Rare variant burden analysis from exomes of three consanguineous families reveals LILRB1 and PRSS3 as potential key proteins in inflammatory bowel disease pathogenesis.

Background: Inflammatory bowel disease (IBD) is a chronic autoimmune disorder characterized by severe inflammation and mucosal destruction of the intestine. The specific, complex molecular processes underlying IBD pathogenesis are not well understood. Therefore, this study is aimed at identifying and uncovering the role of key genetic factors in IBD. Method: The whole exome sequences (WESs) of three consanguineous Saudi families having many siblings with IBD were analyzed to discover the causal genetic defect. Then, we used a combination of artificial intelligence approaches, such as functional enrichment analysis using immune pathways and a set of computational functional validation tools for gene expression, immune cell expression analyses, phenotype aggregation, and the system biology of innate immunity, to highlight potential IBD genes that play an important role in its pathobiology. Results: Our findings have shown a causal group of extremely rare variants in the LILRB1 (Q53L, Y99N, W351G, D365A, and Q376H) and PRSS3 (F4L and V25I) genes in IBD-affected siblings. Findings from amino acids in conserved domains, tertiary-level structural deviations, and stability analysis have confirmed that these variants have a negative impact on structural features in the corresponding proteins. Intensive computational structural analysis shows that both genes have very high expression in the gastrointestinal tract and immune organs and are involved in a variety of innate immune system pathways. Since the innate immune system detects microbial infections, any defect in this system could lead to immune functional impairment contributing to IBD. Conclusion: The present study proposes a novel strategy for unraveling the complex genetic architecture of IBD by integrating WES data of familial cases, with computational analysis.

Exome Sequencing Identifies the Extremely Rare ITGAV and FN1 Variants in Early Onset Inflammatory Bowel Disease Patients.

Background: Molecular diagnosis of early onset inflammatory bowel disease (IBD) is very important for adopting suitable treatment strategies. Owing to the sparse data available, this study aims to identify the molecular basis of early onset IBD in Arab patients. Methods: A consanguineous Arab family with monozygotic twins presenting early onset IBD was screened by whole exome sequencing (WES). The variants functional characterization was performed by a series of computational biology methods. The IBD variants were further screened in in-house whole exome data of 100 Saudi cohorts ensure their rare prevalence in the population. Results: Genetic screening has identified the digenic autosomal recessive mode of inheritance of ITGAV (G58V) and FN1 (G313V) variants in IBD twins with early onset IBD. Findings from pathogenicity predictions, stability and molecular dynamics have confirmed the deleterious nature of both variants on structural features of the corresponding proteins. Functional biology data suggested that both genes show abundant expression in gastrointestinal tract and immune organs, involved in immune cell restriction, regulation of different immune related pathways. Data from knockout mouse models for ITGAV gene has revealed that the dysregulated expression of this gene impacts intestinal immune homeostasis. The defective ITGAV and FN1 involved in integrin pathway, are likely to induce intestinal inflammation by disturbing immune homeostasis. Conclusions: Our findings provide novel insights into the molecular etiology of pediatric onset IBD and may likely pave way in developing genomic medicine.

Metabolic bone disease in children and adolescent patients with ulcerative colitis

Abstract Objective: Metabolic bone disease concerns a broad spectrum of conditions related to reduced bone density. Metabolic bone disease has been linked to chronic inflammatory diseases, such as ulcerative colitis. This study examines the prevalence of metabolic bone disease in ulcerative colitis patients and explores possible clinical predictors. Method: The authors performed a retrospective study involving children and adolescents with confirmed ulcerative colitis between January 2013 and December 2018. Bone density was evaluated through a dual-energy X-ray absorptiometry scan of the spine and total body. Osteoporosis was defined as a bone mineral density Z-score of <−2 and osteopenia as a Z-score of between −1.0 and −2. Results: A total of 37 patients were included in this analysis, with a mean age of 13.4 ± 3.9 years and a mean duration of illness of 2.1 ± 2.4 years. Using lumbar spine Z-scores and total body Z-scores, osteoporosis and osteopenia were identified by dual-energy X-ray absorptiometry scan measurements in 11 patients (29.7%) and 15 patients (40.5%), and in ten patients (27%) and 13 patients (35%), respectively. Lumbar spine Z-scores were significantly positively associated with male gender (B = 2.02; p = 0.0001), and negatively associated with the presence of extraintestinal manifestations (B = −1.51, p = 0.009) and the use of biologics (B = −1.33, p = 0.004). However, total body Z-scores were positively associated with body mass index Z-scores (B = 0.26, p = 0.004) and duration of illness in years (B = 0.35, p = 0.003). Conclusions: Metabolic bone disease is very common in this cohort of Saudi Arabian children and adolescents with ulcerative colitis and its occurrence appears to increase in female patients who suffer from extraintestinal manifestations.

Metabolic bone disease in children and adolescent patients with ulcerative colitis.

OBJECTIVE: Metabolic bone disease concerns a broad spectrum of conditions related to reduced bone density. Metabolic bone disease has been linked to chronic inflammatory diseases, such as ulcerative colitis. This study examines the prevalence of metabolic bone disease in ulcerative colitis patients and explores possible clinical predictors. METHOD: The authors performed a retrospective study involving children and adolescents with confirmed ulcerative colitis between January 2013 and December 2018. Bone density was evaluated through a dual-energy X-ray absorptiometry scan of the spine and total body. Osteoporosis was defined as a bone mineral density Z-score of <-2 and osteopenia as a Z-score of between -1.0 and -2. RESULTS: A total of 37 patients were included in this analysis, with a mean age of 13.4±3.9 years and a mean duration of illness of 2.1±2.4 years. Using lumbar spine Z-scores and total body Z-scores, osteoporosis and osteopenia were identified by dual-energy X-ray absorptiometry scan measurements in 11 patients (29.7%) and 15 patients (40.5%), and in ten patients (27%) and 13 patients (35%), respectively. Lumbar spine Z-scores were significantly positively associated with male gender (B=2.02; p=0.0001), and negatively associated with the presence of extraintestinal manifestations (B=-1.51, p=0.009) and the use of biologics (B=-1.33, p=0.004). However, total body Z-scores were positively associated with body mass index Z-scores (B=0.26, p=0.004) and duration of illness in years (B=0.35, p=0.003). CONCLUSIONS: Metabolic bone disease is very common in this cohort of Saudi Arabian children and adolescents with ulcerative colitis and its occurrence appears to increase in female patients who suffer from extraintestinal manifestations.

Histologically confirmed upper gastrointestinal Crohn's disease: is it rare or are we just not searching hard enough?

BACKGROUND/AIMS: Crohn's disease (CD) may involve the upper parts of the gastrointestinal (GI) tract including the esophagus, stomach, and duodenum. Clinical features of upper GI CD (UGICD) are not well characterized in the Gulf region. We therefore aimed to assess the prevalence and clinical characteristics of patients diagnosed with UGICD. METHODS: We performed a retrospective analysis of all patients diagnosed with CD who underwent upper GI endoscopy between 2012 and 2017 at King Abdulaziz University Hospital, irrespective of age. Patients who had endoscopy of the upper GI tract at baseline and had histologically confirmed UGICD were included. Data on patients' demographics, clinical characteristics, extraintestinal manifestations and complications were reviewed. RESULTS: We identified 78 CD patients who underwent upper GI endoscopy from our medical records. The mean age was 17.2±8.7 years and 55.1% were males. Of the total, 19 out of 78 patients (24.4%) had histologically confirmed UGICD (3 esophageal, 16 gastric, and 9 duodenal), of which 52.6% were symptomatic. Disease distribution was ileal in 57.8%, colonic in 21.1% and ileo-colonic in 21.1%. A non-stricturing and non-penetrating phenotype was reported in 89.4%, stricturing in 5.3%, and penetrating in 5.3%. Perianal disease was found in 10.5%. UGICD was complicated by stricture formation in 2 patients (esophageal and gastric). CONCLUSIONS: The prevalence of UGICD is considered high among CD Saudi patients who undergo upper GI endoscopy at baseline, and is asymptomatic in 47.4% of patients. This reported prevalence is not dissimilar from reports originating from Western countries.

Histologically confirmed upper gastrointestinal Crohn’s disease: is it rare or are we just not searching hard enough?

Background/Aims@#Crohn’s disease (CD) may involve the upper parts of the gastrointestinal (GI) tract including the esophagus, stomach, and duodenum. Clinical features of upper GI CD (UGICD) are not well characterized in the Gulf region. We therefore aimed to assess the prevalence and clinical characteristics of patients diagnosed with UGICD. @*Methods@#We performed a retrospective analysis of all patients diagnosed with CD who underwent upper GI endoscopy between 2012 and 2017 at King Abdulaziz University Hospital, irrespective of age. Patients who had endoscopy of the upper GI tract at baseline and had histologically confirmed UGICD were included. Data on patients’ demographics, clinical characteristics, extraintestinal manifestations and complications were reviewed. @*Results@#We identified 78 CD patients who underwent upper GI endoscopy from our medical records. The mean age was 17.2±8.7 years and 55.1% were males. Of the total, 19 out of 78 patients (24.4%) had histologically confirmed UGICD (3 esophageal, 16 gastric, and 9 duodenal), of which 52.6% were symptomatic. Disease distribution was ileal in 57.8%, colonic in 21.1% and ileo-colonic in 21.1%. A non-stricturing and non-penetrating phenotype was reported in 89.4%, stricturing in 5.3%, and penetrating in 5.3%. Perianal disease was found in 10.5%. UGICD was complicated by stricture formation in 2 patients (esophageal and gastric). @*Conclusions@#The prevalence of UGICD is considered high among CD Saudi patients who undergo upper GI endoscopy at baseline, and is asymptomatic in 47.4% of patients. This reported prevalence is not dissimilar from reports originating from Western countries.

Adaptation and implementation of the "Kidney Disease: Improving Global Outcomes (KDIGO)" guidelines for evaluation and management of mineral and bone disorders in chronic kidney disease for practice in the Middle East countries.

This review presents the views of an expert group of nephrologists from the Middle East along with an international expert on adaptation and implementation of the 2009 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for evaluation and manage-ment of mineral and bone disorders in chronic kidney disease (CKD-MBD) for practice in the Middle East countries. The members of the panel examined the KDIGO guidelines and formulated recommendations that can be implemented practically for the management of CKD-MBD in the Middle East. There was a broad agreement on most of the recommendations made by the KDIGO work-group. However, the panelists commented on specific areas and amplified certain concepts that might help the nephrologists in the Middle East. The final document was reviewed by all participants as well as by members of the Middle East task force implementation group for KDIGO guidelines. Their comments were incorporated. The guideline statements are presented along with detailed rationale and relevant discussion as well as limitations of the evidence. The panel recognized the need to upgrade the suggestion of KDIGO related to lateral abdominal radiograph and echocardiogram in patients with CKD stages 3-5D into a stronger recommendation. The panel underlined the risk of hyper-phosphatemia to CKD-MBD and the importance of prompt initiation or modification of therapy according to rising trends in para-thyroid hormone level. They recommended the use of non-calcium-based phosphate binders as the first-line therapy in CKD patients with signs of vascular calcification. The panel agreed that all aspects of the KDIGO recommendations concerning bone biopsy, evaluation and treatment of bone disease after kidney trans-plantation should be implemented as such.

The Twister laser fiber degradation and tissue ablation capability during 980-nm high-power diode laser ablation of the prostate. A randomized study versus the standard side-firing fiber.

The objective of this work is to test the ablation capability and fiber degradation of the novel Twister fibers (TW), in both the large (LTW) and the standard (STW) sizes, against the standard side-firing (SF) fiber in a clinical setting during the treatment of BPH patients using the 980-nm high-power diode laser (HPDL). One hundred and twenty BPH patients treated with HPDL (Ceralase300, Biolitec AG, Jena, Germany) were randomized to receive treatment by one of the three fibers. Operative time corrected to tissue volume, laser treatment time, and laser energy were measured. Ablation rate was calculated as follows: the decrease of the prostate volume after 6 months/laser time. The fibers' resistance to degradation was defined by the laser energy needed to degrade the fiber completely. Preoperative prostate volume of 76 ± 38, 70 ± 39, and 88 ± 49 cc decreased by 49 ± 16, 51 ± 20, and 63 ± 16% for the SF, STW, and LTW fibers, respectively. This difference was highly significant when the LTW was compared to the other two fibers (p < 0.001). Prostate volume reduction post-operatively within each group as compared to the pre-operative volume was highly significant (p < 0.001). The ablation rate was highest in LTW, being 1.31 ± 0.59, 1.09 ± 0.51, and 1.54 ± 0.44 cc/min for the SF, STW, and LTW fibers, respectively. The LTW fiber resisted degradation more than the other fibers and the STW more than the SF fiber (p < 0.001). This study demonstrates the higher ablation efficiency and resistance to degradation of the LTW fiber as compared to the STW and SF fibers. The STW fiber has a similar ablation rate of the SF fiber but resists degradation better.

Risk factors, management and outcome of subtypes of ischemic stroke: a stroke registry from the Arabian Gulf.

BACKGROUND: Data on the determinants and outcome of ischemic stroke (IS) from the Arabian Gulf countries (AGC) are still scanty. The aim of this study was to characterize IS in six large stroke centers on the Arabian peninsula. METHODS: IS subtypes were evaluated in four AGC from January 2006 to December 2007 in a large prospective multicenter hospital-based stroke registry including demographics, baseline risk factors, outcome and management. RESULTS: A total of 780 patients with IS were included. Mean age was 58.9 years (63.7% males). Large-artery atherosclerosis (LAA) (38.1%) was the most common subtype followed by lacunar stroke (LS)(34.7%), cardioembolic stroke (CE)(13.5%) and other determined causes (7%). LAA and CE were both more commonly observed over the age of 70. LAA showed a higher male preponderance, and the highest prevalence of hypertension, diabetes, obesity and ischemic heart disease among all subtypes. Obesity was a risk factor for both LAA and CE. Anterior circulation stroke was significantly more affected in LAA (21.2%), CE (19%) and LS (15.1%) subtype of stroke than in posterior circulation strokes (4.4%, 2.9% and 2.8%, respectively) (p<0.05). Only 0.8% of patients received thrombolysis. The 90-day outcome was worst in LAA and least affected in LS. The over-all 90-day mortality was 2.1%. CONCLUSIONS: Demographically, our data are different from those in Western registries but the distribution of stroke subtypes is comparable. Compared to Asian registries the ratio LS versus LAA was much lower. For the first time these data allow to study the IS profile in this population.

Prevalence and treatment of cardiovascular risk factors in outpatients with atherothrombosis in the Middle East.

OBJECTIVE: To characterise the risk-factor profile and treatment gaps among patients with, or at risk for, cardiovascular disease in the Middle East. DESIGN: Secondary analysis of a prospective observational study. SETTING: International multicentre study (Reduction of Atherothrombosis for Continued Health). PATIENTS: Stable outpatients with established cardiovascular disease or at least three risk factors for atherothrombosis. The present analysis was based on 840 patients from the Middle East. INTERVENTION: Observational study without a study-specific intervention. MAIN OUTCOME MEASURES: A treatment gap was defined as at least one of the following: current cigarette smoking, total cholesterol ≥200 mg/dl, serum glucose ≥126 mg/dl or blood pressure of ≥140/90. RESULTS: The majority of Middle Eastern patients had hypertension (80.2%), more than half had a history of diabetes mellitus (52.3%), and a third had hypercholesterolaemia (34.1%). There was a high prevalence of obesity (38.6%), and nearly half the patients were former or current smokers (46%). ß-Blockers and angiotensin-converting enzyme inhibitors were the most commonly prescribed antihypertensives (61.1% and 57.5%, respectively). Antiplatelet therapy (most commonly aspirin) and lipid-lowering drugs (most commonly a statin) were used in most patients (90.7% and 85.2%, respectively). Three-quarters of the participants (75.6%) had at least one uncontrolled risk factor. CONCLUSION: Patients with atherothrombosis in the Middle East have a high prevalence of risk factors including alarming rates of diabetes mellitus and obesity. At least one risk factor is uncontrolled in the majority of patients, presenting a pressing need for improving the care of such patients in the Middle East.

The prevalence and outcome of excess body weight among Middle Eastern patients presenting with acute coronary syndrome.

We evaluated the effect of body weight on the outcome of Middle Eastern patients presenting with acute coronary syndrome (ACS). Analysis of the Gulf Registry of Acute Coronary Events (Gulf RACE) survey that included 7843 consecutive patients hospitalized with ACS was made. Patients were categorized as normal weight, overweight, or obese based on their body mass index (BMI). Overall, 67% of patients were overweight or obese; obese and overweight patients were more likely to be female and have diabetes mellitus, hypertension, dyslipidemia, and less likely to be smokers. In-hospital mortality, congestive heart failure, cardiogenic shock, and strokes were comparable between the groups, although patients with obesity were more likely to have recurrent ischemia and major bleeding complication in the ST-elevation myocardial infarction group. Excess body weight with ACS is associated with higher risk profile characteristics without an increase in hospital mortality or cardiovascular events.

Ankle-brachial index and extent of atherosclerosis in patients from the Middle East (the AGATHA-ME study): a cross-sectional multicenter study.

To assess the extent of atherothrombosis and the use of the ankle-brachial index (ABI) in populations from the Middle East, we conducted a multicenter study similar to AGATHA (a Global Atherothrombosis Assessment), AGATHA-ME, which included 1341 patients from 18 centers from 5 countries (United Arab Emirates, Kuwait, Qatar, Bahrain, and Oman). Patients were assigned to 2 groups: the with-disease and at-risk groups. Abnormal ABI (< or =0.9) was seen in 31.5% of at-risk patients and 28.2% of with-disease patients. Patients with peripheral arterial disease had the highest frequency of abnormal ABI (77.6%), with 97.8 negative predictive value. The AGATHA-ME study confirms that atherothrombosis disease often occurs at more than 1 site. The ABI is related to the risk factor profile and to the site and extent of atherothrombosis. Gender and diabetes mellitus are associated with the worst parameters.

Short-term efficacy and safety of valproate sustained-release formulation in newly diagnosed partial epilepsy VIPe-study. A multicenter observational open-label study.

OBJECTIVE: To evaluate the efficacy and safety of valproate (VPA) sustained-released in monotherapy across all ages in newly-diagnosed epileptic patients with partial seizures (PS) with or without secondary generalization. METHODS: This was a multicenter, prospective, observational, open-label, non-comparative study involving the Gulf Cooperation Council (GCC) countries except the Kingdom of Saudi Arabia, and was performed between November 2004 and May 2006. Adults and children (6 years or older with newly diagnosed partial epilepsy [PE]) with or without secondary generalization were enrolled. The primary efficacy parameter was 6 month-remission rate (proportion of seizure-free patients in relation to total number of retained patients). Secondary efficacy parameters included: 6 month-retention rate, investigator's clinical global impression rating, maximal effective dose and safety profile. RESULTS: Seventy-seven patients were enrolled; 56% adults and 44% children, with average duration of epilepsy of 5 months in the pediatric and 17 months in the adult group. Seizures type distribution: PS with secondary generalization (62%), complex PS (53%) and simple PS (14%). The majority had idiopathic seizures (48%). Sixty-six patients completed the study (treatment retention rate 80.5%). At 6 months, 87% of patients became seizure free with VPA sustained-release monotherapy (average dose 22 mg/kg/day). Adverse drug reactions (hair loss and tremor) were recorded in <20% of patients, mostly affecting adults. CONCLUSION: In this population, short-term treatment with VPA sustained-release in monotherapy provides good seizure control and is well tolerated.