Nodal signals through activin receptor-like kinase 7 to inhibit trophoblast migration and invasion: implication in the pathogenesis of preeclampsia

Trophoblast cell invasion into the uterus is an essential process for successful pregnancy, and shallow invasion of trophoblasts into the maternal decidua is linked to preeclampsia. We have reported that Nodal, a member of the transforming growth factor-β superfamily, acts through activin receptor-like kinase 7 (ALK7) to inhibit trophoblast proliferation and to induce apoptosis. In this study, we examined the spatial and temporal expression patterns of Nodal and ALK7 in human placenta from normal and preeclamptic pregnancies and investigated whether Nodal regulated trophoblast migration and invasion. Nodal and ALK7 were detected in villous and extravillous trophoblast cell populations in early gestation, and their levels were strongly up-regulated in preeclamptic placenta. Overexpression of Nodal or constitutively active ALK7 decreased cell migration and invasion, whereas knockdown of Nodal and ALK7 had the opposite effects. In placental explant culture, treatment with Nodal inhibited trophoblast outgrowth, whereas Nodal small-interfering RNA strongly induced the expansion of explants and the migration of extravillous trophoblast cells. Nodal stimulated the secretion of tissue inhibitor of metalloproteinase-1 and inhibited matrix metalloproteinase (MMP)-2 and MMP-9 activity. These findings suggest that the Nodal/ALK7 pathway plays important roles in human placentation and that its abnormal signaling may contribute to the development of preeclampsia.     

Tumoral thrombosis of inferior vena cava and iliac veins resulting in unilateral lower limb edema in a young adult: A rare presentation of skeletal Ewing's sarcoma

Association of venous thromboembolic events (TEs) with malignancy is well known. Ewing's sarcoma usually presents as swelling at the primary site, however presenting as unilateral lower limb edema due to tumoral thrombosis of right iliac vein and IVC is a rare event. A 30-year-old male patient with extensive right lower limb swelling was admitted and imaging studies (plain film, ultrasonography, Doppler, computed tomography) revealed a mass arising from right iliac bone, adjoining sacrum and tumoral thrombosis of right iliac veins extending into inferior vena cava. Histopathological diagnosis was Ewing's sarcoma. Patient was treated successfully with chemotherapy and surgical embolectomy. So a young patient presenting with deep vein thrombosis should be investigated not only to establish any thrombophilic pre-disposition, but also let the clinician to suspect for any local malignancy. Treatment depends upon the proximal extent of tumoral thrombus. With advances in imaging and chemotherapeutic regimens early diagnosis is possible and appropriate treatment planning improves the prognosis. To our knowledge skeletal Ewing's sarcoma with bland thrombosis is a known entity however no such case with direct invasion of tumor into veins leading to tumoral venous thrombosis has been reported in medical literature.     

Haemobilia: a rare cause of gastrointestinal bleeding

Iatrogenic injury to hepatic duct leading to pseudoaneurysm and haemobilia can occur following laparoscopic cholecystectomy. We report a case of a 60 years old man presenting with haematemesis found to have pseudoaneurysm of accessory hepatic artery 4 months after laparoscopic cholecystectomy. Diagnosis was made by computed tomography (CT) scan followed by celiac and mesenteric artery angiogram. The bleeding was successfully treated with coil embolization.     

Prevalence and Impact of Hepatic Steatosis on the Response to Antiviral Therapy in Saudi Patients with Genotypes 1 and 4 Chronic Hepatitis C

Background

Hepatic steatosis in hepatitis C virus (HCV)-infected patients has been shown to enhance the progression of liver fibrosis and decrease the response to antiviral therapy.

Aims

We aimed to determine the role of HCV genotype 4 (HCV-G4) in the prevalence of hepatic steatosis, its impact on antiviral therapy, and its associations and predictive factors in comparison to HCV-G1-infected patients.

Methods

Treatment-naïve HCV patients who were started on pegylated interferon a-2b plus ribavirin therapy in two centers in Saudi Arabia were included. The severity of steatosis was assessed using the METAVIR and NAS (non-alcoholic fatty liver disease [NAFLD] activity score) scoring systems. Sustained virological response (SVR) was studied in relation to the degree of steatosis. Associations between steatosis and multiple demographic, laboratory, and virological factors were examined. HCV-G1 and HCV-G4 patients were compared.

Results

A total of 116 patients (HCV-G4 85 [73.3%]; HCV-G1 31 [26.7%]) were included. The mean age was 50.4 ± 10.7 years and 56.9% were males. In terms of steatosis grading using the NAS scoring system, 50% had steatosis grade 0, 26.7% grade 1, 14.7% grade 2, and 8.6% grade 3, while the overall staging of steatosis revealed that 43.1% had mild steatosis, 42.2% moderate, and 14.7% severe. Gamma-glutamyl transpeptidase (GGT), platelet count, body mass index (BMI), cholesterol level, presence of hyperlipidemia, liver histology stage, and grade were significantly correlated with hepatic steatosis in one or more of the statistical analyses. Twenty-two out of 55 patients (40.0%) had an SVR in the mild steatosis group, compared to 52.7% in the moderate group and 7.3% in the severe group (P = 0.03). The HCV genotype did not correlate with steatosis or SVR.

Conclusion

Our study confirms the high prevalence of steatosis in HCV-G4 and HCV-G1 patients, but with no difference in the grade or score of steatosis between the two genotypes. The grade of steatosis correlates with GGT, platelet count, and BMI, while the NAS score of steatosis correlates with response to antiviral therapy.     

Testosterone or 17{beta}-estradiol exposure reveals sex-specific effects on glucose and lipid metabolism in human myotubes

Changes in sex hormone levels with aging or illness may lead to metabolic disorders. Moreover, the ratio changes in men versus women may have distinct pathological responses. Since little is known about sex hormone action on muscle metabolism, we examined the role of testosterone or 17β-estradiol (E(2)) in metabolism and investigated whether either hormone may mediate a sex-specific effect. Myotubes from postmenopausal women and age-matched male donors were treated with 10?nM testosterone or E(2) for 4 days, and assays were performed to measure metabolic readouts, signal transduction, and mRNA expression. Testosterone and E(2) treatment enhanced insulin-stimulated glucose incorporation into glycogen and AKT phosphorylation in myotubes from female donors, highlighting a sex-specific role of sex hormone in glucose metabolism. Testosterone treatment increased palmitate oxidation in myotubes from both female and male donors, while E(2) enhanced palmitate oxidation in myotubes from male donors only. Testosterone-mediated increase in palmitate oxidation was attenuated at the presence of androgen receptor antagonist, which may indicate a role of nuclear steroid receptor in muscle lipid oxidation. Testosterone treatment increased mRNA expression of the insulin receptor substrate 2 in myotubes from male and female donors, whereas it increased mRNA expression of glycogen synthase 1 only in myotubes from male donors. E(2) treatment increased pyruvate dehydrogenase kinase 4 mRNA expression in myotubes from female donors. Thus, our data suggest that testosterone or E(2) modulates muscle glucose and lipid metabolism and may play a role in metabolism in a sex-dependent manner.     

Expression of the growth factor pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta in the serum,cartilage and subchondral bone of patients with osteoarthritis

ObjectivesPleiotrophin is a heparin-binding growth factor expressed in embryonic but not mature cartilage, suggesting a role in cartilage development. Elucidation of the molecular changes observed during the remodelling process in osteoarthritis is of paramount importance. This study aimed to investigate serum pleiotrophin levels and expression of pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta in the cartilage and subchondral bone of osteoarthritis patients.MethodsSerum samples derived from 16 osteoarthritis patients and 18 healthy donors. Pleiotrophin and receptor protein tyrosine phosphatase beta/zeta in the cartilage and subchondral bone were studied in 29 patients who had undergone total knee or hip replacement for primary osteoarthritis and in 10 control patients without macroscopic osteoarthritis changes.ResultsSerum pleiotrophin levels and expression of pleiotrophin in chondrocytes and subchondral bone osteocytes significantly increased in osteoarthritis patients graded Ahlback II to III. Receptor protein tyrosine phosphatase beta/zeta was mainly detected in the subchondral bone osteocytes of patients with moderate osteoarthritis and as disease severity increased, in the osteocytes and bone lining cells of the distant trabeculae.ConclusionsThese data render pleiotrophin and receptor protein tyrosine phosphatase beta/zeta promising candidates for further studies towards developing targeted therapeutic schemes for osteoarthritis.     

Risk factors for spontaneous abortion among Saudi women

The objective of this study was to identify important risk factors for spontaneous abortion (SA) among Saudi women. It was a casecontrol study conducted at King Khalid University Hospital, Riyadh, Saudi Arabia. The cases were 226 consecutive women hospitalized for SA between October 1992 and January 1993. The controls were 226 consecutive women who had normal delivery in the same hospital during the same period. Bivariate analysis using chi-square tests and estimates of relative risks indicated a positive association of age at menarche with risk of SA (P<0.01). Also, there was a significant higher risk of SA when a woman was married to a blood related husband than if married to a non relative (RR=2.1). The number of previous abortions was also positively related to the risk of SA in the current pregnancy (P<0.01). Compared to primigravidas, the risk of SA was 3.2 times greater than if the outcome of the most recent pregnancy was also an SA. Other factors that had significant bivariate association with SA were a family history of SA, abdominal trauma, and infection during pregnancy. When multiple logistic regression was used to adjust for the effects of confounding variables, all the factors that showed significant bivariate association with SA (except outcome of the last pregnancy) remained significant. Early menarche may be protective, but further study is needed to confirm this. Greater attention should be given to pregnant women who had personal or family history of SA and those who had trauma and/or infection during pregnancy. Premarital counselling concerning consanguineous marriages is recommended.     

Pretransplant psychiatric and medical comorbidity of alcoholic liver disease patients who received liver transplant

The authors examined the pretransplant prevalence of comorbid physical and psychological disorders in 112 alcoholic liver disease patients who received liver transplant. Fifty-six percent of the patients had comorbid hepatitis C or hepatitis B virus, 40% had used other substances in addition to alcohol, 25% met the criteria for a lifetime DSM-IV nonalcohol substance use disorder, 36% for a lifetime depressive disorder, and 12% for a lifetime anxiety disorder. The findings suggest the need for pretransplant psychiatric evaluation of alcoholic liver disease patients to identify nonalcohol substance use disorders and other psychiatric disorders that may require treatment.