Hereditary deficiencies of antithrombin III, protein S, and the protein C pathway in Jordanian thrombosis patients.

Hereditary thrombophilia is caused by various inherited disorders. Most lead to a familial tendency to recurrent venous, not arterial, thrombosis, usually at a young age, and with spontaneous onset. Most of the genetic defects known today affect the function of natural anticoagulant pathways, in particular, the protein C system. In this study, 602 (265 female, 337 male) patients with suspected thrombosis, arterial or venous, were referred to King Hussein Medical Center in Amman, Jordan. The prevalence of hereditary deficiencies of antithrombin (AT), protein S (PS), and protein C (PC) were studied over a seven-year period (1993-2000). Activated protein C (APC-R) resistance subjects were studied over four years (1996-2000). The mean age was 30 years in females and 42 years in males. A diagnosis was established in 22.4% (n = 135) of the subjects (20.3% venous, 2.1% arterial). Protein C deficiency was found in 3.8%, protein S deficiency in 2.3% and antithrombin deficiency in 1.4% of our sample group. An APC-R problem was seen in 23.0% (n = 89) of the surveyed population. Out of the APC-R patients, 75.0% had the DNA analysis of a factor V Leiden mutation present. Of the subjects found to have the mutation 87.0% were heterozygous and 13.0% were homozygous. These results confirm that APC-R, as a result of factor V Leiden mutation, is the most prevalent cause of thrombosis, and thrombophilia is related to venous, not arterial, thrombosis.     

Awareness of the risk of endocarditis associated with tattooing and body piercing among patients with congenital heart disease and paediatric cardiologists in the United Kingdom.

Body art in the form of tattoos and piercing has become increasingly popular amongst children and teenagers, and is nowadays more socially acceptable despite media reports citing tissue destruction and death. Our study explored the awareness and experience of patients with congenital heart disease, and of cardiologists and professionals responsible for their care.     

The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

Drug-resistant tuberculosis (TB) has lent urgency to finding new drug leads with novel modes of action. A high-throughput screening campaign of >65,000 actinomycete extracts for inhibition of Mycobacterium tuberculosis viability identified ecumicin, a macrocyclic tridecapeptide that exerts potent, selective bactericidal activity against M. tuberculosis in vitro, including nonreplicating cells. Ecumicin retains activity against isolated multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis. The subcutaneous administration to mice of ecumicin in a micellar formulation at 20 mg/kg body weight resulted in plasma and lung exposures exceeding the MIC. Complete inhibition of M. tuberculosis growth in the lungs of mice was achieved following 12 doses at 20 or 32 mg/kg. Genome mining of lab-generated, spontaneous ecumicin-resistant M. tuberculosis strains identified the ClpC1 ATPase complex as the putative target, and this was confirmed by a drug affinity response test. ClpC1 functions in protein breakdown with the ClpP1P2 protease complex. Ecumicin markedly enhanced the ATPase activity of wild-type (WT) ClpC1 but prevented activation of proteolysis by ClpC1. Less stimulation was observed with ClpC1 from ecumicin-resistant mutants. Thus, ClpC1 is a valid drug target against M. tuberculosis, and ecumicin may serve as a lead compound for anti-TB drug development.     

In vivo antihyperlipidemic activity of a new series of N-(benzoylphenyl) and N-(acetylphenyl)-1-benzofuran-2-carboxamides in rats

A new series of N‐(benzoylphenyl) and N‐(acetylphenyl)‐1‐benzofuran‐2‐carboxamides ( 3a – 3d and 4a ′– 4c ′) were synthesized. Compounds ( 3a , 3b , and 4a ′– 4c ′) were tested in vivo using Triton‐WR‐1339‐induced hyperlipidemic rats as an experimental model for their hypolipidemic activity. The tested animals were divided into eight groups: control, hyperlipidemic, 3a , 3b , 4a ′, 4b ′, 4c ′, and bezafibrate. At a dose of 15 mg/kg, the elevated plasma triglyceride (TG) levels were significantly reduced in compounds 3b (p <0.0001) and 4c ′ (p <0.05) after 12 and 24 h compared to the normal control group. Furthermore, high‐density lipoprotein‐cholesterol levels were remarkably increased in compounds 3b (p <0.001) and 4c ′ (p <0.05). Meanwhile, compound 4b ′ slightly reduced the TG levels after 12 and 24 h. The present study demonstrated new properties of the novel series of benzofuran‐2‐carboxamides 3b and 4c ′ as potent lipid‐lowering agents. It is, therefore, reasonable to assume that compounds 3b and 4c ′ may have a promising potential in the treatment of hyperlipidemia and coronary heart diseases.     

Functional aberrant expression of CCR2 receptor on chronically activated NK cells in patients with TAP-2 deficiency

Chemokines play a pivotal role in homeostatic and inflammatory migration of naive and activated natural killer (NK) subsets. Recent studies have shown that aberrant chemokine receptor expression on certain immune cells underlies the pathogenesis of clinical conditions in which recruitment of such cells is altered. Progressive accumulation of activated NK cells, subsequently resulting in the formation of chronic granulomatous lesions in the respiratory tract and the skin, has been described in a number of patients with transporter associated with antigen processing 2 (TAP-2) deficiency in the later stages of disease. Therefore, the goal of the present study was to elucidate whether the dysregulation of chemoattracting receptor expression on NK cells could explain abnormal navigation of these cells in TAP-2 deficiency. High-throughput proteomic comparison, followed by verification with flow cytometry, revealed that chronically activated NK cells derived from 3 newly identified patients with TAP-2 deficiency consistently expressed aberrant levels of CC chemokine receptor 2 (CCR2) chemokine receptor in vitro and in vivo. This expression pattern translated into specific responsiveness of chronically activated NK cells derived from patients with TAP-2 deficiency to multiple ligands of CCR2. Moreover, the in vivo elevated levels of interleukin-2 (IL-2) and monocyte chemoattractant protein-1 (MCP-1) detected in serum and bronchoalveolar lavage samples derived from these patients highlight the potential involvement of the CCR2 pathway in aberrant NK-cell retention at chronic inflammatory sites.     

Serum HCV-RNA levels in patients with chronic hepatitis C: Correlation with histological features

Background and study aimsLiver disease in chronic hepatitis C virus (HCV) infection ranges from minimal lesion to liver cirrhosis and sometimes eventually evolving hepatocellular carcinoma. Whether and how HCV determines the different clinical and histological manifestation of the disease is not fully understood. It has not been clearly elucidated whether the extent of liver injury induced by HCV is influenced mainly by direct cytopathic damage or by an immune-mediated response against HCV-infected hepatocytes. The aim of this study is to verify whether the amount of virus in individual patient’s serum could be related to the severity of liver injury.Patients and methodsThis study was carried out in the Gastroenterology and Hepatology Teaching Hospital, Medical City, Baghdad. Serum levels of HCV-RNA were measured in 27 patients with chronic HCV using b-DNA assay. Core liver biopsies of the patients were evaluated according to Ishak histological activity index system.ResultsThe serum HCV RNA concentrations in the patients ranged from 3.2 × 10³ to 1.2 × 10⁷ copies/ml. In all patients no correlation was observed between the variable levels of viraemia and the age of the patients. Furthermore no correlations were observed between the serum HCV RNA concentrations and the biochemical liver function test levels: Total serum bilirubin, AST, ALT, and alkaline phosphatase. Histologically; patients were categorized into four subgroups: four patients (14.8%) had minimal activity, 17 patients (63%) had mild activity, and six patients (22.2%) had moderate activity. No significant correlation was found between viraemic levels and these histological findings or their individual components: Interface hepatitis, confluent necrosis, intralobular liver cell necrosis and portal inflammation. According to the stage of the fibrosis, the patients were categorized into seven subgroups: one patient (3.7%) with stage zero, seven patients with stage one (25.9%), four patients with stage two (14.9%), eight patients with stage three (29.6%), three patients with stage four (11.1%), two patients with stage five (7.4%), and two patients in cirrhotic stage six (7.4%). There was no correlation between the serum HCV RNA concentration and the stage of fibrosis. Hepatic steatosis was observed in 16/27 patients. It was mild in nine patients, moderate in five patients, and severe in two patients. Correlation has not been observed between the serum HCV RNA viraemic level and the severity of steatosis.ConclusionSerum HCV-RNA level does not determine the degree of hepatic injury precisely and liver biopsy is necessary to accurately evaluate the extent of liver damage.     

Prevalence of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in 200 healthy Jordanians.

Thrombophilia is now considered a multi-causal condition, with interplay of acquired genetic risk factors. In order to estimate the frequency of the factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in the Jordanian population, we screened 200 healthy Jordanian individuals. 40% were females. Mean age was 32.1 years for males and 30.0 years for female participants. A PCR method detected 15.0% factor V Leiden (87% heterozygous, 13% homozygous), 2% prothrombin G20210A (100% heterozygous), and 24% MTHFR C677T (67% heterozygous, 33% homozygous). We conclude that the prevalence of factor V Leiden and MTHFR C677T is elevated in this population of Jordanians. However the incidence of G20210A is relatively low. Quantification of these genetic thrombosis risk factors in various populations will contribute to a better understanding of the interaction of genetic and environmental risk factors.     

Acquired and inherited thrombophilia: implication in recurrent IVF and embryo transfer failure

BACKGROUND: The objective of this study was to determine the incidence of undiagnosed thrombophilic factors and its relation to IVF and embryo transfer failure in women who have had three or more previous IVF-embryo transfer cycles. METHODS: The study group comprised of 90 consecutive women with three or more previously failed IVF-embryo transfer cycles (group A). Two control groups were enrolled: group B (n=90) included women who have had successful pregnancy after their first IVF-embryo transfer cycle, and group C (n=100) included women who conceived spontaneously with at least one uneventful pregnancy and no previous history of miscarriage. All women were tested for the presence of inherited [factor V Leiden (FVL) mutation, prothrombin mutation, methylenetetrahydrofolate reductase (MTHFR) mutation and deficiencies in proteins S and C and antithrombin III] or acquired (lupus anticoagulant and anticardiolipin) thrombophilic factors. RESULTS: An increase in the incidences of FVL, MTHFR and antiphospholipid antibodies was found in the study group compared with the two control groups. At least one inherited or acquired thrombophilic factor was detected in 68.9% of women with repeated IVF failure compared with 25.6 and 25% in the groups B and C, respectively (P<0.01). Combined thrombophilia (two or more thrombophilic factors) was significantly higher in women who have had repeated IVF failure as compared with the two control groups (35.6 versus 4.4 and 3%) (P<0.0001). CONCLUSION: Thrombophilia has a significant role in IVF-embryo transfer implantation failure. Women with repeated IVF-embryo transfer failure should be screened for thrombophilia.