The protective effect of parthenolide in an in vitro model of Parkinson's disease through its regulation of nuclear factor-kappa B and oxidative stress.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, and is due to the degeneration of dopaminergic neurons. It is multifactorial, caused by genetic and environmental factors and currently has no definitive cure. We have investigated the protective effects of parthenolide (PTN), a compound with known anti-inflammatory and antioxidant properties, in an in vitro model of PD, that is induced by 6-OHDA, and that causes neurotoxicity in SH-SY5Y human neuroblastoma cells. METHODS AND RESULTS: SH-SY5Y cells were pretreated with PTN to assess its protective effects in 6-OHDA-induced cellular damage. Cell viability was measured using Alamar blue. Apoptosis was evaluated using an Annexin V-FITC/PI kit. Reactive oxygen species (ROS) levels were quantified, and expression levels of apoptotic markers (Bax, Bcl-2, p53) and NF-κB were analyzed via Western blotting and Quantitative real-time- (qRT-) PCR. We found that 6-OHDA reduced cell viability, that was inhibited significantly by pre-treatment with PTN (p < 0.05). Flow cytometry revealed that PTN reduced apoptosis induced by 6-OHDA. PTN also reduced the ROS levels raised by 6-OHDA (p < 0.05). Moreover, PTN decreased the expression of Bax, p53, NF-κB, and p-NF-κB that were increased by treatment with 6-OHDA. CONCLUSION: These findings indicate the potential beneficial effects of PTN in an in vitro model of PD via mitigating oxidative stress and inflammation, suggested PTN as a promising agent to be used for PD therapy, warranting further investigation in preclinical and clinical studies.

Harmaline exerts potentially anti-cancer effects on U-87 human malignant glioblastoma cells in vitro.

BACKGROUND: Harmaline is a ß-carboline alkaloid that can be extracted from the seeds of Peganum harmala. Harmaline has been shown to exhibit a potent cytotoxic effect against tumor cells. In this study, the anti-glioblastoma activity of harmaline was investigated in vitro. METHODS AND RESULTS: Cell viability, apoptosis, and cell cycle arrest were assessed in U-87 cells treated with harmaline at different doses. Reactive oxygen species (ROS) generation and the mRNA expression of apoptosis-associated genes were assessed. The anti-metastatic effect of harmaline on U-87 cells was evaluated by gelatin zymography assay where matrix metalloproteinase [MMP]-2/-9 enzymatic activity was measured, and the scratch assay was used to assess migratory responses. Flow cytometry demonstrated that harmaline could suppress the proliferation and induce sub-G1 cell cycle arrest and apoptotic cell death in glioblastoma cells. Harmaline treatment was also associated with an upregulation of the cell cycle-related genes, p21 and p53, and pro-apoptotic Bax, as well as the induction of ROS. The zymography assay indicated that the essential steps of metastasis were potently suppressed by harmaline through inhibiting the expression of MMP-2 and - 9. In addition, the migration of U-87 cells was significantly reduced after harmaline treatment. CONCLUSION: Our data suggest a basis for further research of harmaline which has potential cytotoxic activities in glioblastoma cells; inducing cell cycle arrest and apoptosis, repression of migration, possibly invasion, and metastasis.

A Mediterranean diet is associated with improved total antioxidant content of human breast milk and infant urine.

BACKGROUND: The composition of breast milk (BM) is dynamic and can be influenced by maternal variables that include the diet and nutritional status. This study examined the association between maternal adherence to a Mediterranean diet (MedDiet) and total antioxidant content of BM and infant urine. METHODS: We collected 350 BM samples from mothers and urine samples from their infants. The dietary intakes of the mothers were recorded using a validated 65 items-food frequency questionnaire (FFQ). The total antioxidant status of the samples was assessed using the ferric reducing/antioxidant power (FRAP), the 1, 1-diphenyl-2-picrylhydrazyl (DPPH), thiobarbituric acid reactive substances (TBARS), and thiol quantification assays. Milk protein, calcium, and triglyceride (TG) were also determined using standard biochemical kits. RESULTS: Subjects with the highest MedDiet scores were among the women in the highest tertile (T3) for consumption of dietary fiber, fruits, vegetables, nuts, legumes, and seeds, low-fat dairy, whole grains, and the lowest consumption of red meat, sweetened beverages, and sodium, compared to women in the first tertile (T1) with the lowest MedDiet scores. After adjustment for potential confounders, the individuals in the highest tertile for MedDiet score had a significantly higher level of milk DPPH, and infant urinary DPPH than the lowest tertile and had a significantly higher level of milk protein, FRAP and infant urinary FRAP compared to the T2 (P < 0.05). In addition, the mothers in the T3 for the MedDiet pattern had a significantly lower level of milk TG compared to those within the T1 (P < 0.05). CONCLUSION: Our findings show that a high maternal adherence to a MedDiet can affect BM composition and their infants' urine.

The association of maternal food quality score (FQS) with breast milk nutrient content and antioxidant content of infant urine: a cross-sectional study.

BACKGROUND: Breast milk (BM) is a complex fluid with a variable composition within women over time and between women in the population. The BM compositional differences are likely to be partly due to maternal dietary patterns. This study aimed to evaluate food quality score (FQS) in lactating mothers and its association with quality indicators of BM and antioxidant content of infant urine. METHODS: This cross-sectional study was undertaken in 350 lactating women aged 20 to 35 years. Data on dietary intake was collected using a validated food frequency questionnaire (FFQ) containing 65 food items. The FQS was calculated by integrating the scores obtained from healthy and unhealthy food groups. Subjects were categorized according to FQS adherence, with the greatest adherence being allocated to the third tertile and those with the lowest FQS in the first tertile. Antioxidant activity of the BM and infant urine samples was assessed using the Ferric reducing antioxidant power (FRAP), 2, 2'-diphenyl-1-picrylhydrazyl (DPPH), thiobarbituric acid reactive substances (TBARs), and Ellman's assay. The total content of BM protein, calcium, and triglyceride was measured using standard biochemical kits. RESULTS: BM from mothers from the third tertile of FQS contained significantly higher DPPH, thiol, calcium, and protein levels compared to BM from those in the lowest tertile (p˂0.05). Infant urinary DPPH and FRAP was also significantly higher in the highest tertile vs. the lowest tertile (p˂0.05). CONCLUSION: High maternal adherence to the FQS was associated with a high BM quality and antioxidant content of infant urine.

Maternal Adherence to a Dietary Approaches to Stop Hypertension (DASH) Dietary Pattern and the Relationship to Breast Milk Nutrient Content.

BACKGROUND: Maternal lifestyle factors, such as diet and nutritional status are likely to affect the composition of breast milk (BM). This study aimed to investigate the association between adherence to a Dietary Approaches to Stop Hypertension (DASH) dietary pattern (DP) and BM nutrient content. METHOD: A total of 700 milk samples were obtained from 350 lactating women. The dietary intakes of the women in the study were estimated using a validated food frequency questionnaire, which included 65 food items. The total antioxidant activity (TAC) of BM samples was evaluated using the Ferric reducing antioxidant power (FRAP), 2,2'-diphenyl-1-picrylhydrazyl (DPPH), thiobarbituric acid reactive substances (TBARS), and Ellman's assay. Also using commercially available kits, the total protein, calcium, and triglyceride contents in milk were determined. RESULTS: Individuals in the 3rd tertile of adherence to the DASH diet (highest adherence) consumed more dietary fiber, fruits, vegetables, nuts, legumes, and seeds, low-fat dairy, whole grain, less red and processed meat, sweetened beverages, and sodium than those in the first tertile (lowest adherence). Subjects in the 3rd tertile of DASH DP had higher values of milk DPPH and calcium compared to those in the first tertile (P < 0.05). Milk MDA and triglyceride were significantly lower in the 3rd tertile of DASH diet versus the first tertile (P < 0.05). CONCLUSION: Our study showed that high adherence to the DASH DP was associated with higher BM DPPH and calcium levels and lower amounts of BM MDA and triglyceride. The adherence to the healthy DPs such as the DASH can improve the quality of BM in lactating women.

Inflammatory Biomarkers for Cardiovascular Risk Stratification in Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is a frequent autosomal genetic disease characterized by elevated concentrations of low-density lipoprotein cholesterol (LDL) from birth with increased risk of premature atherosclerotic complications. Accumulating evidence has shown enhanced inflammation in patients with FH. In vessels, the deposition of modified cholesterol lipoproteins triggers local inflammation. Then, inflammation facilitates fatty streak formation by activating the endothelium to produce chemokines and adhesion molecules. This process eventually results in the uptake of vascular oxidized LDL (OxLDL) by scavenger receptors in monocyte-derived macrophages and formation of foam cells. Further leukocyte recruitment into the sub-endothelial space leads to plaque progression and activation of smooth muscle cells proliferation. Several inflammatory biomarkers have been reported in this setting which can be directly synthetized by activated inflammatory/vascular cells or can be indirectly produced by organs other than vessels, e.g., liver. Of note, inflammation is boosted in FH patients. Inflammatory biomarkers might improve the risk stratification for coronary heart disease and predict atherosclerotic events in FH patients. This review aims at summarizing the current knowledge about the role of inflammation in FH and the potential application of inflammatory biomarkers for cardiovascular risk estimation in these patients.

Review on the Therapeutic Potential of Curcumin and its Derivatives on Glioma Biology.

Gliomas are common and aggressive brain tumors that carry a poor prognosis. The current multimodal therapeutic option for glioma includes surgery subsequently temozolomide chemotherapy and/or radiation; but gliomas are often associated with multidrug resistance, intensive adverse events, and tumor relapse. Thus, novel interventions that can enhance successful chemo-prevention and overcome therapeutic resistance are urgently needed. Phytochemicals have several biological properties with multi-target sites and relatively limited degrees of toxicity. Curcumin is a natural polyphenolic compound with several anti-tumor effects which potentially inhibit tumor growth, development, proliferation, invasion, dissemination, and angiogenesis in different human malignancies. Experimental model studies have demonstrated that curcumin attenuates glioma cell viability by G2/M cell cycle arrest, apoptosis, induction of autophagy, gene expression alteration, and disruption of multi-molecular pathways. Moreover, curcumin has been reported to re-sensitize cancer to chemotherapeutics as well as augment the effect of radiotherapy on glioma cells. In this review, we have provided an update on the in vitro and in vivo effects of curcumin-based therapy on gliomas. We have also discussed the use of curcumin in combination therapies, its effectiveness on drug-resistant cells, and new formulations of curcumin in the treatment of gliomas.

Molecular Targets of Curcumin and Its Therapeutic Potential for Ovarian Cancer.

Ovarian cancer is the fifth most common gynecological cancer in women globally. Conventional chemotherapy is the first therapeutic approach in the treatment of ovarian cancer, but its success is limited by severe side effects, transient response, and the high prevalence of relapse. Curcumin is a natural product found in the rhizome extract of Curcuma longa and has been extensively used over the last decades for its unique biological and medicinal properties, which include: having antioxidant, analgesic, anti-inflammation, and anti-tumor activities. Curcumin exerts its anticancer properties against ovarian cancer via multiple mechanisms: interfering with cellular interactions necessary for metastasis and recurrence of OC cells, increasing pro-apoptotic proteins as well as inducing or suppressing generation of different molecules such as cytokines, transcription factors, enzymes, protein kinases, and growth factors. Moreover, curcumin down-regulates various signaling pathways such as PI3K/Akt, Wnt/ß-catenin, JAK/STAT3, and MEK/ERK1/2 axes, which at least in part have a role in inhibiting further tumor proliferation, growth, and angiogenesis. In this review, we overview the potential of incorporating curcumin into the treatment of ovarian cancer. In particular, we summarize the preclinical evidence supporting its use in combination with current chemotherapeutic regimens as well as new analogues and formulations under investigation.

Thymol has anticancer effects in U-87 human malignant glioblastoma cells.

BACKGROUND: Thymol (2-isopropyl-5-methylphenol) is a colorless crystalline derivative of cymene, that possesses pleotropic pharmacological properties, including analgesic, antibacterial, antispasmodic, and anti-inflammatory activities. Thymol has also been recognized for its beneficial effect as an anti-tumor agent, but the precise mechanism for this has not been fully elucidated. We aimed to identifying whether thymol exerts anti-cancer activity in human U-87 malignant glioblastoma (GB) cells (U-87). METHODS AND RESULTS: Cell viability and apoptosis was evaluated in U-87 cells treated with thymol at different concentrations. Reactive oxygen species (ROS) production, mRNA expressions of apoptosis-related genes and cell cycle characteristics were assessed. The cytotoxic activity of the co-exposure of thymol and temozolomide (TMZ) was also evaluated. The half-maximal inhibitory concentration (IC50) of thymol in the U-87 cells was 230 µM assessed at 24 h after exposure. Thymol did not exhibit any cytotoxic effects on normal L929 cells at this concentration. Thymol treatment increased the expression of Bax and p53, and also increased apoptotic cell death, and excessive generation of ROS. Moreover, the cytotoxic activity of thymol on the U-87 cells may be related to the arrest of the cell cycle at the G0/G1 interface. Combination therapy showed that the cytotoxic effects of thymol synergized with TMZ, and combined treatment had more cytotoxic potential compared to either of the agents alone. CONCLUSIONS: Our data indicate the potential cytotoxic activities of thymol on U-87 cells. Further studies are required to evaluate the spectrum of the antitumor activity of thymol on GB cells.

Effect of Curcumin and Its Derivates on Gastric Cancer: Molecular Mechanisms.

Gastric carcinoma is one of the most prevalent malignancies and is associated with a high mortality. Chemotherapy is the principal therapeutic option in the treatment of gastric cancer, but its success rate is restricted by severe side effects and the prevalence of chemo-resistance. Curcumin is a polyphenolic compound derived from turmeric that has potent antioxidant, anti-inflammatory and anti-tumor effects. There is accumulating evidence that curcumin may prevent gastric cancer through regulation of oncogenic pathways. Furthermore some curcumin analogues and novel formulation of curcumin appear to have anti-tumor activity. The aim of this review was to give an overview of the therapeutic potential of curcumin and its derivatives against gastric cancer in preclinical and clinical studies.

A study of the association of cognitive abilities and emotional function with allergic disorders in young women.

BACKGROUND: Allergic disorders may have a bidirectional causal relationship with mental disorders. In this cross-sectional study, we aimed to assess the associations between cognitive abilities and emotional function tests and quality of life with the presence of allergic disease in young women. METHODS: A diagnosis of allergic disorders, comprising allergic rhinitis (AR), asthma and atopic dermatitis (AD), was confirmed by a specialist in allergy. The presence and severity of depression, anxiety, stress, insomnia and sleepiness were evaluated using validated questionnaires. Cognitive abilities and quality of life were assessed using standard instruments. RESULTS: Among 181 female young participants, the prevalence of AR, asthma and AD were 26.5%, 2.8%, and 14.9% respectively. The AR group had higher scores than the non-AR group for depression, anxiety, insomnia, and lower scores for physical and mental health-related quality of life. Moreover, the AD cases had higher scores on the depression and stress scale compared to those without it (p < 0.05). Asthmatic patients also had significantly higher insomnia severity and lower physical health-related quality of life than non-asthmatic. CONCLUSION: There was a high prevalence of psychological/psychiatric disorders that included: anxiety, and sleep problems among allergic women, and a reduced quality of life that may be associated with it.

Evaluation of the knowledge regarding vitamin D, and sunscreen use of female adolescents in Iran.

BACKGROUND: Vitamin D (Vit D) deficiency/insufficiency is an important risk factor for several chronic conditions. We aimed to evaluate the knowledge and behavior of female adolescents with respect to the association between sunlight exposure, sunscreen use, and Vit D status. METHODS: This cross-sectional survey was performed in northeastern Iran, among 940 female adolescents in January 2015. Each subject completed a questionnaire containing items about demographic characteristics, knowledge about Vit D and their use of sunscreen. Serum Vit D levels were measured using an electrochemiluminescence method and dietary intake of Vit D was assessed using a Food Frequency Questionnaire. Statistical analyses were conducted using SPSS software. A P value < 0.05 was considered statistically significant. RESULTS: Few of the participants were aware of the biological functions of Vit D (8.8%), the causes of Vit D deficiency (16.7%), and the sources of Vit D (9.3%). Less than half of the participants used sunscreen during the day. The serum levels of Vit D in subjects who used sunscreen were significantly lower than those who did not (p = 0.004). However, there was no significant association between their knowledge about Vit D and serum Vit D, or dietary intake of Vit D. CONCLUSION: There appears to be a lack of coherence between lifestyle, behavior and knowledge that may affect the Vit D status of adolescent girls in northeastern Iran. This information provides a basis for developing public health planning (workshops or training at the college level) for the prevention of Vit D deficiency especially in adolescent girls.

Effects of curcumin on menstrual pattern, premenstrual syndrome, and dysmenorrhea: A triple-blind, placebo-controlled clinical trial.

Premenstrual syndrome (PMS) and primary dysmenorrhea are common complaints among young women. This study evaluated the effects of curcumin supplements on symptoms of pain in young women with PMS and dysmenorrhea. A randomized, triple-blinded, placebo-controlled clinical trial was undertaken. Women who suffered from both PMS and dysmenorrhea were enrolled, and were randomly allocated to the curcumin (n = 62), or placebo (n = 62) groups. Each subject received one capsule (500 mg of curcuminoid, or placebo) daily, from 7 days pre- until 3 days post-menstruation for three successive menstrual cycles. Participants recorded the severity of PMS, or dysmenorrhea using a Premenstrual Syndrome Screening Tool (PSST) and the visual analog scale, respectively. Baseline characteristics of participants did not differ between the curcumin and placebo groups. At the end of the trial, the PSST scores were significantly lower in both the curcumin (32.5 ± 9.8 vs. 21.6 ± 9.8); and placebo groups (31.7 ± 9.4 vs. 23.4 ± 12.8). There was a significant reduction of dysmenorrhea pain in both the curcumin and placebo groups (by 64% and 53.3%, respectively). Hence, curcumin had comparable effects as placebo, regarding the amelioration of symptoms of PMS and dysmenorrhea. Further studies are required with larger samples, using higher doses curcumin for longer durations, and perhaps in combination therapy.

Impact of a Nordic diet on psychological function in young students.

BACKGROUND: There has been a rapid increase in the prevalence of psychiatric and psychological disease, and this has attracted interest in identifying modifiable lifestyle factors that may affect an individual's mood. Diet is one potential lifestyle factor that may affect psychological function. AIM: This study aimed to investigate the relationship between adherence to the health-promoting Nordic diet (ND) with neuropsychological function in young women. METHODS: The study comprised 181 female students aged between 18 and 25 years. Psychological function was evaluated using a series of standardized questionnaires, including the Cognitive Ability Questionnaire, Depression Anxiety Stress Scale, Insomnia Severity Index, Epworth Sleep Scale and Quality of Life Questionnaire. A validated food frequency questionnaire, which included 65 types of foods, was used to evaluate the amount of different foods consumed. RESULTS: Evaluation of the dietary composition of the participants showed that the rate of adherence to the ND was positively associated with total energy, carbohydrates, protein, fibre, iron, magnesium, potassium, zinc, folate, phosphorus, vitamin C, thiamine, riboflavin, niacin, vitamins B6 and B12, carotene, whole grain, legumes, cabbage/vegetables, vegetables and fruit (p<0.05). Linear regression showed cabbage/vegetable consumption was inversely related to scores of stress (ß=-0.04; p=0.038) and anxiety (ß=-0.02; p=0.049) and directly associated with the quality-of-life score (0.02; p=0.036). CONCLUSIONS: Adherence to a ND with a high intake of cabbage/vegetables was inversely associated with stress and anxiety scores and directly associated with health-related quality of life.

The Prognostic Value of Small Noncoding microRNA-21 Expression in the Survival of Cancer Patients: A Meta-Analysis.

microRNA-21 (miR-21) is a small noncoding RNA that regulates gene expression in different types of human malignancies. The potential prognostic value of miR-21 in cancer progression is controversial. This meta-analysis includes 76 studies of 10,213 cancer patients to test miR-21 prognostic value in various human cancers. We obtain hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for overall survival (OS) to assess association strength. In the pooled analysis, high miR-21 expression is associated with poor OS, with a combined HR of 1.59 (95% CI, 1.49-1.70; p < 0.001; random-effects model). Furthermore, subgroup analysis demonstrates that high miR-21 expression is related to shorter OS in patients with digestive system cancers (HR = 1.02; 95% CI, 1.002 to 1.04; p = 0.026), respiratory system cancers (HR = 1.93; 95% CI, 1.48 to 2.51; p < 0.001), and breast cancer (HR = 2.20; 95% CI, 1.78 to 2.73; p = 0.001). These results indicate that miR-21 may be a clinically useful prognostic biomarker for cancer progression.

Clinical Association between Phospho-AKT Expression with Clinicopathological Characteristics of Gastrointestinal Cancer Patients: A Meta-Analysis.

Deregulation of AKT (protein kinase B) is frequently observed in human malignancies including gastrointestinal (GI) cancers. Here we have reviewed the association between AKT phosphorylation (activation) and clinical and pathological characteristics of patients with GI cancer. Articles in the EMBASE, PubMed, Cochrane Library, and Web of Science databases were searched up to July 2018. Eighteen studies comprising 1,698 patients with 5 different cancer types were included in the meta-analysis. In the pooled analysis, AKT phosphorylation was positively correlated with tumor size (r = 0.14, 95% CI: 0.06-0.22; P < 0.001), tumor grade (r = 0.08, 95% CI: 0.02-0.14; P < 0.009), tumor stage (r = 0.19, 95% CI: 0.13-0.24; P < 0.001), lymph node status (r = 0.18, 95% CI: 0.09-0.25; P < 0.001) and the presence of distant metastasis (r = 0.14, 95% CI: 0.06-0.22; P < 0.001) in the patients with GI cancer. These findings support the potential clinical value of AKT as a prognostic marker and therapeutic target in patients with GI carcinomas.

The first report of two homozygous sequence variants in FKRP and SELENON genes associated with syndromic congenital muscular dystrophy in Iran: Further expansion of the clinical phenotypes.

BACKGROUND: Congenital muscular dystrophy (CMD) refers to hypotonia and delayed motor development that is manifested at or near the birth. Additional presentations have been observed in CMD syndromes. METHODS: Thorough clinical examinations were performed on two unrelated Iranian families with typical symptoms of CMD and uncommon features such as intellectual disability and nephrolithiasis. The genomic DNA of probands were subjected to whole exome sequencing. Following the detection of candidate variants with a bioinformatic pipeline, the familial co-segregation analysis was carried out using polymerase chain reaction-based Sanger sequencing. RESULTS: We identified a missense homozygous variant in the fukutin-related protein (FKRP) gene (c.968G>A, p.Arg323His) related to CMD-dystroglycanopathy type B5 (MDDGB5) and a frameshift homozygous variant in the selenoprotein N (SELENON) gene (c.1446delC, p.Asn483Thrfs*11) associated with congenital rigid-spine muscular dystrophy 1 (RSMD1), which were completely segregated with the phenotypes in the families. These variants were not found in either the 1000 Genomes Project or the Exome Aggregation Consortium. The present study provides the first report of these homozygous sequence variants in Iran. Moreover, our study was the first observation of nephrolithiasis in FKRP-related dystroglycanopathy and intellectual disability in SELENON-related myopathies. Based on in silico studies and molecular docking, these variations induced pathogenic effects on the proteins. CONCLUSIONS: Our findings extend the genetic database of Iranian patients with CMD and, in general, the phenotypical spectrum of syndromic CMD. It is recommended to consider these variants for a more accurate clinical interpretation, prenatal diagnosis and genetic counseling in families with a history of CMD, especially in those combined with cognitive impairments or renal dysfunctions.

Current status and perspectives regarding the association between allergic disorders and cancer.

While activation of immune system may lead to a lower risk of some diseases, it has been shown that a history of atopic allergic disorders such as asthma, hay fever, eczema, and food allergies could be related to several types of cancer. However, the evidence is not entirely conclusive. Two proposals suggest a possible mechanism for the association between allergic disorders and cancers: immune surveillance and the antigenic stimulation. The association of allergy and cancer may vary by cancer site and the type of exposure. The aim of current review was to summarize the current knowledge of the association between allergic diseases and the risk of cancers with particular emphasis on case-controls and cohort studies to estimate the cancer risk associated with allergy.

Association between dietary inflammatory index and risk of cardiovascular disease in the Mashhad stroke and heart atherosclerotic disorder study population.

The dietary inflammatory index (DII) is a novel way of describing diet that has been studied in relation to various health conditions, including cardiovascular disease (CVD) in several populations. We aimed to investigate the association between DII and CVD events among a representative population sample in northeastern Iran. This prospective cohort study was a subsample of 4,672 adults aged 35-65 years, and recruited as part of Mashhad stroke and heart atherosclerotic disorder cohort study population. The DII was computed at baseline according to a 65-item validated food frequency questionnaire. Cox regression was used to determine the association of DII with incident CVD. One hundred twenty-four participants developed CVD (including 24 cases of myocardial infarction [MI], 34 cases of stable angina [SA], and 66 cases of unstable angina [UA]). After adjusting for potential confounding factors, a hazard ratios of 1.06 (95% confidence interval: 0.70-1.60), 1.36 (95% confidence interval: 0.52-3.52), 1.33 (95% confidence interval: 0.60-2.94), and 0.86 (95% confidence interval: 0.48-1.53) were found for total CVD, MI, SA, and UA events, respectively, among the participants with proinflammatory diet (DII ≥ 0) versus those with anti-inflammatory diet (DII < 0). There was no statistically significant association between the DII and total CVD, MI, SA, or UA in this population of middle-aged Iranian men and women.

A novel homozygous variant in an Iranian pedigree with cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 4.

BACKGROUND: Cerebellar ataxia, mental retardation, and dysequilibrium (CAMRQ) syndrome is a rare and early-onset neurodevelopmental disorder. Four subtypes of this syndrome have been identified, which are clinically and genetically different. To date, altogether 32 patients have been described with ATP8A2 mutations and phenotypic features assigned to CAMRQ type 4. Herein, three additional patients in an Iranian consanguineous family with non-progressive cerebellar ataxia, severe hypotonia, intellectual disability, dysarthria, and cerebellar atrophy have been identified. METHODS: Following the thorough clinical examination, consecutive detections including chromosome karyotyping, chromosomal microarray analysis, and whole exome sequencing (WES) were performed on the proband. The sequence variants derived from WES interpreted by a standard bioinformatics pipeline. Pathogenicity assessment of candidate variant was done by in silico analysis. The familial cosegregation of the WES finding was carried out by PCR-based Sanger sequencing. RESULTS: A novel homozygous missense variant (c.1339G > A, p.Gly447Arg) in the ATP8A2 gene was identified and completely segregated with the phenotype in the family. In silico analysis and structural modeling revealed that the p.G477R substitution is deleterious and induced undesired effects on the protein stability and residue distribution in the ligand-binding pocket. The novel sequence variant occurred within an extremely conserved subregion of the ATP-binding domain. CONCLUSION: Our findings expand the spectrum of ATP8A2 mutations and confirm the reported genotype-phenotype correlation. These results could improve genetic counseling and prenatal diagnosis in families with clinical presentations related to CAMRQ4 syndrome.