the end-users. However, fog computing inherits the same security and privacy challenges encountered by traditional cloud computing. This paper proposed a fine-grained data access control approach by integrating the ciphertext policy attribute-based encryption (CP-ABE) algorithm and blockchain technology to secure end-users&rsquo; data security against rogue fog nodes in case a compromised fog node is ousted. In this approach, we proposed federations of fog nodes that share the same attributes, such as services and locations. The fog federation concept minimizes the time latency and communication overhead between fog nodes and cloud servers. Furthermore, the blockchain idea and the CP-ABE algorithm integration allow for fog nodes within the same fog federation to conduct a distributed authorization process. Besides that, to address time latency and communication overhead issues, we equip each fog node with an off-chain database to store the most frequently accessed data files for a particular time, as well as an on-chain access control policies table (on-chain files tracking table) that must be protected from tampering by rogue fog nodes. As a result, the blockchain plays a critical role here because it is tamper-proof by nature. We assess our approach&rsquo;s efficiency and feasibility by conducting a simulation and analyzing its security and performance