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BACKGROUND AND OBJECTIVE: Autosomal recessive genetic disorders pose significant health challenges in regions where consanguineous marriages are prevalent. The utilization of exome sequencing as a frequently employed methodology has enabled a clear delineation of diagnostic efficacy and mode of inheritance within multiplex consanguineous families. However, these aspects remain less elucidated within simplex families. METHODS: In this study involving 12 unrelated simplex Iranian families presenting syndromic autism, we conducted singleton exome sequencing. The identified genetic variants were validated using Sanger sequencing, and for the missense variants in FOXG1 and DMD, 3D protein structure modeling was carried out to substantiate their pathogenicity. To examine the expression patterns of the candidate genes in the fetal brain, adult brain, and muscle, RT-qPCR was employed. RESULTS: In four families, we detected an autosomal dominant gene (FOXG1), an autosomal recessive gene (CHKB), and two X-linked autism genes (IQSEC2 and DMD), indicating diverse inheritance patterns. In the remaining eight families, we were unable to identify any disease-associated genes. As a result, our variant detection rate stood at 33.3% (4/12), surpassing rates reported in similar studies of smaller cohorts. Among the four newly identified coding variants, three are de novo (heterozygous variant p.Trp546Ter in IQSEC2, heterozygous variant p.Ala188Glu in FOXG1, and hemizygous variant p.Leu211Met in DMD), while the homozygous variant p.Glu128Ter in CHKB was inherited from both healthy heterozygous parents. 3D protein structure modeling was carried out for the missense variants in FOXG1 and DMD, which predicted steric hindrance and spatial inhibition, respectively, supporting the pathogenicity of these human mutants. Additionally, the nonsense variant in CHKB is anticipated to influence its dimerization - crucial for choline kinase function - and the nonsense variant in IQSEC2 is predicted to eliminate three functional domains. Consequently, these distinct variants found in four unrelated individuals with autism are likely indicative of loss-of-function mutations. CONCLUSIONS: In our two syndromic autism families, we discovered variants in two muscular dystrophy genes, DMD and CHKB. Given that DMD and CHKB are recognized for their participation in the non-cognitive manifestations of muscular dystrophy, it indicates that some genes transcend the boundary of apparently unrelated clinical categories, thereby establishing a novel connection between ASD and muscular dystrophy. Our findings also shed light on the complex inheritance patterns observed in Iranian consanguineous simplex families and emphasize the connection between autism spectrum disorder and muscular dystrophy. This underscores a likely genetic convergence between neurodevelopmental and neuromuscular disorders.
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Consanguinidade , Sequenciamento do Exoma , Linhagem , Humanos , Irã (Geográfico) , Masculino , Feminino , Transtorno Autístico/genética , Criança , Fatores de Transcrição Forkhead/genética , Proteínas do Tecido Nervoso/genética , Adulto , Síndrome , Exoma/genética , Pré-EscolarRESUMO
Aim: We aim to investigate the relationship between hsa_circ_0009361 plus hsa_circ_0009362 expression levels and the clinicopathological features of colorectal cancer (CRC) patients. Background: Circular RNAs (circRNAs) are implicated in the progression and development of CRC. CircRNAs have been recognized as diagnostic and prognostic biomarkers, opening up a new window to comprehend the molecular basis of CRC. Given the significance of circRNAs and the G protein subunit b1 (GNB1) gene in malignancies, the goal of the current investigation was to determine the expression levels of GNB1 derivative circular RNAs circGNB1 (hsa_circ_0009361 and hsa_circ_0009362) in CRC and adjacent control tissues. Methods: The expression levels of the GNB1 derivative circular RNAs (hsa_circ_0009361 and hsa_circ_0009362) were evaluated using the quantitative real-time PCR (qRT-PCR) method in 45 CRC tissues and adjacent control tissues. Furthermore, we analyzed the diagnostic power of the mentioned circRNAs by plotting the receiver operating characteristic (ROC) curve. The association between the expression levels of hsa_circ_0009361 and hsa_circ_0009362 was evaluated using correlation analysis. Results: Our results revealed that the expression levels of hsa_circ_0009361 and hsa_circ_0009362 were significantly down-regulated in CRC tissues compared to the adjacent control group. Analysis of patients' clinicopathological features indicated that expressions of hsa_circ_0009361 and hsa_circ_0009362 were differently related to lymph vascular invasion (P<0.001). ROC curve results showed that these circRNAs are good candidate diagnostic biomarkers in CRCs. Pearson's correlation test revealed a positive correlation between hsa_circ_0009361 and hsa_circ_0009362 expression levels (P<0.0001). Conclusion: These results demonstrated that hsa_circ_0009361 and hsa_circ_0009362 expression levels may be used as possible diagnostic biomarkers for CRC.
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AIM: The purpose of this study is to evaluate the oral probiotic effect on pregnancy outcomes in pregnant women undergoing cerclage compared to placebo. METHODS: This study was a double-blind randomized clinical trial undertaken in Yasuj, Iran. 114 eligible participants who have undergone cerclage were randomly divided to either receive probiotic adjuvant or 17α-OHP (250 mg, IM) with placebo from the 16th -37th week of pregnancy by "block" randomization method. Our primary outcomes were preterm labor (PTB) (late and early) and secondary outcomes were other obstetrical and neonatal outcomes included preterm pre-labor rupture of membranes (PPROM), pre-labor rupture of membranes (PROM), mode of delivery, and neonatal outcomes including anthropometric characterize and Apgar score (one and fifth-minute). RESULTS: Results show that there are no statistically significant differences between the two groups in terms of PTB in < 34th (15.51% vs. 17.86%; P = 0.73) and 34-37th weeks of pregnancy (8.7% vs. 16.1%; P = 0.22), and mode of delivery (P = 0.09). PPROM (8.7% vs. 28.5%; P = 0.006) PROM (10.3% vs. 25%; P = 0.04) was significantly lower in patients receiving probiotic adjuvant compared to the control group. After delivery, the findings of the present study showed that there were no significant differences in newborn's weight (3082.46 ± 521.8vs. 2983.89 ± 623.89), head circumstance (36.86 ± 1.53vs. 36.574 ± 1.52), height (45.4 ± 5.34 vs. 47.33 ± 4.92) and Apgar score in one (0.89 ± 0.03 vs. 0.88 ± 0.05) and five minutes (0.99 ± 0.03vs. 0.99 ± 0.03) after birth. CONCLUSION: Our result has shown that the consumption of Lactofem probiotic from the 16th week until 37th of pregnancy can lead to a reduction of complications such as PPROM and PROM.
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Cerclagem Cervical , Resultado da Gravidez , Probióticos , Humanos , Gravidez , Feminino , Probióticos/uso terapêutico , Probióticos/administração & dosagem , Método Duplo-Cego , Adulto , Irã (Geográfico) , Cerclagem Cervical/métodos , Recém-Nascido , Ruptura Prematura de Membranas Fetais , Adulto Jovem , Nascimento Prematuro/prevenção & controle , Trabalho de Parto Prematuro/prevenção & controle , Administração OralRESUMO
Elexacaftor, tezacaftor, ivacaftor (ETI) is a CFTR modulator combination approved for use in â¼90 % of people with cystic fibrosis (pwCF) over 2 years old. While most pwCF tolerate this therapy well, some are intolerant to standard dosing, and others show little response. Clinical providers may adjust ETI dosing to combat these issues, but these adjustments are not well guided by pharmacokinetic evidence. Our post-approval study aimed to describe pharmacokinetic variability of ETI plasma concentrations in 15 participants who were administered a standard or reduced dose. ETI were quantified by LC-MS/MS in plasma samples taken prior to the morning dose. Results showed non-significant differences for each compound regardless of dosing regimen and after dose equivalence normalization. The majority of participants in both dosing groups had concentrations expected to elicit clinical response to ETI therapy. These findings indicate that dose reduction may be a viable strategy to maintain clinical benefit while managing intolerance.
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BACKGROUND: New York State (NYS) utilizes a three-tiered cystic fibrosis newborn screening (CFNBS) algorithm that includes cystic fibrosis transmembrane conductance regulator (CFTR) gene sequencing. Infants with >1 CFTR variant of potential clinical relevance, including variants of uncertain significance or varying clinical consequence are referred for diagnostic evaluation at NYS cystic fibrosis (CF) Specialty Care Centers (SCCs). AIMS: As part of ongoing quality improvement efforts, demographic, screening, diagnostic, and clinical data were evaluated for 289 CFNBS-positive infants identified in NYS between December 2017 and November 2020 who did not meet diagnostic criteria for CF and were classified as either: CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID) or CF carriers. RESULTS: Overall, 194/289 (67.1%) had CFTR phasing to confirm whether the infant's CFTR variants were in cis or in trans. Eighteen complex alleles were identified in cis; known haplotypes (p.R117H+5T, p.F508del+p.L467F, and p.R74W+p.D1270N) were the most common identified. Thirty-two infants (16.5%) with all variants in cis were reclassified as CF carriers rather than CRMS/CFSPID. Among 263 infants evaluated at an NYS SCC, 70.3% were reported as having received genetic counseling about their results by any provider, with 96/263 (36.5%) counseled by a certified genetic counselor. CONCLUSION: Given the particularly complex genetic interpretation of results generated by CFNBS algorithms including sequencing analysis, additional efforts are needed to ensure families of infants with a positive CFNBS result have CFTR phasing when needed to distinguish carriers from infants with CRMS/CFSPID, and access to genetic counseling to address implications of CFNBS results.
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Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Aconselhamento Genético , Genótipo , Triagem Neonatal , Pais , Humanos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , New York , Fibrose Cística/genética , Recém-Nascido , Masculino , Feminino , Triagem Neonatal/métodos , Fenótipo , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , LactenteRESUMO
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.
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Síndrome Congênita de Insuficiência da Medula Óssea , Humanos , Recém-Nascido , New York , Seguimentos , Feminino , MasculinoRESUMO
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.
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BACKGROUND: The ultra-rare autosomal recessive genetic disorder, You-Hoover-Fong Syndrome (YHFS), is caused by defects in the TELO2 gene and is characterized by intellectual disability, developmental delay, and ocular impairments. This study aims to contribute to a better understanding of YHFS by reviewing previous cases and introducing a novel variant in a new case. METHODS: Whole exome sequencing (WES) was conducted on the proband to identify genetic variants, and Sanger sequencing was used to confirm variants within the family. This article presents a comprehensive collection of reported cases of YHFS, incorporating both molecular and clinical data, through an extensive literature search and analysis of English-language studies published until June 2023. RESULTS: Using WES, a novel homozygous missense variant, c.1799A > G (p. Tyr600Cys), was identified in the TELO2 gene in a 4-year-old Iranian male patient. Novel clinical features, including choanal atresia and clubfoot, were also identified. A comprehensive literature review identified 27 patients with YHFS, with 20 variants in the TELO2 gene. Missense pathogenic variants were the most common type of pathogenic variant, and the most common features were microcephaly and intellectual impairment. CONCLUSION: This study presents the first case of pathogenic variants in TELO2 gene in Iran, expands the genotypic and phenotypic spectrum of YHFS and contributes to the growing body of literature pertaining to YHFS. Furthermore, our findings highlight the importance of genetic testing for non-consanguineous carrier screening, as compound heterozygosity may be a significant factor in the development of YHFS. Further research is needed to clarify the molecular mechanisms underlying YHFS pathogenesis.
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Deficiência Intelectual , Fenótipo , Humanos , Masculino , Irã (Geográfico) , Deficiência Intelectual/genética , Pré-Escolar , Mutação de Sentido Incorreto , Deficiências do Desenvolvimento/genética , Genótipo , Sequenciamento do Exoma , Microcefalia/genética , FemininoRESUMO
BACKGROUND: Pontocerebellar hypoplasia is an umbrella term describing a heterogeneous group of prenatal neurodegenerative disorders mostly affecting the pons and cerebellum, with 17 types associated with 25 genes. However, some types of PCH lack sufficient information, which highlights the importance of investigating and introducing more cases to further elucidate the clinical, radiological, and biochemical features of these disorders. The aim of this study is to provide an in-depth review of PCH and to identify disease genes and their inheritance patterns in 12 distinct Iranian families with clinically confirmed PCH. METHODS: Cases included in this study were selected based on their phenotypic and genetic information available at the Center for Comprehensive Genetic Services. Whole-exome sequencing (WES) was used to discover the underlying genetic etiology of participants' problems, and Sanger sequencing was utilized to confirm any suspected alterations. We also conducted a comprehensive molecular literature review to outline the genetic features of the various subtypes of PCH. RESULTS: This study classified and described the underlying etiology of PCH into three categories based on the genes involved. Twelve patients also were included, eleven of whom were from consanguineous parents. Ten different variations in 8 genes were found, all of which related to different types of PCH. Six novel variations were reported, including SEPSECS, TSEN2, TSEN54, AMPD2, TOE1, and CLP1. Almost all patients presented with developmental delay, hypotonia, seizure, and microcephaly being common features. Strabismus and elevation in lactate levels in MR spectroscopy were novel phenotypes for the first time in PCH types 7 and 9. CONCLUSIONS: This study merges previously documented phenotypes and genotypes with unique novel ones. Due to the diversity in PCH, we provided guidance for detecting and diagnosing these heterogeneous groups of disorders. Moreover, since certain critical conditions, such as spinal muscular atrophy, can be a differential diagnosis, providing cases with novel variations and clinical findings could further expand the genetic and clinical spectrum of these diseases and help in better diagnosis. Therefore, six novel genetic variants and novel clinical and paraclinical findings have been reported for the first time. Further studies are needed to elucidate the underlying mechanisms and potential therapeutic targets for PCH.
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Doenças Cerebelares , Proteínas Nucleares , Feminino , Gravidez , Humanos , Irã (Geográfico) , Genótipo , Fenótipo , MutaçãoRESUMO
This review article presents an in-depth analysis of the current state of research on receptor tyrosine kinase regulatory non-coding RNAs (RTK-RNAs) in solid tumors. RTK-RNAs belong to a class of non-coding RNAs (nc-RNAs) responsible for regulating the expression and activity of receptor tyrosine kinases (RTKs), which play a critical role in cancer development and progression. The article explores the molecular mechanisms through which RTK-RNAs modulate RTK signaling pathways and highlights recent advancements in the field. This include the identification of potential new RTK-RNAs and development of therapeutic strategies targeting RTK-RNAs. While the review discusses promising results from a variety of studies, encompassing in vitro, in vivo, and clinical investigations, it is important to acknowledge the challenges and limitations associated with targeting RTK-RNAs for therapeutic applications. Further studies involving various cancer cell lines, animal models, and ultimately, patients are necessary to validate the efficacy of targeting RTK-RNAs. The specificity of ncRNAs in targeting cellular pathways grants them tremendous potential, but careful consideration is required to minimize off-target effects, the article additionally discusses the potential clinical applications of RTK-RNAs as biomarkers for cancer diagnosis, prognosis, and treatment. In essence, by providing a comprehensive overview of the current understanding of RTK-RNAs in solid tumors, this review emphasizes their potential as therapeutic targets for cancer while acknowledging the associated challenges and limitations.
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BACKGROUND: Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder characterized by a range of physical, cognitive, and behavioral abnormalities. This study aimed to perform a comprehensive review of the literature on CdLS and investigate two cases of CdLS with distinct phenotypes that underwent WES to aid in their diagnosis. METHODS: We conducted a comprehensive review of the literature on CdLS along with performing whole-exome sequencing on two CdLS patients with distinct phenotypes, followed by Sanger sequencing validation and in-silico analysis. RESULTS: The first case exhibited a classic CdLS phenotype, but the initial WES analysis of blood-derived DNA failed to identify any mutations in CdLS-related genes. However, a subsequent WES analysis of skin-derived DNA revealed a novel heterozygous mutation in the NIPBL gene (NM_133433.4:c.6534_6535del, p.Met2178Ilefs*8). The second case was presented with a non-classic CdLS phenotype, and WES analysis of blood-derived DNA identified a heterozygous missense variant in the SMC1A gene (NM_006306.4:c.2320G>A, p.Asp774Asn). CONCLUSIONS: The study shows the importance of considering mosaicism in classic CdLS cases and the value of WES for identifying genetic defects. These findings contribute to our understanding of CdLS genetics and underscore the need for comprehensive genetic testing to enhance the diagnosis and management of CdLS patients.
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Proteínas de Ciclo Celular , Síndrome de Cornélia de Lange , Humanos , Proteínas de Ciclo Celular/genética , Exoma , Mutação , Fenótipo , DNA , Biópsia , Síndrome de Cornélia de Lange/genética , Síndrome de Cornélia de Lange/diagnósticoRESUMO
BACKGROUND: Approximately 5% of colorectal cancers (CRCs) are hereditary. Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common form of recognized hereditary CRC. Although Iran, as a developing country, has a high incidence of CRC, the spectrum of variants has yet to be thoroughly investigated. AIMS: This study aimed to investigate pathogenic and non-pathogenic variants in MLH1 and MSH2 genes in Iranian patients with suspected Lynch syndrome (sLS). METHODS AND RESULTS: In the present study, 25 peripheral blood samples were collected from patients with sLS and high microsatellite instability (MSI-H). After DNA extraction, all samples underwent polymerase chain reaction and Sanger sequencing to identify the variants in the exons of MLH1 and MSH2 genes. The identified variants were interpreted using prediction tools, and were finally reported under ACMG guidelines. In our study population, 13 variants were found in the MLH1 gene and 8 in the MSH2 gene. Interestingly, 7 of the 13 MLH1 variants and 3 of the 8 MSH2 variants were novel, whereas the remaining variants were previously reported or available in databases. In addition, some patients with sLS did not have variants in the exons of the MLH1 and MSH2 genes. The variants detected in the MLH1 and MSH2 genes had specific characteristics regarding the number, area of occurrence, and their relationship with demographic and clinicopathologic features. CONCLUSION: Overall, our results suggest that analysis of MLH1 and MSH2 genes alone is insufficient in the Iranian population, and more comprehensive tests are recommended for detecting LS.
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Neoplasias Colorretais Hereditárias sem Polipose , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Proteína 2 Homóloga a MutS/genética , Irã (Geográfico)/epidemiologia , Proteína 1 Homóloga a MutL/genética , Proteínas de Ligação a DNA/genética , NucleotídeosRESUMO
OBJECTIVE: To identify predictors of change in lung function and body weight during health care transition in cystic fibrosis (CF). METHODS: We conducted a retrospective cohort study using data from the CF Foundation Patient Registry and the web-based transition program CF RISE (Responsibility. Independence. Self-care. Education) for patients aged 16-25 years who transitioned to adult care from 2013 through 2019. We modeled change in forced expiratory volume in 1 second % predicted and weight using linear regression fit with generalized estimating equations. Predictors included gap in care (time between last pediatric and first adult outpatient visit), transition program engagement, and sociodemographic and medical factors. RESULTS: Among 12â420 adolescents and young adults (AYAs), 3876 transitioned to adult care with a median gap in care of 7.6 months. Patients from CF centers with greater rates of CF RISE engagement had improved lung function and weight at their first adult outpatient visit. Coverage on a parent's insurance plan and absence of CF complications predicted increased lung function. History of a nonlung transplant and sinus disease predicted increased weight. Comorbid diabetes mellitus and gaps in care >3 months predicted decreased lung function with longer gaps in care associated with greater decrease. A gap in care of 6-9 months predicted decreased weight. Control variables including baseline forced expiratory volume in 1 second and weight, and exacerbation status were also statistically significant. CONCLUSIONS: Findings suggest 2 promising targets to improve transition of AYAs with CF: increasing AYA engagement in CF RISE and reducing gaps in care during the transition period.
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Fibrose Cística , Transição para Assistência do Adulto , Adolescente , Adulto Jovem , Humanos , Criança , Fibrose Cística/complicações , Estudos Retrospectivos , Autocuidado , Volume Expiratório Forçado , Sistema de RegistrosRESUMO
Aberrant activation of Wnt pathway is linked to dysregulation of several genes. DACT1 and DACT2 are members of the DACT family that participate in antagonizing of the Wnt signaling cascade. Thus in this study, we assessed the mRNA levels of DACT1, DACT2, and CYCLIN D1 in 70 pairs of CRC tissues compared to the adjacent tissues. Determination of the mRNA levels of DACT1, DACT2, and CYCLIN D1 was done by Quantitative Real-Time PCR (qRT-PCR). The correlation between DACT1, DACT2, and CYCLIN D1 genes was also examined. Receiver operating characteristic (ROC) curves was plotted to assess the diagnostic power. The association between histopathological parameters and the DACT1, DACT2, and CYCLIN D1 genes was investigated. The expression levels of DACT1 and CYCLIN D1 were remarkably higher in CRC tissues compared to the adjacent tissues (p < 0.0001). However, the expression of DACT2 was decreased (p < 0.001). Our results showed a significant correlation between the expression of DACT1 and CYCLIN D1 (p < 0.0001). DACT1 (AUC = 0.74, p < 0.0001), DACT2 (AUC = 0.69, p < 0.0003), and CYCLIN D1 (AUC = 0.75, p < 0.0001) had good effectiveness in separation between CRC samples and adjacent tissues. We found a significant association between DACT1 expression with tumor site (p < 0.01). Also, a significant association was detected between DACT2 and CYCLIN D1 with tumor stage (p < 0.005 and p < 0.038, respectively). The findings suggested that DACT1 could function as an oncogene, whereas DACT2 was downregulated and can be considered as a tumor suppressor in CRC.
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Neoplasias Colorretais , Ciclina D1 , Humanos , Ciclina D1/genética , Ciclina D1/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Genes bcl-1 , Via de Sinalização Wnt , Neoplasias Colorretais/genética , RNA Mensageiro , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismoRESUMO
Background: Sitagliptin is an antidiabetic drug that inhibits dipeptidyl peptidase-4 enzyme. This study aimed to investigate the antinociceptive and anti-inflammatory effects of sitagliptin in formalin and carrageenan tests and determine the possible mechanism(s) of its antinociceptive activity. Methods: Male Swiss mice (25-30 g) and male Wistar rats (180-220 g) were used for formalin and carrageenan tests, respectively. In the formalin test, paw licking time and in the carrageenan test, paw thickness were considered as indexes of pain behavior and inflammation respectively. Three doses of sitagliptin (2.5, 5, and 10 mg/kg) were used in these tests. Also, several antagonists and enzyme inhibitors were used to evaluate the role of adrenergic, serotonergic, dopaminergic, and opioid receptors as well as the NO/cGMP/KATP pathway in the antinociceptive effect of sitagliptin (5 mg/kg). Results: Sitagliptin showed significant antinociceptive and anti-inflammatory effects in the formalin and carrageenan tests respectively. In the carrageenan test, all three doses of sitagliptin significantly (P < 0.001) reduced paw thickness. Pretreatment with yohimbine, prazosin, propranolol, naloxone, and cyproheptadine could not reverse the antinociceptive effect of sitagliptin (5 mg/Kg), which indicates that adrenergic, opioid, and serotonin receptors (5HT2) are not involved in the antinociceptive effects. L-NAME, methylene blue, glibenclamide, ondansetron, and sulpiride were able to reverse this effect. Conclusions: NO/cGMP/KATP, 5HT3 and D2 pathways play an important role in the antinociceptive effect of sitagliptin. Additionally significant anti-inflammatory effects observed in the carrageenan test might contribute in reduction of pain response in the second phase of the formalin test.
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INTRODUCTION: Cystic fibrosis (CF) is a systemic autosomal recessive condition characterised by progressive lung disease. CF pulmonary exacerbations (PEx) are episodes of worsening respiratory status, and frequent PEx are a risk factor for accelerated lung function decline, yet many people with CF (PwCF) go untreated at the time of decline. The goal of this quality improvement (QI) initiative was to improve recognition, treatment and follow-up of PEx in PwCF. METHODS: Using the Model for Improvement, the Cystic Fibrosis Learning Network (CFLN) initiated a QI innovation laboratory (iLab) with a global aim to decrease the rate of lung function decline in PwCF. The iLab standardised definitions for signals of PEx using a threshold for decline in forced expiratory volume in one second (FEV1) and/or changes in symptoms. The FEV1 decline signal was termed FIES (FEV1-indicated exacerbation signal). Processes for screening and recognition of FIES and/or symptom changes, a treatment algorithm and follow-up in the presence of a signal were tested concurrently in multiple settings. SPECIFIC AIMS: The specific aim is to increase the per cent of PwCF assessed for a PEx signal at ambulatory encounters and to increase the per cent of recommendations to follow-up within 6 weeks for PwCF experiencing a PEx signal. RESULTS: FIES recognition increased from 18.6% to 73.4% across all teams during the iLab, and every team showed an improvement. Of PwCF assessed, 15.8% experienced an FIES event (>10% decline in FEV1 per cent predicted (FEV1pp)). Follow-up within 6 weeks was recommended for an average of 70.5% of those assessed for FIES and had an FEV1pp decline greater than 5%. CONCLUSION: The CFLN iLab successfully defined and implemented a process to recognise and follow-up PEx signals. This process has the potential to be spread to the larger CF community. Further studies are needed to assess the impact of these processes on PwCF outcomes.
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Fibrose Cística , Humanos , Fibrose Cística/complicações , Fibrose Cística/diagnóstico , Melhoria de Qualidade , Pulmão , Volume Expiratório Forçado , Testes de Função RespiratóriaRESUMO
Background and objective: Pulmonary fibrosis (PF) is a chronic and progressive respiratory disease representing the final stage of lung inflammatory disorders. Reactive oxygen species (ROS), an essential factor in the formation and progression of pulmonary fibrosis, are a significant adverse effect of Bleomycin (BLM). Antioxidant activities have been found in Daphne oleoides. In this study, we attempted to explore the function of hydroalcoholic extract of Daphne oleoides (D. oleoides) and Betulin in inhibiting bleomycin (BLM)-induced pulmonary fibrosis in rat". Materials and methods: The current experimental study used 36 male Wistar rats (180-220). Following a random process, the animals were divided into six groups six (n = 6). Group, I (the control group) received normal saline, while Group II (the hazardous group) received intratracheal BLM (7.5 units per kg). Following the administration of BLM, Groups V and VI received daily doses of vitamin E (500 mg/kg/d, p.o.) and Betulin (10 mg kg/d, p.o.), whereas Groups III and IV received daily doses of Daphne oleoides extract (300 and 600 mg/kg/d, p.o.). Then, blood samples from the hearts of the animals were taken to assess the plasma concentrations of nitric oxide (NO) and malondialdehyde (MDA). Finally, the rats were euthanized, and the lung tissues were taken out for histological analysis and assessments of the levels of lung hydroxyproline (HP), ferric-reducing ability (FRAP), NO, Glutathione Concentration (GSH), thiol content (tSH) and MDA. Findings: Elevated lung index, lung hydroxyproline, NO, and MDA plasma levels, and a reduction in total body thiol content (tSH) in the group receiving BLM were evidence of pulmonary toxicity. Treatment with D. oleoides extracts, Betulin, and Vit E, especially at 600 mg/kg, led to a marked reduction in the above parameters compared with the BLM-received group (p < 0.01). Histological Analysis of the BLM-treated group showed a considerable Lung injury with interstitial infiltration, collapsed alveolar spaces, and alveolar septal thickening. These changes were mitigated with D. oleoides 600, Betulin-, and vitamin E. These changes were mitigated with D. oleoides 600, Betulin-, and vitamin E. Conclusion: These findings suggest that D. oleoides and Betulin prevent bleomycin-induced lung fibrosis in rats by decreasing inflammatory and antioxidant markers. Daphne oleoides, therefore, have the potential to be used therapeutically to treat pulmonary fibrosis.
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Background: FTO gene is associated with obesity, dietary intake, and the risk of colorectal cancer (CRC). In this study, patients with colorectal cancer were assessed for the interactions between FTO gene polymorphisms and dietary intake. Methods: This case-control study was carried out on 450 participants aged 35-70 years including 150 patients with colorectal cancer and 300 healthy controls. Blood samples were collected in order to extract DNA and genotyping of FTO gene for rs9939609 polymorphism. A validated 168-item food frequency questionnaire (FFQ) and the Nutritionist-IV software were used to assess dietary intake. Results: In the participants with the TT genotype of FTO rs9939609 polymorphism, CRC risk was significantly associated with higher intake of dietary fat (OR:1.87 CI95%:1.76-1.99, p = 0.04), vitamin B3 (OR:1.20 CI95%:1.08-1.65, p = 0.04), and vitamin C (OR:1.06 CI95%:1.03-1.15, p = 0.04) and lower intake of ß-carotene (OR:0.98 CI95%:0.97-0.99, p = 0.03), vitamin E (OR:0.77 CI95%:0.62-0.95, p = 0.02), vitamin B1 (OR:0.15 CI95%:0.04-0.50, p < 0.01), and biotin (OR:0.72 CI95%:0.0.57-0.92, p = 0.01). No significant association was found between CRC and dietary intake in carriers of AA/AT genotypes after adjustments for the confounders. Conclusion: CRC risk may be decreased by ß-carotene, vitamins E, B1, and biotin only in those without the risk allele of the FTO gene. The association of CRC and diet may be influenced by FTO genotype. Further studies are warranted.
RESUMO
Vanishing bile duct syndrome (VBDS) has been postulated that may be related to Hodgkin's lymphoma (HL). In the present study, we present a 75-year-old male patient with HL who received chemotherapy but has not received any radiotherapy. The patient's condition worsened in further days, and he died with the diagnosis of cirrhosis and hepatic failure.