Protein S Gla-domain mutations causing impaired Ca(2+)-induced phospholipid binding and severe functional protein S deficiency

We have identified 2 PROS1 missense mutations in the exon that encodes the vitamin K-dependent Gla domain of protein S (Gly11Asp and Thr37Met) in kindred with phenotypic protein S deficiency and thrombosis. In studies using recombinant proteins, substitution of Gly11Asp did not affect production of protein S but resulted in 15.2-fold reduced protein S activity in a factor Va inactivation assay. Substitution of Thr37Met reduced expression by 33.2% (P <.001) and activity by 3.6-fold. The Gly11Asp variant had 5.4-fold reduced affinity for anionic phospholipid vesicles (P <.0001) and decreased affinity for an antibody specific for the Ca(2+)-dependent conformation of the protein S Gla domain (HPS21). Examination of a molecular model suggested that this could be due to repositioning of Gla29. In contrast, the Thr37Met variant had only a modest 1.5-fold (P <.001), reduced affinities for phospholipid and HPS21. This mutation seems to disrupt the aromatic stack region. The proposita was a compound heterozygote with free protein S antigen levels just below the lower limit of the normal range, and this is now attributed to the partial expression defect of the Thr37Met mutation. The activity levels were strongly reduced to 15% of normal, probably reflecting the functional deficit of both protein S variants. Her son (who was heterozygous only for Thr37Met) had borderline levels of protein S antigen and activity, reflecting the partial secretion and functional defect associated with this mutation. This first characterization of natural protein S Gla-domain variants highlights the importance of the high affinity protein S-phospholipid interaction for its anticoagulant role.     

Podoplanin,ezrin, and Rho-A proteins may have joint participation in tumor invasion of lip cancer

Introduction

Podoplanin and ezrin connection through Rho-A phosphorylation have been suggested as part of the activation pathway, in the process of tumor invasion and cell movement in oral squamous cell carcinomas.

Objective

The aim of this study was to evaluate the correlation among podoplanin, ezrin, and Rho-A immunoexpressions in 91 squamous cells carcinomas of the lower lip and their influence in patient’s prognosis.

Material and methods

The immunoexpressions of podoplanin, ezrin, and Rho-A were evaluated through a semi-quantitative score method, based on the capture of 10 microscopic fields at the front of tumor invasion. The association and correlation of these proteins with the clinicopathological features were verified by Fischer’s exact test and Spearman’s test. The prognostic values were analyzed by Kaplan-Meier method and log-rank test.

Results

A statistically significant association between strong cytoplasmic podoplanin expression and alcohol (p = 0.024), loco-regional recurrences (p = 0.028), and lymph node metastasis (pN+) (p = 0.010) was found. The membranous (p = 0.000 and r = 0.384) and cytoplasmic (p = 0.000 and r = 0.344) podoplanin expression was statistically correlated with ezrin expression. Also, membranous podoplanin was significantly correlated with Rho-A expression (p = 0.006 and r = 0.282). The expressions of podoplanin, ezrin, and Rho-A were not significant prognostic factors for patients with squamous cell carcinomas of the lower lip.

Conclusions

Therefore, our results confirm a correlation among podoplanin, ezrin, and Rho-A expressions in squamous cell carcinoma of the lip suggesting a cooperative participation of these proteins in cell movement and invasion.

Clinical relevance

Furthermore, strong cytoplasmic podoplanin expression could be helpful to identify patients with squamous cell carcinoma of the lip and lower risk of loco-regional recurrences.

     

Socioeconomic position and duration of disability benefit due to work-related musculoskeletal disorders

This study estimated the effect of socioeconomic position on the duration of disability benefits due to musculoskeletal disorders affecting the neck and/or upper limbs. A cohort study including 563 insured workers from the city of Salvador, Bahia, Brazil, registered in the General Social Security System and who received temporary disability benefits due to musculoskeletal disorders affecting the neck and/or upper limbs, was performed in 2008 using data from the National Social Security Institute. The results show that among union member workers with high psychosocial demands at work, those with low socioeconomic status are almost twice as likely to receive benefit for a shorter period of time compared to those with a higher socioeconomic position (RR = 1.89; 95%CI: 1.25-2.87). These results reveal an inequitable situation or unnecessary use of insurance for workers with a higher socioeconomic position. Future research aimed at elucidating the differences in the use of benefits are needed so that social insurance system managers may take the appropriate steps to resolve this issue.     

Oxidative process in erythrocytes of individuals with hemoglobin S

The understanding of the oxidative stress mechanisms helps to explain many of the processes of cellular lesion and death, especially those related to the hemolytic diseases. Sickle cell anemia, thalassemias and G6-PD deficiency are among the more frequent genetic anomalies accompanied by oxidative stress. In the sickle cells, one of the factors that predisposes to the hemolytic process is the oxidative degradation of the hemoglobin S due to its deoxigenation leading to hemichrome formation and precipitation as Heinz bodies. The oxidative stress contributes to the sickle process and shortening of the erythrocyte survival. Here we analyzed the oxidative process in erythrocytes of patients with two different genotypes for HbS (AS and SS). Units of blood from donors of the Center of Hematology and Hemotherapy of Paraná (HEMEPAR), from normal individuals (AA) and from heterozygote individuals (AS), and venous blood collected from patients with sickle cell anemia (SS) were analyzed. In order to evaluate the protective action of the vitamins C and E in oxidative stress, erythrocytes were treated with antioxidant substances, vitamin C and vitamin E, and then treated with the oxidant tert-butilhydroperoxide (TBHP). The oxidative action induced by TBHP was observed in erythrocytes AA相似文献   

Leptin is associated with insulin resistance in Japanese migrants

Background: Leptin and insulin are both influenced by body adiposity. Insulin plays an important role in the context of the metabolic syndrome (MS). We evaluated whether leptin was associated with insulin resistance and MS after adjusting for confounders in Japanese-Brazilian women. Methods: A total of 717 Japanese-Brazilian women aged >/=30 years were investigated for the presence of MS. They were submitted to clinical examination and laboratory measurements, including oral GTT, lipid profile, uric acid, C-reactive protein (CRP), insulin, and leptin levels. Insulin sensitivity was assessed by HOMA. Diagnosis of MS was based on the National Cholesterol Education Program criteria modified for Asians. Pearson correlation coefficient and logistic regression analysis were used. Results: MS was diagnosed in 56% (95% CI 52-59); these subjects were older and had higher body mass index (BMI) and fat mass, and worse metabolic profile. Leptin and CRP levels were statistically greater in women with MS when compared to those without the syndrome (8.6 +/- 8.0 vs. 7.2 +/- 5.9 ng/mL and 0.219 +/- 0.848 vs. 0.360 +/- 0.852 mg/dL, p < 0.05). Leptin was significantly correlated to BMI, fat mass, waist circumference, HOMA-IR, and insulin but not to other components of MS, such as fasting plasma glucose, blood pressure, HDL-cholesterol, triglyceride, and CRP levels. Correlation between leptin and HOMA-IR or fasting insulinemia was maintained after adjustments for body adiposity. However, in logistic regression model, age, BMI, 2-h glucose, and uric acid were independently associated with MS, but not leptin. Conclusions: Adiposity-adjusted correlation of leptin with HOMA-IR and fasting insulinemia suggested that the former is associated with insulin resistance, despite the lack of independent association with the definition of the MS according to NCEP-ATP III. These findings in such Japanese-Brazilian population of high prevalence of MS need to be confirmed in other populations.     

USEFULNESS OF kDNA PCR IN THE DIAGNOSIS OF VISCERAL LEISHMANIASIS REACTIVATION IN CO-INFECTED PATIENTS

SUMMARY

It is important to develop new methods for diagnosing relapses in the co-infection of visceral leishmaniasis (VL) and HIV to enable earlier detection using less invasive methods. We report a case of a co-infected patient who had relapses after VL treatment, where the qualitative kDNA PCR showed a good performance. The kDNA PCR seems to be a useful tool for diagnosing VL and may be a good marker for predicting VL relapses after treatment of co-infected patients with clinical symptoms of the disease.