Low Prevalence of Syndromic Respiratory Tract Infections among Returning Hajj Pilgrims Amidst the COVID-19 Pandemic: A Post-Hajj Survey.

This study estimates the point prevalence of symptomatic respiratory tract infections (RTIs) among returned Hajj pilgrims and their contacts in 2021. Using the computer-assisted telephone interview (CATI) technique, domestic pilgrims were invited to participate in this cross-sectional survey two weeks after their home return from Hajj. Of 600 pilgrims approached, 79.3% agreed to participate and completed the survey. Syndromic definitions were used to clinically diagnose possible influenza-like illnesses (ILI) and COVID-19. Median with range was applied to summarise the continuous data, and frequencies and proportions were used to present the categorical variables. Simple logistic regression was carried out to assess the correlations of potential factors with the prevalence of RTIs. The majority of pilgrims (88.7%) reported receiving at least two doses of the COVID-19 vaccine before Hajj. Eleven (2.3%) pilgrims reported respiratory symptoms with the estimated prevalence of possible ILI being 0.2%, and of possible COVID-19 being 0.4%. Among those who were symptomatic, five (45.5%) reported that one or more of their close contacts had developed similar RTI symptoms after the pilgrims' home return. The prevalence of RTIs among pilgrims who returned home after attending the Hajj 2021 was lower compared with those reported in the pre-pandemic studies; however, the risk of spread of infection among contacts following Hajj is still a concern.

Misleading localization by 18F-fluorocholine PET/CT in familial hypocalciuric hypercalcemia type-3: a case report.

BACKGROUND: Familial hypocalciuric hypercalcemia (FHH) is a heterogeneous autosomal-dominant disorder of calcium hemostasis that may be difficult to distinguish clinically from mild primary hyperparathyroidism. Loss-of-function mutations mainly involving Arg15 residue of the adaptor-related protein complex 2, sigma subunit 1 (AP2S1) cause a rarer, more recently recognized form of FHH, FFH type-3. Recently, 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) showed superior sensitivity to conventional imaging in localizing parathyroid adenomas. We report a new FFH type-3 patient who underwent unnecessary parathyroidectomy in association with misleading FCH-PET/CT imaging. CASE PRESENTATION: A 29-year old woman was initially evaluated for parathyroid hormone (PTH)-dependent hypercalcemia in 2013. Medical history was positive only for chronic constipation and malaise with no personal or family history of hypercalcemia, kidney stones, or neck surgery. Over seven years, serum calcium level was 2.51-2.89 mmol/L with concomitant PTH level of 58.7-94.8 mmol/L. Serum phosphate levels were in the low/low normal range. Serum creatinine and magnesium levels were normal. 25-hydroxy vitamin D level was 13 nmol/L. 24-hour urine calcium level was 1.92 mmol/day but increased to 6.99 mmol/day after treatment with cholecalciferol 1000 IU daily. Bone mineral density and renal ultrasound were normal. Parathyroid ultrasound showed two hypoechoic nodules inferior to the left and right thyroid lobes; however, 99mtechnitium-sestamibi scans (2013, 2016, 2018) were negative. FCH-PET/CT (2019) showed focal uptake co-localizing with the nodule inferior to the left thyroid lobe. The patient underwent left inferior parathyroidectomy and pathology was consistent with parathyroid hyperplasia. However, postoperatively, serum calcium and PTH levels remained elevated and FCH-PET/CT and ultrasound showed persistence of the uptake/nodule. Whole exome sequencing showed Arg15Cys mutation in the AP2S1 gene characteristic of FHH type-3. CONCLUSIONS: In this new case of FHH type-3, FCH-PET/CT failed to localize to the hyperplastic parathyroid glands and localized instead to apparently a lymph node. This, together with increased urinary calcium after vitamin D supplementation, led to unnecessary parathyroidectomy. Given the increasingly lower cost of genetic testing and the cost of follow up and unnecessary surgery, it may prudent to include genetic testing for FHH early on in patients with mild PTH-dependent hypercalcemia.

Polycystic ovary syndrome is linked with the fat mass obesity (FTO) gene variants rs17817449 and rs1421085 in western Saudi Arabia.

Polycystic ovary syndrome (PCOS) is characterised by infertility, obesity, insulin resistance and clinical and/or biochemical signs of hyperandrogenism. Obesity is known to be correlated with PCOS causing ovulatory dysfunction and hormone imbalances. Moreover, fat mass and the obesity gene (FTO) were linked with obesity and PCOS. Therefore, it is of interest to determine the genotype and allele frequency for three FTO variants - rs17817449 (G/T), rs1421085 (C/T) and rs8050136 (A/C) -in western Saudi population. 95 PCOS patients and 94 controls were recruited for this study. The genetic variants were assayed using real-time polymerase chain reaction using TaqMan genotyping assays. The chi-squared test was applied to investigate the difference between single nucleotide polymorphisms on PCOS and control subjects, and binary logistic regression was used to determine the association of FTO variants with PCOS symptoms. Variants rs17817449 and rs1421085 were significantly linked with PCOS susceptibility in the study population. Rs17817449 and rs8050136 were significantly associated with hair loss in the PCOS group. Furthermore, rs1421085 and rs8050136 were associated with a high body mass index (BMI>30 kg/m2). Risk alleles in our population associated with hair loss and elevated BMI in women with PCOS were homozygous C for rs8050136. This data will help in defining the genetic predisposition of PCOS among women in western Saudi Arabia.

The Effect Sizes of PPARγ rs1801282, FTO rs9939609, and MC4R rs2229616 Variants on Type 2 Diabetes Mellitus Risk among the Western Saudi Population: A Cross-Sectional Prospective Study.

Type 2 diabetes mellitus (T2DM) is a common polygenic disease with associated comorbidities. Obesity is a major risk factor for the development of T2DM. The aim of this study is to determine the allele and genotype frequency of peroxisome proliferator-activated receptor-γ (PPARγ) rs1801282, fat mass and obesity-associated protein (FTO) rs9939609, and melanocortin 4 receptor (MC4R) rs2229616 polymorphisms and their association with risk of T2DM in the western Saudi population as mediators of adiposity phenotypes. In a cross-sectional prospective study, genomic DNA from control and T2DM patients were isolated and genotyped for these single-nucleotide polymorphisms. There was a significant association of the MC4R rs2229616 variant with T2DM, but no association with T2DM was detected with PPARγ rs1801282 or FTO rs9939609. The combination of C/C for PPARγ rs1801282, A/A for FTO rs9939609, and C/C for MC4R rs2229616 increased the risk of T2DM by 1.82. The A/T genotype for FTO rs9939609 was predicted to decrease the risk of T2DM when combined with C/C for PPARγ rs1801282 and C/C for MC4R rs2229616 or C/C for PPARγ rs1801282 and C/T MC4R rs2229616. In conclusion, our study showed the risk of the assessed variants for the development of T2DM in the Saudi population.

Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies.

Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. In the large majority of cancer cells, telomere length is maintained by telomerase. Thus, telomere length and telomerase activity are crucial for cancer initiation and the survival of tumors. Several pathways that regulate telomere length have been identified, and genome-scale studies have helped in mapping genes that are involved in telomere length control. Additionally, genomic screening for recurrent human telomerase gene hTERT promoter mutations and mutations in genes involved in the alternative lengthening of telomeres pathway, such as ATRX and DAXX, has elucidated how these genomic changes contribute to the activation of telomere maintenance mechanisms in cancer cells. Attempts have also been made to develop telomere length- and telomerase-based diagnostic tools and anticancer therapeutics. Recent efforts have revealed key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents. Here, we summarize telomere organization and function and its role in oncogenesis. We also highlight genomic mutations that lead to reactivation of telomerase, and mechanisms of telomerase reconstitution and trafficking that shed light on its function in cancer initiation and tumor development. Additionally, recent advances in the clinical development of telomerase inhibitors, as well as potential novel targets, will be summarized.

Anti-inflammatory role of sesamin in STZ induced mice model of diabetic retinopathy.

Diabetic retinopathy (DR) is the common cause of diabetic vascular complications that leads to the blindness in the working age population throughout the world. Free radicals mediated oxidative stress and inflammation play a significant role in pathophysiology of DR. To find a new and safe drug to treat DR is still challenging and for that purpose the natural compounds may be therapeutic agents. Here we show that sesamin (SES), which is the main component of sesame seed and its oil, and has been reported as potent antioxidant and neuroprotective, could be a therapeutic agent in DR. In the present study, we investigated protective effect of SES in Streptozotocin (STZ) induced DR in mice. The mice were divided into three groups (Control, DR and DR+SES) for the study. After two weeks post-diabetic establishment, mice were treated with SES (30mg/kg BW, i.p, alternate day) for four weeks. Mice body weight and blood glucose level were measured from each group. The microglial activation of retina was determined by immunohistochemistry analysis by using Iba-1 as a microglia marker. Retinal mRNA levels of Iba-1, tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) and Intercellular Adhesion Molecule 1 (ICAM-1) were examined by qRT-PCR. The level of iNOS protein expression was examined by immunoblotting. Together these data demonstrate that SES treatment lowered the progression of diabetic retinal injury by: 1) decreasing blood glucose level, 2) suppressing microglia activation, 3) reducing retinal TNF-α and ICAM-1 levels and 4) quenching iNOS expression. In conclusion, the results suggest that SES treatment may be of therapeutic benefit in reducing the progression of DR by ameliorating hyperglycemia and inflammation in diabetic retina.

Metformin improves the angiogenic potential of human CD34⁺ cells co-incident with downregulating CXCL10 and TIMP1 gene expression and increasing VEGFA under hyperglycemia and hypoxia within a therapeutic window for myocardial infarction.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with diabetes mellitus (DM). To identify the most effective treatment for CVD, it is paramount to understand the mechanism behind cardioprotective therapies. Although metformin has been shown to reduce CVD in Type-2 DM clinical trials, the underlying mechanism remains unexplored. CD34(+) cell-based therapies offer a new treatment approach to CVD. The aim of this study was to investigate the effect of metformin on the angiogenic properties of CD34(+) cells under conditions mimicking acute myocardial infarction in diabetes. METHODS: CD34(+) cells were cultured in 5.5 or 16.5 mmol/L glucose ± 0.01 mmol/L metformin and then additionally ± 4 % hypoxia. The paracrine function of CD34(+) cell-derived conditioned medium was assessed by measuring pro-inflammatory cytokines, vascular endothelial growth factor A (VEGFA), and using an in vitro tube formation assay for angiogenesis. Also, mRNA of CD34(+) cells was assayed by microarray and genes of interest were validated by qRT-PCR. RESULTS: Metformin increased in vitro angiogenesis under hyperglycemia-hypoxia and augmented the expression of VEGFA. It also reduced the angiogenic-inhibitors, chemokine (C-X-C motif) ligand 10 (CXCL10) and tissue inhibitor of metalloproteinase 1 (TIMP1) mRNAs, which were upregulated under hyperglycemia-hypoxia. In addition metformin, increased expression of STEAP family member 4 (STEAP4) under euglycemia, indicating an anti-inflammatory effect. CONCLUSIONS: Metformin has a dual effect by simultaneously increasing VEGFA and reducing CXCL10 and TIMP1 in CD34(+) cells in a model of the diabetic state combined with hypoxia. Therefore, these angiogenic inhibitors are promising therapeutic targets for CVD in diabetic patients. Moreover, our data are commensurate with a vascular protective effect of metformin and add to the understanding of underlying mechanisms.

Biomarkers of Chondrocyte Apoptosis and Autophagy in Osteoarthritis.

Cell death with morphological and molecular features of apoptosis has been detected in osteoarthritic (OA) cartilage, which suggests a key role for chondrocyte death/survival in the pathogenesis of OA. Identification of biomarkers of chondrocyte apoptosis may facilitate the development of novel therapies that may eliminate the cause or, at least, slow down the degenerative processes in OA. The aim of this review was to explore the molecular markers and signals that induce chondrocyte apoptosis in OA. A literature search was conducted in PubMed, Scopus, Web of Science and Google Scholar using the keywords chondrocyte death, apoptosis, osteoarthritis, autophagy and biomarker. Several molecules considered to be markers of chondrocyte apoptosis will be discussed in this brief review. Molecular markers and signalling pathways associated with chondroycte apoptosis may turn out to be therapeutic targets in OA and approaches aimed at neutralizing apoptosis-inducing molecules may at least delay the progression of cartilage degeneration in OA.

A machine learning heuristic to identify biologically relevant and minimal biomarker panels from omics data.

BACKGROUND: Investigations into novel biomarkers using omics techniques generate large amounts of data. Due to their size and numbers of attributes, these data are suitable for analysis with machine learning methods. A key component of typical machine learning pipelines for omics data is feature selection, which is used to reduce the raw high-dimensional data into a tractable number of features. Feature selection needs to balance the objective of using as few features as possible, while maintaining high predictive power. This balance is crucial when the goal of data analysis is the identification of highly accurate but small panels of biomarkers with potential clinical utility. In this paper we propose a heuristic for the selection of very small feature subsets, via an iterative feature elimination process that is guided by rule-based machine learning, called RGIFE (Rule-guided Iterative Feature Elimination). We use this heuristic to identify putative biomarkers of osteoarthritis (OA), articular cartilage degradation and synovial inflammation, using both proteomic and transcriptomic datasets. RESULTS AND DISCUSSION: Our RGIFE heuristic increased the classification accuracies achieved for all datasets when no feature selection is used, and performed well in a comparison with other feature selection methods. Using this method the datasets were reduced to a smaller number of genes or proteins, including those known to be relevant to OA, cartilage degradation and joint inflammation. The results have shown the RGIFE feature reduction method to be suitable for analysing both proteomic and transcriptomics data. Methods that generate large 'omics' datasets are increasingly being used in the area of rheumatology. CONCLUSIONS: Feature reduction methods are advantageous for the analysis of omics data in the field of rheumatology, as the applications of such techniques are likely to result in improvements in diagnosis, treatment and drug discovery.

The crossroads between cancer stem cells and aging.

The cancer stem cell (CSC) hypothesis suggests that only a subpopulation of cells within a tumour is responsible for the initiation and progression of neoplasia. The original and best evidence for the existence of CSCs came from advances in the field of haematological malignancies. Thus far, putative CSCs have been isolated from various solid and non-solid tumours and shown to possess self-renewal, differentiation, and cancer regeneration properties. Although research in the field is progressing extremely fast, proof of concept for the CSC hypothesis is still lacking and key questions remain unanswered, e.g. the cell of origin for these cells. Nevertheless, it is undisputed that neoplastic transformation is associated with genetic and epigenetic alterations of normal cells, and a better understanding of these complex processes is of utmost importance for developing new anti-cancer therapies. In the present review, we discuss the CSC hypothesis with special emphasis on age-associated alterations that govern carcinogenesis, at least in some types of tumours. We present evidence from the scientific literature for age-related genetic and epigenetic alterations leading to cancer and discuss the main challenges in the field.

pecific nutrient combination effects on tax, NF- κB and MMP-9 in human T-cell lymphotropic virus -1 positive malignant T-lymphocytes.

BACKGROUND: Adult T-cell Leukemia (ATL) is a disease with no known cure. The disease manifests itself as an aggressive proliferation of CD4+ cells with the human T-cell Lymphotropic virus type 1 (HTLV-1). The leukemogenesis of the virus is mainly attributed to the viral oncoprotein. Tax activates the Nuclear Factor kappa B (NF-κB) which stimulates the activity and expression of the matrix metalloproteinase-9 (MMP-9). The objective of this study was to investigate the efficacy of a specific nutrient synergy (SNS) on proliferation, Tax expression, NF-κB levels as well as on MMP-9 activity and expression both at the transcriptional and translational levels in two HTLV-1 positive cell lines, HuT-102 and C91-PL at 48h and 96h of incubation. Cytotoxicity of Epigallocatechin-3-gallate (EGCG) was assayed using CytoTox 96 Non-radioactive and proliferation was measured using Cell Titer96TM Nonradioactive Cell Proliferation kit (MTT- based assay). Enzyme linked immunosorbant assay (ELISA) and electrophoretic mobility shift assay (EMSA) were used to assess the effect of SNS on NF-κB mobility. Zymography was used to determine the effects of SNS on the activity and secretion of MMP-9. The expression of MMP-9 was done using RT-PCR at the translational level and Immunoblotting at the transcriptional level. RESULTS: A significant inhibition of proliferation was seen in both cell lines starting at a concentration of 200µg/ml and in a dose dependent manner. SNS induced a dose dependent decrease in Tax expression, which was paralleled by a down-regulation of the nuclearization of NF-κB. This culminated in the inhibition of the activity of MMP-9 and their expression both at the transcriptional and translational levels. CONCLUSIONS: The results of this study indicate that a specific nutrient synergy targeted multiple levels pertinent to the progression of ATL. Its activity was mediated through the NF-κB pathway, and hence has the potential to be integrated in the treatment of this disease as a natural potent anticancer agent.

Protective Effect of Solanum nigrum Leaves Extract on Immobilization Stress Induced Changes in Rat's Brain.

The prophylactic or curative antioxidant efficacy of crude extract and the active constituent of S. nigrum leaves were evaluated in modulating inherent antioxidant system altered due to immobilization stress in rat brain tissues, in terms of measurement of glutathione (GSH), lipid peroxidation (thiobarbituric acid reactive substances, TBARS), and free radical scavenging enzymes activities. Rats were treated with single dose of crude extract of S. nigrum prior to and after 6 h of immobilization stress exposure. Exposure to immobilization stress resulted in a decrease in the brain levels of glutathione, SOD, GST, and catalase, with an increase in thiobarbituric acid reactive substances (TBARS) levels. Treatment of S. nigrum extract and its active constituents to both pre- and poststressed rats resulted in significant modulation in the above mentioned parameters towards their control values with a relative dominance by the latter. Brain is vulnerable to stress induced prooxidant insult due to high levels of fat content. Thus, as a safe herbal medication the S. nigrum leaves extract or its isolated constituents can be used as nutritional supplement for scavenging free radicals generated in the brain due to physical or psychological stress or any neuronal diseases per se.

Current view from Alzheimer disease to type 2 diabetes mellitus.

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to memory problems. It has been associated with type 2 diabetes mellitus at both the molecular and biochemical level. Pancreatic cells have molecular similarities to the brain at the transcriptomic and proteomic levels. Several genes have been reported to be responsible for both AD and diabetes. Currently, no proper treatment is available but various therapeutic approaches are utilized worldwide for the management of these disorders and may be nanoparticles and herbal treatment of Bacopa monnieri will make promise for the treatment of AD in future. The formation of amyloids in neurons and the formation of amylin in pancreatic cells are potential links between these two disorders, which can be silent killers.

Role of gut microbiota in obesity, type 2 diabetes and Alzheimer's disease.

In recent years, there is a growing interest in research to investigate the importance of gut microbiome in health and diseases. This opens a new area of research for the role of microbial flora of the human gut in inflammation, energy homeostasis, pathogenesis of obesity and other associated disorders. Recent studies propose association of the gut microbiome with development of obesity and metabolic syndromes, such as type 2 diabetes mellitus (T2DM). The T2DM is a metabolic disease that is mainly caused by obesity-linked insulin resistance. The vascular effects of obesity appears to play a role in the development of Alzheimer's disease (AD) that is one of the rapidly growing diseases of a late stage of life all over the world. Studies from both humans and mice models have been demonstrated the engagement of gut microbial flora in the pathogenesis of obesity and host metabolism. The aim of this review is to discuss the current findings that may explain the cascade of gut microbial flora participation in the development of obesity, T2DM and further initiation of AD. In addition, the available data regarding the mechanisms that have been proposed to elucidate the role of gut microbiota in weight gain and possible cause of T2DM and AD have been examined.

Nitric oxide-induced regulatory T cells inhibit Th17 but not Th1 cell differentiation and function.

NO is a free radical with pleiotropic functions. We have shown earlier that NO induces a population of CD4(+)CD25(+)Foxp3(-) regulatory T cells (NO-Tregs) that suppress the functions of CD4(+)CD25(-) effector T cells in vitro and in vivo. We report in this study an unexpected finding that NO-Tregs suppressed Th17 but not Th1 cell differentiation and function. In contrast, natural Tregs (nTregs), which suppressed Th1 cells, failed to suppress Th17 cells. Consistent with this observation, NO-Tregs inhibited the expression of retinoic acid-related orphan receptor γt but not T-bet, whereas nTregs suppressed T-bet but not retinoic acid-related orphan receptor γt expression. The NO-Treg-mediated suppression of Th17 was partially cell contact-dependent and was associated with IL-10. In vivo, adoptively transferred NO-Tregs potently attenuated experimental autoimmune encephalomyelitis. The disease suppression was accompanied by a reduction of Th17, but not Th1 cells in the draining lymph nodes, and a decrease in the production of IL-17, but an increase in IL-10 synthesis. Our results therefore demonstrate the differential suppressive function between NO-Tregs and nTregs and indicate specialization of the regulatory mechanism of the immune system.

Ovarian mucinous cystadenoma in a female with Turner syndrome.

The development of an epithelial tumor, especially mucinous type, in a female with a streak gonad is rare and not fully understood. We report a case of a 19-year-old; a single female known to have Turner syndrome presented with an increased abdominal girth and was found to have a huge pelvic and abdominal mass. Ultrasound and magnetic resonance imaging revealed a huge cystic ovarian mass with no ascites. Laparotomy and right oophorectomy were performed for the ovarian mass. Histology revealed a large mucinous cyst adenoma. Further study of these tumors may help to eludicate the underlying cause and pathogenesis.