Astrocytic accumulation of tau fibrils isolated from Alzheimer's disease brains induces inflammation, cell-to-cell propagation and neuronal impairment.

Accumulating evidence highlights the involvement of astrocytes in Alzheimer's disease (AD) progression. We have previously demonstrated that human iPSC-derived astrocytes ingest and modify synthetic tau fibrils in a way that enhances their seeding efficiency. However, synthetic tau fibrils differ significantly from in vivo formed fibrils. To mimic the situation in the brain, we here analyzed astrocytes' processing of human brain-derived tau fibrils and its consequences for cellular physiology. Tau fibrils were extracted from both AD and control brains, aiming to examine any potential differences in astrocyte response depending on the origin of fibrils. Our results show that human astrocytes internalize, but fail to degrade, both AD and control tau fibrils. Instead, pathogenic, seeding capable tau proteoforms are spread to surrounding cells via tunneling nanotubes and exocytosis. Notably, accumulation of AD tau fibrils induces a stronger reactive state in astrocytes, compared to control fibrils, evident by the augmented expression of vimentin and GFAP, as well as by an increased secretion of the pro-inflammatory cytokines IL-8 and MCP-1. Moreover, conditioned media from astrocytes with AD tau fibril deposits induce synapse and metabolic impairment in human iPSC-derived neurons. Taken together, our data suggest that the accumulation of brain-derived AD tau fibrils induces a more robust inflammatory and neurotoxic phenotype in human astrocytes, accentuating the nature of tau fibrils as an important contributing factor to inflammation and neurodegeneration in AD.

Astrocytic uptake of neuronal corpses promotes cell-to-cell spreading of tau pathology.

Tau deposits in astrocytes are frequently found in Alzheimer's disease (AD) and other tauopathies. Since astrocytes do not express tau, the inclusions have been suggested to be of neuronal origin. However, the mechanisms behind their appearance and their relevance for disease progression remain unknown. Here we demonstrate, using a battery of experimental techniques that human astrocytes serve as an intermediator, promoting cell-to-cell spreading of pathological tau. Human astrocytes engulf and process, but fail to fully degrade dead neurons with tau pathology, as well as synthetic tau fibrils and tau aggregates isolated from AD brain tissue. Instead, the pathogenic tau is spread to nearby cells via secretion and tunneling nanotube mediated transfer. By performing co-culture experiments we could show that tau-containing astrocytes induce tau pathology in healthy human neurons directly. Furthermore, our results from a FRET based seeding assay, demonstrated that the tau proteoforms secreted by astrocytes have an exceptional seeding capacity, compared to the original tau species engulfed by the cells. Taken together, our study establishes a central role for astrocytes in mediating tau pathology, which could be of relevance for identifying novel treatment targets for AD and other tauopathies.

PLA2G6-associated late-onset parkinsonism in a Sudanese family.

INTRODUCTION: The phospholipase A2 group VI gene (PLA2G6) encodes an enzyme that catalyzes the hydrolytic release of fatty acids from phospholipids. Four neurological disorders with infantile, juvenile, or early adult-onset are associated with PLA2G6 genetic alterations, namely infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), dystonia-parkinsonism (DP), and autosomal recessive early-onset parkinsonism (AREP). Few studies in Africa reported PLA2G6-associated disorders and none with parkinsonism of late adult onset. MATERIAL AND METHODS: The patients were clinically assessed following UK Brain Bank diagnostic criteria and International Parkinson and Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Brain MRI without contrast was performed. Genetic testing was done using a custom-made Twist panel, screening 34 known genes, 27 risk factors, and 8 candidate genes associated with parkinsonism. Filtered variants were PCR-amplified and validated using Sanger sequencing and also tested in additional family members to study their segregation. RESULT: Two siblings born to consanguineous parents developed parkinsonism at the age of 58 and 60 years, respectively. MRI showed an enlarged right hippocampus in patient 2, but no overt abnormalities indicative of INAD or iron deposits. We found two heterozygous variants in PLA2G6, an in-frame deletion NM_003560:c.2070_2072del (p.Val691del) and a missense variant NM_003560:c.956C>T (p.Thr319Met). Both variants were classified as pathogenic. CONCLUSION: This is the first case in which PLA2G6 is associated with late-onset parkinsonism. Functional analysis is needed to confirm the dual effect of both variants on the structure and function of iPLA2ß.

Intrafamilial and interfamilial heterogeneity of PINK1-associated Parkinson's disease in Sudan.

PINK1 is the second most predominant gene associated with autosomal recessive Parkinson's disease. Homozygous mutations in this gene are associated with an early onset of symptoms. Bradykinesia, tremors, and rigidity are common features, while dystonia, motor fluctuation, and non-motor symptoms occur in a lower percentage of cases and usually respond well to levodopa. We investigated 14 individuals with parkinsonism and eleven symptom-free siblings from three consanguineous Sudanese families, two of them multigenerational, using a custom gene panel screening 34 genes, 27 risk variants, and 8 candidate genes associated with parkinsonism. We found a known pathogenic nonsense PINK1 variant (NM_032409.3:c.1366C>T; p.(Gln456*)), a novel pathogenic single base duplication (NM_032409.3:c.1597dup; p.(Gln533Profs*29)), and another novel pathogenic insertion (NM_032409.3:c.1448_1449ins[1429_1443; TTGAG]; p.(Arg483Serfs*7)). All variants were homozygous and co-segregated in all affected family members. We also identified intrafamilial and interfamilial phenotypic heterogeneity associated with PINK1 mutations in these Sudanese cases, possibly reflecting the nature of the Sudanese population that has a large effective population size, which suggests a higher possibility of novel findings in monogenic and polygenic diseases in Sudan.

Prevalence of Toxoplasma gondii infection in animals of the Arabian Peninsula between 2000-2020: A systematic review and meta-analysis.

BACKGROUND: Toxoplasma gondii (T. gondii) is a zoonotic parasite that can be transmitted from animals to humans, with felids acting as its definitive host. Thus, understanding the epidemiology of this parasite in animal populations is vital to controlling its transmission to humans as well as to other animal groups. OBJECTIVES: This systematic review and meta-analysis aims to summarise and analyse reports of T. gondii infection in animal species residing in the Arabian Peninsula. METHODS: It was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), with relevant studies being retrieved from MEDLINE/PubMed, Scopus, Cochrane Library, Google Scholar and ScienceDirect. All articles published in Arabic or English languages between January 2000 and December 2020 were screened for eligibility. Random effects model was used to calculate the pooled prevalence of T. gondii infection in different animal populations which were found to harbour this infection. The critical appraisal tool for prevalence studies designed by the Joanna Briggs Institute (JBI) was used to assess the risk of bias in all included studies. RESULTS: A total of 15 studies were retrieved, reporting prevalence estimates from 4 countries in this region and in 13 animal species. Quantitative meta-analysis estimated a pooled prevalence of 43% in felids [95% confidence interval (CI) = 23-64%, I2 index = 100%], 48% in sheep (95% CI = 27-70%, I2 = 99%) and 21% in camels (95% CI = 7-35%, I2 = 99%). Evidence of possible publication bias was found in both felids and sheep. CONCLUSIONS: This meta-analysis estimates a high prevalence of T. gondii infection in animal species which are of high economic and cultural importance to countries of this region. Hence, these findings provide valuable insight to public health authorities as well as economic and animal resources advisors in countries of the Arabian Peninsula.

Methylation of alpha-synuclein in a Sudanese cohort.

BACKGROUND: Several studies suggested a significant role of epigenetic changes, including alterations in miRNA, histone modifications, and DNA methylation of α-synuclein (SNCA) in Parkinson's disease (PD) pathogenicity. As of yet, only very few studies have been carried out in this field in Africa and none in Sudan. MATERIALS AND METHODS: We collected DNA from 172 Sudanese individuals (90 cases, 82 controls) who donated saliva for DNA extraction (mean age of onset: 40.6 ± 22.4 years). A family history of PD was evident in 64 patients. DNA preparation and bisulfite sequencing of SNCAintron1 was performed as described earlier. RESULTS: Of the fourteen analyzed CpGs of SNCAintron1, CpGs 16-23 were hypomethylated in PD (P-value ranged from 0.023 to 0.003). P-values improved, when sporadic cases were excluded from the analysis. CONCLUSION: We identified the presence of a specific pattern of DNA methylation in a young Sudanese cohort of familial PD, which confirms the importance of the methylation of SNCAintron1 for PD. This phenomenon appears to be independent of ethnicity, the impact of environmental factors, drug history, or familial clustering.

Bilateral basal ganglia infarction and bilateral thalamic lesions in sudanese pediatric patient with COVID-19 and malaria co-infection, a case report.

COVID-19 is of uncommon diagnosis in pediatric with their presentation in much of time of a non-specific entity; here, we experienced the case of a 2-year-old female with malaria presented with fever, cough, rhinorrhea, hemoptysis, and convulsion diagnosed as COVID-19, complicated with encephalitis, received treatment, and improved over weeks.

Dengue Virus Infection in Sub-Saharan Africa Between 2010 and 2020: A Systematic Review and Meta-Analysis.

Dengue virus (DENV) infection has garnered a global interest in the past few decades. Nevertheless, its epidemiology in certain developing and low-income regions remains poorly understood, due to the absence of comprehensive surveillance and reporting systems. This systematic review and meta-analysis aimed to determine the prevalence of DENV infection in the population of Sub-Saharan Africa using DENV infection markers, and to track any changes in its prevalence during the past ten years. It was conducted in accordance with the PRISMA guidelines, targeting the literature available at MEDLINE/PubMed, ScienceDirect, Cochrane library and Google Scholar. All articles published in English language between January 2010 and June 2020 were screened for eligibility. Random effects model was used to calculate the pooled prevalence of all infection markers. The Inconsistency Index (I2) was used to assess the level of heterogeneity between studies. Subgroup analysis according to country and time-frame of studies was conducted to provide possible explanations to substantial heterogeneity. The critical appraisal tool for prevalence studies designed by the Joanna Briggs Institute (JBI) was used to assess the risk of bias in all included studies. A total of 84 articles, covering 21 countries, were included in this review. Quantitative meta-analysis estimated a pooled IgG prevalence of 25% (95% CI: 21-29%, I2 = 99%), a pooled IgM prevalence of 10% (95% CI: 9-11%, I2 = 98%) and a pooled DENV RNA prevalence of 14% (95% CI: 12-16%, I2 = 99%). Evidence for possible publication bias was also found in all three meta-analyses. Subgroup analysis according to the time of sample collection was performed to closely track the changing prevalence of DENV infection markers between 2010 and 2019. This meta-analysis estimates a high prevalence of DENV infection in Sub-Saharan Africa. More cost-efficient vector control strategies should be designed and implemented in order to adapt to the low-resource nature of this region.

Rodent Ectoparasites in the Middle East: A Systematic Review and Meta-Analysis.

Rodents carry many ectoparasites, such as ticks, lice, fleas, and mites, which have potential public health importance. Middle Eastern countries are hotspots for many emerging and re-emerging infectious diseases, such as plague, leishmaniasis, Crimean Congo hemorrhagic fever, and Q fever, due to their ecological, socioeconomic, and political diversity. Rodent ectoparasites can act as vectors for many of these pathogens. Knowledge of rodent ectoparasites is of prime importance in controlling rodent ectoparasite-borne zoonotic diseases in this region. The current systematic review and meta-analysis performs a comprehensive synthesis of the available knowledge, providing an evidence-based overview of the ectoparasites detected on rodents in Middle Eastern countries. Following a systematic search in Pubmed, Scopus, and Web of Science, a total of 113 published articles on rodent ectoparasites were studied and analyzed. A total of 87 rodent species were documented, from which Mus musculus, Rattus norvegicus, and Rattus rattus were found to be the most common. Fleas were the most reported ectoparasites (87 articles), followed by mites (53), ticks (44), and lice (25). Xenopsylla cheopis, Polyplax spinulosa, Ornithonyssus bacoti, and Hyalomma rhipicephaloides were the most commonly described fleas, lice, mites, and ticks, respectively. Based on the reviewed articles, the median flea, louse, mite, and tick indices were highest in Israel (4.15), Egypt (1.39), Egypt (1.27), and Saudi Arabia (1.17), respectively. Quantitative meta-analysis, using a random-effects model, determined the overall pooled flea prevalence in the Middle East as 40% (95% CI: 25-55, I2 = 100%, p < 0.00001), ranging between 13% (95% CI: 0-30, I2 = 95%, p < 0.00001) in Iran and 59% (95% CI: 42-77, I2 = 75%, p < 0.00001) in Israel. The overall pooled louse prevalence was found to be 30% (95% CI: 13-47, I2 = 100%, p < 0.00001), ranging between 25% in Iran (95% CI: 1-50, I2 = 99%) and 38% in Egypt (95% CI: 7-68, I2 = 100%). In the case of mites, the pooled prevalence in this region was 33% (95% CI: 11-55, I2 = 100%, p < 0.00001), where the country-specific prevalence estimates were 30% in Iran (95% CI: 4-56, I2 = 99%) and 32% in Egypt (95% CI: 0-76, I2 = 100%). For ticks, the overall prevalence was found to be 25% (95% CI: 2-47, I2 = 100%, p < 0.00001), ranging from 16% in Iran (95% CI: 7-25, I2 = 74%) to 42% in Egypt (95% CI: 1-85, I2 = 100%). The control of rodent ectoparasites should be considered to reduce their adverse effects. Using the One Health strategy, rodent control, and precisely control of the most common rodent species, i.e., Mus musculus, Rattus norvegicus, and Rattus rattus, should be considered to control the rodent-borne ectoparasites in this region.

Occult hepatitis B virus infection in Sudan: A systematic review and meta-analysis.

In its occult form, hepatitis B virus infection can only be detected using molecular techniques such as polymerase chain reaction, increasing the cost of the screening process. Certain population subgroups are considered to have a higher risk of transmission and reactivation of occult hepatitis B virus infection (OBI). This review aims to estimate the prevalence of OBI among these high-risk groups in Sudan. It was conducted under the PRISMA guidelines, targeting the literature available in MEDLINE/PubMed, ScienceDirect, Google Scholar, and Cochrane Library databases. Full-text articles published in the last 10 years that provide prevalence estimates of OBI in Sudan were examined for fulfillment of eligibility criteria. Quality assessment of selected articles was performed using the critical appraisal tool reported by Munn et al. Publication bias was assessed by visual examination of the funnel plot. Meta-analysis using the random-effects model with 95% confidence interval was used to calculate the overall and subgroup pooled prevalence of OBI. Literature search yielded a total of 717 studies, of which only 11 articles fulfilled all selection criteria. The overall pooled prevalence of OBI was found to be 15.51%, with a high level of heterogeneity. Subgroup analysis demonstrated a prevalence of 16.48% among blood donors, 13.36% among hemodialysis patients, and 12.59% among febrile patients. Evidence for possible publication bias was detected. This review provides crucial evidence for health authorities in Sudan, outlining the necessity for re-evaluation of the current screening strategies, especially among these high-risk groups.

Drug Utilization Evaluation of Vancomycin among Patients in Jafar Ibn Auf Pediatric Hospital, 2018.

Background: Vancomycin is an antibiotic of growing importance in the treatment of hospital-acquired infections; with a particular emphasis on its value in the fight against Methicillin-resistant Staphylococcus aureus. Increasing reports of Vancomycin resistance have raised concerns about the effectiveness of this drug. Drug utilization evaluation has an important role in controlling rational use of antibiotics to prevent the emergence of resistance. Methods: We conducted a retrospective 6-months study at Jafar Ibn Auf pediatric hospital. Data including patient's demographics, diagnosis, Dosage regimen, and treatment duration were reviewed. The concordance of practice with the Hospital Infection Control Practices Advisory Committee (HICPAC) guidelines and principles of antibiotic therapy was assessed. Results: 127 medical records were reviewed in this study. Sepsis (29%) and Pneumonia (19.6%) were the most common indications. Culture test was requested in 20.5% of patients. Monitoring of serum creatinine was carried in 81.1% of patients. Based on HICPAC guidelines vancomycin was administered appropriately in 67.7% percent of cases. Considering the infusion rate, most of patients with specific order were received vancomycin in 1 hour. Conclusions: The results showed that vancomycin was used empirically without subsequent adjustment of the antimicrobial agent according to culture and sensitivity data and lack of paying enough attention to the infusion rate and serum creatinine monitoring.