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Background Dysregulation of cation-chloride cotransporters NKCC1 and KCC2 expression was shown to be related to drug-resistant epilepsy. Previous studies suggested that bumetanide, an inhibitor of NKCC1, might have antiepileptic effects. Objective The aim of this study was to investigate the safety and efficacy of bumetanide add-on therapy in patients with drug-resistant epilepsy and its relation to cation-chloride cotransporters NKCC1 and KCC2. Methods We conducted an open-label, single-arm clinical trial in drug-resistant temporal lobe epilepsy (TLE) patients. This study consisted of three phases: pretreatment (3 months), titration (3 weeks), and active treatment (6 months). During the pretreatment phase, the dose of antiepileptic drugs was stabilized, and bumetanide was then added at an initial dose of 0.5 mg/day, increasing by 0.5 mg/week until a target dose of 2 mg/day was achieved. Bumetanide treatment was then continued for 6 months. Seizure frequency and adverse events were assessed at every monthly visit. Blood samples were collected from patients and 12 healthy controls were used for polymerase chain reaction and Western blot analyses. Primary clinical outcomes were drug safety and change in seizure frequency. Changes in NKCC1 and KCC2 expression were the non-clinical endpoints. Results A total of 30 patients were enrolled, 27 of whom completed the study. The mean duration of epilepsy was 16.5 years. Median seizure frequency per month was 9 [interquartile range (IQR) 7–14.5] at baseline, 3.67 (IQR 1.84–6.17) at the first 3 months, and 2 (IQR 0.84–4.34) at the last 3 months ( p  < 0.001). Five adverse events were detected in six patients. The reported adverse events were anorexia in four patients, nausea and vomiting in two patients, and agitation, headache and increased seizure frequency in one patient each. The level of NKCC1 and KCC2 gene transcripts and KCC2 protein did not change significantly following treatment ( p  > 0.05); however, we observed a significant reduction in NKCC1 protein levels ( p  = 0.042). Conclusions Bumetanide might be an effective and relatively tolerable drug in patients with drug-resistant TLE. Downregulation of NKCC1 protein following bumetanide treatment may be responsible for its antiepileptic effects. Iranian Registry of Clinical Trials Identifier IRCT 201012115368N1.

PurposeSelenium (Se) supplementation may help reduce inflammation and disease activity in ulcerative colitis (UC) patients. We investigated the therapeutic effects of Se administration in cases with mild-to-moderate active UC.MethodsA multicenter, double-blind, randomized clinical trial (RCT) was conducted on 100 cases with active mild-to-moderate UC. The patients were randomly allocated to be given an oral selenomethionine capsule (200 mcg/day, n = 50) or a placebo capsule (n = 50) for 10 weeks. The primary outcome was defined as disease activity via the Simple Clinical Colitis Activity Index (SCCAI), and secondary outcomes were measured at the end of the study.ResultsAfter 10 weeks, the SCCAI score's mean was reduced in the Se group (P < 0.001). At the end of the intervention, clinical improvement (decline of 3 ≥ score from baseline score) was observed in 19 patients (38%) of the Se group and 3 patients (6%) of the placebo group. The patients with clinical remission (defined as SCCAI ≤ 2) were assigned in the Se group (P = 0.014). The Se group’s quality of life and Se serum levels were enhanced at the end of the study (P < 0/001). In the Se group, the mean concentration of interleukin-17 decreased (P < 0/001). However, the levels of interleukin-10 showed no considerable change between the two groups in the 10th week (P = 0.23).ConclusionSe supplementation as add-on therapy with medical management induced remission and improved the quality of life in patients with active mild-to-moderate UC.Trial registration number and date of registrationIRCT20091114002709N51; 2020-04-13.

Professional sports performance relies critically on the interaction between the brain and muscles during movement. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique which modulates cortical excitability and can be used to improve motor performance in athletes. The present study aimed to investigate the effect of bilateral anodal tDCS (2 mA, 20 min) over the premotor cortex or cerebellum on motor and physiological functions and peak performance of professional gymnastics athletes. Seventeen professional gymnastics athletes participated in a randomized, sham-controlled, crossover study. In this study, we assessed the efficacy of two anodal tDCS protocols (2 mA, 20 min) with stimulation over the bilateral premotor cortex or cerebellum with the return electrodes placed over the opposite supraorbital areas. Power speed, strength coordination, endurance, static and dynamic strength, static and dynamic flexibility, and rating of perceived exertion were measured before and immediately after tDCS interventions (bilateral anodal tDCS over premotor cortices, anodal tDCS over the cerebellum, and sham tDCS). Additionally, physiological muscle performance parameters, including maximum voluntary isometric contraction (MVIC) of upper body muscles, were assessed during tDCS. Bilateral anodal tDCS over the premotor cortex, compared to anodal tDCS over the cerebellum and sham tDCS conditions, significantly improved power speed, strength coordination, and static and dynamic strength variables of professional gymnastics athletes. Furthermore, bilateral anodal tDCS over the cerebellum, compared to sham tDCS, significantly improved strength coordination. Moreover, bilateral premotor anodal tDCS significantly increased MVIC of all upper body muscles during stimulation, while anodal tDCS over the cerebellum increased MVIC in only some muscles. Bilateral anodal tDCS over the premotor cortex, and to a minor degree over the cerebellum, might be suited to improve some aspects of motor and physiological functions and peak performance levels of professional gymnastics athletes. Clinical Trial Registration ID: IRCT20180724040579N2.

Astaxanthin (ASX), as a natural carotenoid compound, exists in various types of seafood and microorganisms. It has several possible beneficial therapeutic effects for patients with polycystic ovary syndrome (PCOS). Patients with PCOS also suffer from endoplasmic reticulum (ER) stress. In the present work, it was hypothesized that ER stress could be improved by ASX in PCOS patients. Granulosa cells (GCs) were obtained from 58 PCOS patients. The patients were classified into ASX treatment (receiving 12 mg/day for 60 days) and placebo groups. The expression levels of ER stress pathway genes and proteins were explored using Western blotting and quantitative polymerase chain reaction. To assess oxidative stress markers, follicular fluid (FF) was gained from all patients. The Student’s t test was used to perform statistical analysis. After the intervention, ASX led to a considerable reduction in the expression levels of 78-kDa glucose-regulated protein (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), and X-box-binding protein 1 compared to the placebo group, though the reduction in the messenger RNA (mRNA) expression level of activating transcription factor 6 was not statistically significant. However, ASX significantly increased the ATF4 expression level. GRP78 and CHOP protein levels represented a considerable decrease in the treatment group after the intervention. In addition, a statistically significant increase was found in the FF level of total antioxidant capacity in the treatment group. Based on clinical outcomes, no significant differences were found between the groups in terms of the oocyte number, fertilization rate, and fertility rate, but the ASX group had higher rates of high-quality oocytes, high-quality embryo, and oocyte maturity compared to the placebo group. Our findings demonstrated that ER stress in the GCs of PCOS patients could be modulated by ASX by changing the expression of genes and proteins included in the unfolding protein response. Trial registration This study was retrospectively registered on the Iranian Registry of Clinical Trials website ( www.irct.ir ; IRCT-ID: IRCT20201029049183N, 2020-11-27).

Purpose Recent evidence suggests that adherence to dietary approaches to stop hypertension (DASH) diet can be effective in managing non-alcoholic fatty liver disease (NAFLD). We investigated the effect of DASH diet on hepatic fibrosis, steatosis and liver enzymes in patients with NAFLD. Methods This 12-week randomized controlled trial was conducted among seventy patients with NAFLD who were randomly assigned into two groups including intervention group (DASH diet containing 50–55% carbohydrate, 15–20% protein, and 30% total fat) and the control group (a healthy diet containing 50–55% carbohydrate, 15–20% protein, and 30% total fat). Both diets were calorie-restricted (500–700 kcal lower than the energy requirement). The primary outcomes included hepatic fibrosis, hepatic steatosis, alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyl transpeptidase (GGT). Results At the baseline, there was no significant difference between two groups in the level of hepatic fibrosis (P = 0.63), hepatic steatosis (P = 0.53), ALT (P = 0.93), AST (P = 0.18) and GGT (P = 0.76). A significant reduction was found in the intervention group compared to the control group in hepatic fibrosis (23 grades reduction vs. 7 grades reduction; P = 0.008) and hepatic steatosis (31 grades reduction vs. 9 grades reduction; P = 0.03) after intervention. In addition, a significant change was observed in the intervention group compared to control group in ALT ( – 8.50 ± 8.98 vs.  – 2.09 ± 7.29; P = 0.002), and AST ( – 5.79 ± 6.83 vs.  – 0.51 ± 6.62; P = 0.002). Conclusions Adherence to DASH diet may be effective in management of NAFLD. Trial registration The trial was registered on 06 February 2022 at Iranian Registry of Clinical Trials (IRCT20170117032026N3) with URL: https://www.irct.ir/trial/60887 .

Neck pain and forward head posture (FHP) are typical in prolonged smartphone users and need to be targeted for treatment. We aimed to compare the effect of a routine therapeutic program with and without respiratory exercises on smartphone users with FHP and non-specific chronic neck pain (NSCNP). Sixty patients (aged 24.7 ± 2.1 years) with FHP and NSCNP were randomly assigned to the routine therapeutic program (n = 20), combined respiratory exercises with a routine therapeutic program (n = 20), or control (n = 20) groups. At baseline, there was no difference among groups at all variables. Each programme was implemented three times a week for eight weeks. Primary Outcome was pain measured by visual analogue scale (VAS), and secondary ones were forward head angle, the activity of specific muscles, and respiratory patterns, measured by photogrammetry, electromyography and manual, respectively. All outcomes were measured at baseline and eight weeks post-treatment. We used the repeated measures analysis of variance to examine the interaction between time and group, paired t-test for intragroup comparison, one-way analysis of variance for intergroup comparison, and Tukey post hoc test at a significant level 95% was used. There were significant differences in the combined group compared with the routine therapeutic group ( P  = 0.03) for diaphragm muscle activation, respiratory balance ( P  = 0.01), and the number of breaths ( P  = 0.02). There were significant within-group changes from baseline to post-treatment in the combined group for all outcomes above, but no changes in the therapeutic exercise routine group. Despite respiratory pattern, none of the secondary outcomes proved to be superior in the combination group compared to the routine therapeutic program in smartphone users with FHP and NSCNP. Future studies with longer follow-up assessments could strengthen these results. Trial registration : Current Controlled Trials using the IRCT website with ID number of, IRCT20200212046469N1 “Prospectively registered” at 04/03/2020.

In this study, the efficacy of sublingual squalene in decreasing the mortality rate among patients with COVID-19 was investigated. Squalene was extracted from pumpkin seed oil with a novel method. Then, the microemulsion form of squalene was prepared for sublingual usage. In the clinical study, among 850 admitted patients, 602 eligible COVID-19 patients were divided in two groups of control (N = 301) and cases (N = 301) between Nov 2021 and Jan 2022. Groups were statistically the same in terms of age, sex, BMI, lymphocyte count on 1 st admission day, hypertension, chronic kidney disease, chronic respiratory disease, immunosuppressive disease, and required standard treatments. The treatment group received five drops of sublingual squalene every 4 h for 5 days plus standard treatment, while the control group received only standard treatment. Patients were followed up for 30 days after discharge from the hospital. The sublingual form of squalene in the microemulsion form was associated with a significant decrease in the mortality rate (p < 0.001), in which 285 (94.7%) cases were alive after one month while 245 (81.4%) controls were alive after 1 month of discharge from the hospital. In addition, squalene appears to be effective in preventing re-hospitalization due to COVID-19 (p < 0.001), with 141 of controls (46.8%) versus 58 cases (19.3%). This study suggests sublingual squalene in the microemulsion as an effective drug for reducing mortality and re-hospitalization rates in COVID-19 patients. Trial Registration Number: IRCT20200927048848N3.

IntroductionMesh fixation in inguinal hernia repair, has been a controversial subject for many years. Therefore, in this study, we evaluated and compared fixation and non-fixation of mesh in Transabdominal Preperitoneal (TAPP) Inguinal hernia repair.MethodsIn this randomized control trial, 100 patients diagnosed with unilateral inguinal hernia were included. We divided the study population into two groups of fifty. For both groups, a 15 × 13 cm Prolene(polypropylene) mesh was used for repair. In the fixation group, mesh was fixed to the abdominal wall by endoscopic tacks, while in the non-fixation group, mesh was secured at the proper place without any fixation. Postoperative outcomes were complications, recurrence, and pain intensity after 1-, 3- and 6-months.ResultsPostoperative pain intensity in the 1st month [Median of 2 and 0, (P < 0.001)], and 3rd month [Median of 0.5 and 0, (P < 0.001)], in the fixation group were significantly higher than the non-fixation group. However, 6 months after surgery, pain intensity was almost similar for both groups. In the 6th postoperative month, only one patient experienced recurrence who was in the fixation group. The rate of recurrence and urinary retention between the groups was not significant.ConclusionIt was observed that until 6 months after surgery patients who received the non-fixating method of TAPP repair experienced lower levels of pain in comparison to the fixation group while other complications did not differ between the two groups.This trail was registered at www.irct.ir with Trial Registration Number of IRCT20210224050491N1.

The present study is the first effort to evaluate the effects of vitamin B12 supplementation on the serum level of liver enzymes, homocysteine, grade of hepatic steatosis, and metabolic profiles in patients with non-alcoholic fatty liver disease (NAFLD). Forty patients with NAFLD were enrolled in a double-blind placebo-controlled trial to receive either one oral tablet of vitamin B12 (1000 µg cyanocobalamin) or a placebo per day for 12 weeks. We investigated serum levels of homocysteine, aminotransferases, fasting blood glucose (FBG), lipids, malondialdehyde (MDA), and homeostasis model assessment of insulin resistance (HOMA-IR). The grade of liver steatosis and fibrosis was measured by real-time 2-dimensional shear wave elastography. Vitamin B12 supplementation significantly decreased serum levels of homocysteine compared to placebo (medians: − 2.1 vs. − 0.003 µmol/l; P  = 0.038). Although serum alanine transaminase (ALT) in the vitamin B12 group decreased significantly, this change did not reach a significant level compared to the placebo group (medians: − 7.0 vs. 0.0 IU/l; P  > 0.05). Despite the significant within-group decrease in FBG, MDA, and liver steatosis in the vitamin B12 group, between-group comparisons did not reveal any significant difference. Vitamin B12 supplementation might decrease serum levels of homocysteine in patients with NAFLD. The fasting blood glucose and serum levels of MDA were significantly improved in the trial group who received vitamin B12. However, these changes did not reach a significant level compared to the placebo group. In this respect, further studies with larger sample sizes, different doses, and types of vitamin B12 will reveal additional evidence. Trial Registration: At  http://irct.ir/  as IRCT20120718010333N5 on December 25, 2019.

AimsOxidative stress plays a pivotal role in the pathogenesis of type 2 diabetes (T2D). In vitro and animal studies have shown that resveratrol exerts an antioxidant effect, but clinical trials addressing this effect in patients with T2D are limited. The aim of this study was to determine whether resveratrol supplementation affects oxidative stress markers in a randomized, placebo-controlled, double-blind clinical trial.MethodsA total of 48 patients with T2D randomly were assigned to receive 800 mg/day resveratrol or placebo for 2 months. Plasma total antioxidant capacity, malondialdehyde concentration, protein carbonyl and total thiol contents, intracellular superoxide anion (O2−·) and hydrogen peroxide (H2O2) in PBMCs, the expression of genes involved in oxidative stress responses (Nrf2, SOD, Cat, HO-1, RAGE, NOS) in PBMCs, and metabolic and anthropometric parameters were measured at the baseline and at the trial end.ResultsCompared with the placebo group, resveratrol reduced plasma protein carbonyl content and PBMCs O2−· level and significantly increased plasma total antioxidant capacity and total thiol content. Furthermore, the expression of Nrf2 and SOD was significantly increased after resveratrol consumption. Resveratrol had no significant effects on the metabolic and anthropometric parameters except for a significant reduction in weight, BMI, and blood pressure levels. Resveratrol was well tolerated, and no serious adverse event was occurred.ConclusionsOur study demonstrated that 8 weeks of supplementationwith 800 mg/day resveratrol has an antioxidant effect in the blood and PBMCs of patients with T2D.Clinical Trial Registry number and website IRCT registration number: IRCT2015072523336N1 and http://en.search.irct.ir/view/24752.