Bi-allelic Variants in TKFC Encoding Triokinase/FMN Cyclase Are Associated with Cataracts and Multisystem Disease.

We report an inborn error of metabolism caused by TKFC deficiency in two unrelated families. Rapid trio genome sequencing in family 1 and exome sequencing in family 2 excluded known genetic etiologies, and further variant analysis identified rare homozygous variants in TKFC. TKFC encodes a bifunctional enzyme involved in fructose metabolism through its glyceraldehyde kinase activity and in the generation of riboflavin cyclic 4',5'-phosphate (cyclic FMN) through an FMN lyase domain. The TKFC homozygous variants reported here are located within the FMN lyase domain. Functional assays in yeast support the deleterious effect of these variants on protein function. Shared phenotypes between affected individuals with TKFC deficiency include cataracts and developmental delay, associated with cerebellar hypoplasia in one case. Further complications observed in two affected individuals included liver dysfunction and microcytic anemia, while one had fatal cardiomyopathy with lactic acidosis following a febrile illness. We postulate that deficiency of TKFC causes disruption of endogenous fructose metabolism leading to generation of by-products that can cause cataract. In line with this, an affected individual had mildly elevated urinary galactitol, which has been linked to cataract development in the galactosemias. Further, in light of a previously reported role of TKFC in regulating innate antiviral immunity through suppression of MDA5, we speculate that deficiency of TKFC leads to impaired innate immunity in response to viral illness, which may explain the fatal illness observed in the most severely affected individual.

Transcatheter Mitral Valve Replacement in High-Surgical Risk Patients: A Single-Center Experience and Outcome.

Background: Re-operative mitral valve (MV) replacement is a high-risk procedure, therefore, transcatheter MV replacement (TMVR) is a promising therapeutic option. Aim: In this study, we aimed to evaluate the feasibility and safety of TMVR in patients with high surgical risk with degenerated mitral bioprostheses (TMViV), failed surgical rings (TMViR), and mitral annular calcification (TMViMAC). Methods: This is a retrospective cohort study that enrolled patients with high surgical risk who underwent TMVR from February 2017 to September 2020. The TMVR procedure was performed using Edwards SAPIEN-3 valves through the transseptal approach. Results: Sixty-four patients aged 62.7 ± 16.1 years with an STS score of 9.2 ± 3.7% underwent TMVR [35 (55%) TMViV, 16 (25%) TMViR, and 13 (20%) TMViMAC]. Mitral stenosis was more frequent in TMViV, mitral regurgitation was more frequent in TMViR, and combined mitral stenosis and regurgitation were more frequent in TMViMAC (P < 0.05). The MV gradient was 14.3 ± 5.3 mmHg and the MV area was 1.5±0.6 cm2. The 29 mm valve was frequently used in TMViV and TMViMAC, while the 23 mm valve was frequently used in TMViR (P=0.003 ∗ ). The procedural and fluoroscopy times were 58.7 ± 8.9 and 41.1 ± 8.2 minutes, respectively. Technical success was reported in 62 (98.4%) patients; 1 TMViR patient experienced valve embolization and salvage surgery, and 1 TMViMAC patient experienced slight valve malposition. At 3 months, 2 (3.1%) patients showed valve thrombosis (treated with anticoagulation), and 1 (1.6%) patient developed a paravalvular leak (underwent surgical MV replacement). At 6 months, 3 (4.7%) patients showed valve degeneration (underwent surgical MV replacement). Throughout follow-up, no patient exhibited mortality. Conclusions: TMVR is a feasible and safe approach in patients with high surgical risk. TMViV and TMViR are reasonable as the first treatment approaches, and TMViMAC seems encouraging.

Transcatheter Closure of Residual and Iatrogenic Ventricular Septal Defects: Tertiary Center Experience and Outcome.

Residual or iatrogenic ventricular septal defects (VSDs) may result in significant hemodynamic effect. This study aimed to review our center experience in transcatheter closure of post-surgical and post-intervention residual and iatrogenic VSDs and to report on their 12-month long-term outcome. All patients who underwent transcatheter closure of residual/iatrogenic VSDs after surgical or transcatheter CHD interventions between January-2015 and January-2020 were included. Patients' medical records were reviewed and analyzed. Twenty-three patients with a mean age of 14.3 ± 8.8 years were included. The VSD was residual in 18 (78.3%) patients and iatrogenic in 5 (21.7%) patients, post-operative in 19 (82.6%) patients and post-transcatheter in 4 (17.4%) patients. The VSD site was peri-membranous in 9 (39.1%) patients, high-muscular in 6 (26.1%) patients, mid-muscular in 4 (17.4%) patients, and Gerbode shunt in 4 (17.4%) patients. The QP/QS ratio was 2.5 ± 0.7, and the VSD diameter was 6.1 ± 2.1 mm. Most, 16 (71.43%) patients underwent antegrade device deployment, and 7 (28.57%) patients underwent retrograde transaortic device deployment with 3 (13.0%) patients required two devices. Amplatzer™ Muscular VSD devices were used in 16 (69.6%) patients, Amplatzer™ Duct occlude-I devices were used in 4 (17.4%) patients, and Amplatzer™ Duct Occluder-II devices were used in 3 (13.0%) patients with a mean device size of 8.8 ± 2.8 mm. Procedural and fluoroscopy times were 55.1 ± 16.2 and 16.3 ± 4.0 min respectively. During follow-up (23.3 ± 15.9 months), no patient required re-intervention or exhibited mortality. Transcatheter closure of post-operative and post-intervention residual/iatrogenic VSDs represents a safe, feasible, and effective therapeutic approach.

Quantitative assessment of contractile reserve of systemic right ventricle in post-Senning children: Incorporating speckle-tracking strain and dobutamine stress echocardiography.

INTRODUCTION: The systemic load on the right ventricle (RV) after Senning atrial switch leads to ventricular dysfunction. Quantitative assessment of RV contractile reserve is mandatory to anticipate the need for anti-fibrotic treatment. We aimed to quantitatively assess RV contractile reserve in Senning children by estimating speckle-based global longitudinal strain (GLS) during dobutamine stress echocardiography (DSE). METHODS: This prospective study compared thirty-one post-Senning children (group I) and thirty controls (group II). In post-Senning children, echocardiographic RV systolic function using one-plane ejection fraction (RVEF), RV fractional area change (RVFAC), tricuspid annulus plane systolic excursion (TAPSE), its Z-score, and RVGLS were recorded at rest and peak DSE. Contractile reserve was defined as improvement >5% in RVEF, >2% in GLS, and/or to near normal TAPSE. RESULTS: RVEF, RVFAC, TAPSE, and TAPSE Z-score were significantly lower in patients than controls [RVEF:40.13 ± 2.93% vs 53.17 ± 3.17% (P < .001*), RVFAC: 21.17 ± 2.37% vs 37.23 ± 2.13% (P < .001*), TAPSE:13.81 ± 1.26 vs 17.45 ± 2.93 mm (P < .001*), TAPSE Z-score: -3.47 ± 0.46 vs -2.09 ± 0.48 (P < .001*)]. Also, RVGLS was significantly impaired in Senning children than controls[ (-11.89 ± 2.31% vs -22.35 ± 6.73% (P < .001*)]. At peak DSE, contractile reserve was not evident as measured by RVEF which increased none significantly to 42.47 ± 2.80% (P = .063). However, RVGLS improved significantly to -15.78 ± 0.93% (P < .001*) and discovered the masked contractile reserve in Senning children. The 19(61.29%) children who showed masked contractile reserve (improvement in RVGLS > 2%) underwent continuation of anti-fibrotic medications. CONCLUSIONS: Despite systemic RV function in post-Senning children was impaired at rest and during DSE, RVGLS was useful in quantitative assessment of masked contractile thus promoted continuing anti-fibrotic treatment.

Evaluation of the Growth of Central Pulmonary Arteries Following Patent Ductus Arteriosus Stenting in Patients with Duct Dependent Pulmonary Circulation.

Pulmonary arteries' (PAs) growth can be promoted by stenting of patent ductus arteriosus (PDA). This may result in better angle between the PDA and the PAs, allowing improved growth. In this study, we sought to evaluate the effect of PDA stenting on the growth of the pulmonary arteries by comparing their dimensions pre-stenting to their dimensions in the pre-second stage operations in patients with congenital heart diseases-duct-dependent pulmonary (CHD-DDP) circulation. Between January 2015 and December 2016, 58 neonates with CHD-DDP circulation underwent transcatheter PDA stenting and had evaluation of PAs growth before the second stage. Various parameters [Pre-branching right and left pulmonary artery (RPA, LPA) diameters, their Z scores, LPA/RPA ratio, McGoon's ratio and Nakata index] were recorded and compared pre-stenting and pre-second stage. The evaluation was done using catheterization or multislice computed tomography (MSCT). PDA stenting was successful in 49 patients out of 58 (84.5%) patients with an age of 13.5 ± 10.4 days and a weight of 2.9 ± 0.5 kg. Twenty-two (44.9%) patients had complex CHD-DDP, 14 (28.6%) patients had PA/IVS and 13 (26.5%) patients had PA/VSD. Pre-second stage RPA, LPA diameters and their Z scores increased significantly (RPA increased from 0.36 ± 0.05 cm to 0.60 ± 0.11 cm, P < 0.001, RPA Z-score increased from - 1.29 ± 0.91 to 0.81 ± 0.18, P < 0.001; LPA increased from 0.34 ± 0.06 cm to 0.58 ± 0.10 cm, P < 0.001, LPA Z-score increased from - 1.17 ± 0.86 to 0.97 ± 0.48, P < 0.001). McGoon's ratio increased significantly from 1.20 ± 0.11 to 1.61 ± 0.15 (P < 0.001). Nakata index increased from 105.94 ± 33.53 to 183.48 ± 40.58 mm2/m2 (P < 0.001). However, LPA/RPA ratio did not change (0.96 ± 0.05 and 0.98 ± 0.16, P = 0.288). PDA stenting is effective in promoting the global and the individual pulmonary artery growth in congenital heart diseases with duct-dependent pulmonary circulation. In this study, we presented our experience with this approach in 2 tertiary care centers in the DELTA region of Egypt. PDA stenting, generally, showed symmetric growth of the pulmonary arteries with comparable results to the international figures.

Hydrogen sulfide modulates SIRT1 and suppresses oxidative stress in diabetic nephropathy.

DN is recognized as not only a leading cause of end stage renal disease (ESRD) but also an independent risk factor for cardiovascular disease (CVD). Novel therapeutic approaches to diabetic nephropathy (DN) are needed, or else, healthcare resources will be overwhelmed by the expected worldwide increase in associated cases of ESRD and CVD. Reactive oxygen species (ROS) and advanced glycation end product (AGE) are implicated in the development of DN. Hydrogen sulfide (H2S) is known for its antioxidant and antiapoptotic characteristics. Simultaneously diabetics have lower H2S levels. Thus, it is worth investigating the use of H2S in treatment of DN. To investigate the potential therapeutic role of H2S in DN. Sixty male rats were divided into four groups: control, DN, DN+NaHS30 µmol/kg/day and DN+NaHS100 µmol/kg/day. Fasting blood sugar (FBS), kidney function tests, SIRT1 activity, superoxide dismutase activity (SOD), malondialdehyde (MDA) and expression of caspase3 and p53 in renal tissues were assessed. Kidney was examined histopathologically. DN rats had higher FBS, renal dysfunction, decreased SIRT1 and SOD activity levels, increased caspase3 and p53 relative expression and increased MDA in renal tissues. NaHS increased SIRT1 and reversed biochemical, apoptotic, oxidant and pathologic parameters characteristic of DN, with better results using a dose of 100 µmol/kg/day. H2S has a protective role against DN through decreasing FBS, ROS, apoptosis and upregulating SIRT1, thus preserving renal cells from further damage caused by DM.

Role of 3D transesophageal echocardiography in transcatheter closure of atrial septal aneurysms.

BACKGROUND: Three dimensional transesophageal echocardiography (3DTEE) is superior to two dimensional transesophageal echocardiography (2DTEE) as it provides all atrial septal information from a single view. AIM: To evaluate 3DTEE role in analysis of atrial septal aneurysm (ASA) and in device closure guiding. METHODS: Three dimensional transesophageal echocardiography were recorded with Vivid*E9,GE system over 14 months. ASAs were classified into 4 types (A: with PFO, B: with one ASD, C: with 2 ASDs, and D: with multiple fenestrations). Each aneurysm was assessed according to its type, shape, dimensions, orientation, aneurysmal tissue, and the surrounding rims. All patients passed to transcatheter aneurysm closure. RESULTS: A total of 26 patients with ASAs were assessed (7 imperforated aneurysms excluded). The remaining 19 patients' age was 12.84 ± 5.82years. Four patients had type A aneurysms, 6 had type B, 4 had type C, and 5 had type D. 3DTEE demonstrated oval aneurysms in 17 patients. The orientation was oblique in 8 patients, vertical in 7, and horizontal in 4. The ASAs dimensions were 23.5 ± 5.1, 23.2 ± 5.1, and 22.0 ± 4.0 mm for oblique, vertical, and horizontal axes. Percutaneous closure succeeded in 18 patients. Balloon sizing was used in 4 patients. Devices used were: In type A:PFO devices, in type B:ASO devices, in type C:two patients required two ASO devices in each patient and two patients required one cribriform device, and in type D:Cribriform devices used for three patients, PFO for one and ASO for one. LA, LUPV, and RUPV approaches were used. Aspirin was received for 6 months. CONCLUSION: Three dimensional transesophageal echocardiography helps to select aneurysms suitable for transcatheter closure, select the suitable devices, and guide the transcatheter procedure.

Two problems and a single solution: Covered stent implantation to close an anterograde pulmonary flow and treat hypoplastic left pulmonary artery after Fontan operation.

Several issues may impact on the function of a Fontan circulation including accessory source of pulmonary blood flow and pulmonary artery anatomy. Here we report on a 5.5-year-old boy who showed failing Fontan circulation due to left pulmonary artery stenosis/hypoplasia and significant forward pulmonary blood flow through the native pulmonary artery. Successful implantation of a 34-mm CP covered stent in the left pulmonary artery in a Fontan patient was useful for simultaneous successful treatment of residual antegrade flow from the systemic ventricle to the pulmonary artery and enlargement of hypoplastic left pulmonary artery. © 2015 Wiley Periodicals, Inc.

Assessment of lipid peroxidation and p53 as a biomarker of carcinogenesis among workers exposed to formaldehyde in the cosmetic industry.

Despite the wide use of cosmetic products, they exert a number of health effects on tissues ranging from irritation to cancer. Our study aimed at assessing the effect of formaldehyde on lipid peroxidation and verifying the susceptibility to carcinogenesis using p53 as a biomarker among workers exposed to formaldehyde in cosmetic industry. Our entire exposed group (n = 40) and the controls (n = 20) were subjected to estimation of formate in urine, serum malondialdehyde (MDA), and p53. Also, complete blood picture, liver, and kidney function tests were carried out. The study revealed significant increase in the levels of formate, MDA, and p53 in the exposed group compared with their control group. Our results showed that workers in cosmetic industry had significant exposure to formaldehyde. Furthermore, the study pointed to the negative impact of formaldehyde as a cause of oxidative stress and suspicious carcinogen.

Association between TNF promoter -308 G>A and LTA 252 A>G polymorphisms and systemic lupus erythematosus.

Tumor necrosis factor (TNF) and lymphotoxin alpha (LTA) are pivotal cytokines in the pathogenesis of systemic lupus erythematosus (SLE). To investigate the possible association of the polymorphism of the TNF promoter gene -308 and that of the LTA gene 252 with susceptibility to SLE and with phenotypic disease features in Egyptian patients. A case control study involving 100 SLE patients and 100 unrelated healthy controls. Polymerase chain reaction and restriction fragment length polymorphism methods were applied to detect genetic polymorphism. We found that TNF-308 genotype AA was significantly increase by 26 % in SLE patients compared to 10 % in the control group (p = 0.003; OR 3.16; CI 1.43-6.98) and the frequency of the A allele of the TNF promoter -308 was significantly higher in the SLE patients (42 %) than in the control subjects (24 %) (p < 0.001; OR 2.29; 95 % CI 1.49-3.52). Genotype LTA 252 GG showed a significant increase by 22 % in SLE patients compared to 6 % in the control group (p = 0.001; OR 4.42; 95 % CI 1.71-11.44), and the frequency of the G allele of the LTA was significantly higher in the SLE patients (38 %) than in the control subjects (21 %) (p < 0.001; OR 2.31; 95 % CI 1.48-3.6). Genotype (AA+GA) of TNF was significantly associated with clinical manifestations as malar rash, arthritis, oral ulcers, serositis and systemic lupus erythematosus disease activity index. Genotype (GG+GA) of LTA was significantly associated with arthritis. These results suggest that TNF and LTA genetic polymorphisms contribute to SLE susceptibility in the Egyptian population and are associated with disease characteristics. TNF-308 and LTA+252 polymorphic markers may be used for early diagnosis of SLE and early prediction of clinical manifestations, like arthritis.

Liver functions in silica-exposed workers in Egypt: possible role of matrix remodeling and immunological factors.

BACKGROUND: Brick manufacturing constitutes an important industrial sector in Egypt with considerable exposure to silica. OBJECTIVES: We aimed for evaluating hepatic functions in silica-exposed workers in the clay brick industry, and the possible role of matrix remodeling and immunological factors. METHODS: A case-control study, 87 workers as exposed and 45 as control subjects. Questionnaire, clinical examination, and laboratory investigations: liver functions, matrix metalloproteinase-9, immunoglobulins G and E, and anti-liver kidney microsomal antibody. RESULTS: In the exposed workers, mean levels of liver functions, matrix metalloproteinase-9 (MMP-9), and IgG and IgE were significantly higher. In the silicotic subgroup the mean level of GGT was almost twice the level in the non-silicotic subjects. Logistic regression showed that abnormal GGT and ALT were associated with production workers. CONCLUSION: Workers in the clay brick industry showed evidence of liver disease that could be related to matrix remodeling.

Qatar biomedical and cancer publications in PubMed between 2000 and 2012.

BACKGROUND: The aim of this work was to analyse the past trends of biomedical and cancer publications from Qatar listed on PubMed for the years 2000-2012. These findings were then compared with the corresponding global number of publications. METHODS: PubMed was searched for cancer publications, clinical trials, publications on humans or other species. Searching for "Qatar*" in the "Affiliation" field yielded the lowest number of publications; searching for "Qatar*" in the "Affiliation" or in "Title/Abstract" yielded a moderate number of results and searching for "Qatar*" in the "Affiliation" or "Title/Abstract" or "Text Word" fields yielded the highest number of publications. The annual percentage change (APC) from one year to the next was calculated for the population and each type of publication. Information on the population of Qatar was gathered from the website of Qatar Statistics Authority to determine the correlation of papers published per 1000 population. RESULTS: The number of publications retrieved from PubMed was not particularly different for each variation of search carried out. However, the most representative number of publications was retrieved upon searching for "Qatar*" in the "Affiliation" or in "Title/Abstract" fields. Between the years 2000 and 2012, the total number of biomedical publications from Qatar increased 24 times with an average APC of 33.4%, which was found to be more than the APC of the population in Qatar which averaged at 9%. The number of biomedical publications per 1000 population increased from 0.02 in 2000 to 0.15% in 2012. Most publications retrieved were humans studies and occasionally were for other animal species. Cancer publications in Qatar represented 16.9% of the total publications and the number of cancer publications per 1000 population increased from 0% in 2000 to 0.02% in 2012. Publications classified as clinical trials represented 4.6% of Qatar biomedical publications. Publication of cancer clinical trials were very rare (0.4%). CONCLUSIONS: Despite the obvious increase in Qatar biomedical and cancer publications in PubMed, the absolute numbers were relatively small. While strategies are in place, leaders of Qatar biomedical research need to consider increasing cancer research and clinical trials to meet the country's needs. Linking research output to researchers, research facilities and research funding is needed.

The Tie2 receptor antagonist angiopoietin-2 in systemic lupus erythematosus: its correlation with various disease activity parameters.

BACKGROUND: Systemic lupus erythematosus is one of the autoimmune diseases characterized by multisystem involvement associated with autoantibody and immune complex vasculitis along with endothelial cell damage. OBJECTIVE: to study the possible role of Angiopoietin- 2 (Ang-2) as a recently highlighted inflammatory and angiogenic mediator in the pathogenesis of SLE and its correlation with the state of another inflammatory marker, P-Selectin, as well as with various markers of the disease activity. PATIENTS AND METHODS: The present study included 3 main groups: active SLE patients (group I), inactive SLE patients (group II) and healthy normal control subjects (group III). Groups I and II were subjected to disease activity assessment using the SLEDAI scoring system and measurement of plasma Ang-2 and P-Selectin by ELISA in addition to various laboratory investigations to assess disease activity as: Complete blood count, ESR, serum creatinine, C3, C4 and 24-h urinary proteins. RESULTS: The mean level of Plasma Ang-2 and P-selectin showed a high significant increase in active group compared to inactive SLE patients and control subjects (p < 0.001).There was a significant positive correlation between Ang-2, P-Selectin, and each of SLEDAI score and 24-h urinary proteins in all SLE patients as well as in the active group, and Ang-2 was a significant independent marker for proteinuria. A significant negative correlation was found between Ang-2, P-Selectin and each of C3, C4. Ang-2 and P-Selectin showed a high sensitivity and specificity in the patients with SLE. CONCLUSION: Our study suggests that Ang-2 may be a more useful marker than P-Selectin, C3 and C4 in the assessment of disease activity.

Transcatheter Mitral Valve Repair Technique in Specific Severe Mitral Regurgitation: Tips, Tricks, and Outcomes.

Background: In specific patients with severe mitral regurgitation (MR), mitral valve (MV) pathology is unique and requires creative transcatheter repair techniques. This study aimed to evaluate the feasibility and safety of a new transcatheter MV repair technique, using occluder devices in symptomatic high-surgical-risk patients with severe MR, either due to MV leaflet (MVL) perforations or due to post-clips residual MR, and to report on their 6-month outcomes. Methods: The study enrolled all high-risk patients with severe MR due to MVL perforations and post-clips residual MR who underwent transcatheter MV repair using occluder devices, from November 2016 to August 2019. Results: The study enrolled 16 patients; 9 (56.25%) with MVL perforations and 7 (43.75%) with post-MitraClip (Abbott Laboratories, Abbott Park, Illinois) residual MR, with a mean age of 55.75 ± 16.69 years. Mean perforation/jet diameters were 5.75 ± 1.67 and 6.5 ± 1.93 mm, and the mean 3D-vena contracta area was 0.54 ± 0.14 cm2. Perforations were crossed retrograde (transaortic in 7 [43.75%] patients and transapical in 2 [12.5%] patients), and post-MitraClip devices residual jets were crossed antegrade (transvenous/transseptal). Six (37.5%) patients required arteriovenous loop formation for device deployment, that was antegrade transvenous/transseptal in 13 (81.25%) patients and retrograde transapical in 3 (18.75%) patients. Devices used were Amplatzer-ASO in 10 (62.5%) patients and Amplatzer-VP-II in 6 (37.5%) patients. Mean procedural and fluoroscopy times were 55.13 ± 16.24 and 16.25 ± 4.03 â€‹minutes, respectively. Patients passed successfully, without MV gradient change or device-related complications. Conclusions: Transcatheter MV repair of MVL perforations/post-clips residual MR is a new, feasible, and safe technique for high-surgical-risk patients.

The association between vitamin D levels and oxidative stress markers in Egyptian Behcet's disease patients.

BACKGROUND: Oxidative stress is postulated to have a major role in the pathophysiology of Bechet's Disease (BD). Growing evidence suggests that vitamin D has important roles in enhancing the expression of anti-inflammatory cytokines as well as certain antioxidants. However, there is little evidence currently about the antioxidant properties of vitamin D in BD. OBJECTIVE: To study the relationship between vitamin D levels and the oxidative stress markers in patients with BD in addition to its association with disease activity and severity. METHODS: Sixty BD patients (45 males, 15 females; mean age: 34.2 ± 9.6 years) were enrolled in this study and compared to a sex and age matched control group. Plasma 25-Hydroxy vitamin D (25-OH-D) was measured using Human (25-OH-D) ELISA assay. Plasma malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), superoxide dismutase (SOD) activity, catalase (CAT) activity and total antioxidant capacity (TAC) were determined by spectrophotometric methods in both groups. Plasma calcium (Ca) was measured by ELISA assay. RESULTS: When compared to controls vitamin D, GSH, CAT activity, TAC and Ca were significantly lower in BD patients, while MDA and NO levels were significantly increased in BD patients. Our Results Found that vitamin D was inversely correlated to BD current Activity form (BDCAF), disease severity score, ESR, CRP, MDA and NO, while vitamin D was significantly positively correlated to GSH, SOD, TAC and Ca. CONCLUSION: Our study confirms that a lower level of vitamin D is associated with the oxidative stress state in BD patients as detected by MDA and NO elevation as well as decreased GSH, SOD activity, CAT activity and TAC. Hence, Vitamin D fortified foods and beverages or supplementation may improve disease severity and oxidative stress in BD patients.

Inhibition of T-cell-mediated immune response via the PD-1/ PD-L1 axis in cholangiocarcinoma cells.

Cholangiocarcinoma (CCA) is a malignant biliary tract epithelium tumor. The programmed death-1 (PD-1)/programmed receptor-ligand 1 (PD-L1) signaling pathway has been implicated as an immune escape mechanism in several cancers. The present study aimed to assess the expression of PD-L1 on human CCA cell lines and its potential role in suppressing CD8+ T- cell function. A panel of intrahepatic CCA cell lines was evaluated for immune regulatory checkpoint ligands and inflammation markers. Effects of pro-inflammatory cytokine, interferon gamma (IFN-γ), on the expression of immune regulatory checkpoint ligands and inflammation markers were determined. The PD-L1 function was measured by co-culturing CCA cells with lymphocytes. Most of the selected Thai CCA cell lines, including HuCCA-1, RMCCA-1, KKU-100, and KKU-213, expressed higher PD-L1 than normal cholangiocyte MMNK-1 and ANK-1 cells. Both PD-L1 and cyclooxygenase-2 (COX-2) expressions were highest in HuCCA-1 cells. A 48 h treatment with IFN-γ increased the expression of PD-L1 and COX-2 in CCA cells. The expression of CTLA-4 ligands, including H7-1 and H7-2, did not change after IFN-γ treatment. Rofecoxib, a specific COX-2 inhibitor, mitigated IFN-γ-induced PD-L1 expression. After 48 h co-incubation, CD8+ T-cell apoptosis was increased as compared to the control group. Pretreatment of CCA cells with IFN-γ further increased CD8+ T-cell apoptosis. Pembrolizumab, an anti-PD-1 antibody, mitigated CCA cell escape phenomenon. The inhibition of T-cell-mediated immune response via the PD-L1/PD-1 axis are evidenced in intrahepatic CCA. Immunotherapy with checkpoint inhibitor offers a potentially therapeutic strategy for CCA patients; however, further in vivo and clinical studies are required.

Concomitant transcatheter closure of post-myocardial infarction ventricular septal defect and inferior wall aneurysm: case report.

BACKGROUND: The incidence of the post-infarct ventricular septal defect (VSD) is 0.17%. Surgical repair is the definitive treatment and percutaneous closure is an alternative in high-risk patients. We report a case of post-myocardial infarction inferior wall aneurysm associated with a large ventricular septal rupture, with a communication between the aneurysm and right ventricle. Successful percutaneous closure of both the aneurysm and the post-infarct (VSD) was performed using two Amplatzer septal occluder devices. CASE SUMMARY: A 76-year-old man was referred to the clinic 2 weeks after an inferior wall myocardial infarction. A harsh, pansystolic murmur was appreciated on his left parasternal area and across the pericardium. An echocardiogram demonstrated a large, true aneurysm in the mid-cavity inferior wall. The inferior septum was ruptured and dissected, with a large, left-to-right shunt. The patient's coronary angiography revealed a multi-vessel disease. The patient was considered as high surgical risk and thus transcatheter closure of both the post-infarct VSD and inferior wall aneurysm was recommended. We crossed the VSD from the venous side. An Amplatzer septal occluder (18 mm) was deployed to close the VSD completely. We crossed the aneurysm mouth from the arterial side. Another Amplatzer septal occluder (26 mm) was deployed with the large disc inside the aneurysm, sealing it with no more flow. After discharge from the intensive care unit, the patient underwent complete revascularization for his right coronary artery, left main artery, proximal left anterior descending artery, and ramus intermedius. At his 3-month follow-up, the patient remained well with reasonable exercise tolerance. DISCUSSION: Percutaneous closure of a post-infarct VSD and aneurysm is an option for patients whose comorbidities preclude surgical repair and whose septal anatomy is favourable to device placement.

Systems Biology Approaches Toward Understanding Primary Mitochondrial Diseases.

Primary mitochondrial diseases form one of the most common and severe groups of genetic disease, with a birth prevalence of at least 1 in 5000. These disorders are multi-genic and multi-phenotypic (even within the same gene defect) and span the entire age range from prenatal to late adult onset. Mitochondrial disease typically affects one or multiple high-energy demanding organs, and is frequently fatal in early life. Unfortunately, to date there are no known curative therapies, mostly owing to the rarity and heterogeneity of individual mitochondrial diseases, leading to diagnostic odysseys and difficulties in clinical trial design. This review aims to discuss recent advances and challenges of systems approaches for the study of primary mitochondrial diseases. Although there has been an explosion in the generation of omics data, few studies have progressed toward the integration of multiple levels of omics. It is evident that the integration of different types of data to create a more complete representation of biology remains challenging, perhaps due to the scarcity of available integrative tools and the complexity inherent in their use. In addition, "bottom-up" systems approaches have been adopted for use in the iterative cycle of systems biology: from data generation to model prediction and validation. Primary mitochondrial diseases, owing to their complex nature, will most likely benefit from a multidisciplinary approach encompassing clinical, molecular and computational studies integrated together by systems biology to elucidate underlying pathomechanisms for better diagnostics and therapeutic discovery. Just as next generation sequencing has rapidly increased diagnostic rates from approximately 5% up to 60% over two decades, more recent advancing technologies are encouraging; the generation of multi-omics, the integration of multiple types of data, and the ability to predict perturbations will, ultimately, be translated into improved patient care.

Clinical significance of CCN2/connective tissue growth factor in Behçet's disease patients.

AIM: Behçet's disease (BD) is a chronic autoimmune vasculitic disorder of unclear pathogenesis. CCN2/CTGF (connective tissue growth factor) is one of the CCN family members which carry out pro-angiogenic biological functions and play an important role in inflammatory and autoimmune diseases. The aim of the present study was to assess CCN2 plasma concentrations in BD patients and to analyze their association with clinical features of the disease, activity and laboratory parameters. METHODS: We included 87 BD patients and 60 healthy control subjects matched for age and gender. Demographic, clinical, disease activity and severity data were recorded. Plasma CCN2 concentrations were measured using enzyme-linked immunosorbent assay. RESULTS: The plasma concentrations of CCN2 in BD patients were significantly elevated compared to healthy controls. The mean plasma CCN2 levels in patients with major organ involvement were significantly higher than those without. Patients who received steroids or cyclophosphamide showed a significant reduction in CCN2 levels. This was confirmed by the results of multivariate analysis. Patients with active ocular disease had a significant increase in CCN2 compared to the inactive group. On the other hand, CCN2 levels were not significantly correlated with overall disease activity and severity scores. CONCLUSION: Behçet's disease patients showed a significant increase of CCN2 levels, especially in the group of patients with major organ involvement. A significant reduction of these levels was found in patients who received steroids or cyclophosphamide. Larger studies with further investigations of the precise role of CCN2 in BD pathogenesis might lead to novel therapies for the clinical management of this disease.

The Egyptian clinical trials' registry profile: Analysis of three trial registries (International Clinical Trials Registry Platform, Pan-African Clinical Trials Registry and clinicaltrials.gov).

Registering clinical trials (CTs) in public domains enhances transparency, increases trust in research, improves participation and safeguards against publication bias. This work was done to study the profile of clinical research in Egypt in three CT registries with different scopes: the WHO International CT Registry Platform (ICTRP), the continental Pan-African CT Registry (PACTR) and the US clinicaltrials.gov (CTGR). In March 2014, ICTRP, PACTR and CTGR were searched for clinical studies conducted in Egypt. It was found that the number of studies conducted in Egypt (percentage) was 686 (0.30%) in ICTRP, 56 (11.3%) in PACTR and 548 (0.34%) in CTGR. Most studies were performed in universities and sponsored by university/organization, industry or individual researchers. Inclusion of adults from both genders predominated. The median number of participants per study in the three registries ranged between 63 and 155. The conditions researched differed among the three registries and study purpose was mostly treatment followed by prevention. Endpoints were mostly efficacy followed by safety. Observational:Interventional studies (i.e. clinical trials) represented 15.5%:84.5% in ICTRP, 0%:100% in PACTR and 16.4%:83.6% in CTGR. Most interventions were drugs or procedures. Observational studies were mostly prospective and cohort studies. Most CTs were phase 3 and tested drugs or procedures. Parallel group assignment and random allocation predominated. Blinding was implemented in many of trials and was mostly double-blind. We conclude that CTs from Egypt in trial registries are apparently low and do not accurately reflect clinical research conducted in Egypt or its potential. Development of an Egyptian CT registry is eagerly needed. Registering all Egyptian CTs in public domains is highly recommended.