Chemoprophylaxis and Management of Venous Thromboembolism in Microvascular Surgery.

This review aims to highlight the common pharmacological and nonpharmacological interventions utilized for thromboprophylaxis as well as flap salvage in microsurgery. A literature review was conducted in PubMed/National Center for Biotechnology Information, Scopus, Web of Science, and MEDLINE databases. Articles with a focus on thromboprophylaxis in microsurgical procedures spanning head and neck surgery, breast and extremity microvascular reconstruction, deep venous thrombosis/pulmonary embolus in microvascular surgery, and flap thrombosis and salvage were included in this review. The majority of available evidence supports mechanical venous thromboembolism (VTE) prophylaxis in all patients undergoing microsurgery given the presence of multiple risk factors for VTE within this particular patient population. Based on the literature review, addition of VTE chemoprophylactic agents is beneficial and an algorithmic approach to thromboprophylaxis in microsurgery patients and management of patients with thrombosis based on literature review and senior authors' experience is recommended and outlined.

Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin.

Some osteoblasts embed within bone matrix, change shape, and become dendrite-bearing osteocytes. The circuitry that drives dendrite formation during "osteocytogenesis" is poorly understood. Here we show that deletion of Sp7 in osteoblasts and osteocytes causes defects in osteocyte dendrites. Profiling of Sp7 target genes and binding sites reveals unexpected repurposing of this transcription factor to drive dendrite formation. Osteocrin is a Sp7 target gene that promotes osteocyte dendrite formation and rescues defects in Sp7-deficient mice. Single-cell RNA-sequencing demonstrates defects in osteocyte maturation in the absence of Sp7. Sp7-dependent osteocyte gene networks are associated with human skeletal diseases. Moreover, humans with a SP7R316C mutation show defective osteocyte morphology. Sp7-dependent genes that mark osteocytes are enriched in neurons, highlighting shared features between osteocytic and neuronal connectivity. These findings reveal a role for Sp7 and its target gene Osteocrin in osteocytogenesis, revealing that pathways that control osteocyte development influence human bone diseases.

Gain-of-function mutation of microRNA-140 in human skeletal dysplasia.

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders1-5, but neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported. Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia. Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice6. This mutant miRNA gene yields abundant mutant miR-140-5p expression without miRNA-processing defects. In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects. Furthermore, the mutant miR-140-5p seed competes with the conserved RNA-binding protein Ybx1 for overlapping binding sites. This finding may explain the potent target repression and robust in vivo effect by this mutant miRNA even in the absence of evolutionary selection of miRNA-target RNA interactions, which contributes to the strong regulatory effects of conserved miRNAs7,8. Our study presents the first case of a pathogenic gain-of-function miRNA mutation and provides molecular insight into neomorphic actions of emerging and/or mutant miRNAs.

Distinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models.

Feingold syndrome is a skeletal dysplasia caused by loss-of-function mutations of either MYCN (type 1) or MIR17HG that encodes miR-17-92 microRNAs (type 2). Since miR-17-92 expression is transcriptionally regulated by MYC transcription factors, it has been postulated that Feingold syndrome type 1 and 2 may be caused by a common molecular mechanism. Here we show that Mir17-92 deficiency upregulates TGF-ß signaling, whereas Mycn-deficiency downregulates PI3K signaling in limb mesenchymal cells. Genetic or pharmacological inhibition of TGF-ß signaling efficiently rescues the skeletal defects caused by Mir17-92 deficiency, suggesting that upregulation of TGF-ß signaling is responsible for the skeletal defect of Feingold syndrome type 2. By contrast, the skeletal phenotype of Mycn-deficiency is partially rescued by Pten heterozygosity, but not by TGF-ß inhibition. These results strongly suggest that despite the phenotypical similarity, distinct molecular mechanisms underlie the pathoetiology for Feingold syndrome type 1 and 2.

Ras signaling regulates osteoprogenitor cell proliferation and bone formation.

During endochondral bone development, osteoblasts are continuously differentiated from locally residing progenitor cells. However, the regulation of such endogenous osteoprogenitor cells is still poorly understood mainly due to the difficulty in identifying such cells in vivo. In this paper, we genetically labeled different cell populations of the osteoblast linage using stage-specific, tamoxifen-inducible Cre transgenic mice to investigate their responses to a proliferative stimulus. We have found that overactivation of Kras signaling in type II collagen-positive, immature osteoprogenitor cells, but not in mature osteoblasts, substantially increases the number of their descendant stromal cells and mature osteoblasts, and subsequently increases bone mass. This effect was mediated by both, the extracellular signal-regulated kinase (ERK) and phosphoinositide 3 kinase (PI3K), pathways. Thus we demonstrate that Ras signaling stimulates proliferation of immature osteoprogenitor cells to increase the number of their osteoblastic descendants in a cell-autonomous fashion.

Polycomb repressive complex 2 regulates skeletal growth by suppressing Wnt and TGF-ß signalling.

Polycomb repressive complex 2 (PRC2) controls maintenance and lineage determination of stem cells by suppressing genes that regulate cellular differentiation and tissue development. However, the role of PRC2 in lineage-committed somatic cells is mostly unknown. Here we show that Eed deficiency in chondrocytes causes severe kyphosis and a growth defect with decreased chondrocyte proliferation, accelerated hypertrophic differentiation and cell death with reduced Hif1a expression. Eed deficiency also causes induction of multiple signalling pathways in chondrocytes. Wnt signalling overactivation is responsible for the accelerated hypertrophic differentiation and kyphosis, whereas the overactivation of TGF-ß signalling is responsible for the reduced proliferation and growth defect. Thus, our study demonstrates that PRC2 has an important regulatory role in lineage-committed tissue cells by suppressing overactivation of multiple signalling pathways.

MicroRNA-140 Provides Robustness to the Regulation of Hypertrophic Chondrocyte Differentiation by the PTHrP-HDAC4 Pathway.

Growth plate chondrocytes go through multiple differentiation steps and eventually become hypertrophic chondrocytes. The parathyroid hormone (PTH)-related peptide (PTHrP) signaling pathway plays a central role in regulation of hypertrophic differentiation, at least in part, through enhancing activity of histone deacetylase 4 (HDAC4), a negative regulator of MEF2 transcription factors that drive hypertrophy. We have previously shown that loss of the chondrocyte-specific microRNA (miRNA), miR-140, alters chondrocyte differentiation including mild acceleration of hypertrophic differentiation. Here, we provide evidence that miR-140 interacts with the PTHrP-HDAC4 pathway to control chondrocyte differentiation. Heterozygosity of PTHrP or HDAC4 substantially impaired animal growth in miR-140 deficiency, whereas these mutations had no effect in the presence of miR-140. miR-140-deficient chondrocytes showed increased MEF2C expression with normal levels of total and phosphorylated HDAC4, indicating that the miR-140 pathway merges with the PTHrP-HDAC4 pathway at the level of MEF2C. miR-140 negatively regulated p38 mitogen-activated protein kinase (MAPK) signaling, and inhibition of p38 MAPK signaling reduced MEF2C expression. These results demonstrate that miR-140 ensures the robustness of the PTHrP/HDAC4 regulatory system by suppressing MEF2C-inducing stimuli. © 2014 American Society for Bone and Mineral Research © 2015 American Society for Bone and Mineral Research.

MicroRNAs involved in bone formation.

During skeletal development, mesenchymal progenitor cells undergo a multistage differentiation process in which they proliferate and become bone- and cartilage-forming cells. This process is tightly regulated by multiple levels of regulatory systems. The small non-coding RNAs, microRNAs (miRNAs), post-transcriptionally regulate gene expression. Recent studies have demonstrated that miRNAs play significant roles in all stages of bone formation, suggesting the possibility that miRNAs can be novel therapeutic targets for skeletal diseases. Here, we review the role and mechanism of action of miRNAs in bone formation. We discuss roles of specific miRNAs in major types of bone cells, osteoblasts, chondrocytes, osteoclasts, and their progenitors. Except a few, the current knowledge about miRNAs in bone formation has been obtained mainly by in vitro studies; further validation of these findings in vivo is awaited. We also discuss about several miRNAs of particular interest in the light of future therapies of bone diseases.

MicroRNAs in cartilage development, homeostasis, and disease.

microRNAs (miRNAs) regulate gene expression mainly at the posttranscriptional level. Many different miRNAs are expressed in chondrocytes, and each individual miRNA can regulate hundreds of target genes, creating a complex gene regulatory network. Experimental evidence suggests that miRNAs play significant roles in various aspects of cartilage development, homeostasis, and pathology. The possibility that miRNAs can be novel therapeutic targets for cartilage diseases led to vigorous investigations to understand the role of individual miRNAs in skeletal tissues. Here, we summarize our current understanding of miRNAs in chondrocytes and cartilage. In the first part, we discuss roles of miRNAs in growth plate development and chondrocyte differentiation. In the second part, we put a particular focus on articular cartilage and discuss the significance of variety of findings in the context of osteoarthritis, the most common degenerative joint disease.

Determinants of developing diabetes mellitus and vascular complications in patients with impaired fasting glucose.

AIMS: To detect the risk factors of diabetes mellitus (DM) and cardiovascular complications in subjects with impaired fasting glucose (IFG). MATERIALS AND METHODS: One hundred and twenty three subjects with proved IFG in Zanjan Healthy Heart Study (2002-2003) were recalled and participated in this study (2009-2010). Demographic and laboratoryinformation of the participants were collected.Ischemic heart disease (IHD) was assessed by the exercise tolerance test (ETT). All the subjects with abnormal ETT or documented past history of IHD confirmed by angiographic evaluation. Ophthalmic complications including cataract, glaucoma, and diabetic retinopathy were estimated by an ophthalmologist. RESULTS: Incidence of DM was 19.5%. All the diabetic and pre-diabetic patients had at least one of the other components of metabolic syndrome. Obesity (P: 0.04, OR: 1.8, 95%CI: 1.2-9) and low physical activity (P < 0.001, OR: 9.6, 95%CI: 3.4-32) were the only independent prognostic risk factors for progression to DM in patients with IFG. Total incidence of IHD was 14.6% and had a strong correlation with sex (P: 0.01, OR: 1.8, 95%CI: 1.2-1.5), age (P < 0.001, OR: 23, 95%CI: 2.1-67) and cigarette smoking (P < 0.001, OR: 36.5, 95%CI: 3.9-337). Non-proliferative diabetic retinopathy was shown in 2 (1.6%) subjects who were all women. CONCLUSION: Obesity and low physical activity are the main factors of developing DM and its macrovascular complications in subjects with IFG.

Evaluation of X-Chromosome Inactivation Patterns in Patients with Acute Myeloid Leukemia during Remission.

The aim of this study was to evaluate the patterns of X-chromosome inactivation during the remission in acute myeloid leukemia (AML) at the RNA level. Two hundred normal females and 45 female patients with AML entered the study. The frequency of heterozygosity was 48.5% (119/245) for P55, 40% (93/245) for IDS, and only 28.9% (71/245) for G6PD. Some individuals were heterozygous for more than one gene polymorphism. Overall, one hundred normal individuals proved showed to be heterozygous for at least one of the above polymorphisms. 92/100 (92%) normal females showed a polyclonal pattern. Clonal patterns were observed in 44/45 (98%) AML patients at presentation. Of 27 patients who were followed after remission, 23 (85.2%) patients showed a clonal pattern. Ten patients were available for a longer followup (up to 12 months) and the clonal pattern was observed in seven patients. It can be concluded that clonality at remission is a frequent event in AML and does not necessarily mean relapse of the disease. There is also a possibility of conversion of clonality to polyclonality over time.

The effects of unripe grape juice on lipid profile improvement.

Introduction. Consumption of unripe grape juice (verjuice) has been portrayed by the traditional belief, as a means of combating dyslipidemia. We aimed to evaluate the effects of unripe grape juice consumption on lipid profile in healthy human volunteers. Methods. We asked 42 enrolled volunteers to drink 10 cc of verjuice within 30 minutes to 2 hours after lunch and 10 cc of it after dinner. After taking 120 doses of verjuice, another fasting lipid profile was obtained from each participant. The statistical analysis was performed by SPSS 13 software. Results. After analysis of the data, the mean ± standard deviation for all the variables was obtained. Among those improvement of HDL-C was significant after the trial (P value < 0.001). TG, TC, and LDL improvement were not significant. Conclusion. Our study declared that verjuice has a dramatic effect on improving HDL-C level of serum but no any other lipid improvement effect was obtained.

Independent Predictors of Erectile Dysfunction in Type 2 Diabetes Mellitus: Is It True What They Say about Risk Factors?

Introduction. The aim of this study was to evaluate the independent predictors of ED in adult men with type 2 diabetes mellitus (T2DM). Methods. We have recruited 200 T2DM patients referred to our center between March 1, 2009 and March 1, 2010. All the patients were scored with the International Index of Erectile Function (IIEF)-5 questionnaires. Contribution of age, body mass index (BMI), smoking, blood pressure, lipid profile, fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), free testosterone concentration, and duration of diabetes to risk of ED were evaluated. Results. Of 200 men with T2DM, 59.5% had ED (95%CI: 52%-67%). A negative significant correlation was found between potency score and HbA1c (r: 0.20,P: 0.01), FPG (r: 0.17, P: 0.03) and SBP (r: 0.18, P: 0.02) but not between other risk factors such as lipid profile, BMI, and serum testosterone level. By using multivariate logistic regression analysis, we found out that the only two independent predictors of ED in these group of patients are age (OR: 2.8, P: 0.01), and taking calcium channel blockers (CCB) (OR: 4.1, P: 0.01). Conclusions. Aging and taking CCB were the only two major predictors for ED but surprisingly other metabolic or sexual covariates in this study did not have predictive value for ED risk in T2DM patients.

Comparison of azithromycin and clarithromycin triple therapy regimens for helicobacter pylori eradication in hemodialysis patients.

BACKGROUND: Helicobacter pylori eradication with clarithromycin is more expensive than with azithromycin. OBJECTIVES: This study aimed to compare the effectiveness of these two antibiotics in eradicating H. pylori in hemodialysis (HD) patients. PATIENTS AND METHODS: This is a prospective, randomized, double-blinded clinical trial analysis of HD patients. Patients who had dyspepsia and showed positive results for two of three tests, anti-H. pylori serology, H. pylori stool antigen (HpSAg), or Urease Breath Test (UBT), were included in the study. The subjects consisted of 39 dialysis patients who were randomly divided into two groups that received medication twice daily. Group OAC received 20 mg omeprazol, 500 mg amoxycilin, and 250 mg clarithromycin, and Group OAAz received 20 mg omeprazol, 500 mg amoxicillin, and 250 mg azithromycin. Both regimens were administered for 14 days. Eradication was investigated by performing the UBT and the HpSAg test eight weeks later. RESULTS: This study began with 39 patients, 37 of which completed the treatment schedule (20 males and 17 females, mean age 59 years). Two patients died due to MI before beginning treatment. In the OAC group, negative results on the UBT and HpSAg tests were found in 82.4% and 88.2% of the participants, respectively. In the OAAz group, these values were 80% and 85%, respectively. The data showed that the difference between the two regimens was not significant (P = 1.0). CONCLUSIONS: According to the data, no differences in eradication rates were apparent between the azitromycin and the claritromycin regimens. However, lower cost and fewer complaints could be considered as an advantage of the triple therapy with azithromycin.

Prevalence of metabolic syndrome in a hemodialysis population.

INTRODUCTION: The role of metabolic syndrome (MS) in hemodialysis population has not been thoroughly studied. This study aimed to determine the prevalence of MS and to identify its correlates among hemodialysis patients. MATERIALS AND METHODS: This cross-sectional study was conducted on patients in a hemodialysis center. The MS was defined according the Adult Treatment Panel III criteria. Clinical data of the patients were collected and blood samples were studied to measure fasting blood glucose and lipid profile. RESULTS: Eighty hemodialysis patients, including 47 men (58.8%) and 33 women (41.2%) with a mean age of 55.6 ± 15.6 years, were enrolled in this study. Metabolic syndrome was diagnosed in 23 patients (28.7%). Hypertension was present in 55 patients (68.8%). Fifteen patients (18.8%) were diabetic, 24 (30.0%) had a high serum triglyceride, 22 (27.5%) had a low high-density lipoprotein cholesterol, and 20 (25.0%) had evidence of abdominal obesity. Patients with MS had significantly higher body mass indexes (P < .001), fasting blood glucose levels (P < .001), and triglyceride levels (P = .004). Metabolic syndrome was not associated with gender, age, and duration of hemodialysis. Men showed significant abnormality in glucose metabolism (P = .008). Prevalence of low high-density lipoprotein cholesterol was significantly higher in the women than in the men (P = .02). CONCLUSIONS: The prevalence of MS in our hemodialysis patients was relatively high, with the most common element being hypertension. We suggest that there needs to be a new set of criteria defined for MS in hemodialysis patients.

Association of Helicobacter pylori infection and serum albumin in patients on hemodialysis.

INTRODUCTION. Helicobacter pylori infection in gastric mucosa may cause systemic inflammatory reaction. We investigated the inflammatory effect of H pylori infection on nutritional factors such as serum albumin in hemodialysis patients and influence of eradication of H pylori on this association. MATERIALS AND METHODS. Ninety-eight patients on hemodialysis were divided into 2 groups according to H pylori infection. Eradication of H pylori, 8 weeks after treatment, was confirmed by urease breath test and H pylori stool antigen. Serum albumin, lipid profile, and metabolite levels were checked before and after 8 weeks and 6 months of eradication of H pylori. RESULTS. Thirty-nine patients (39.8%) were infected with H pylori. There were no significant differences between the two groups in age, dialysis duration, serum albumin, serum creatinine, blood urea nitrogen, hemoglobin, serum calcium, serum phosphorus, and lipid profile. Thirty-seven patients with H pylori completed the treatment period. Eradication was successful in 30 patients (81.1%). Eight weeks and 6 months after anti-H pylori drug therapy, the mean serum albumin level significantly decreased from 4.2 mg/dL to 3.6 mg/dL (P < .001) and 3.7 mg/dL (P < .001), respectively. Significant decreases were seen in serum cholesterol (P = .001), blood urea nitrogen (P = .005), and serum calcium level (P = .03) and a significant increase in hemoglobin level (P = .02). CONCLUSIONS. Our study did not demonstrate nutritional benefits after H pylori eradication treatment, as the level of nutritional markers reduced. This relationship needs to be confirmed by further prospective studies.