Effect of oral versus parenteral vitamin D3 supplementation on nuclear factor-κB and platelet aggregation in type 2 diabetic patients.

Platelet hyperactivity is one of the key factors implicated in the development and progression of diabetic vascular complications. Activated platelets mediate leukocyte recruitment that further enhances inflammatory responses in vascular wall ultimately resulting in atherosclerotic complications. Since vitamin D insufficiency is highly prevalent in diabetics, we aimed to evaluate the effect of three dosage forms of vitamin D supplementation on lipid profile, NF-κB, platelet aggregation, and platelet calcium content in type 2 diabetic patients. Type 2 diabetic patients were randomized to receive daily (4000 IU/day) or weekly (50 000 IU/week) oral vitamin D3 for 3 months. Another group received a single parenteral dose (300 000 IU) of vitamin D3, whereas the control group received their antidiabetic drug(s) alone. Serum 25(OH)D, total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, NF-κB, and platelet aggregation were measured at the beginning and 3 months after vitamin D supplementation. Platelet calcium content was evaluated by measuring the fluorescence intensity of Rhod-2-stained platelets by confocal fluorescence microscopy. Results showed that serum 25(OH)D3 levels significantly increased in all vitamin D3-treated groups. However, the mean level for parenteral treated group was significantly lower than oral-treated groups. Oral and parenteral treatment were also able to decrease NF-κB level, platelet aggregation, and platelet calcium content. However, both oral doses of vitamin D3 were superior to the single parenteral dose. In conclusion, restoring normal levels of vitamin D is an important determinant to maintain normal platelet function and reduce inflammation. Nevertheless, further long-term studies are still needed.

Dehydration study of apple slices by a non-thermal process.

This study investigated the impacts of a drying process under low temperature and reduced pressure (non-thermal drying) on the final dehydrated products characteristics. This process is based on the retention of water on molecular sieves with a good selectivity against these molecules. In this study, drying experiments of 7mm thick apple slices (AS) were performed and compared to apple slices pretreated by freezing. It was concluded that the dehydrated apple slices were depleted of the maximum amount of water after 12 hours of drying, with a final water content equal to 12 ± 1.75%, whereas after freezing pretreatment, a decrease in drying time to 7 hours was observed, as well as a decrease in water content to 10 ± 0.5%. This explains the effect of freezing pretreatment on accelerating water transfer. In addition, a convective drying was performed on the apple slices at 60°C, which allows comparison with the slices dried by our non-thermal drying process. In order to characterize the obtained fruits, characteristic analyses such as water activity (Aw), color, texture (hardness), and dimensions (diameter and thickness) were performed before and after each drying experiment. Thus, continuous measurements of temperature, humidity, and pressure, within the enclosure, were determined during the experiments using a wireless sensor system controlled by a programming Arduino. Finally, mathematical modeling by various models (Newton, Page, Midilli, etc.) was performed to determine the most suitable model describing the non-thermal and convective drying of apple slices.

Antiapoptotic Protein FAIM2 is targeted by miR-3202, and DUX4 via TRIM21, leading to cell death and defective myogenesis.

Inappropriate expression of DUX4, a transcription factor that induces cell death at high levels of expression and impairs myoblast differentiation at low levels of expression, leads to the development of facioscapulohumeral muscular dystrophy (FSHD), however, the pathological mechanisms downstream of DUX4 responsible for muscle loss are poorly defined. We performed a screen of 1972 miR inhibitors for their ability to interfere with DUX4-induced cell death of human immortalized myoblasts. The most potent hit identified by the screen, miR-3202, is known to target the antiapoptotic protein FAIM2. Inhibition of miR-3202 led to the upregulation of FAIM2, and remarkably, expression of DUX4 led to reduced cellular levels of FAIM2. We show that the E3 ubiquitin ligase and DUX4 target gene, TRIM21, is responsible for FAIM2 degradation downstream of DUX4. Human myoblasts overexpressing FAIM2 showed increased resistance to DUX4-induced cell death, whereas in wild-type cells FAIM2 knockdown resulted in increased apoptosis and failure to differentiate into myotubes. The necessity of FAIM2 for myogenic differentiation of WT cells led us to test the effect of FAIM2 overexpression on the impairment of myogenesis by DUX4. Strikingly, FAIM2 overexpression rescued the myogenic differentiation defect caused by low-level expression of DUX4. These data implicate FAIM2 levels, modulated by DUX4 through TRIM21, as an important factor mediating the pathogenicity of DUX4, both in terms of cell viability and myogenic differentiation, and thereby open a new avenue of investigation towards drug targets in FSHD.

Predictive Factors Increasing the Risk of Radiation Toxicity in Patients with Early Breast Cancer.

OBJECTIVES: Radiation induces adverse events on healthy tissues which may be augmented by certain factors. This study aimed to assess patients; tumor and treatment-related factors which increase the risk of radiation-induced toxicity in breast cancer patients. METHODS: This prospective study included postmenopausal early breast cancer patients treated at the clinical oncology department, Assiut University, Egypt between January 2015 and December 2018. Patients treated with mastectomy followed by conventional radiotherapy (25x 2 Gy) and either concurrent or sequential letrozole. Acute and late radiation toxicity was scored according to EORTC/RTOG and risk factors were analyzed. RESULTS: A total of 75 patients were included in the study. After a median follow-up of 24 months, 12 patients had > grade 2 acute dermatitis, 5 patients had > grade 2 cardiac toxicity and 3 patients had > grade 2 lung toxicity. Multivariate analysis revealed that trastuzumab use was associated with a decrease risk of acute dermatitis (p= 0.01) but boost irradiation was significantly associated with increased risk of acute dermatitis (p= 0.01). Late toxicity > grade 2 was observed in 6 patients, 14 patients, and 2 patients for skin, heart, and lung respectively. CONCLUSION: The use of boost irradiation was associated with increased risk of acute dermatitis, in the contrary; the use of trastuzumab seemed to be protective as observed in this study.

Candida antigen immunotherapy versus steroid in the treatment of alopecia areata.

Alopecia areata (AA) is an autoimmune hair follicle disorder that is challenging to treat. Although there are multiple topical immunotherapeutic agents, their side effects limit their use. Candida antigen can serve as another immunotherapeutic treatment, with an easier application and fewer side effects. To evaluate the efficacy of Candida antigen versus intralesional steroids for the treatment of AA. About 48 adult patients with AA were divided into two groups. The Candida group included 24 patients who were injected monthly with 0.1 mL of Candida albicans antigen in one patch of alopecia, and the intralesional corticosteroid group included 24 patients who were injected monthly with 0.1 mL of triamcinolone acetonide, as a control group, in all alopecia patches. After 5 months, there was a highly significant decrease in the severity of AA in both groups with no significant difference between them. In the Candida group, 8 patients showed complete hair regrowth and 9 patients showed partial regrowth. Side effects were mild and transient such as pain during injection, which was significantly lower in the Candida group than in the corticosteroid group. Intralesional Candida antigen is a promising effective treatment for AA with differing severities.

Evaluation of serum amino acids and non-enzymatic antioxidants in drug-naïve first-episode major depressive disorder.

BACKGROUND: The alterations of biological markers are thought to be effective tools to understand the pathophysiology and management of major depressive disorder (MDD). A lot of researches has implied many markers for depression, but any of them fully discovered the association between the markers and depression. The present study investigated the serum levels of amino acids and non-enzymatic antioxidants in major depression, and also explained their association with depression. METHODS: This study examined 247 MDD patients and 248 healthy controls (HCs) matched by age and sex. The Hamilton Depression Rating Scale (Ham-D) was used to all the participants to measure the severity of depression. Quantification of serum amino acids, vitamin A and E were carried out using the HPLC system whereas vitamin C levels were measured by UV-spectrophotometer. All the statistical analysis was performed by SPSS statistical software (version 23.0). The independent sample t-test, the Mann-Whitney U test, and the Fisher's exact test were applied to detect the group differences where a Bonferroni correction applied to the p value. RESULTS: It was observed that serum levels of four amino acids (methionine, phenylalanine, tryptophan, and tyrosine) along with three non-enzymatic antioxidants (vitamin A, E, and C) were significantly dropped in MDD patients compared to HCs (Cohen's d (d): - 0.45, - 0.50, - 0.68, - 0.21, - 0.27, - 0.65, and - 0.24, respectively). Furthermore, Ham-D scores of cases were negatively correlated with serum levels of methionine (r = - 0.155, p = 0.015) and tyrosine (r = - 0.172, p = 0.007). CONCLUSION: The present study suggests that lowered serum methionine, phenylalanine, tryptophan, tyrosine, and non-enzymatic antioxidants are associated with depression. The reduction of these parameters in MDD patients may be the consequence, and not the cause, of major depression.

Pomegranate arils osmotic dehydration: effect of pre-drying on mass transfer.

In this work, the effect of ambient drying prior to osmotic dehydration (OD) of Tunisian pomegranate arils has been investigated. The whole fruit was pre-dried under ambient climate conditions, 20 °C and a climate humidity of 66%, until obtaining hard peels. Fresh and pre-dried pomegranate arils were dehydrated in sucrose osmotic solution at optimized conditions (50 °Brix, 40 °C, 440 rpm, foodstuff to solution weight ratio of 1:4 and 420 min). Water and solute transfer during OD where monitored. Mass transfer kinetics were modeled according to Peleg equation. This model showed a relatively good fitting of experimental data of both fresh and pre-dried samples. The pre-drying prior to OD of pomegranate arils gave lower solid gain. The sucrose uptake was about 0.403, 0.173, 0.116 g/g of dry matter for 81%, 70%, 59% initial moisture content, respectively. The highest water loss to solid gain ratio was obtained for dehydrated pomegranate arils of 70% initial moisture content. Effective diffusion coefficients were determined using the analytical solution of Fick's second law. The effective diffusion coefficients decrease with decreasing arils moisture contents. The average effective diffusion coefficients were 8.3 × 10-9 and 4.6 × 10-9 m2 s-1 for water loss and solid gain, respectively.

Correlation of levetiracetam concentration in peripheral blood mononuclear cells with clinical efficacy: A sensitive monitoring biomarker in patients with epilepsy.

PURPOSE: Therapeutic drug monitoring (TDM) is increasingly recommended in antiepileptic drug (AED) therapy, yet a complex relationship exists between the unbound-drug serum concentration (Cu.serum) as a monitoring biomarker and clinical efficacy. The study was designed to investigate the validity of the intracellular unbound-drug concentration in Peripheral Blood Mononuclear Cells (Cu.PBMC) as a feasible TDM tool in relation to levetiracetam (LEV). METHODS: Patients from epilepsy out-patient centre were included in a 4-month descriptive prospective study. Trough serum and PBMC LEV concentrations were monthly determined using HPLC and correlated with clinical features, demographic data, and P-glycoprotein (P-gp) expression. RESULTS: Seventy-patients completed the study with a LEV dose range of 500-3000 mg/day. An absolute range for LEV Cu.serum and Cu.PBMC was 1.00-26.99 and 0.33-4.43 µg/mL, respectively. Unlike Cu.serum, the average four-month LEV Cu.PBMC displayed a significant positive correlation with clinical features and P-gp expression; where patients with higher LEV Cu.PBMC experienced less number of seizure/month, better cognition and quality of life, and had a more reduction in P-gp expression, but no significant correlation with LEV daily dose was observed. A therapeutic response threshold of ≥ 0.82 µg/mL for LEV Cu.PBMCwas perceived by using a receiver operating characteristic curve that related the number of seizure/month to the LEV Cu.PBMC. The validity of this therapeutic threshold was significant in contrast to LEV Cu.serum. CONCLUSION: Levetiracetam PBMC concentration is a more sensitive biomarker for LEV efficacy and correlates better with clinical events than Cu.serum and could represent a novel tool for more precise LEV monitoring.

Prevalence, pattern and factors associated with ocular disorders in small-scale welders in Katwe, Kampala.

BACKGROUND: Welders are at an increased risk of eye disorders as a result of their occupation, leading to enormous vocational and economic consequences. With limited published studies among welders in low resource settings, we sought to determine the prevalence, pattern and factors associated with ocular disorders among small-scale welders in Katwe, Kampala. METHODS: In a field-based cross-sectional study, we recruited 343 small-scale welders. Simple random sampling was done to select the study participants. A pretested questionnaire was used to collect information on demographics, ocular, general history, systemic and ocular examination. The proportion of small-scale welders with ocular disorders (defined as any abnormal finding on eye examination) was determined. The bivariate and multivariate analyses were carried out, using logistic regression methods at a level of significance of 0.05. RESULTS: The mean age of the participants was 36 years (SD ± 12). The overall prevalence of ocular disorders was found to be 59.9%. The common ocular disorders included conjunctiva disorders (32%) and presbyopia (27%). There was a statistically significant relationship between females (OR = 4.279, P-value = 0.007), age 35 and above (OR = 4.244, P-value< 0.001), history of foreign body removal (OR = 1.677, P-value = 0.041), and ocular disorders. CONCLUSIONS: There is a high prevalence of ocular disorders among small-scale welders. Conjunctiva disorders, presbyopia and myopia were the commonest. Being female, age 35 and above and foreign body removal, were significantly associated with ocular disorders among welders. Policies should be put in place to ensure all welders use proper personal -protective equipment (welding helmets), and also receive regular eye checkup and health education.

The Circulating Micro-RNAs (-122, -34a and -99a) as Predictive Biomarkers for Non-Alcoholic Fatty Liver Diseases.

BACKGROUND: It remains essential for patient safety to develop non-invasive diagnostic tools to diagnose non-alcoholic fatty liver rather than invasive techniques. AIM: Our case-control study was to address the value of circulating miRNAs as a potential non-invasive biomarker for the diagnosis of non-alcoholic fatty acid diseases (NAFLD) and monitoring of disease progression. METHODS: Routine clinical assessment, laboratory tests, anthropometric study, and liver biopsy results reported for 210 patients with NAFLD (124 patients of simple steatosis (SS) and 86 of non-alcoholic steatohepatitis (NASH)). Apparently matched for age and gender, healthy participants (n= 90) were enrolled as a control group. Serum samples were tested for micro-RNAs (-122, -34a and -99a) by quantitative-PCR. RESULTS: By histopathology, 124 of the NAFLD group were of SS and 86 patients were of NASH. Compared with the control subjects, both mi-RNA-122 and -34a levels were increased in NAFLD (p< 001) and at a cut-off = 1.261, mi-RNA-122 had 92% sensitivity, 85% specificity to differentiate NAFLD from healthy controls, while mi-RNA-99a were significantly decreased in NAFLD patients with an observed decrease in disease severity, and at a cut-off = 0.46, miRNA-99a had 94% sensitivity and 96% specificity to discriminate SS from NASH. CONCLUSION: The integration of a circulating mi-RNA panel to diagnose NAFLD cases and to discriminate between SS and NASH. Large-scale study is still needed to verify the other mi-RNA profiles and their role in NAFLD pathogenesis and targeting therapy.

Synthesis and evaluation of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines as Bcl-2 inhibitory anticancer agents.

A series of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines 8a-j has been designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents based on our previous lead compound 8a. Synthesis of the target compounds was readily accomplished through a cyclisation reaction between indole-3-carboxylic acid hydrazide (5) and substituted isothiocyanates 6a-j, followed by oxidative cyclodesulfurization of the corresponding thiosemicarbazide 7a-j using 1,3-dibromo-5,5-dimethylhydantoin. Active compounds of the series 8a-j were found to have sub-micromolar IC50 values selectively in Bcl-2 expressing human cancer cell lines; notably the 2-nitrophenyl analogue 8a was found to exhibit potent activity, and compounds 8a and 8e possessed comparable Bcl-2 binding affinity (ELISA assay) to the established natural product-based Bcl-2 inhibitor, gossypol. Molecular modeling studies helped to further rationalise anti-apoptotic Bcl-2 binding, and identified compounds 8a and 8e as candidates for further development as Bcl-2 inhibitory anticancer agents.

Suppression of connective tissue growth factor mediates the renoprotective effect of Sitagliptin rather than Pioglitazone in type 2 diabetes mellitus.

AIM: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease, and thus, the ability of antidiabetic drugs to ameliorate renal microvascular disease may be as important as their ability to control blood glucose. Therefore, we investigated the reno-protective effect of the antidiabetic drugs, Sitagliptin and Pioglitazone, versus combined Metformin/Enalapril in a rat model of type 2 diabetes. METHOD: Male Wistar rats were randomly assigned to be either normal control or diabetic. Induction of type 2 diabetes was done by intraperitoneal injection of\ low dose streptozotocin (35mg/kg) on top of 2 weeks of high fat diet. Hyperglycemic animals were divided into 4 groups: untreated diabetic, Sitagliptin (10mg/kg), Pioglitazone (10mg/kg) and Metformin/Enalapril (500, 10mg/kg, respectively) treated. After 6 weeks, fasting blood glucose, plasma insulin, ß-cell function, insulin resistance, serum lipids, urea & creatinine, albuminurea, kidney weight, renal oxidative stress, plasma connective tissue growth factor (CTGF) and renal histopathology were assessed. KEY FINDINGS: Sitagliptin decreased microalbuminurea, urea & creatinine, renal tropism, oxidative stress and CTGF to levels similar to Metformin/Enalapril group. It also preserved near normal renal histology. Although Pioglitazone treatment reduced urea, creatinine, renal tropism and oxidative stress, it did not improve renal pathological changes or significantly alter CTCF. SIGNIFICANCE: Early Sitagliptin treatment in type 2 diabetes can equally ameliorate renal functions and structural changes as combined Metformin/Enalapril. Moreover Sitagliptin is a better renoprotective than Pioglitazone, probably due to its suppressor effect on CTGF, a key factor mediating diabetic renal injury.

Vitamin D3 supplementation and body composition in persons with obesity and type 2 diabetes in the UAE: A randomized controlled double-blinded clinical trial.

BACKGROUND & AIM: The co-existence of vitamin D deficiency with obesity and type 2 diabetes is highly prevalent in the United Arab Emirates. We do not have studies evaluating the vitamin D dose response and sufficiency, and if sufficient substitution dose during a longer period could decrease obesity or change fat distribution in obese type 2 diabetic vitamin D deficient Emiratis. METHODS: A randomized double-blind clinical trial was conducted for 6 months followed by another 6 months of un-blinded follow up with 87 obese, type 2 diabetic participants. Serum 25-hydroxy vitamin D (S-25(OH)D), anthropometric data, and life-style factors such as diet and sunlight exposure were measured. The study was executed in 3 phases in two arms vitamin D arm (n = 45) and placebo arm (n = 42); in Phase 1 the vitamin D arm received 6000 IU vitamin D3/day (3 months) followed by Phase 2 with 3000 IU vitamin D3/day. During follow up (phase 3) both the arms were un-blinded and supplemented with 2200 IU vitamin D3/day for another 6 months. RESULTS: At the baseline a significant (p < 0.01) positive association between body fat mass and body weight (r = 0.97) muscle mass (r = 0.47), water mass (r = 0.54), waist circumference (r = 0.82) and serum PTH (r = 0.28) was observed. On supplementation no significant changes in anthropometric dimensions was observed. S-25(OH) D peaked in phase 1 (77.2 ± 30.1 vs 28.5 ± 9.2, p = 0.003) followed by a decrease in phase 2 (62.3 ± 20.8, p = 0.006) paralleled by a decrease in parathyroid hormone in phase 2 (5.9 ± 2.4 vs 4.5 ± 1.8, p < 0.01) compared to baseline in vitamin D group. CONCLUSION: This study shows no significant influence of vitamin D supplementation on weight, fat mass or waist circumference in type 2 diabetic obese vitamin D deficient participants of Arab ethnicity after one year. Despite a relatively high daily dose of vitamin D3 we did not achieve target levels of S-25(OH)D above 75 nmol/L in this population. However, supplementation was safe, improved s- 25 (OH)D also reducing the incidence of eucalcemic parathyroid hormone elevation. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT02101151.

Preoperative beta blocker use associated with cerebral ischemia during carotid endarterectomy.

PURPOSE: Cerebral ischemia is a known complication of carotid cross-clamping during carotid endarterectomy. Selective intraluminal shunting for cerebral protection is not always effective and carries risks. The purpose of this study was to identify potentially modifiable risk factors for intraoperative cerebral ischemia and shunting during carotid endarterectomy. METHODS: We performed an historical case-control chart review of primary carotid endarterectomies with electroencephalographic (EEG) monitoring and selective shunting. Randomized controls and cases that showed ischemic EEG changes and required shunting were matched by year of surgery and the presence or absence of a contralateral carotid occlusion. Detailed perioperative data were collected for all cases. Results were analyzed using the Mantel-Haenszel test, analysis of variance, and a multivariate logistic regression model. RESULTS: Of 523 charts screened, 69 patients had experienced evidence of cerebral ischemia on clamping of the carotid and required shunting. These patients were more likely than their matched controls to have been receiving regular preoperative beta blockers (33/69 vs 18/69, respectively; P = 0.01; odds ratio [OR] 2.5; 95% confidence interval [CI] 1.2 to 5.1). Ipsilateral moderate carotid stenosis (60-80%) was also associated with increased risk. An adjusted multivariate regression model estimated an OR of 3.6 (95% CI 1.5 to 8.9; P = 0.005) for the association between use of a beta blocker and shunting. Intraoperative hemodynamic values were similar for the shunt and control groups as well as for patients receiving and not receiving preoperative beta blockers. CONCLUSION: The current study found an association between regular preoperative use of beta blockers and intraoperative cerebral ischemia in patients undergoing carotid endarterectomy. This effect did not relate to intraoperative hemodynamics.

Synthesis and evaluation of 3-(benzylthio)-5-(1H-indol-3-yl)-1,2,4-triazol-4-amines as Bcl-2 inhibitory anticancer agents.

A series of substituted 3-(benzylthio)-5-(1H-indol-3-yl)-4H-1,2,4-triazol-4-amines has been synthesised and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents. Synthesis of the target compounds was readily accomplished in good yields through a cyclisation reaction between indole-3-carboxylic acid hydrazide and carbon disulfide under basic conditions, followed by S-benzylation. Active compounds, such as the nitrobenzyl analogue 6c, were found to exhibit sub-micromolar IC50 values in Bcl-2 expressing human cancer cell lines. Molecular modelling and ELISA studies further implicated anti-apoptotic Bcl-2 as a candidate molecular target underpinning anticancer activity.