Diverse potential of secretome from natural killer cells and monocyte-derived macrophages in activating stellate cells.

Chronic liver diseases, such as non-alcoholic steatohepatitis (NASH)-induced cirrhosis, are characterized by an increasing accumulation of stressed, damaged, or dying hepatocytes. Hepatocyte damage triggers the activation of resident immune cells, such as Kupffer cells (KC), as well as the recruitment of immune cells from the circulation toward areas of inflammation. After infiltration, monocytes differentiate into monocyte-derived macrophages (MoMF) which are functionally distinct from resident KC. We herein aim to compare the in vitro signatures of polarized macrophages and activated hepatic stellate cells (HSC) with ex vivo-derived disease signatures from human NASH. Furthermore, to shed more light on HSC activation and liver fibrosis progression, we investigate the effects of the secretome from primary human monocytes, macrophages, and NK cells on HSC activation. Interleukin (IL)-4 and IL-13 treatment induced transforming growth factor beta 1 (TGF-ß1) secretion by macrophages. However, the supernatant transfer did not induce HSC activation. Interestingly, PMA-activated macrophages showed strong induction of the fibrosis response genes COL10A1 and CTGF, while the supernatant of IL-4/IL-13-treated monocytes induced the upregulation of COL3A1 in HSC. The supernatant of PMA-activated NK cells had the strongest effect on COL10A1 induction in HSC, while IL-15-stimulated NK cells reduced the expression of COL1A1 and CTGF. These data indicate that other factors, aside from the well-known cytokines and chemokines, might potentially be stronger contributors to the activation of HSCs and induction of a fibrotic response, indicating a more diverse and complex role of monocytes, macrophages, and NK cells in liver fibrosis progression.

An optimized protocol for isolation of hepatic leukocytes retrieved from murine and NASH liver biopsies.

Immune dysregulation and inflammation by hepatic-resident leukocytes is considered a key step in disease progression of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis toward cirrhosis and hepatocellular carcinoma. Here, we provide a protocol for isolation and characterization of liver-resident immune cells from fine-needle biopsies obtained from a rodent model and humans. We describe steps for isolating leukocytes, cell sorting, and RNA extraction and sequencing. We then detail procedures for low-input mRNA sequencing analyses.

Combined proteomics and CRISPR‒Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo.

BACKGROUND: Acute leukemias represent deadly malignancies that require better treatment. As a challenge, treatment is counteracted by a microenvironment protecting dormant leukemia stem cells. METHODS: To identify responsible surface proteins, we performed deep proteome profiling on minute numbers of dormant patient-derived xenograft (PDX) leukemia stem cells isolated from mice. Candidates were functionally screened by establishing a comprehensive CRISPR‒Cas9 pipeline in PDX models in vivo. RESULTS: A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as an essential vulnerability required for the survival and growth of different types of acute leukemias in vivo, and reconstitution assays in PDX models confirmed the relevance of its sheddase activity. Of translational importance, molecular or pharmacological targeting of ADAM10 reduced PDX leukemia burden, cell homing to the murine bone marrow and stem cell frequency, and increased leukemia response to conventional chemotherapy in vivo. CONCLUSIONS: These findings identify ADAM10 as an attractive therapeutic target for the future treatment of acute leukemias.

In vivo PDX CRISPR/Cas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance.

Resistance towards cancer treatment represents a major clinical obstacle, preventing cure of cancer patients. To gain mechanistic insights, we developed a model for acquired resistance to chemotherapy by treating mice carrying patient derived xenografts (PDX) of acute lymphoblastic leukemia with widely-used cytotoxic drugs for 18 consecutive weeks. In two distinct PDX samples, tumors initially responded to treatment, until stable disease and eventually tumor re-growth evolved under therapy, at highly similar kinetics between replicate mice. Notably, replicate tumors developed different mutations in TP53 and individual sets of chromosomal alterations, suggesting independent parallel clonal evolution rather than selection, driven by a combination of stochastic and deterministic processes. Transcriptome and proteome showed shared dysregulations between replicate tumors providing putative targets to overcome resistance. In vivo CRISPR/Cas9 dropout screens in PDX revealed broad dependency on BCL2, BRIP1 and COPS2. Accordingly, venetoclax re-sensitized derivative tumors towards chemotherapy, despite genomic heterogeneity, demonstrating direct translatability of the approach. Hence, despite the presence of multiple resistance-associated genomic alterations, effective rescue treatment for polychemotherapy-resistant tumors can be identified using functional testing in preclinical models.

Discovering the pros and cons of participation of Iranian women with substance use disorder in women's only narcotics anonymous meetings and offering strategies for harm reduction: A grounded theory study.

Women with substance use disorder participate in women's only narcotics anonymous meetings. Therefore, this study aimed to discover the advantages and disadvantages of Iranian women's participation in this type of meetings. Accordingly, this research was done in Behboud Gostaran Hamgam Women's Rehab Center in Tehran. The research method was a qualitative method of grounded theory, and samples of the research were chosen by theoretical sampling method. Data was collected using in-depth, face-to-face, unstructured interviews and nonparticipation observations. First, 4 women with substance use disorder who had referred to the center to quit addiction were interviewed. The researcher then interviewed 2 informant groups of the center's medical staff, consisting of 2 social workers and 2 mentors with long-term experience in the field of women's addiction, and at the end of each interview, the interviews were analyzed. Finally, according to theoretical sampling principles and achieving saturation, the researcher participated in the women's only narcotics anonymous meetings, which were held weekly inside the center, and took notes on the content of the sessions in relation to the purpose of the study. After each session, the notes were analyzed and finally, after participating in 4 sessions, saturation was achieved by the researcher. By analyzing the research data, the theme of pros of participating in the women's only narcotics anonymous meetings, and the theme of cons of participating in the women's only narcotics anonymous meetings were yielded. Using the research findings could enhance the quality of these meetings.

Introduce a New Intervention Model Based on Islamic Lifestyle for Decreasing the Risk of Cardiovascular Disease in People at Risk: A Comparative Study.

The main purpose of the present study was designing and assessing the common lifestyle and Islamic lifestyle interventions and comparison of them. Sample of the study was thirty-nine subjects participated in a healthy lifestyle program. The Islamic group were received the Islamic healthy lifestyle program. In comparison with common, in the Islamic group the CVD risk was significantly lower; the psychological well-being was increased significantly; the psychological distress was decreased significantly; and the spiritual well-being was increased significantly. The most powerful element of Islamic lifestyle was to strengthen the spirituality that can positively affect the life.

A pilot randomized controlled trial to assess the effect of Islamic spiritual intervention and of breathing technique with heart rate variability feedback on anxiety, depression and psycho-physiologic coherence in patients after coronary artery bypass surgery.

BACKGROUND: This study investigated the effects of Islamic religious and breathing techniques with heart rate variability (HRV) biofeedback therapies on HRV and psycho-physiologic coherence (resonance frequency), depression and anxiety in coronary artery bypass graft surgery (CABG) patients. METHODS: Sixty CABG patients were chosen and randomly assigned to religious, breathing techniques and control groups. The experimental groups received 8  weeks of treatments; a 2-h session with home works in each week. The control group received only their normal hospital interventions. The groups' depression, anxiety, HRV and psycho-physiologic coherence levels were assessed before and after the interventions by DASS-21 for depression and anxiety, and em-wave desktop software for HRV and psycho-physiologic coherence. The data were analyzed using ANCOVA with Bonferroni Comparison test and descriptive tests in SPSS software. RESULTS: The findings showed that there were significant differences in psycho-physiologic coherence (HRV), depression and anxiety scores among the three groups in the post-tests. In fact, depression and anxiety were reduced more in the religious group, while psycho-physiologic coherence raised more in the breathing with the HRV feedback group. CONCLUSION: The results showed that both Islamic religious and breathing techniques with HRV biofeedback therapies can be used in rehabilitation programs for CABG patients in clinics and hospitals.

Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.

WordCommentsAnalyzer: A windows software tool for qualitative research.

There is a lack of free software that provides a professional and smooth experience in text editing and markup for qualitative data analysis. Word processing software like Microsoft Word provides a good editing experience, allowing the researcher to effortlessly add comments to text portions. However, organizing the keywords and categories in the comments can become a more difficult task when the amount of data increases. We present WordCommentsAnalyzer, a software tool that is written in C# using .NET Framework and OpenXml, which helps a qualitative researcher to organize codes when using Microsoft Word as the primary text markup software. WordCommentsAnalyzer provides an effective user interface to count codes, to organize codes in a code hierarchy, and to see various data extracts belonging to each code. We illustrate how to use the software by conducting a preliminary content analysis on Tweets with the #successfulaging hashtag. We hope this open-source software will facilitate qualitative data analysis by researchers who are interested in using Word for this purpose.

Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes.

We identify SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2), also known as BAF60b (BRG1/Brahma-associated factor 60b), as a critical regulator of myeloid differentiation in humans, mice, and zebrafish. Studying patients from three unrelated pedigrees characterized by neutropenia, specific granule deficiency, myelodysplasia with excess of blast cells, and various developmental aberrations, we identified three homozygous loss-of-function mutations in SMARCD2. Using mice and zebrafish as model systems, we showed that SMARCD2 controls early steps in the differentiation of myeloid-erythroid progenitor cells. In vitro, SMARCD2 interacts with the transcription factor CEBPɛ and controls expression of neutrophil proteins stored in specific granules. Defective expression of SMARCD2 leads to transcriptional and chromatin changes in acute myeloid leukemia (AML) human promyelocytic cells. In summary, SMARCD2 is a key factor controlling myelopoiesis and is a potential tumor suppressor in leukemia.

Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations.

BACKGROUND: Myb-like, SWIRM, and MPN domains 1 (MYSM1) is a transcriptional regulator mediating histone deubiquitination. Its role in human immunity and hematopoiesis is poorly understood. OBJECTIVES: We sought to investigate the clinical, cellular, and molecular features in 2 siblings presenting with progressive bone marrow failure (BMF), immunodeficiency, and developmental aberrations. METHODS: We performed genome-wide homozygosity mapping, whole-exome and Sanger sequencing, immunophenotyping studies, and analysis of genotoxic stress responses. p38 activation, reactive oxygen species levels, rate of apoptosis and clonogenic survival, and growth in immune and nonimmune cells were assessed. The outcome of allogeneic hematopoietic stem cell transplantation (HSCT) was monitored. RESULTS: We report 2 patients with progressive BMF associated with myelodysplastic features, immunodeficiency affecting B cells and neutrophil granulocytes, and complex developmental aberrations, including mild skeletal anomalies, neurocognitive developmental delay, and cataracts. Whole-exome sequencing revealed a homozygous premature stop codon mutation in the gene encoding MYSM1. MYSM1-deficient cells are characterized by increased sensitivity to genotoxic stress associated with sustained induction of phosphorylated p38 protein, increased reactive oxygen species production, and decreased survival following UV light-induced DNA damage. Both patients were successfully treated with allogeneic HSCT with sustained reconstitution of hematopoietic defects. CONCLUSIONS: Here we show that MYSM1 deficiency is associated with developmental aberrations, progressive BMF with myelodysplastic features, and increased susceptibility to genotoxic stress. HSCT represents a curative therapy for patients with MYSM1 deficiency.

Psychometric Properties of Farsi Version of the Revised Fear Survey Schedule for Children.

This study examined the psychometric properties of the Farsi version of the Revised Fear Survey Schedule for Children (Ollendick, 1983), namely the FSSC-FA, in a sample of Iranian children and adolescents (N = 394, 206 girls) aged 9-11:11 years. The internal consistency coefficient was found to range from .79 to .96 for total and subscale scores. The authors used exploratory and confirmatory factor analyses to determine the factor structure of the FSSC-FA. The results showed that a 71-item, six-factor model provided a satisfactory fit for the structure of the FSSC-FA (RMSEA = .07, 90% CIs [.068, .072], CFI = .94, NNFI = .94, χ2/df = 2.94). With regard to gender and age differences in fears of the present sample, girls typically reported more fears than boys (Cohen's d = .28, 95% CIs [.08, .48], p < .001), but differences between older and younger participants were modest. The study also reported most common fears in the sample which were very similar to those reported by other studies except one item being specific to the Iranian population. Bearing in mind the limitations discussed, the results generally show that the FSSC-FA scores are valid and reliable to assess fears in Iranian youth.

Psychometric properties of Farsi version of the revised fear survey schedule for children

This study examined the psychometric properties of the Farsi version of the Revised Fear Survey Schedule for Children (Ollendick, 1983), namely the FSSC-FA, in a sample of Iranian children and adolescents (N = 394, 206 girls) aged 9-11:11 years. The internal consistency coefficient was found to range from .79 to .96 for total and subscale scores. The authors used exploratory and confirmatory factor analyses to determine the factor structure of the FSSC-FA. The results showed that a 71-item, six-factor model provided a satisfactory fit for the structure of the FSSC-FA (RMSEA = .07, 90% CIs [.068, .072], CFI = .94, NNFI = .94, χ2/df = 2.94). With regard to gender and age differences in fears of the present sample, girls typically reported more fears than boys (Cohen's d = .28, 95% CIs [.08, .48], p < .001), but differences between older and younger participants were modest. The study also reported most common fears in the sample which were very similar to those reported by other studies except one item being specific to the Iranian population. Bearing in mind the limitations discussed, the results generally show that the FSSC-FA scores are valid and reliable to assess fears in Iranian youth (AU)

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Insulin and leptin levels in overweight and normal-weight Iranian adolescents: The CASPIAN-III study.

BACKGROUND: In this study, we aim to compare insulin and leptin levels in adolescents with or without excess weight and in those with or without abdominal obesity. MATERIALS AND METHODS: This case-control study was conducted among 486 samples. We randomly selected 243 overweight and an equal number of normal-weight adolescents from among participants of the third survey of a national surveillance program entitled Childhood and Adolescence Surveillance and PreventIon of Adult Non-communicable diseases study. Serum insulin and leptin were compared between two groups and their correlation was determined with other variables. RESULTS: The mean age and body mass index (BMI) of participants were 14.10 ± 2.82 years and 22.12 ± 6.49 kg/m(2), respectively. Leptin and insulin levels were higher in overweight than in normal-weight adolescents (P < 0.05). Leptin level was higher in children with abdominal obesity than in their other counterparts (P < 0.001). Leptin level was correlated with age, fasting blood glucose, BMI, and insulin level. CONCLUSION: Insulin and leptin levels were higher among overweight and obese children, which may reflect insulin and leptin-resistance. Given the complications of excess weight from early life, prevention and controlling childhood obesity should be considered as a health priority.

Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease.

BACKGROUND & AIMS: Very early onset inflammatory bowel diseases (VEOIBD), including infant disorders, are a diverse group of diseases found in children younger than 6 years of age. They have been associated with several gene variants. Our aim was to identify the genes that cause VEOIBD. METHODS: We performed whole exome sequencing of DNA from 1 infant with severe enterocolitis and her parents. Candidate gene mutations were validated in 40 pediatric patients and functional studies were carried out using intestinal samples and human intestinal cell lines. RESULTS: We identified compound heterozygote mutations in the Tetratricopeptide repeat domain 7 (TTC7A) gene in an infant from non-consanguineous parents with severe exfoliative apoptotic enterocolitis; we also detected TTC7A mutations in 2 unrelated families, each with 2 affected siblings. TTC7A interacts with EFR3 homolog B to regulate phosphatidylinositol 4-kinase at the plasma membrane. Functional studies demonstrated that TTC7A is expressed in human enterocytes. The mutations we identified in TTC7A result in either mislocalization or reduced expression of TTC7A. Phosphatidylinositol 4-kinase was found to co-immunoprecipitate with TTC7A; the identified TTC7A mutations reduced this binding. Knockdown of TTC7A in human intestinal-like cell lines reduced their adhesion, increased apoptosis, and decreased production of phosphatidylinositol 4-phosphate. CONCLUSIONS: In a genetic analysis, we identified loss of function mutations in TTC7A in 5 infants with VEOIBD. Functional studies demonstrated that the mutations cause defects in enterocytes and T cells that lead to severe apoptotic enterocolitis. Defects in the phosphatidylinositol 4-kinase-TTC7A-EFR3 homolog B pathway are involved in the pathogenesis of VEOIBD.

Sexual desire in Iranian female university students: role of marital satisfaction and sex guilt.

OBJECTIVE: To determine association between sexual desire and marital satisfaction and sex guilt among a sample of Iranian female university students. METHODS: The data presented here were obtained from a total of 192 married Iranian female university students who were selected via a multi-cluster sampling method from universities of Social Welfare and Rehabilitation, Tarbiat Modarres, and Islamic Azad. The subjects' sociodemographic data, marital satisfaction (using ENRICH Marital Satisfaction Questionnaire), sex guilt (using Mosher Revised Sex-Guilt Inventory), and sexual desire (using Hurlbert Index of Sexual Desire) were gathered. Pearson correlation coefficient and regression analysis methods were used to analyse the data. RESULTS: Findings showed there are significant relationships between sexual desire and marital satisfaction (r = 0.51, p < 0.01) and also between sexual desire and sex guilt (r = -0.44, p < 0.01). Also marital satisfaction and sex guilt were able to predict 31 percent of the variance of sexual desire. CONCLUSION: Marital satisfaction and sex guilt are two factors that significantly affect fluctuations in sexual desire of Iranian female university students.

Relationship between left ventricular ejection fraction and depression following myocardial infarction: an original article.

BACKGROUND: The aim of this study was to examine the association between left ventricular ejection fraction (LVEF) and incidence of depression following the myocardial infarction (MI). METHODS: In a prospective study, 176 patients aged 32-84 years with the mean age of 56 years (SD = 10.05) with a definitive diagnosis of myocardial infarction and admitted to one of the coronary care units (CCU) of Isfahan during April to August 2006 were selected through consecutive sampling method. The demographic and medical characteristics were collected by their medical record and also the results of the LVEF assessment of the patients were obtained through echocardiography or angiography following the myocardial infarction. Thereafter, the patients were given Beck Depression Inventory for the primary care (BDI-PC) in three months after myocardial infarction. The collected data were analyzed during the hospitalization and follow-up periods using logistic regression method. RESULTS: The findings indicated that left ventricular dysfunction identified by the Left ventricular ejection fraction index was significantly correlated with depression three months after the myocardial infarction (P < 0.01). In addition, the exploratory model (which only includes LVEF variable) had the predictive validity of 64.8% with 55.7% sensitivity and 72.1% specificity. CONCLUSION: Left ventricular dysfunction is associated with increased risk of depression following the myocardial infarction.

Seroprevalence of NMO-IgG among patients with neuromyelitis optica and opticospinal multiple sclerosis.

OBJECTIVES: In this study we sought to compare the seropositivity of NMO-IgG in patients presenting with demyelinative involvement of optic nerve and spinal cord with and without longitudinally extensive spinal cord lesion (LESCL). METHODS: Patients who were referred to Isfahan Multiple Sclerosis Clinic and Isfahan Devic's Disease Clinic at Al-Zahra Hospital in Iran were screened for this study. Patients with signs and symptoms indicating the demyelinating involvement of optic nerve(s) and spinal cord were included. Patients were evaluated by a neurologist and spinal cord and brain magnetic resonance imaging (MRI) were obtained. Patients with normal first brain MRI and with spinal cord demyelinative lesions visible on spinal MRI were included. Patients were then put into two groups: (i) patients with LESCL [neuromyelitis optica (NMO)] and (ii) patients with spinal plaques which do not extend over three vertebrae [opticospinal multiple sclerosis (OSMS)]. NMO-IgG was measured in the serum of the included patients. RESULTS: Totally we recruited 33 patients with LESCL and 32 patients without LESCL. The mean age of patients without LESCL was 34.61±10.98 and it was 33.48±11.93 for the NMO patients. In both groups there were 24 females and the rest were males. Among the NMO patients 16 (48.5%) were positive for NMO-IgG, while in the OSMS group there were none. CONCLUSION: The results of this study are in line with previous observations, and imply that the presence of LESCL is associated with the presence of NMO-IgG and thus an indicator of NMO.

Restricted leptin antagonism as a therapeutic approach to treatment of autoimmune diseases.

Leptin, the adipocyte derived hormone, has a pivotal role in regulating energy homeostasis and appetite. Beyond this essential role in bodyweight control, leptin also regulates the immune responses. Leptin has pro-inflammatory effects on T cell populations, shifting the T helper balance towards a TH1 phenotype, through induction of pro-inflammatory cytokines and stimulation of macrophage and natural killer cell function. Acute starvation reduces serum leptin levels, resulting in an impaired cellular immune response. The TH1 pro-inflammatory immune response, a homeostatic response mediated by the low leptin levels, is also impaired during starvation. Leptin-deficient or leptin receptor mutant mice are protected against the development of several inflammatory or various T cell-dependent autoimmune diseases. Therefore, leptin appears to have a central role in the immune response and low leptin levels may protect against autoimmune disease. Here we review the role of leptin in the immune responses, with emphasis on autoimmune diseases. We will also discuss the application of leptin antagonist therapy for prevention and treatment of immunity related disorders.