Matrix Metalloproteinases 2 and 9 Polymorphism in Patients With Myeloproliferative Diseases: A STROBE-Compliant Observational Study

Chronic myeloproliferative disorders such as polycythemia vera (PV), essential thrombocytosis (ET), and idiopathic myelofibrosis arise from clonal proliferation of neoplastic stem cells in the bone marrow. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that have potential to degrade all types of extracellular matrix (ECM) and also play a role in remodeling of the ECM. It is known that MMPs play a role in bone marrow remodeling.The primary goal of our study is to explore the relationship between chronic myeloproliferative diseases and some of MMP gene polymorphisms. The demonstration of a relationship will help to understand whether these polymorphisms may be a potential early diagnosis marker of the diseases.Patients were selected from outpatient clinics of Turgut Ozal University Hospital, Ankara, Turkey, between December 2010 and May 2011. Twenty-eight patients that previously diagnosed and followed-up with PV, 17 with secondary polycythemia (SP), and 12 with ET were enrolled in the study, along with a control group of 22 healthy people.DNA was isolated from peripheral blood. Using polymerase chain reaction–restriction fragment length polymorphism method, MMP2 and MMP9 gene polymorphisms were analyzed with agarose gel electrophoresis. There was a statistically significant difference between the study groups and the control group in terms of Gln279Arg polymorphisms rates of MMP9. The highest MMP9 Gln279Arg polymorphism rate was observed in the ET group. But nobody from the control group had polymorphic MMP9. There was no statistically significant difference between the groups in terms of MMP2-735 C > T polymorphism rates.In conclusion, MMP9 gene Gln279Arg polymorphism was associated with ET, SP, and PV diseases. Hence, we believe that these gene polymorphisms may play a role in the mechanism of bone marrow fibrosis and may be a factor that increases the risk of thrombosis. Illumination of the molecular basis of the relationship between MMP-thrombosis and MMP-fibrosis provides a better understanding of the pathophysiology of PV and ET diseases and will allow new approaches to diagnosis and treatment.     

Is serum leptin level regulated by thyroid functions, lipid metabolism and insulin resistance in polycystic ovary syndrome?

Our aim was to determine whether serum leptin level is regulated by thyroid hormones, lipid metabolic products and insulin resistance status in women with polycystic ovary syndrome (PCOS). A prospective case-controlled study was carried out in Istanbul University, Cerrahpasa School of Medicine in 25 lean PCOS (L-PCOS) women, 19 obese PCOS (O-PCOS) women and 28 normal women. The diagnosis of PCOS was established according to the clinical, hormonal (elevated luteinizing hormone and serum androgens) and ultrasonographic findings. Fasting serum levels of thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), fasting glucose, insulin, total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), very low-density lipoprotein-cholesterol (VLDL-C) and leptin were measured and compared in the three groups and the correlations between serum levels of leptin and other parameters were evaluated. Serum leptin levels were higher in the O-PCOS group, while its level was comparable between the L-PCOS and control groups. Serum levels of FT4 were significantly lower in both L-PCOS and O-PCOS groups than the control group. Women in both L-PCOS and O-PCOS groups were found to be significantly hyperinsulinemic and insulin resistant. Serum levels of TC, VLDL-C and TG were significantly higher in the O-PCOS group, while serum HDL-C level was lower. There was a poor correlation between serum leptin, and FT4, TC, TG, HDL-C and VLDL-C levels. A significant correlation was observed between serum leptin levels and both BMI and insulin resistance status in PCOS. We believe that, although thyroid hormones and lipid metabolic products do not seem to participate in the regulation of serum leptin levels, BMI and insulin resistance status may have a key role in women with PCOS.     

Expression of proliferative and preapoptotic molecules in human myometrium and leiomyoma throughout the menstrual cycle

The pathogenesis of leiomyoma may be related to an imbalance in the interaction of sex steroids with paracrine growth factors that may control the modulation of mitogenesis and local immunity. The authors investigate the temporal and spatial expression of proliferative and preapoptotic molecules that may participate in the modulation of myometrial function and leiomyoma pathogenesis. Immunohistochemistry and Western blot analysis are used to investigate Fas ligand (FasL), phosphatase and tensin homolog deletion on chromosome 10 (PTEN), and proliferating cell nuclear antigen (PCNA) expression in myometrium and leiomyoma. Western blot results show that in the secretory phase, FasL expression is 1.8-fold and 2.3-fold higher compared with the proliferative phase in the myometrium and leiomyoma, respectively (P = .022 and .047, respectively). A paired comparison between myometrium and leiomyoma reveals higher FasL expression in the leiomyoma (P = .003). On the contrary, when compared with the secretory phase, PCNA expression during the proliferative phase is 4.6-fold and 3.7-fold higher in the myometrium and leiomyoma, respectively (P = .041 and .034, respectively). A paired comparison between myometrium and leiomyoma reveals higher PCNA expression in the leiomyoma. Furthermore, lower PTEN expression is detected in the leiomyoma compared with the myometrium (P < .032). Immunohistochemistry results reveal that FasL, PTEN, and PCNA are expressed in the myometrium and leiomyoma, consistent with the results from the Western blot analysis. The results suggest that FasL, PTEN, and PCNA may be involved in the pathophysiology of leiomyoma. A higher FasL level in the leiomyoma is likely to correspond to suppression of local immunity by inducing apoptosis of immune cells, while a higher level of PCNA and a lower level of PTEN may be related to increased mitogenesis and decreased apoptosis in leiomyoma.     

Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by mutations in the type I BMP receptor gene ACVR1, which enable ACVR1 to utilize its natural antagonist, activin A, as an agonistic ligand. The physiological relevance of this property is underscored by the fact that HO in FOP is exquisitely dependent on activation of FOP-mutant ACVR1 by activin A, an effect countered by inhibition of anti–activin A via monoclonal antibody treatment. Hence, we surmised that anti-ACVR1 antibodies that block activation of ACVR1 by ligands should also inhibit HO in FOP and provide an additional therapeutic option for this condition. Therefore, we generated anti-ACVR1 monoclonal antibodies that block ACVR1’s activation by its ligands. Surprisingly, in vivo, these anti-ACVR1 antibodies stimulated HO and activated signaling of FOP-mutant ACVR1. This property was restricted to FOP-mutant ACVR1 and resulted from anti-ACVR1 antibody–mediated dimerization of ACVR1. Conversely, wild-type ACVR1 was inhibited by anti-ACVR1 antibodies. These results uncover an additional property of FOP-mutant ACVR1 and indicate that anti-ACVR1 antibodies should not be considered as therapeutics for FOP.     

Is radiological appearance of lower respiratory tract infection due to respiratory syncytial virus a predictor of clinical outcome?

Objective: Respiratory syncytial virus (RSV) lower respiratory tract infection is the most common viral infection in childhood. RSV-infected infants demonstrate various radiographic findings. The aim of the study is to evaluate whether assessment of radiological characteristics of lower tract infection due to RSV may be a predictor of clinical outcome in newborns.

Methods: The study included 36 newborn infants hospitalized for lower tract infection. In order to detect RSV, RSV Respi-Strip (Coris Bioconcept Organization) test kits were used on admission. Chest X-rays and clinical characteristics of the study group were reviewed.

Results: Of 36 patients hospitalized for lower tract infection from October 2012 to April 2013, 18 (50%) newborns were infected with RSV. The study included 36 neonates. Patients with RSV-positive infants at admission had greater need for respiratory support, supplemental oxygen and prolonged stay in the NICU. Newborns with an atelectasis pattern on admission chest radiograph had greater at RSV-positive infants.

Conclusion: Chest radiological patterns with lower respiratory tract infection in newborn infants due to RSV are a predictor of clinical outcome.