The results obtained in the present study provide good basis for prospective randomized controlled clinical trials with respect to the use of AD-MSCs in the treatment of osteoarthritis.
Primary ciliary dyskinesia (PCD) is a rare inherited autosomal recessive or X-linked disorder that mainly affects lungs. Dysfunction of respiratory cilia causes symptoms such as chronic rhinosinusitis, coughing, rhinitis, conductive hearing loss and recurrent lung infections with bronchiectasis. It is now well known that pathogenic genetic changes lead to ciliary dysfunction. Here we report usage of clinical-exome based NGS approach in order to reveal underlying genetic causes in cohort of 21 patient with diagnosis of PCD. By detecting 18 (12 novel) potentially pathogenic genetic variants, we established the genetic cause of 11 (9 unrelated) patients. Genetic variants were detected in six PCD disease-causing genes, as well as in SPAG16 and SPAG17 genes, that were not detected in PCD patients so far, but were related to some symptoms of PCD. The most frequently mutated gene in our cohort was DNAH5 (27.77%). Identified variants were in homozygous, compound heterozygous and trans-heterozygous state. For detailed characterization of one novel homozygous genetic variant in DNAI1 gene (c. 947_948insG, p. Thr318TyrfsTer11), RT-qPCR and Western Blot analysis were performed. Molecular diagnostic approach applied in this study enables analysis of 29 PCD disease-causing and related genes. It resulted in mutation detection rate of 50% and enabled discovery of twelve novel mutations and pointed two possible novel PCD candidate genes.
Introduction: Tuberculosis (TBC) is a contagious chronic respiratory disease which despite the known cause, Mycobacterium tuberculosis (Mtb), and many decades of successful therapy, remains one of the leading global health problems. Immune responses against Mtb infection involve both of types of immunity, but cellular immunity, in which certain cytokines and Th1 cells play a key role, is crucial. A better understanding of the functions of the cytokine network involved in the state and progression of TBC could identify specific molecular markers for monitoring of disease activity as well as therapy outcomes in TBC patients. Methodology: We investigated expression of TNF-α, IL-6 and IRAK1 genes using an RT-qPCR technique in peripheral blood mononuclear cells of 33 TBC patients and 10 healthy individuals. Results: Comparison between TBC patients and healthy individuals revealed statistically significant differences for all analyzed genes. The levels of expression of TNF-α and IL-6 mRNA were higher, while the level of IRAK1 mRNA was lower in the TBC group compared to controls. Moreover, a strong positive correlation was observed between TNF-α and IL-6 gene expression. When clinical parameters were analyzed, increased levels of TNF-α mRNA were detected in patients with a longer duration of therapy (>2 months) compared to those with a shorter therapy duration (< 2 months), and in patients without anemia. Conclusions: Our results indicate that the inflammatory genes we examined play a crucial role in the pathogenesis of tuberculosis, and that the expression of the TNF-α gene could be a marker for monitoring the clinical effect of the ant-tuberculosis drugs during therapy.
Systemic sclerosis (SSc) is a rare, chronic, multisystem autoimmune disease clinically characterized by progressive fibrosis of the skin and internal organs. The basic mechanism appears to involve endothelial cell injury, overproduction of extracellular matrix proteins, and aberrant immune activation. So far, there have been a few attempts to find genetic biomarkers for monitoring disease activity or for correlation with certain symptoms. In order to reveal reliable biomarkers, we analyzed the expression of four genes representing three important signaling pathways, TLR7, TLR9, and JAK2-STAT3. Using RT-qPCR technique, we analyzed the expression of TLR7, TLR9, JAK2, and STAT3 genes in peripheral blood mononuclear cells of 50 SSc patients and 13 healthy individuals. We detected significant upregulation of TLR7 gene expression in a group of SSc patients compared to non-SSc group. Receiver operating characteristic (ROC) analysis showed that TLR7 expression efficiently discriminates SSc cases from healthy individuals. High TLR7 expression positively correlated with the late form of disease, active SSc, and the presence of digital ulcers. Decreased levels of TLR9 and JAK2 mRNA were found in the patient's cohort in comparison to non-SSc individuals, but showed no correlation with specific clinical outcomes. The expression level of the STAT3 gene did not differ between the analyzed groups. This is the first study on the expression of TLR7, TLR9, and STAT3 genes in SSc patients. Our results show that TLR7, TLR9, and JAK2 genes are potential biomarkers for SSc. The results obtained in this study could contribute to better classification, monitoring, and outcome prediction of patients with SSc based on genetics.
Background: Intracranial germinomas (ICG) are uncommon brain neoplasms with extremely rare familial occurrence. Because ICG invades the hypothalamus and/or pituitary, endocrine dysfunction is one of the common determinants of these tumours. We present two brothers with a history of ICG. Patient 1 is a 25-year-old male who suffered from weakness of the right half of his body at the age of 18 years. Cranial MRI revealed a mass lesion in the left thalamus. He underwent neurosurgery, and the tumour was removed completely. Histopathological (HP) and immunohistochemical analyses verified the diagnosis of pure germinoma. He experienced complete remission of the tumour after radiation therapy. At the age of 22 years a diagnosis of isolated growth hormone deficiency (IGHD) was established and GH replacement was initiated. Molecular genetic analysis of the tumour tissue detected the mutation within exon 2 in KRAS gene. Patient 2 is a 20-year-old man who presented with diabetes insipidus at the age of 12 years. MRI detected tumour in the third ventricle and pineal region. After endoscopic tumour biopsy the HP diagnosis was pure germinoma. He received chemotherapy followed by radiotherapy and was treated with GH during childhood. At the age of 18 years GH replacement was reintroduced. A six-month follow-up during the subsequent two years in both brothers demonstrated the IGF1 normalisation with no MRI signs of tumour recurrence. Conclusion: To the best of our knowledge, so far only six reports have been published related to familial ICG. The presented two brothers are the first report of familial ICG case outside Japan. They have been treated successfully with GH therapy in adulthood. (Endokrynol Pol 2018; 69 (5): 612-618) StreszczenieWstęp: Rozrodczaki wewnątrzczaszkowe (intracranial germinomas, ICG) to rzadkie nowotwory mózgu, a szczególnie rzadko stwierdza się ich występowanie rodzinne. W związku z tym, że ICG zajmuje podwzgórze i/lub przysadkę mózgową, zaburzenia endokrynologiczne są jednym z najczęstszych wyznaczników obecności tych guzów. W pracy przedstawiono dwóch braci z ICG. Pacjent 1 to 25-letni mężczyzna, u którego w wieku 18 lat wystąpiło osłabienie mięśni po lewej stronie ciała. Badanie metodą rezonansu magnetycznego (MRI) czaszki ujawniło masę w lewym wzgórzu. Chorego poddano zabiegowi neurochirurgicznemu, podczas którego guz został całkowicie usunięty. Badania histopatologiczne i immunohistochemiczne potwierdziły rozpoznanie czystej postaci rozrodczaka. Po radioterapii nastąpiła całkowita remisja guza. W wieku 22 lat u chorego zdiagnozowano izolowany niedobór hormonu wzrostu (isolated growth hormone deficiency, IGHD) i wdrożono terapię zastępczą hormonem wzrostu (growth hormone, GH). Genetyczna analiza molekularna tkanki guza wykazała mutację w eksonie 2 w genie KRAS. Pacjent 2 to 20-letni mężczyzna, u którego w wieku 12 lat stwierdzono moczówkę prostą. W badaniu MRI wykryto guz w okolicy trzeciej komory i szyszynki. Po ocenie histopatologicznej materiału pobranego za pomocą biopsji endoskopowej postawiono di...
Genetic predisposition to systemic sclerosis (SSc) has still not been fully revealed. Interleukin-6 (IL-6) is a mediator of T cell proliferation and fibrotic events in SSc. Polymorphisms in the IL-6 are found to be important in susceptibility to development of SSc. We aimed to assess the frequency of -174 C/G of IL-6 gene polymorphism in SSc patients and healthy controls, as well as correlation with disease manifestations. In the case-control study, 102 patients with SSc and 93 controls were included. PCR-RFLP method was performed for genotyping promotor variants -174 C/G of IL-6 gene. The expression level of IL-6 was determined by qRT-PCR on subset of 50 patients and 13 healthy controls with different IL-6 genotypes. We used UCLA GIT 2.0 questionnaire to assess gastrointestinal involvement in SSc patients. The expression level of IL-6 gene was significantly higher in patients with SSc in comparison with healthy controls (p < 0.05). Carriers of C-allele of IL-6 gene compared to those with G allele, showed higher expression of IL-6 gene (95.8 vs. 41.2, p < 0.05), higher GIT total score (0.85 vs. 0.5, p < 0.05) and higher distension scale score (1.4 ± 0.9 vs. 0.78 ± 0.8, p = 0.05). No significant differences in genotype distribution and allele frequency were observed between patients and controls. The expression of IL6 gene varies significantly during the course of SSc. The IL-6 gene variant -174 C/G (presence of C-allele) is associated with higher IL-6 gene expression and greater GIT impairment in patients with SSc.
Tuberculosis (TB) is granulomatous diseases caused by Mycobacterium tuberculosis (MTB). TB is a highly infectious disease that primarily affects the lungs. One-third of human population is infected with MTB, therefore it is of utmost significance to determine the factors that influence the individual susceptibility to the disease. Host genetic factors have been recognized as essential for susceptibility to TB, since only 5% to 10% of infected individuals develop the disease. A number of candidate genes has been intensively studied, the most of which were connected with the function of macrophages, thus participating in immune response. Here we examined the gene variants of VDR (FokI) and NRAMP1 (INT4, D543N, 3?UTR) genes in aim to make the correlation between these genetic factors and risk of TB in Serbian patients. This study included 110 TB patients and 67 healthy controls. Pulmonary TB was diagnosed by clinical symptoms, radiological evidence of TB and bacteriological criteria (Culture- positive/ smear- positive). Genotyping was performed using PCR-RFLP method. Our findings revealed significant prevalence of ff genotype and variant allele f of the FokI VDR gene variant in patients compared to control group. Based on the our results the carriers of ff genotype are five times more at risk to tuberculosis than carriers of FF and Ff genotype in our population. The results of analyzed SNPs in NRAMP1 gene showed no statistically significant difference in distribution of the gene variants between patient and control groups. Therefore, we could conclude that the genotype ff of the VDR gene is factor that strongly contribute to susceptibility to TB in Serbian population. [Projekat Ministarstva nauke Republike Srbije, br. 175046 i br. III41004]
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