Broadening the Phenotype and Genotype Spectrum of Glycogen Storage Disease by Unraveling Novel Variants in an Iranian Patient Cohort.

Glycogen storage diseases (GSDs) are a group of rare inherited metabolic disorders characterized by clinical, locus, and allele heterogeneity. This study aims to investigate the phenotype and genotype spectrum of GSDs in a cohort of 14 families from Iran using whole-exome sequencing (WES) and variant analysis. WES was performed on 14 patients clinically suspected of GSDs. Variant analysis was performed to identify genetic variants associated with GSDs. A total of 13 variants were identified, including six novel variants, and seven previously reported pathogenic variants in genes such as AGL, G6PC, GAA, PYGL, PYGM, GBE1, SLC37A4, and PHKA2. Most types of GSDs observed in the cohort were associated with hepatomegaly, which was the most common clinical presentation. This study provides valuable insights into the phenotype and genotype spectrum of GSDs in a cohort of Iranian patients. The identification of novel variants adds to the growing body of knowledge regarding the genetic landscape of GSDs and has implications for genetic counseling and future therapeutic interventions. The diverse nature of GSDs underscores the need for comprehensive genetic testing methods to improve diagnostic accuracy. Continued research in this field will enhance our understanding of GSDs, ultimately leading to improved management and outcomes for individuals affected by these rare metabolic disorders.

Investigating perceived core disaster competencies of nurses in Iran: A case study of northwest hospitals.

AIM: This study was carried out to investigate the perception of the main competencies of disaster management in Iranian emergency department nurses in 2023 in hospitals affiliated with Kermanshah University of Medical Sciences. The present study was conducted to explore the perceived core disaster competencies in nurses of hospitals affiliated with Kermanshah University of Medical Sciences in 2023. BACKGROUND: Due to the rise in natural disasters, their escalating severity and associated regulatory response necessitate a closer look at the preparedness and core competencies of nursing personnel. The main competencies of nurses are necessary to deal with disasters in unexpected events, and they are expected to use their professional expertise to provide the required nursing services to reduce the risks caused by disasters. METHODOLOGY: This descriptive-analytical study was conducted cross-sectionally between May and September 2023. In the study, a sample of 384 nurses working in the departments of four hospitals affiliated with Kermanshah University of Medical Sciences was selected through a random stratification. The data collection instrument was a 45-item scale of nurses' perceived core competencies (NPDCC) in handling disasters. The data were analyzed using the Mann-Whitney U-test, Kruskal-Wallis test, and independent samples t-test. The significance level was set at 5%. RESULTS: The mean total score of perceived core disaster competencies was 139.11 ± 37.65. The technical skills subscale got the highest score (51.81 ± 11.28) and critical thinking skills received the lowest (9.74 ± 3.92). Also, "technical skills" had the highest average and "critical thinking skills" had the lowest average in all three age groups. The results found a significant difference between the scores of nurses in perceived core disaster competencies in age groups, work environments, education degrees, marital statuses, and experiences of attending disaster workshops (p ≤ 0.05). CONCLUSIONS: The results showed that nurses had different levels of core disaster competencies in the department. There are gaps in the core disaster nursing competencies that need to be filled. Nursing managers should consistently evaluate the core nursing competencies to achieve efficacious disaster preparedness. To this aim, it is recommended that authorities implement training courses and programs to enhance the preparedness of nurses in responding to disasters.

Vision-related quality of life in patients with retinal vein occlusion.

PURPOSE: This study aims to assess the vision-related quality of life in patients with retinal vein occlusion (RVO) among those referred to Labbafinejad Medical Center and Imam Hossein Hospital between 2019 and 2021. METHODS: This comparative study included 37 eligible patients diagnosed with various types of RVO, with an average age of 61 ± 9. To ensure data validity, we included 74 age- and sex-matched healthy individuals. Only cases with a definitive diagnosis of RVO, confirmed by two retina specialists (ND and RN), were included. We assessed the vision-related quality of life of our participants using the National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25). All participants underwent interviews. RESULTS: In our study, we examined the vision-related quality of life in different subgroups of RVO patients. Overall, RVO patients had a significantly lower total VRQoL score compared to healthy individuals (P < 0.001), except in the subscale analysis of specific factors such as ocular pain, color vision, and driving, where no statistically significant difference was observed. A statistically significant difference was found in the comparison of subgroups, indicating lower VRQoL in central retinal vein occlusion (CRVO) patients (P = 0.010). Furthermore, a significant correlation was observed between lower VRQoL and decreased vision (P = 0.009) as well as longer disease duration (P = 0.011). CONCLUSION: Retinal vein occlusion can significantly reduce vision-related quality of life, particularly in more severe cases.

Suicide gene therapy using allogeneic adipose tissue-derived mesenchymal stem cell gene delivery vehicles in recurrent glioblastoma multiforme: a first-in-human, dose-escalation, phase I clinical trial.

BACKGROUND: Glioblastoma multiforme (GBM) is associated with remarkably poor prognosis, and its treatment is challenging. This investigation aimed to evaluate the safety of suicide gene therapy using allogeneic adipose tissue-derived mesenchymal stem cells (ADSCs) carrying herpes simplex virus-thymidine kinase (HSV-TK) gene for the first time in patients with recurrent GBM. METHODS: This study was a first-in-human, open-label, single-arm, phase I clinical trial with a classic 3 + 3 dose escalation design. Patients who did not undergo surgery for their recurrence were included and received this gene therapy protocol. Patients received the intratumoral stereotactic injection of ADSCs according to the assigned dose followed by prodrug administration for 14 days. The first dosing cohort (n = 3) received 2.5 × 105 ADSCs; the second dosing cohort (n = 3) received 5 × 105 ADSCs; the third dosing cohort (n = 6) received 10 × 105 ADSCs. The primary outcome measure was the safety profile of the intervention. RESULTS: A total of 12 patients with recurrent GBM were recruited. The median follow-up was 16 (IQR, 14-18.5) months. This gene therapy protocol was safe and well tolerated. During the study period, eleven (91.7%) patients showed tumor progression, and nine (75.0%) died. The median overall survival (OS) was 16.0 months (95% CI 14.3-17.7) and the median progression-free survival (PFS) was 11.0 months (95% CI 8.3-13.7). A total of 8 and 4 patients showed partial response and stable disease, respectively. Moreover, significant changes were observed in volumetric analysis, peripheral blood cell counts, and cytokine profile. CONCLUSIONS: The present clinical trial, for the first time, showed that suicide gene therapy using allogeneic ADSCs carrying the HSV-TK gene is safe in patients with recurrent GBM. Future phase II/III clinical trials with multiple arms are warranted to validate our findings and further investigate the efficacy of this protocol compared with standard therapy alone. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT), IRCT20200502047277N2. Registered 8 October 2020, https://www.irct.ir/ .

The efficacy of corticosteroids therapy in patients with moderate to severe SARS-CoV-2 infection: a multicenter, randomized, open-label trial.

BACKGROUND: We performed a multicenter, randomized open-label trial in patients with moderate to severe Covid-19 treated with a range of possible treatment regimens. METHODS: Patients were randomly assigned to one of three regimen groups at a ratio of 1:1:1. The primary outcome of this study was admission to the intensive care unit. Secondary outcomes were intubation, in-hospital mortality, time to clinical recovery, and length of hospital stay (LOS). Between April 13 and August 9, 2020, a total of 336 patients were randomly assigned to receive one of the 3 treatment regimens including group I (hydroxychloroquine stat, prednisolone, azithromycin and naproxen; 120 patients), group II (hydroxychloroquine stat, azithromycin and naproxen; 116 patients), and group III (hydroxychloroquine and lopinavir/ritonavir (116 patients). The mean LOS in patients receiving prednisolone was 5.5 in the modified intention-to-treat (mITT) population and 4.4 days in the per-protocol (PP) population compared with 6.4 days (mITT population) and 5.8 days (PP population) in patients treated with Lopinavir/Ritonavir. RESULTS: The mean LOS was significantly lower in the mITT and PP populations who received prednisolone compared with populations treated with Lopinavir/Ritonavir (p = 0.028; p = 0.0007). We observed no significant differences in the number of deaths, ICU admission, and need for mechanical ventilation between the Modified ITT and per-protocol populations treated with prednisolone and Lopinavir/Ritonavir, although these outcomes were better in the arm treated with prednisolone. The time to clinical recovery was similar in the modified ITT and per-protocol populations treated with prednisolone, lopinavir/ritonavir, and azithromycin (P = 0.335; P = 0.055; p = 0.291; p = 0.098). CONCLUSION: The results of the present study show that therapeutic regimen (regimen I) with low dose prednisolone was superior to other regimens in shortening the length of hospital stay in patients with moderate to severe COVID-19. The steroid sparing effect may be utilized to increase the effectiveness of corticosteroids in the management of diabetic patients by decreasing the dosage.

Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure.

Aims: Iron deficiency (ID) is associated with adverse outcomes in heart failure (HF) but the underlying mechanisms are incompletely understood. Intracellular iron availability is secured by two mRNA-binding iron-regulatory proteins (IRPs), IRP1 and IRP2. We generated mice with a cardiomyocyte-targeted deletion of Irp1 and Irp2 to explore the functional implications of ID in the heart independent of systemic ID and anaemia. Methods and results: Iron content in cardiomyocytes was reduced in Irp-targeted mice. The animals were not anaemic and did not show a phenotype under baseline conditions. Irp-targeted mice, however, were unable to increase left ventricular (LV) systolic function in response to an acute dobutamine challenge. After myocardial infarction, Irp-targeted mice developed more severe LV dysfunction with increased HF mortality. Mechanistically, the activity of the iron-sulphur cluster-containing complex I of the mitochondrial electron transport chain was reduced in left ventricles from Irp-targeted mice. As demonstrated by extracellular flux analysis in vitro, mitochondrial respiration was preserved at baseline but failed to increase in response to dobutamine in Irp-targeted cardiomyocytes. As shown by 31P-magnetic resonance spectroscopy in vivo, LV phosphocreatine/ATP ratio declined during dobutamine stress in Irp-targeted mice but remained stable in control mice. Intravenous injection of ferric carboxymaltose replenished cardiac iron stores, restored mitochondrial respiratory capacity and inotropic reserve, and attenuated adverse remodelling after myocardial infarction in Irp-targeted mice but not in control mice. As shown by electrophoretic mobility shift assays, IRP activity was significantly reduced in LV tissue samples from patients with advanced HF and reduced LV tissue iron content. Conclusions: ID in cardiomyocytes impairs mitochondrial respiration and adaptation to acute and chronic increases in workload. Iron supplementation restores cardiac energy reserve and function in iron-deficient hearts.

Aquaporin-4 inhibition attenuates Pentylenetetrazole-induced behavioral seizures and cognitive impairments in kindled rats.

Epilepsy is a neurological condition distinguished by recurrent and unexpected seizures. Astrocytic channels and transporters are essential for maintaining normal neuronal functionality. The astrocytic water channel, aquaporin-4 (AQP4), which plays a pivotal role in regulating water homeostasis, is a potential target for epileptogenesis. In present study, we examined the effect of different doses (10, 50, 100 µM and 5 mM) of AQP4 inhibitor, 2-nicotinamide-1, 3, 4-thiadiazole (TGN-020), during kindling acquisition, on seizure parameters and seizure-induced cognitive impairments. Animals were kindled by injection of pentylenetetrazole (PTZ: 37.5 mg/kg, i.p.). TGN-020 was administered into the right lateral cerebral ventricle 30 min before PTZ every alternate day. Seizure parameters were assessed 20 min after PTZ administration. One day following the last PTZ injection, memory performance was investigated using spontaneous alternation in Y-maze and novel object recognition (NOR) tests. The inhibition of AQP4 during the kindling process significantly decreased the maximal seizure stage and seizure duration (two-way ANOVA, P = 0.0001) and increased the latency of seizure onset and the number of PTZ injections required to induce different seizure stages (one-way ANOVA, P = 0.0001). Compared to kindled rats, the results of the NOR tests showed that AQP4 inhibition during PTZ-kindling prevented recognition memory impairment. Based on these results, AQP4 could be involved in seizure development and seizure-induced cognitive impairment. More investigation is required to fully understand the complex interactions between seizure activity, water homeostasis, and cognitive dysfunction, which may help identify potential therapeutic targets for these conditions.

Effect of time-restricted eating and intermittent fasting on cognitive function and mental health in older adults: A systematic review.

Objective: Emerging evidence suggests that dietary interventions hold promise for promoting cognitive function and mental well-being in aging populations. This systematic review aimed to examine the potential relationship between Time-Restricted Eating (TRE) and Intermittent Fasting (IFA) with cognitive function and mental health in older adults. Methods: A thorough exploration was undertaken on electronic databases such as PubMed, Scopus, Web of Science, Science Direct, and Google Scholar, up to October 2023, following PRISMA standards. The evaluation of the quality and potential bias in the incorporated articles involved the use of the Newcastle-Ottawa Scale and Consolidated Standards of Reporting Trials (CONSORT). Results: From a total of 539 articles initially identified, eight studies met the eligibility criteria for inclusion in this review. Out of these eight studies, six focused on cognitive function, and 2 focused on mental health. The reviewed articles encompassed a wide range of population sizes, with the number of older adults studied varying from 10 to 1357, reflecting a diverse cohort of individuals. Conclusions.The findings suggest that TRE and IFA may have a positive impact on cognitive function and mental health in this population. However, additional research is needed to fully comprehend this relationship. Therefore, future research should specifically examine factors such as the duration and timing of the eating window in TRE, as well as the physical condition of older adults, to provide a more nuanced understanding of the cognitive and mental health benefits of TRE and IFA in older adults.

PDL1 targeting by miR-138-5p amplifies anti-tumor immunity and Jurkat cells survival in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) has constituted over 80% of the lung cancer population with a poor prognosis. Over the past decade, immunotherapy has been constructed in the enlargement of immune checkpoint inhibitors as a promising approach for NSCLC treatment. Evading the immune system using the PD-1/PD-L1 axis is an intelligent way for cancers, and T cells cannot respond fully and confront cancer. Recently, the miR-138 was reported as a PD-L1 regulator in NSCLC. However, its inhibitory impact on T-cell exhaustion has not been characterized. The present study aims to impair PD-L1 (B7-H1) expression in Adenocarcinoma cell lines using miR-138-5p and determines how it prevents Jurak cell exhaustion. To gain the purpose, first, 18 highly significant dysregulated miRNAs containing hsa-miR-138 and CD274-mRNA network were detected in NSCLC based on bioinformatics analysis. Moreover, our study revealed a high level of miR-138-5p could make significant changes like PDL1 downregulation, proliferation, and mortality rate in A549/Calu6 cells. We also simulate cancer environmental conditions by culturing Jurak cells and NSCLC cell lines under the influence of stimulator cytokines to show how miR-138-5p survives Jurak cells by targeting PD-L1/PD-1pathway.

Identification of novel mutations in TPK1 and SLC19A3 genes in families exhibiting thiamine metabolism dysfunction syndrome.

Background and aims: The occurrence of thiamine metabolism dysfunction syndrome (THMD), a rare autosomal recessive condition, may be linked to various mutations found in the TPK1 and SLC19A3 genes. The disease chiefly manifests through ataxia, muscle hypotonia, abrupt or subacute onset encephalopathy, and a decline in developmental milestones achieved during the early stages of infancy. We present findings from an investigation that involved two individuals from Iran, both of whom experienced seizures along with ataxia and hypotonia. The underlying genetic causes were found with the use of next-generation sequencing (NGS) technology, which has facilitated the detection of causal changes in a variety of genetic disorders. Material and methods: The selection of cases for this study was based on the phenotypic and genetic information that was obtainable from the Center for Comprehensive Genetic Services. The genetic basis for the problems observed among the participants was determined through the application of whole-exome sequencing (WES). Subsequently, sanger sequencing was employed as a means of validating any identified variations suspected to be causative. Results: The first patient exhibited a homozygous mutation in the TPK1 gene, NM_022445.4:c.224 T > A:p.I75 N, resulting in the substitution of isoleucine for asparagine at position 75 (p.I75 N). In our investigation, patient 2 exhibited a homozygous variant, NM_025243.4:c.1385dupA:pY462X, within the SLC19A3 gene. Conclusions: Collectively, when presented with patients showcasing ataxia, encephalopathy, and basal ganglia necrosis, it is essential to account for thiamine deficiency in light of the potential advantages of prompt intervention. At times, it may be feasible to rectify this deficiency through the timely administration of thiamine dosages. Accordingly, based on the results of the current investigation, these variations may be useful for the diagnosis and management of patients with THMD.

A novel transdermal delivery route for energy supplements: Electrospun chitosan/polyvinyl alcohol nanofiber patches loaded with vitamin B12.

Nanofibrous patches have attracted much attention as a solution to resolve drug delivery challenges. In this study, vitamin B12- loaded polyvinyl alcohol (PVA)/chitosan (Cs) nanofiber patch (NFP) was electrospun and cross-linked by glutaraldehyde (GA). The physicochemical properties of the nanofiber patches were assessed by morphological studies, FTIR analysis, hydrophilicity test, mechanical tests, and in-vitro evaluations including biodegradability, MTT assay, and cumulative release test of vitamin. In-vivo studies were also carried out by measuring vitamin B12 levels in the bloodstream and conducting histopathology studies on the animal models. The results showed that the mean diameter of Cs/PVA/B12 and cross-linked patch were approximately 207 and 256 nm, respectively. Cross-linking of NFP led to the lower, slower, and more continuous release of the vitamin with a slight decrease in biodegradability, and an increase in the mechanical properties of the nanofiber patches. Furthermore, the cytocompatibility assay, MTT, and in vivo results revealed no cytotoxicity of Cs/PVA/B12 NFP towards L929 cell line. No lesion or tissue damage was observed in the skin tissue of the animal models wearing these skin patches. Therefore, B12-loaded NFP can be introduced as a potential candidate for commercial transdermal routes.

Memory impairment was ameliorated by corticolimbic microinjections of arachidonylcyclopropylamide (ACPA) and miRNA-regulated lentiviral particles in a streptozotocin-induced Alzheimer's rat model.

The present study aimed to investigate the effect of corticolimbic cannabinoid CB1 receptors activity on memory impairment in the intracerebroventricular (ICV)-streptozotocin (STZ) animal model of Alzheimer's like-disease. This study also assessed whether the corticolimbic overexpression of miRNA-137 or -let-7a could increase the endocannabinoids by inhibiting the monoglyceride lipase (MAGL) to ameliorate STZ response. The results showed that ICV microinjection of STZ (3 mg/kg/10 µl) impaired passive avoidance memory retrieval. The chronic microinjection of arachidonylcyclopropylamide (ACPA; 10 ng/0.5 µl), a selective cannabinoid CB1 receptor agonist, into the hippocampal CA1 region, the central amygdala (CeA) or the medial prefrontal cortex (mPFC) ameliorated the amnesic effect of ICV-STZ. Intra-CA1 or -CeA microinjection of ACPA alone did not affect memory retrieval, while its microinjection into the mPFC impaired memory formation. Based on bioinformatics analysis and verification of the MAGL gene, miRNA-137 and -let-7a were chosen to target the expression levels of MAGL in the corticolimbic regions. The chronic corticolimbic microinjection of lentiviral particles containing miRNA-137 or -let-7a ameliorated ICV-STZ-induced memory impairment. The high transfection efficiency was determined for each virus using comparing fluorescent and conventional vision. Corticolimbic overexpression of miRNA-137 or -let-7a decreased the MAGL gene expression that encodes the MAGL enzyme to increase the endocannabinoids. Thus, among the molecular mechanisms and signaling pathways involved in the pathophysiology of Alzheimer's disease (AD), it is worth mentioning the role of endocannabinoids in the corticolimbic regions. CB1 receptor agonists, miRNA-137 or -let-7a, may be potential therapeutic targets against cognitive decline in AD.

Case report: Stem cell-based suicide gene therapy mediated by the herpes simplex virus thymidine kinase gene reduces tumor progression in multifocal glioblastoma.

Introduction: The prognosis for glioblastoma multiforme (GBM), a malignant brain tumor, is poor despite recent advancements in treatments. Suicide gene therapy is a therapeutic strategy for cancer that requires a gene to encode a prodrug-activating enzyme which is then transduced into a vector, such as mesenchymal stem cells (MSCs). The vector is then injected into the tumor tissue and exerts its antitumor effects. Case presentation: A 37-year-old man presented to our department with two evident foci of glioblastoma multiforme at the left frontal and left parietal lobes. The patient received an injection of bone marrow-derived MSCs delivering the herpes simplex virus thymidine kinase (HSV-tk) gene to the frontal focus of the tumor, followed by ganciclovir administration as a prodrug for 14 days. For follow-up, the patient was periodically assessed using magnetic resonance imaging (MRI). The growth and recurrence patterns of the foci were assessed. After the injection on 09 February 2019, the patient's follow-up appointment on 19 December 2019 MRI revealed a recurrence of parietal focus. However, the frontal focus had a slight and unremarkable enhancement. On the last follow-up (18 March 2020), the left frontal focus had no prominent recurrence; however, the size of the left parietal focus increased and extended to the contralateral hemisphere through the corpus callosum. Eventually, the patient passed away on 16 July 2020 (progression-free survival (PFS) = 293 days, overall survival (OS) = 513 days). Conclusion: The gliomatous focus (frontal) treated with bone marrow-derived MSCs carrying the HSV-TK gene had a different pattern of growth and recurrence compared with the non-treated one (parietal). Trial registration: IRCT20200502047277N2. Registered 10 May 2020-Retrospectively registered, https://eng.irct.ir/trial/48110.

Pre-emptive iron supplementation prevents myocardial iron deficiency and attenuates adverse remodelling after myocardial infarction.

AIMS: Heart failure (HF) after myocardial infarction (MI) is a major cause of morbidity and mortality. We sought to investigate the functional importance of cardiac iron status after MI and the potential of pre-emptive iron supplementation in preventing cardiac iron deficiency (ID) and attenuating left ventricular (LV) remodelling. METHODS AND RESULTS: MI was induced in C57BL/6J male mice by left anterior descending coronary artery ligation. Cardiac iron status in the non-infarcted LV myocardium was dynamically regulated after MI: non-haem iron and ferritin increased at 4 weeks but decreased at 24 weeks after MI. Cardiac ID at 24 weeks was associated with reduced expression of iron-dependent electron transport chain (ETC) Complex I compared with sham-operated mice. Hepcidin expression in the non-infarcted LV myocardium was elevated at 4 weeks and suppressed at 24 weeks. Hepcidin suppression at 24 weeks was accompanied by more abundant expression of membrane-localized ferroportin, the iron exporter, in the non-infarcted LV myocardium. Notably, similarly dysregulated iron homeostasis was observed in LV myocardium from failing human hearts, which displayed lower iron content, reduced hepcidin expression, and increased membrane-bound ferroportin. Injecting ferric carboxymaltose (15 µg/g body weight) intravenously at 12, 16, and 20 weeks after MI preserved cardiac iron content and attenuated LV remodelling and dysfunction at 24 weeks compared with saline-injected mice. CONCLUSION: We demonstrate, for the first time, that dynamic changes in cardiac iron status after MI are associated with local hepcidin suppression, leading to cardiac ID long term after MI. Pre-emptive iron supplementation maintained cardiac iron content and attenuated adverse remodelling after MI. Our results identify the spontaneous development of cardiac ID as a novel disease mechanism and therapeutic target in post-infarction LV remodelling and HF.

The -4817 G>A (rs2238136) variant of the vitamin D receptor gene: a probable risk factor for colorectal cancer.

Vitamin D appears to have anti-tumor activities in the large bowel. Our aim was to investigate whether -4817 G>A (rs2238136) polymorphism located at 5'-untranslated region (5'-UTR) of the human vitamin D receptor (VDR) gene was associated with colorectal cancer (CRC) risk. We conducted a case-control study and VDR genotypes, determined by Bpu10I restriction endonuclease digestion of PCR-amplified DNA, were performed on 327 cases with CRC and 327 controls. The distribution of VDR -4817 G>A genotypes and alleles differed significantly between cases with CRC and controls even after adjustment for confounding factors such as age, BMI, sex, and smoking status. Individuals carrying the "AA" genotype had a 2.09-fold increased risk compared with those with "GG" genotype (P = 0.016, OR = 2.09, 95% CI = 1.15-3.78) and a 1.87-fold increased risk compared with those with "GG and GA" genotypes (P = 0.033, OR = 1.87, 95% CI = 1.05-3.33) for CRC. Furthermore, the VDR "A" allele was significantly overrepresented in cases with CRC than controls (P = 0.044; OR = 1.28, 95% CI = 1.01-1.63). Interestingly, the analysis of the SNP revealed that all these associations were stronger for women subjects than for all subjects combined. These data indicated for the first time a direct association between "AA" genotype of VDR gene -4817 G>A polymorphism and CRC, with a stronger association for female subjects. However, our findings remain to be confirmed in other populations.

Numerical simulation of undular jumps on graveled bed using volume of fluid method.

Undular hydraulic jumps are characterized by a smooth rise of the free surface, followed by a train of stationary waves. These jumps sometimes occur in natural waterways and rivers. Numerical difficulties are especially distinct when the flow condition is close to the critical value because of the high sensitivity of the near-critical flow field to flow and channel conditions. Furthermore, the free surface has a wavy shape, which may indicate the occurrence of several transitions from supercritical to subcritical states and vice versa (i.e., undular hydraulic jumps). In this study, a flow model is used to predict an undular hydraulic jump in a rectangular open channel. The model is based on the general two-dimensional, Reynolds-averaged, Navier-Stokes flow equations. The resulting set of partial differential equations is solved using the FLOW-3D solver. The results are compared with the experimental data to validate the model. The comparative analysis shows that the proposed model yields good results. Several types of undular hydraulic jumps occurring in different situations are then simulated to prove the potential application of the model.

Spontaneous Complete Remission of Acute Myeloid Leukemia in the Absence of Disease-Modifying Therapy following Severe Pulmonary Involvement by Coronavirus Infectious Disease-19.

Coronavirus infectious disease-19 (COVID-19) usually alters the innate and adaptive immune setting by excessive production of proinflammatory cytokines, leading to a deviation in the natural course of simultaneous malignant disease. In the absence of disease-modifying therapy, complete remission of acute myeloid leukemia (AML) is an extraordinary event caused mainly by an immune-related mechanism secondary to a severe infectious process. We present a 57-year-old woman with a new diagnosis of AML associated with a 11q23/KMT2A abnormality who had achieved temporary spontaneous remission in the absence of disease-modifying therapy following the severe pulmonary infection with coronavirus lasting for six months. We review the literature and explain the potential impact of stimulated immune responses by COVID-19 on induction of remission in a patient with AML that could provide an excellent opportunity for new immune-based therapies to evolve for the hematologic malignancies. Despite the high ability of the immune process to destroy the malignant cells, the remission of duration is usually short. Therefore, it seems that continuing treatment after SR of AML by a consolidation regimen or bone marrow transplantation, based on a risk-adapted treatment approach, may reduce the recurrence risk.

Transitions between the stages of smoking in Iranian adolescents.

OBJECTIVE: This study examined the prevalence of smoking, the rates of transitions, and predictors of transition through the three stages of smoking. METHODS: A total of 1785 high school students in Tabriz (northwest of Iran) were assessed at 2 time points with a 12-month interval in 2005 and 2006, regarding changes in smoking stages. The predictor variables were measured when the students were in the 10th grade. Logistic regression was employed to predict the different smoking stages at grade 11. RESULTS: The results showed that 14.3% (95% confidence interval, 12.3%-16.4%) and 2.8% (2.0%-4.0%) of the never smokers became experimenters and regular smokers, respectively, whereas 16.5% (12.4%-21.7%) of the experimenters became regular smokers. Among never smokers, participation in groups with at least one smoker (odds ratio, 1.24 (95% confidence interval, 1.05-1.47)), having smoker friends (1.85 (1.21-2.83)), and a positive attitude toward smoking (1.22 (1.02-1.46)) predicted smoking experience. Among the experimenters, those who had general risk behaviors (2.56 (1.12-5.87)) and participated in groups with at least one smoker (2.58 (1.26-5.31)) significantly progressed to becoming a regular smoker at the follow-up. CONCLUSION: Prevention of smoking in adolescence should begin by focusing on the predictors of transition through smoking stages, especially participating in smoker groups.

Coating of ferulic acid-loaded silk fibroin nanoparticles with neutrophil membranes: A promising strategy against the acute pancreatitis.

Nanotechnology-based approaches have enabled overcoming the challenging issues such as the rapid clearance, poor solubility, and non-specific action or cellular uptake of drugs. In this study, we have evaluated the therapeutic effects of the phenolic compound, ferulic acid (FA), in the acute pancreatitis (AP) as this phenolic compound has demonstrated promising effects against the oxidative stress and inflammatory reactions. In order to overcome the poor solubility and bioavailability of FA, it was entrapped into the nanoparticles (NPs) based on the silk fibroin (SF) as a biomimetic substance. Neutrophil membrane-coated SF-NPs with appropriate capacity of FA loading and physicochemical characteristics, released FA in a controlled fashion, selectively delivered FA into the inflammatory pancreas lesion, and demonstrated protective effects against the detrimental aspects of the disease. The prepared nanoformulation by improving the pharmacological profile of FA and targeted delivery could be of therapeutic importance against the AP via suppressing the inflammation and oxidative stress.

Development of a novel nanoformulation against the colorectal cancer.

Colorectal cancer (CRC) with high metastasis rates has been known as a major cause of death worldwide. Lack of the specificity and insufficient concentrations of traditional chemotherapeutics at tumor site and their severe adverse effects necessitate development of new treatment strategies such as designing suitable nanocarriers for delivery of drugs, improving their pharmacological profiles and reducing adverse effects. We have developed a platform based on the poly-ursolic acid (poly-UA), a polymeric system with potential anticancer effect. Following the self-assembly of poly-UA into the nanoparticles (NPs), they were applied for delivery of mithramycin A (Mith-A), a promising candidate for CRC therapy, however, with some limitations such as rapid clearance and serious side effects. Mith-A-loaded poly-UA NPs with suitable physicochemical properties and efficient drug entrapment, released Mith-A in a controlled manner and provided suitable toxicity against the CT-26 colorectal cancer cells, increased accumulation in tumor, and protection against the detrimental features of the disease. Poly-UA NPs demonstrated therapeutic efficiency (in vivo and in vitro) by themselves. The prepared NPs induced no remarkable alteration of body weights or damages to the major organs in animals bearing tumor indicating the safety of NPs. The bioactive nanoformulation along with improving the pharmacological profile of Mith-A could provide a synergistic toxicity against the CRC.