Apparent mineralocorticoid excess (AME) syndrome

Apparent mineralocorticoid excess (AME) syndrome is a rare autosomal recessive disorder due to the deficiency of 11β hydroxysteroid dehydrogenase type 2 enzyme (11beta-HSD2). Mutations in this gene affect the enzymatic activity resulting to an excess of cortisol, which causes its inappropriate access to mineralocorticoid receptor leading to inherited hypertension. This is a potentially fatal but treatable disorder. We present clinical and molecular studies on two sisters diagnosed as AME.     

Post-transplant infections: single center experience from the developing world.

OBJECTIVE: To describe our experience of post-transplant infections in allogeneic stem cell transplants at the Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan. METHODS: From July 2001 to September 2006, patients with malignant and non-malignant hematological disorders having human leukocyte antigen (HLA)-matched sibling donors were selected for transplant. Pre-transplant infection surveillance was carried out, and strict prophylaxis against infection was observed. After admission to the hospital, patients were kept in protective isolation rooms, equipped with a HEPA filter positive-pressure laminar airflow ventilation system. Bone marrow and/or peripheral blood stem cells were used as the stem cell source. Cyclosporin and prednisolone were used as prophylaxis against graft-versus-host disease (GVHD). The engraftment was monitored with cytogenetic/molecular analysis and change of blood group. Survival was calculated from the date of transplant to death or last follow-up. RESULTS: One hundred and fifty-four patients received allogeneic stem cell transplants from HLA-matched siblings for various hematological disorders at the Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan between July 2001 and September 2006. Indications for transplant included aplastic anemia (n=66), beta-thalassemia major (n=40), chronic myeloid leukemia (n=33), acute leukemia (n=8), and miscellaneous disorders (n=7). One hundred and twenty patients were male and 34 were female. The median age of the patient cohort was 14 years (range 1 1/4-54 years). One hundred and thirty-six patients and 135 donors were cytomegalovirus (CMV) IgG-positive. One hundred and forty patients (90.9%) developed febrile episodes in different phases of post-transplant recovery. Infective organisms were isolated in 150 microbiological culture specimens out of 651 specimens from different sites of infections (23.0% culture positivity). Post-transplant infections were confirmed in 120 patients (77.9%) on the basis of clinical assessment and microbiological, virological, and histopathological examination. Mortality related to infections was 13.0%. Fatal infections included CMV disease (100% mortality, 6/6), disseminated aspergillosis (66.7% mortality, 4/6), pseudomonas septicemia (42.9% mortality, 9/21), and tuberculosis (25% mortality, 1/4). CONCLUSIONS: More than 90% of our patients developed febrile episodes with relatively low culture yield. The majority of infections were treated effectively, however CMV, aspergillosis, and pseudomonas infections remained problematic with high mortality.     

Comparison of lesion sizes produced by cryoablation and open irrigation radiofrequency ablation catheters

Introduction: The relative lesion sizes created by large electrode cryoablation catheter and irrigated radiofrequency (RF) ablation are not known. The purpose of this study was to directly compare lesion sizes created by cryoablation and irrigated RF under controlled conditions.
Methods and Results : Ablation lesions were created in freshly harvested porcine left ventricular myocardium in a blood-filled tissue bath using an 8-mm-tip cryoablation catheter and a 3.5-mm-tip open-irrigated RF ablation catheter. Lesions were created under all permutations of the following conditions: electrode orientation vertical (perpendicular) or horizontal (parallel) to the tissue, electrode contact pressure at 6 or 20 g, and blood flow at 0.2 or 0.4 m/s over the electrode-tissue interface. The largest lesion volumes created with cryoablation were 961 ± 103 mm³, compared with the largest lesions volumes created with RF of 680 ± 48 mm³ (P < 0.001). The 3-way interactions among electrode orientation, contact pressure, and superfusate blood velocity accounted for the variation in lesion volumes for both catheters (both r²= 0.97, both P < 0.0001). The greater contact pressure increased lesion size for both cryoablation and RF. For cryoablation, lesion sizes were increased by the horizontal orientation and by the lower blood flow velocity. For open-irrigated RF, lesion sizes were significantly reduced by the horizontal orientation, however.
Conclusions : Depending on conditions of electrode orientation, contact pressure, and blood velocity, either 8-mm-tip cryoablation or open-irrigated RF may produce the larger lesion volumes. Open-irrigated RF lesion sizes are reduced in the horizontal catheter orientation.     

Gene-Specific Differential DNA Methylation and Chronic Arsenic Exposure in an Epigenome-Wide Association Study of Adults in Bangladesh

Background: Inorganic arsenic is one of the most common naturally occurring contaminants found in the environment. Arsenic is associated with a number of health outcomes, with epigenetic modification suggested as a potential mechanism of toxicity.Objective: Among a sample of 400 adult participants, we evaluated the association between arsenic exposure, as measured by blood and urinary total arsenic concentrations, and epigenome-wide white blood cell DNA methylation.Methods: We used linear regression models to examine the associations between arsenic exposure and methylation at each CpG site, adjusted for sex, age, and batch. Differentially methylated loci were subsequently examined in relation to corresponding gene expression for functional evidence of gene regulation.Results: In adjusted analyses, we observed four differentially methylated CpG sites with urinary total arsenic concentration and three differentially methylated CpG sites with blood arsenic concentration, based on the Bonferroni-corrected significance threshold of p < 1 × 10^–7. Methylation of PLA2G2C (probe cg04605617) was the most significantly associated locus in relation to both urinary (p = 3.40 × 10^–11) and blood arsenic concentrations (p = 1.48 × 10^–11). Three additional novel methylation loci—SQSTM1 (cg01225779), SLC4A4 (cg06121226), and IGH (cg13651690)—were also significantly associated with arsenic exposure. Further, there was evidence of methylation-related gene regulation based on gene expression for a subset of differentially methylated loci.Conclusions: We observed significant associations between arsenic exposure and gene-specific differential white blood cell DNA methylation, suggesting that epigenetic modifications may be an important pathway underlying arsenic toxicity. The specific differentially methylated loci identified may inform potential pathways for future interventions.Citation: Argos M, Chen L, Jasmine F, Tong L, Pierce BL, Roy S, Paul-Brutus R, Gamble MV, Harper KN, Parvez F, Rahman M, Rakibuz-Zaman M, Slavkovich V, Baron JA, Graziano JH, Kibriya MG, Ahsan H. 2015. Gene-specific differential DNA methylation and chronic arsenic exposure in an epigenome-wide association study of adults in Bangladesh. Environ Health Perspect 123:64–71; http://dx.doi.org/10.1289/ehp.1307884     

Inhibition of hepatitis B virus DNA replicative intermediate forms by recombinant interferon-γ

AIM: To evaluate the in vitro anti-HBV activity of recombinant human IFN-γ, alone and in combination with lamivudine.METHODS: A recombinant baculovirus-HBV/HepG2 culture system was developed which could support productive HBV infection in vitro. Expression of HBsAg and HBeAg in infected HepG2 culture medium was detected by commercial enzyme immunoassays. HBV DNA replication intermediates were detected in infected cells by Southern hybridization and viral DNA load was determined by dot hybridization.RESULTS: IFN-γ at 0.1 to 5 μg/L efficiently down regulated HBsAg expression in transduced HepG2 cells.At 5 μg/L, IFN-γ also suppressed HBV DNA replication in these cells. While treatment with a combination of lamivudine and IFN-γ showed no additive effect,sequential treatment first with lamivudine and then IFN-γ was found to be promising. In this culture system the best HBV suppression was observed with a pulse of 2 μmol/L lamivudine for two days, followed by 1 μg/L IFN-γ for another four days. Compared to treatment with lamivudine alone, the sequential use of 0.2 μmol/L lamivudine for two days, followed by 5 μg/L IFN-γ for six days showed a 72% reduction in HBV cccDNA pool.CONCLUSION: This in vitro study warrants further evaluation of a combination of IFN-γ and lamivudine,especially in IFN-α non-responder chronic hepatitis B patients. A reduced duration of lamivudine treatment would also restrict the emergence of drug-resistant HBV mutants.     

Nonionic contrast medium: effects on blood coagulation and complement activation in vitro

A nonionic contrast medium was evaluated in vitro for its effects on coagulation and complement activation in comparison to a low osmolal contrast agent. In clotting assays each contrast medium was mixed with blood and clotting parameters were analyzed by using a thromboelastographic machine. Platelet function was studied by incubating platelet-rich plasma with individual contrast medium, and the subsequent challenge of a platelet aggregating agent. Complement activation was assessed by the hydrolysis of C3 protein into C3c fragment in contrast medium-incubated serum. Immunoelectrophoresis was used to detect C3c protein. Both the nonionic contrast medium and the low osmolal contrast agent acted as anticoagulant and antiplatelet agents, however, results with the low osmolal contrast agent were more pronounced compared to the nonionic contrast medium. Even at nonphysiologic concentration of contrast medium, no significant conversion at C3 to C3c was seen. Since these two agents caused hypocoagulable states in vitro, it is likely that patients with thrombocytopenia, severe liver disease and with clotting factor deficiencies may present hemostatic complications during angiographic procedures.