Hedgehog signaling mastery: R51211's promise in augmenting the therapeutic efficacy of sorafenib.

Sorafenib is a multikinase inhibitor employed for managing hepatocellular carcinoma (HCC). The emergence of sorafenib resistance presents an obstacle to its therapeutic efficacy. One notable approach to overcoming sorafenib resistance is the exploration of combination therapies. The role of hedgehog signaling in sorafenib resistance has been also examined in HCC. R51211, known as itraconazole, has been safely employed in clinical practice. Through in vitro and in vivo investigations, we assessed the potential of R51211 to enhance the therapeutic efficacy of sorafenib by inhibiting the hedgehog signaling. The zero-interaction potency synergy model demonstrated a synergistic interaction between R51211 and sorafenib, a phenomenon reversed by the action of a smoothened receptor agonist. This dual therapy exhibited an increased capacity to induce apoptosis, as evidenced by alterations in the Bax/BCL-2 ratio and caspase-3, along with a propensity to promote autophagy, as indicated by changes in BECN1, p62, and the LC3I/LC3II ratio. Furthermore, the combination therapy resulted in significant reductions in biomarkers associated with liver preneoplastic alterations, improved liver microstructure, and mitigated changes in liver function enzymes. The substantial decrease in hedgehog components (Shh, SMO, GLI1, and GLI2) following R51211 treatment appears to be a key factor contributing to the increased efficacy of sorafenib. In conclusion, our study highlights the potential of R51211 as an adjunct to sorafenib, introducing a new dimension to this combination therapy through the modulation of the hedgehog signaling pathway. Further investigations are essential to validate the therapeutic efficacy of this combined approach in inhibiting the development of liver cancer.

A novel combination therapy targets sonic hedgehog signaling by the dual inhibition of HMG-CoA reductase and HSP90 in rats with non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is characterized by liver inflammation, fat accumulation, and collagen deposition. Due to the limited availability of effective treatments, there is a pressing need to develop innovative strategies. Given the complex nature of the disease, employing combination approaches is essential. Hedgehog signaling has been recognized as potentially promoting NASH, and cholesterol can influence this signaling by modifying the conformation of PTCH1 and SMO activity. HSP90 plays a role in the stability of SMO and GLI proteins. We revealed significant positive correlations between Hedgehog signaling proteins (Shh, SMO, GLI1, and GLI2) and both cholesterol and HSP90 levels. Herein, we investigated the novel combination of the cholesterol-lowering agent lovastatin and the HSP90 inhibitor PU-H71 in vitro and in vivo. The combination demonstrated a synergy score of 15.09 and an MSA score of 22.85, as estimated by the ZIP synergy model based on growth inhibition rates in HepG2 cells. In a NASH rat model induced by thioacetamide and a high-fat diet, this combination therapy extended survival, improved liver function and histology, and enhanced antioxidant defense. Additionally, the combination exhibited anti-inflammatory and anti-fibrotic potential by influencing the levels of TNF-α, TGF-ß, TIMP-1, and PDGF-BB. This effect was evident in the suppression of the Col1a1 gene expression and the levels of hydroxyproline and α-SMA. These favorable outcomes may be attributed to the combination's potential to inhibit key Hedgehog signaling molecules. In conclusion, exploring the applicability of this combination contributes to a more comprehensive understanding and improved management of NASH and other fibrotic disorders.

miRNAs dysregulation in ankylosing spondylitis: A review of implications for disease mechanisms, and diagnostic markers.

Epigenetic processes, including non-coding RNA, histone modifications, and DNA methylation, play a vital role in connecting the environment to the development of a disorder, especially when there is a favorable genetic background. Ankylosing Spondylitis (AS) is a chronic type of spinal arthritis that highlights the significance of epigenetics in diseases related to autoimmunity and inflammation. MicroRNAs (miRNAs) are small non-coding RNAs that are involved in both normal and aberrant pathological and physiological gene expression. This study focuses on the pathophysiological pathways to clarify the role of miRNAs in AS. We have conducted a thorough investigation of the involvement of miRNAs in several processes, including inflammation, the production of new bone, T-cell activity, and the regulation of pathways such as BMP, Wnt, and TGFß signaling. Undoubtedly, miRNAs play a crucial role in enhancing our comprehension of the pathophysiology of AS, and their promise as a therapeutic strategy is quickly expanding.

Item analysis: the impact of distractor efficiency on the difficulty index and discrimination power of multiple-choice items.

BACKGROUND: Distractor efficiency (DE) of multiple-choice questions (MCQs) responses is a component of the psychometric analysis used by the examiners to evaluate the distractors' credibility and functionality. This study was conducted to evaluate the impact of the DE on the difficulty and discrimination indices. METHODS: This cross-sectional study was conducted from April to June 2023. It utilizes the final exam of the Principles of Diseases Course with 45 s-year students. The exam consisted of 60 type A MCQs. Item analysis (IA) was generated to evaluate KR20, difficulty index (DIF), discrimination index (DIS), and distractor efficiency (DE). DIF was calculated as the percentage of examinees who scored the item correctly. DIS is an item's ability to discriminate between higher and lower 27% of examinees. For DE, any distractor selected by less than 5% is considered nonfunctional, and items were classified according to the non-functional distractors. The correlation and significance of variance between DIF, DI, and DE were evaluated. RESULTS: The total number of examinees was 45. The KR-20 of the exam was 0.91. The mean (M), and standard deviation (SD) of the DIF of the exam was 37.5(19.1), and the majority (69.5%) were of acceptable difficulty. The M (SD) of the DIS was 0.46 (0.22), which is excellent. Most items were excellent in discrimination (69.5%), only two were not discriminating (13.6%), and the rest were of acceptable power (16.9%). Items with excellent and good efficiency represent 37.3% each, while only 3.4% were of poor efficiency. The correlation between DE and DIF (p = 0.000, r= -0.548) indicates that items with efficient distractors (low number of NFD) are associated with those having a low difficulty index (difficult items) and vice versa. The correlation between DE and DIS is significantly negative (P = 0.0476, r=-0.259). In such a correlation, items with efficient distractors are associated with low-discriminating items. CONCLUSIONS: There is a significant moderate negative correlation between DE and DIF (P = 0.00, r = -0.548) and a significant weak negative correlation between DE and DIS (P = 0.0476, r = -0.259). DIF has a non-significant negative correlation with DIS (P = 0.7124, r = -0.0492). DE impacts both DIF and DIS. Items with efficient distractors (low number of NFD) are associated with those having a low difficulty index (difficult items) and discriminating items. Improving the quality of DE will decrease the number of NFDs and result in items with acceptable levels of difficulty index and discrimination power.

Tracking the therapeutic efficacy of a ketone mono ester and ß-hydroxybutyrate for ulcerative colitis in rats: New perspectives.

Ulcerative colitis (UC) is an inflammatory condition that affects the colon's lining and increases the risk of colon cancer. Despite ongoing research, there is no identified cure for UC. The recognition of NLRP3 inflammasome activation in the pathogenesis of UC has gained widespread acceptance. Notably, the ketone body ß-hydroxybutyrate inhibits NLRP3 demonstrating its anti-inflammatory properties. Additionally, BD-AcAc 2 is ketone mono ester that increases ß-hydroxybutyrate blood levels. It has the potential to address the constraints associated with exogenous ß-hydroxybutyrate as a therapeutic agent, including issues related to stability and short duration of action. However, the effects of ß-hydroxybutyrate and BD-AcAc 2 on colitis have not been fully investigated. This study found that while both exogenous ß-hydroxybutyrate and BD-AcAc 2 produced the same levels of plasma ß-hydroxybutyrate, BD-AcAc 2 demonstrated superior effectiveness in mitigating dextran sodium sulfate-induced UC in rats. The mechanism of action involves modulating the NF-κB signaling, inhibiting the NLRP3 inflammasome, regulating antioxidant capacity, controlling tight junction protein expression and a potential to inhibit apoptosis and pyroptosis. Certainly, BD-AcAc 2's anti-inflammatory effects require more than just increasing plasma ß-hydroxybutyrate levels and other factors contribute to its efficacy. Local ketone concentrations in the gastrointestinal tract, as well as the combined effect of specific ketone bodies, are likely to have contributed to the stronger protective effect observed with ketone mono ester ingestion in our experiment. As a result, further investigations are necessary to fully understand the mechanisms of BD-AcAc 2 and optimize its use.

Prevalence and Comorbidities Among Individuals With Rheumatoid Arthritis in the Saudi Arabian Context.

BACKGROUND:  Rheumatoid arthritis (RA) in Saudi Arabia (SA) is a significant health concern with a notable impact on individuals and the healthcare system. This study aimed to investigate the prevalence and profile of comorbidities in patients with RA. METHODOLOGY:  This is a retrospective descriptive study involving 150 RA patients from August 2022 to August 2023, which was conducted at Khamis Mushait General Hospital, a major healthcare institution in SA. We examined the medical records to gather pertinent information. Stata Statistical Software: Release 18 (2023; StataCorp LLC, College Station, Texas, United States) was used for data analysis. The examination focused on sociodemographic factors, disease duration, prescribed medications (including methotrexate and biologic therapy), and the presence of comorbidities. Approval for the study was obtained from the Institutional Review Board of the Aseer Ministry of Health (approval number: H-06-B-091). RESULTS:  The study found a high prevalence of comorbidities in patients with RA. Around 96.7% of the patients had at least one documented comorbidity, highlighting this population's burden of additional health conditions. The most common comorbidity observed was anemia, affecting 48.7% of the patients. Other frequently observed comorbidities include hypertension, hyperlipidemia, diabetes mellitus, osteoporosis, interstitial lung disease, chronic renal disease, stroke, and coronary artery disease. The factors influencing comorbidities included an odds ratio of 1.086 (p=0.025), while being male was associated with lower odds (odds ratio=0.529, p=0.017). Additionally, disease duration (odds ratio=1.164, p=0.007), methotrexate use (odds ratio=2.553, p=0.001), and receiving biologic therapy (odds ratio=3.488, p<0.001) were significant contributors to comorbidities. CONCLUSION:  These findings highlight the need for comprehensive approaches to address RA and its associated comorbidities. Research and awareness initiatives are essential to understand better the specific nuances of RA in SA, leading to improved diagnostic and treatment strategies for the needs of the local population.

Itraconazole halts hepatocellular carcinoma progression by modulating sonic hedgehog signaling in rats: A novel therapeutic approach.

Liver cancer stands as the fourth leading global cause of death, and its prognosis remains grim due to the limited effectiveness of current medical interventions. Among the various pathways implicated in the development of hepatocellular carcinoma (HCC), the hedgehog signaling pathway has emerged as a crucial player. Itraconazole, a relatively safe and cost-effective antifungal medication, has gained attention for its potential as an anticancer agent. Its primary mode of action involves inhibiting the hedgehog pathway, yet its impact on HCC has not been elucidated. The main objective of this study was to investigate the effect of itraconazole on diethylnitrosamine-induced early-stage HCC in rats. Our findings revealed that itraconazole exhibited a multifaceted arsenal against HCC by downregulating the expression of key components of the hedgehog pathway, shh, smoothened (SMO), and GLI family zinc finger 1 (GLI1), and GLI2. Additionally, itraconazole extended survival and improved liver tissue structure, attributed mainly to its inhibitory effects on hedgehog signaling. Besides, itraconazole demonstrated a regulatory effect on Notch1, and Wnt/ß-catenin signaling molecules. Consequently, itraconazole displayed diverse anticancer properties, including anti-inflammatory, antiangiogenic, antiproliferative, and apoptotic effects, as well as the potential to induce autophagy. Moreover, itraconazole exhibited a promise to impede the transformation of epithelial cells into a more mesenchymal-like phenotype. Overall, this study emphasizes the significance of targeting the hedgehog pathway with itraconazole as a promising avenue for further exploration in clinical studies related to HCC treatment.

The emerging role of miRNAs in myocardial infarction: From molecular signatures to therapeutic targets.

Globally, myocardial infarction (MI) and other cardiovascular illnesses have long been considered the top killers. Heart failure and mortality are the results of myocardial apoptosis, cardiomyocyte fibrosis, and cardiomyocyte hypertrophy, all of which are caused by MI. MicroRNAs (miRNAs) play a crucial regulatory function in the progression and advancement of heart disease following an MI. By consolidating the existing data on miRNAs, our aim is to gain a more comprehensive understanding of their role in the pathological progression of myocardial injury after MI and to identify potential crucial target pathways. Also included are the primary treatment modalities and their most recent developments. miRNAs have the ability to regulate both normal and pathological activity, including the key signaling pathways. As a result, they may exert medicinal benefits. This review presents a comprehensive analysis of the role of miRNAs in MI with a specific emphasis on their impact on the regeneration of cardiomyocytes and other forms of cell death, such as apoptosis, necrosis, and autophagy. Furthermore, the targets of pro- and anti-MI miRNAs are comparatively elucidated.

Red Blood Cell Distribution Width: A Potential Inexpensive Marker for Disease Activity in Patients with Rheumatic Diseases; Scoping Review.

Background: Rheumatic diseases encompass a diverse group of autoimmune disorders that affect the joints and connective tissues. The red blood cell distribution width (RDW) has been widely investigated as an inflammatory marker. This scoping review aimed to explore the potential utility of RDW as an inexpensive marker for disease activity in patients with rheumatic diseases. By summarizing the available evidence, we aimed to determine whether RDW can serve as a reliable and accessible indicator of disease activity in these patients. Methods: A comprehensive search was systematically performed across electronic databases, encompassing PubMed, Embase, and Web of Science. Studies have explored the relationship between RDW and disease activity in rheumatic diseases. Data extraction focused on the study characteristics, methodologies, and findings related to RDW as a disease activity marker. Results: After removing duplicates, the initial search yielded 25 relevant studies. These studies encompassed a variety of rheumatic diseases, with rheumatoid arthritis being the most frequently studied condition. The association between RDW and disease activity was assessed by using various disease activity indices and clinical parameters. While some studies have reported a significant correlation between elevated RDW and disease activity, others have yielded inconclusive results. Conclusion: From this review, we concluded that RDW is an inexpensive potential marker for the evaluation of disease activity in rheumatic diseases. RDW is promising as an inexpensive and readily available marker; however, its clinical utility in assessing disease activity in rheumatic conditions warrants more rigorous investigation through well-designed prospective studies.

Medical students' perception and academic performance after team-based and seminar-based learning in human anatomy.

Objectives: Student-centered educational strategies like problem-based learning (PBL), case-based learning (CBL), team-based learning (TBL), and seminars enhance group and self-learning. This study was carried out to evaluate students' achievements in anatomy topics delivered through TBL sessions and seminars and to survey student preferences regarding these two modalities in anatomy learning. Methods: TBL was conducted through individual readiness assurance tests (IRATs), group readiness assurance tests (GRATs), mini-lectures, and application exercises. Seminars included pretests, peer lecturing, and posttests. The performance of 117 students in three TBL sessions and three seminars was compared after standardizing the questions. The students were second-year (42), third-year (40), and fourth-year (35) students at the College of Medicine, University of Bisha, KSA, during the 2019/2020 academic year. Results: A gradual increase in the means of TBL grades was noticed among second-, third-, and four-year students (means ± SD: 68.6 ± 9.56, 82.8 ± 12.25, and 92.7 ± 4.70, respectively), but their seminar grades were nearly stationary (means ± SD: 80.0 ± 9.66, 85.11 ± 10.16, and 85.9 ± 8.80, respectively). Cohen's d-test to check the strength of the relationship between the two activities showed 1.03, 0.16, and 0.74 in the same order. We statistically analyzed perception and preference questionnaire results received from 39, 35, and 28 second-, third-, and four-year students, respectively. The majority of the students selected TBL as their preferred learning modality. However, their acceptance of the seminars was very poor. Conclusions: It can be concluded that TBL is more beneficial to the students, even in practical sciences like anatomy, most likely because group peer teaching enhances the sense of collegial competition, as opposed to the self-learning nature of seminars, which might suppress the sense of competition.

Molecular Epidemiology of Carbapenem-Resistant K. pneumoniae Clinical Isolates from the Adult Patients with Comorbidities in a Tertiary Hospital, Southern Saudi Arabia.

Hospitalized patients are likely to have chronic illnesses and are at an increased risk of mortality due to infection caused by MDR bacteria. We aimed to identify carbapenem-resistant genes carrying Klebsiella pneumoniae (K. pneumoniae) isolates and their risk factors recovered from adult patients with comorbidities. A cross-sectional study was carried out between April 2021 and December 2021 at King Abdullah Hospital (KAH) in Bisha province, Saudi Arabia. Seventy-one multi-drug resistant K. pneumoniae recovered from clinical samples and screened for carbapenemase genes of blaOXA-48-like, blaNDM-1, blaKPC, blaVIM, and blaIMP. Of 71 MDR K. pneumoniae examined, 47 (66.2%) isolates harbored various carbapenemase genes. The most prevalent single resistance gene was blaOXA-48-like (62.5%; n = 25), and 33.3% of them were recovered from sputum isolates. The blaNDM-1 gene was detected in 12 (30.0%) isolates, and eight of them were recovered from urine (n = 4) and blood (n = 4). Two (5.0%) single blaKPC genes were recovered from the sputum (n = 1) and blood (n = 1) isolates. In contrast, no blaIMP- and blaVIM-carrying isolates were detected. The co-existence of two resistance genes between blaOXA-48-like and blaNDM-1 was found in six strains, whereas only one strain was found to be produced in the three genes of blaNDM-1, blaKPC, and blaOXA-48-like. There were statistically significant associations between the presence of carbapenem-gene-carrying K. pneumoniae and patients' gender (χ2(1) = 5.94, p = 0.015), intensive care unit admission (χ2(1) = 7.649, p = 0.002), and chronic obstructive pulmonary disease (χ2(1) = 4.851, p = 0.028). The study highlighted the existence of carbapenemase-producing K. pneumoniae, particularly blaOXA-48-like and blaNDM-1, in patients with comorbidities. Our findings emphasize the importance of the molecular characterization of resistance-determinant-carrying bacterial pathogens as a part of infection control and prevention in hospital settings.

Magnitude of diabetic peripheral neuropathy in Saudi Arabia: a systematic review and meta-analysis.

BACKGROUND: Diabetic peripheral neuropathy (DPN), due to its potential for causing morbidity and disability from foot ulcers and amputations, is increasingly becoming a source of concern in Saudi Arabia and worldwide. However, wide variability exists in the prevalence of DPN reported in previous studies in Saudi Arabia, limiting the utility of existing data in national public health policy. Therefore, the aim of this study was to systematically evaluate the magnitude of DPN in patients living with DM in Saudi Arabia in order to inform policymakers during the implementation of appropriate preventive and treatment strategies for DPN. METHODS: PubMed, Google Scholar, African Journals Online, Scopus, Web of Science, Embase, and Wiley Online Library were searched systematically to acquire relevant articles based on preset criteria. We evaluated heterogeneity and publication bias and employed a random-effects model to estimate the pooled prevalence of DPN from the included studies. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in conducting the meta-analysis. Analysis was performed using the STATA Version 12 software. RESULTS: Twelve studies with a total of 4,556 participants living with DM, of whom 2,081 were identified as having DPN were included in the meta-analysis. The overall prevalence of DPN was 39% (95% CI [30%, 49%]). Subgroup analysis based on diagnostic method showed that prevalence estimates for DPN using screening questionnaires and clinical examination were 48% (95% CI [46%, 50%]) and 40% (95% CI: [38%, 42%]), respectively, while the estimated prevalence using nerve conduction studies was 26% (95% CI [15%, 36%]). CONCLUSION: This study showed a high magnitude of DPN in Saudi Arabia (39%), thus highlighting the need for sustained efforts to reduce the prevalence of diabetes mellitus and DPN in the kingdom.

Differential Association of Selected Adipocytokines, Adiponectin, Leptin, Resistin, Visfatin and Chemerin, with the Pathogenesis and Progression of Type 2 Diabetes Mellitus (T2DM) in the Asir Region of Saudi Arabia: A Case Control Study.

BACKGROUND: Sedentary lifestyles, urbanization and improvements in socio-economic status have had serious effects on the burden of diabetes across the world. Diabetes is one of the 10 leading causes of death globally, and individuals with diabetes have a 2-3-fold increased risk of all-cause mortality. Adipose tissue is increasingly understood as a highly active endocrine gland that secretes many biologically active substances, including adipocytokines. However, the exact and discrete pathophysiological links between obesity and T2DM are not yet fully elucidated. METHODS: In the current study, we present the association of five diverse adipocytokines, adiponectin, leptin, resistin, visfatin and chemerin, with T2DM in 87 patients (46 males and 41 females) with type 2 diabetes mellitus and 85 healthy controls (44 males and 41 females) from the Asir region of Saudi Arabia. The patients were divided into four groups: normal BMI, overweight, obese and severely obese. The baseline biochemical characteristics, including HbA1c and anthropometric lipid indices, such as BMI and waist-hip ratio, were determined by standard procedures, whereas the selected adipokine levels were assayed by ELISA. RESULTS: The results showed significantly decreased levels of adiponectin in the T2DM patients compared to the control group, and the decrease was more pronounced in obese and severely obese T2DM patients. Serum leptin levels were significantly higher in the females compared to the males in the controls as well as all the four groups of T2DM patients. In the male T2DM patients, a progressive increase was observed in the leptin levels as the BMI increased, although these only reached significantly altered levels in the obese and severely obese patients. The serum leptin levels were significantly higher in the severely obese female patients compared to the controls, patients with normal BMI, and overweight patients. The leptin/adiponectin ratio was significantly higher in the obese and severely obese patients compared to the controls, patients with normal BMI, and overweight patients in both genders. The serum resistin levels did not show any significant differences between the males and females in thr controls or in the T2DM groups, irrespective of the BMI status of the T2DM patients. The visfatin levels did not reveal any significant gender-based differences, but significantly higher levels of visfatin were observed in the T2DM patients, irrespective of their level of obesity, although the higher values were observed in the obese and highly obese patients. Similarly, the serum chemerin levels in the controls, as well as in T2DM patients, did not show any significant gender-based differences. However, in the T2DM patients, the chemerin levels showed a progressive increase, with the increase in BMI reaching highly significant levels in the obese and severely obese patients, respectively. CONCLUSION: In summary, it is concluded that significantly altered concentrations of four adipokines, adiponectin, leptin, visfatin and chemerin, were found in the T2DM patient group compared to the controls, with more pronounced alterations observed in the obese and highly obese patients. Thus, it can be surmised that these four adipokines play a profound role in the onset, progression and associated complications of T2DM. In view of the relatively small sample size in our study, future prospective studies are needed on a large sample size to explore the in-depth relationship between adipokines and T2DM.

Differential impact of the angiotensin-converting enzyme-2 (ACE2 rs4343 G>A) and miR-196a2 rs11614913 C>T gene alterations in COVID-19 disease severity and mortality.

The recent coronavirus outbreak from Wuhan China in late 2019 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulted in a global pandemic of coronavirus-19 disease (COVID-19). Understating the underlying mechanism of the pathogenesis of coronavirus infection is important not only because it will help in accurate diagnosis and treatment of the infection but also in the production of effective vaccines. The infection begins when SARS-CoV-2 enters the cells through binding of its envelope glycoprotein to angiotensin-converting enzyme2 (ACE2). Gene variations of ACE2 and microRNA (miR)-196 are associated with viral infection and other diseases. The present study investigated the association of the ACE2 rs4343 G>A and miR-196a2 rs11614913 C>T gene polymorphisms with severity and mortality of COVID-19 using amplification refractory mutation system PCR in 117 COVID-19 patients and 103 healthy controls from three regions of Saudi Arabia. The results showed that ACE2 rs4343 GA genotype was associated with severity of COVID-19 (OR=2.10, P-value 0.0028) and ACE2 rs4343 GA was associated with increased mortality with OR=3.44, P-value 0.0028. A strong correlation between the ACE2 rs4343 G>A genotype distribution among COVID-19 patients was reported with respect to their comorbid conditions including sex (P<0.023), coronary artery disease (P<0.0001), oxygen saturation <60 mm Hg (P<0.0009) and antiviral therapy (0.003). The results also showed that the CT genotype and T allele of the miR-196a2 rs11614913 C>T were associated with decreased risk to COVID-19 with OR=0.76, P=0.006 and OR=0.54, P=0.005, respectively. These results need to be validated with future molecular genetic studies in a larger sample size and different populations.

Clinical Implications of Glyoxalase1 Gene Polymorphism and Elevated Levels of the Reactive Metabolite Methylglyoxal in the Susceptibility of Type 2 Diabetes Mellitus in the Patients from Asir and Tabuk Regions of Saudi Arabia.

Diabetes mellitus constitutes a big challenge to the global health care system due to its socioeconomic impacts and very serious complications. The incidence and the prevalence rate are increased in the Gulf region including the KSA. Type 2 diabetes mellitus (T2DM) is caused by diverse risk factors including obesity, unhealthy dietary habits, physical inactivity, smoking and genetic factors. The molecular genetic studies have helped in the detection of many single nucleotide polymorphisms (SNP) with different diseases including cancers, cardiovascular diseases and T2DM. The glyoxalase 1 (GLO1) is a detoxifying enzyme and catalyzes the elimination of the cytotoxic product methylglyoxal (MG) by converting it to D-lactate, which is not toxic to tissues. MG accumulation is associated with the pathogenesis of different diseases including T2DM. In this study, we have investigated the association of the glyoxalase 1 SNPs (rs2736654) rs4746 C>A and rs1130534 T>A with T2DM using the amplification refractory mutation system PCR. We also measured the concentration of MG by ELISA in T2DM patients and matched heathy controls. Results show that the CA genotype of the GLO rs4647 A>C was associated with T2DM with OR = 2.57, p-value 0.0008 and the C allele was also associated with increased risk to T2DM with OR = 2.24, p-value = 0.0001. It was also observed that AT genotype of the rs1130534 was associated with decreased susceptibility to T2DM with OR = 0.3, p-value = 0.02. The A allele of rs1130534 was also associated with reduced risk to T2DM with PR = 0.27 = 0.006. In addition, our ELISA results demonstrate significantly increased MG concentrations in serum of the T2DM patients. We conclude that the GLO1 SNP may be associated with decreased enzyme activity and a resultant susceptibility to T2DM. Further well-designed studies in different and large patient populations are recommended to verify these findings.

Disease-specific quality of life in patients with diabetic neuropathy.

OBJECTIVES: To compare health-related quality of life (HRQoL) among patients with diabetes mellitus (DM) and diabetic neuropathy (DN) (D+N) with patients with DM without DN (D-DN) and healthy participants. To evaluate factors associated with poor HRQoL in patients with DN. METHODS: This study included 306 participants residing in Bisha, Saudi Arabia. Patients with DM were screened for DN using the Michigan Neuropathy Screening Instrument. Neuropathy severity, disability and HRQoL were determined using the Neuropathy Severity Scale (NSS), the Neuropathy Disability Score (NDS), and the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) tool, respectively. Nerve conduction studies (NCSs) were also performed. RESULTS: The D+DN group had poorer overall and domain HRQoL scores compared to the D-DN group (p<0.001). There was a strong correlation between overall HRQoL score and both NDS and NSS scores in the D+DN group (ρ= -0.71 and p<0.0001; ρ= -0.81 and p<0.0001, respectively). There was also a significant difference in all mean HRQoL domain scores between D+DN participants with normal and abnormal NCS. Physical inactivity (p=0.043), duration of DM (p<0.0001), abnormal NCS, NSS (p<0.0001), and NDS (p<0.0001) predicted HRQoL in the D+DN group. CONCLUSION: D+DN participants had a worse HRQoL compared with D-DN and healthy counterparts. NDS, NNS, physical inactivity, abnormal NCS, and duration of DM independently predicted poor HRQoL in D+DN participants.

Potential impact of GCK, MIR-196A-2 and MIR-423 gene abnormalities on the development and progression of type 2 diabetes mellitus in Asir and Tabuk regions of Saudi Arabia.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by persistent hyperglycemia and is associated with serious complications. The risk factors for T2DM include both genetic and lifestyle factors. Genome­wide association studies have indicated the association of genetic variations with many diseases, including T2DM. Glucokinase (GCK) plays a key role in the regulation of insulin release in the pancreas and catalyzes the first step in glycolysis in the liver. Genetic alterations in the GCK gene have been implicated in both hyperglycemia and hypoglycemia. MicroRNAs (miRNAs/miRs) are small non­coding RNA molecules that are involved in the important physiological processes including glucose metabolism. In the present study, the association of the single nucleotide polymorphisms (SNPs) in the GCK, MIR­196A­2 and MIR­423 genes with susceptibility to T2DM in patients from two regions of Saudi Arabia were examined, using the tetra­primer amplification refractory mutation system. The results showed that the AA genotype and the A allele of GCK rs1799884 were associated with T2DM [odds ratio (OR)=2.25, P=0.032 and OR=1.55, P=0.021, respectively]. Likewise, the CT genotype and T allele of MIR­196A­2 rs11614913 were associated with an increased risk of T2DM (OR=2.36, P=0.0059 and OR=1.74, P=0.023, respectively). In addition, the CA genotype of MIR­423 rs6505162 C>A was found to be linked with T2DM (OR=2.12 and P=0.021). It was concluded in the present research study that gene variations in GCK, MIR­196A­2 and MIR­423 are potentially associated with an increased risk of T2DM. These results, in the future, may help in the identification and stratification of individuals susceptible to T2DM. Future longitudinal studies with larger sample sizes and in different ethnic populations are recommended to validate these findings.

Expert recommendations on early diagnosis and referral of axial spondyloarthritis in the Kingdom of Saudi Arabia.

Axial spondyloarthritis is a chronic inflammatory disorder that primarily involves the axial skeleton (sacroiliac joints and spine), causing stiffness, severe pain and fatigue. In some patients, definitive structural damage of sacroiliac joints is visible on imaging and is known as radiographic axial spondyloarthritis. Some patients do not have a clear radiographic damage of the sacroiliac joints, and this subtype is known as non-radiographic axial spondyloarthritis. Early diagnosis is important for reducing the risk of irreversible structural damage and disability. Management of axial spondyloarthritis is challenging in Saudi Arabia because of inadequate disease knowledge and the unavailability of local guidelines. Therefore, this expert consensus is intended to provide recommendations, including the referral pathway, the definition of remission and the treat-to-target approach, to all healthcare professionals for the management of patients with axial spondyloarthritis. A Delphi technique of consensus was developed by involving an expert panel of 10 rheumatologists, 1 dermatologist and 1 general physician. The experts offered consensus-based recommendations based on a review of available scientific evidence and clinical experience for the referral, screening and management of patients with axial spondyloarthritis.

Consensus-based recommendations on the diagnosis, referral and clinical management of patients with psoriatic arthritis.

Psoriatic arthritis (PsA) is a highly heterogeneous disease with complex manifestations. Limited understanding of the disease and non-availability of local guidelines pose challenges in the management of PsA in Saudi Arabia. Therefore, this expert consensus is aimed to provide recommendations on the management of patients with PsA, including referral pathway, definition of remission and treat-to-target (T2T) approach. A Delphi technique of consensus development was used involving an expert panel comprised of 10 rheumatologists, one dermatologist and one family physician. Based on the review of available published evidence and the opinions of clinical experts, key recommendations were developed. A consensus was achieved in defining the following: management guideline adaptable for Saudi Arabia, most useful screening tool, laboratory investigations, imaging tests and criteria for referring suspected PsA patients to a rheumatologist. In addition, an agreement was achieved in defining the T2T strategy and remission for the clinical management of PsA. Overall, these recommendations provide an evidence-based framework for the management of PsA patients in Saudi Arabia.

Strong Association of Angiotensin Converting Enzyme-2 Gene Insertion/Deletion Polymorphism with Susceptibility to SARS-CoV-2, Hypertension, Coronary Artery Disease and COVID-19 Disease Mortality.

BACKGROUND: The ongoing outbreak of SARS-CoV-2 represents a significant challenge to international health. Several reports have highlighted the importance of ACE2 on the pathogenesis of COVID-19. The spike protein of SARS-CoV-2 efficiently binds to the angiotensin-converting enzyme 2 (ACE2) receptors and facilitates virus entry into the host cell. In the present study, we hypothesize that a functional insertion/deletion polymorphism-rs4646994 I/D and rs4240157 T > C in the ACE gene could be associated with SARS-CoV-2 infection and mortality. METHODOLOGY: This study included 117 consecutive COVID-19 patients and 150 age matched healthy controls (ACE2-rs4646994 I/D) and 100 age matched healthy controls with ACE2 rs4240157 T > C. We used Mutation specific PCR (MSP) for ACE2-rs4646994 I/D genotyping and amplification refractory mutation system (ARMS-PCR) for ACE2 rs4240157 T > C genotyping. RESULTS: Results indicated that there were significant differences in the genotype distributions of ACE2-rs4646994 I/D polymorphisms (p < 0.030) and ACE2 rs4240157 T > C between COVID-19 patients and controls (p-values < 0.05). Higher frequency of DD genotype (48.71%) and D allele (0.67) was reported in COVID-19 patients than controls. Our results showed that the ACE2-DD genotype was strongly associated with increased COVID-19 severity (OR 2.37 (95%) CI = (1.19-4.70), RR = 1.39 (1.09-1.77), p < 0.013) and also a strong association was seen with ACE2-ID genotype with COVID-19 severity (OR 2.20 (95%) CI = (1.08-4.46), p < 0.020) in the codominant model. In allelic comparison, the D allele was strongly associated with COVID-19 severity (OR 1.58 (95% CI) (1.11-2.27), RR 1.21 (1.05-1.41) p < 0.010). A significant correlation of ACE2-I/D genotypes was reported with Age (p < 0.035), T2D (p < 0.0013), hypertension (p < 0.0031) and coronary artery disease (p < 0.0001). Our results indicated ACE2-DD genotype was strongly associated with increased COVID-19 mortality (OR 8.25 (95%) CI = (2.40 to 28.34), p < 0.008) and also ACE2-DD + DI genotype was strongly associated with increased COVID-19 mortality with OR 4.74 (95%) CI = (1.5214 to 14.7915), p < 0.007. A significant correlation was reported between COVID-19 patients and age matched controls (p < 0.0007). Higher frequency of heterozygosity TC (40%) followed by ACE2-CC genotype (24.78%) was reported among COVID-19 patients. Using multivariate analysis, ACE2-CT genotype was strong associated with SARS-CoV-2 severity with an OR 2.18 (95% CI) (1.92-3.99), p < 0.010 and also ACE2-CC genotype was linked with COVID-19 severity with an OR 2.66 (95% CI) (1.53-4.62), p < 0.005. A significant correlation of ACE2-T > C genotypes was reported with gender (p < 0.04), T2D (p < 0.035). ACE2-CC genotype was strongly associated with increased COVID-19 mortality OR 3.66 (95%) CI = (1.34 to 9.97), p < 0.011 and also ACE2-C allele was associated with COVID-19 mortality OR 2, 01 (1.1761-3.45), p < 0.010. CONCLUSIONS: It is concluded that ACE-DD genotype and D allele was strongly associated with increased COVID-19 patient severity. In addition, ACE I/D polymorphism were strongly associated with advanced age, diabetes and ischemic heart disease in COVID-19 patients whereas ACE-II genotype was a protective factor against the development of severe COVID-19. ACE2-DD genotype was strongly associated with increased COVID-19 mortality. Additionally, ACE2-CC and CT genotypes were strongly associated with COVID-19 severity. Therefore, our study might be useful for identifying the susceptible population groups for targeted interventions and for making relevant public health policy decisions.