Effect of α1-blockade with doxazosin in pulmonary hypertension associated with cirrhosis

Abstract

Background and objectives. Cardiovascular complications are common in liver transplant recipient. This study aims to evaluate functional and morphological myocardial changes in hepatitis C virus (HCV) patients with end-stage liver disease (ESLD) by cardiac magnetic resonance (CMR). Methods. This cross-sectional study included 84 patients with HCV-related ESLD. They were subjected to 2D-echocardiography and CMR. The presence, distribution, and percentage of delayed myocardial enhancement (DME) were estimated. Results. The mean Model for End-Stage Liver Disease score was 21.5 ± 6.3. In CMR, all patients showed good global left ventricular (LV) systolic function (mean ejection fraction = 66.5 ± 8.6%; range: 55–80) with normal wall thickness and motion. Left ventricle was mildly dilated in 25 patients (30%). Grade I and grade II diastolic dysfunction was detected in 81 patients (96.4%) with dilated left atrium in 25 patients (30%). Variable degrees of DME were detected in 70 patients (83.3%) with mean percentage of DME (%DME) being 19.5 ± 16% (range: 4–52). A significant negative correlation was found between %DME and LV ejection fraction (r = -0.7; p < 0.001), cardiac output (r = -0.5; p = 0.013), cardiac index (r = -0.5; p = 0.02), and serum albumin level (r = -0.5; p = 0.01). The %DME ≥19% was associated with 85.7% sensitivity and 85.7% specificity for detection of LV ejection fraction <60% as assessed by echocardiography (area under curve = 0.89; p = 0.001). Conclusion. DME with CMR is a common finding among patients with HCV-related ESLD. The extent of DME is significantly associated with global LV systolic function.     

Are bone defects in rare patients with Glanzmann's thrombasthenia associated with ITGB3 or ITGA2B mutations?

The question as to whether Glanzmann thrombasthenia patients with ITGB3 defects and deficiencies of both αIIbβ3 and αvβ3 show phenotypic differences to those with abnormalities exclusive to αIIbβ3 is unresolved. Studies on β3-deficient mice have shown an increased bone mass. Here we review the literature on bone defects in thrombasthenia patients and report the molecular analysis of a patient associating a lifelong thrombasthenia-like syndrome with skeletal defects. We show that the patient is compound heterozygote for Arg327His and Gly391Arg mutations in αIIb, with one mutation inherited from each parent. Modelling strongly suggested that both mutations act by destabilizing the αIIb beta propeller. So it appears likely that this patient has a combination of co-expressed genetic defects.     

Are differences in interleukin 10 production associated with joint damage?

OBJECTIVE: Constitutive differences between individuals in cytokine production may determine the variation in the course of inflammatory arthritis. METHODS: The association between interleukin 10 (IL-10) production and joint destruction was studied by comparing IL-10 mRNA content in synovial biopsies from seven patients with destructive joint disease and six patients with non-destructive joint disease. The IL-10 mRNA content was 0.4 +/- 0.6 arbitrary units in erosive joints compared with 2.3 +/- 1.2 arbitrary units in non-erosive joints (P: < 0.03, Mann-Whitney U:-test). As this difference suggested that IL-10 production was associated with joint destruction, we tested whether the IL-10 locus determined the extent of joint damage. RESULTS: Innate differences in IL-10 production are locus-dependent. In line with these data, we showed that innate differences in IL-10 protein production were also present as differences in IL-10 mRNA levels. We tested if polymorphisms in the promoter of IL-10 were associated with the extent of joint damage. DISCUSSION: In a cohort study of female rheumatoid arthritis patients followed for 12 yr, the extent of joint destruction differed significantly between patients with different IL-10 genotypes. In patients with the -1082AA genotype who were studied prospectively, the mean increase in radiographic damage score (modified Sharp score of X-rays of hands and feet) during the first 6 yr was 9 +/- 9 per yr vs 19 +/- 16 per yr for patients with the genotype -1082GG (P: < 0.02). In line with these data, cultures of endotoxin-stimulated whole blood from 158 donors showed that the presence of the allele associated with less joint destruction correlated with slightly higher IL-10 production. CONCLUSIONS: Both the immunogenetic and the synovial biopsies suggest that a variation in IL-10 production is associated with joint destruction.     

Are bone defects in rare patients with Glanzmann's thrombasthenia associated with ITGB3 or ITGA2B mutations?

The question as to whether Glanzmann thrombasthenia patients with ITGB3 defects and deficiencies of both αIIbβ3 and αvβ3 show phenotypic differences to those with abnormalities exclusive to αIIbβ3 is unresolved. Studies on β3-deficient mice have shown an increased bone mass. Here we review the literature on bone defects in thrombasthenia patients and report the molecular analysis of a patient associating a lifelong thrombasthenia-like syndrome with skeletal defects. We show that the patient is compound heterozygote for Arg327His and Gly391Arg mutations in αIIb, with one mutation inherited from each parent. Modelling strongly suggested that both mutations act by destabilizing the αIIb beta propeller. So it appears likely that this patient has a combination of co-expressed genetic defects.     

Risk factors for retinopathy associated with interferon α-2b and ribavirin combination therapy in patients with chronic hepatitis C

AIM: To elucidate the frequency and risk factors for retinopathy in patients with chronic hepatitis C who are treated by interferon-ribavirin combination therapy. METHODS: We prospectively analyzed 73 patients with histologically confirmed chronic hepatitis C, who underwent combination therapy for 24 wk. Optic fundi were examined before, and 2, 4, 12 and 24 wk after the start of combination therapy. RESULTS: Fourteen patients (19%) developed retinopathy, which was initially diagnosed by the appearance of a cotton wool spot in 12 patients. Retinal hemorrhage was observed in 5 patients. No patient complained of visual disturbance. Retinopathy disappeared in 9 patients (64%) despite the continuation of combination therapy. However, retinopathy persisted in 5 patients with retinal hemorrhage. A comparison of the clinical background between the groups with and without retinopathy showed no significant differences in age, gender, viral genotype, RNA level, white blood cell count, platelet count, prothrombin time, complications by diabetes mellitus or hypertension, or pretreatment arteriosclerotic changes in the optic fundi. However, multiple logistic regression analysis revealed that complication by hypertension was observed with a high frequency in the group with retinopathy (P = 0.004, OR = 245.918, 95% CI = 5.6-10786.2). CONCLUSION: Retinopathy associated with combination therapy of interferon alpha-2b and ribavirin tends to develop in patients with hypertension.     

Up-regulation of α-catenin is associated with increased lymph node involvement in colorectal cancer

AIM： To investigate the changing pattern of α-catenin expression and its relationship to clinical and pathological features of colorectal cancer （CRC） patients. METHODS： Archival tumor samples were analyzed using immunohistochemistry （IHC） for α-catenin in 91 patients with advanced CRC. RESULTS： The values of α-catenin membrane index （MI） and cytoplasmic index （CI） were significantly related to the depth of tumor invasion （P = 0.027, P = 0.020, respectively）, high indices being associated with increased depth of the primary tumor invasion （T3 and T4）. Similarly, patients with high α-catenin expression had a significantly increased risk of lymph node metastasis （32/39 vs 37/52 for MI and 37/45 vs 32/46 for CI） （P = 0.001, P = 0.0001, respectively, for LNN status）. An altered expression （i.e., cytoplasmic pattern） was also related （P = 0.047） to the response to chemotherapy; patients with low CI were more responsive （CR： 7/46） than patients with high CI values （CR： 0/45）. There was a marginal effect on survival in patients time with metastases （SWM） （P = 0.087）; patients with low CI showing slightly longer SWM, but no such effect on disease free survival （DFS） or disease specific survival （DSS）. As to co-expression with another member of the adhesion complex （β-catenin）, high α-catenin/β-catenin MI index was of marginal significance in predicting longer DSS （P = 0.063, log-rank）. CONCLUSION： The results implicate that high α-catenin expression is intimately involved in the key regulatory mechanisms leading to invasive phenotype, lymph node metastases, and progressive disease in CRC.     

Hb Chad or α223(B4)GLU→LYSβ2 Observed in Members of a Surinam Family in Association with α-Thalassemia-2 and with HB S

Three different hemoglobinopathies, i.e. Hb S, Hb Chad [α23 (B4)Glu→Lys], and α-thalassemia-2 (?3.7) have been observed in eight members of a family from Surinam. The proposita had all three abnormalities, while her mother and four of her half-brothers had Hb Chad together with an α-thalassemia-2 heterozygosity or homozygosity. Gene mapping and dot-blot analysis of amplified DNA identified a G→A mutation in codon 23 of the α2αl hybrid gene resulting in the Glu→Lys substitution. The quantity of the α-Chad chain averaged 31.5% in its carriers with an additional α-thalassemia-2 heterozygosity [-α^Cnad(?3.7 kb)/ α α], and 43% in the two carriers with an additional α-thalassemia-2 homozygosity [-α^Chad(?3.7 kb)/- α (3.7 kb)]. These quantities are considerably higher than those reported for families from Chad, China, and Japan; the low levels of 14.5-24% Hb Chad in members of previously reported cases suggest a mutation on a chromosome with two α-globin genes [α α^Chad/α α or α^Chadα/ α α].     

Platelet FcγRIIA expression is associated with the α2 integrin C807T gene polymorphism in type 2 diabetes

“Patelet” FcγRIIA is stably overexpressed in type 2 diabetes and may also play a role in collagen-mediated platelet activation. Platelet surface integrin α₂β₁–collagen interaction is an early step associated with platelet adhesion and activation and plays an important role in arterial thrombosis. The objective of this study was to characterize the relationship in diabetes and non-diabetes platelets between FcγRIIA expression and a polymorphism associated with arterial thrombotic events, polymorphism C807T on the gene encoding α₂β₁. Platelet flow cytometry and allele-specific PCR revealed a significant correlation in type 2 diabetes between low platelet FcγRIIA expression and the 807TT genotype that is associated with increased platelet α₂β₁ receptor density. We conclude that uni- or bi-directional modulation of surface expression may exist between the platelet FcγRIIA receptor and a α₂β₁ thrombogenic polymorphism that could play a role in platelet sensitivity to collagen in type 2 diabetes.     

Anti-β<Subscript>2</Subscript>-glycoprotein I in Sjogren’s syndrome is associated with parkinsonism

The nervous system may be involved in up to 30% of patients with Sjogren’s syndrome (SS). We describe three patients with Sjogren’s syndrome and a concomitant parkinsonian syndrome. Elevated titers of anti-β₂-glycoprotein I IgG were found in the serum of all three patients. This autoantibody is strongly associated with anticardiolipin (aCL) antibodies, antiphospholipid syndrome (APS), and thromboembolic phenomena, but its role in the pathogenesis of the parkinsonian disorder in SS is unclear. These patients may present a subtype of SS patients in which the presence of aCL antibodies is associated with central nervous system involvement predominantly in the basal ganglia. Sharon Hassin-Baer and Levy Yair contributed equally to this work.     

Protection by Intragastric Polyethylene Glycol 400 in Rat Stomach Against Ethanol Damage Involves α2-Adrenoceptors

The aim of this study was to investigate the role of ₂-adrenoceptors in the mechanism of intragastric polyethylene glycol 400 (PEG-400) protection against ethanol-induced gastric mucosal damage. In the injury study, 0.5 hr after subcutaneous control or yohimbine (5 mg/kg), a selective ₂-adrenoceptor antagonist, rats were treated with intragastric vehicle or PEG-400 (5500 mg/kg). One hour later animals received 96% ethanol (gavage needle), 5 ml/kg, and the rats were killed after another hour. Total lengths of the gastric mucosal lesions were measured by an unbiased observer in a blinded fashion using a binocular magnifier having 5× magnification. In a separate set of experiments, 0.5 hr after subcutaneous control or yohimbine (5 mg/kg) rats received intragastric vehicle or PEG-400 (5500 mg/kg). One hour later gastric mucus volume, gastric juice volume, and gastric acid output in the gastric juice were measured. The protective effect offered by intragastric PEG-400 against ethanol-induced gastric mucosal damage was significantly diminished although not completely abolished by a selective ₂-adrenoceptor antagonist (yohimbine). Yohimbine also significantly diminished both the basal and PEG-400-stimulated increase in gastric mucus volume. These findings suggest that the protective effect afforded by intragastric PEG-400 against ethanol-induced gastric mucosal damage is partially mediated by ₂-adrenoceptors, and a mucus-dependent mechanism may be involved.     

Serum α2-HS glycoprotein concentration in patients with hematological malignancies

Summary We observed significantly reduced serum ₂-HS glycoprotein concentrations in patients with acute lymphocytic, acute nonlymphocytic, chronic granulocytic and chronic myelomonocytic leukemias, Hodgkin's and non-Hodgkin's lymphomas, myelofibrosis, and multiple myeloma, but not in patients with chronic lymphocytic leukemia and polycythemia vera, as compared with healthy controls. We followed the serum level of the protein for 18 months. Patients with infectious complications, those receiving cytostatic treatment, and those in the preterminal period had further reduced serum ₂-HS glycoprotein levels. The reduction of serum ₂-HS glycoprotein concentration was primarily due to decreased production caused by infiltration of the liver, a hepatotoxic effect of cytostatic treatment, and, to a lesser degree, to increased consumption. We found statistically significant negative correlations between serum ₂-HS glycoprotein concentration and erythrocyte sedimentation rate, serum aspartate aminotransferase and alkaline phosphatase activities, and IgG and IgM concentrations. The determination of the ₂-HS glycoprotein concentration is useful for the assessment and follow-up of the clinical status and therapy of patients with hematological malignancies and also has prognostic significance.This work was supported by the Hungarian Academy of Sciences OTKA No. 161     

Immunosuppressive treatment in patient with pure red cell aplasia associated with chronic myelomonocytic leukemia: harm or benefit?

Acquired pure red cell aplasia (PRCA) can be primary or secondary to other diseases. PRCA association with chronic myelomonocytic leukemia (CMML) is very rarely reported. Although treatment is directed to underlying cause in secondary PRCA treatment, optimal treatment in patients with CMML and PRCA is unknown, because only four case reports are available. In addition, the effect of hypomethylating agents can be detrimental due to myelosuppression, at least in the early phase of treatment. Bone marrow examination of a 66-year-old woman with severe anemia revealed PRCA and was suspicious for CMML. There was no HLA-matched sibling for bone marrow transplantation. The patient received immunosuppressive therapy with steroids and cyclosporine with temporary response in anemia; however, progressed to acute leukemia over 8 months and died. Immunosuppressive therapy in patients with CMML and PRCA should be cautiously used because it may accelerate acute leukemia transformation.     

Proteinuric renal disease in type 2 diabetes—Is remission of proteinuria associated with improved mortality and morbidity?

Aims

Patients with type 2 diabetes and macroalbuminuria are at high risk for end stage renal disease (ESRD), cardiovascular disease and death, but remission of proteinuria may improve prognosis. We examine the effectiveness of currently recommended treatments on inducing remission of proteinuria, and on morbidity and mortality.

Methods

Observational study of 78 patients with type 2 diabetes (46 male) with mean age (SD) of 61.5 (11) years, with a urinary albumin/creatinine ratio (ACR) ≥ 50 mg/mmol. All were treated with agents blocking the renin–angiotensin system. Follow-up was from recognition of ACR ≥ 50 mg/mmol until death or March 2011 (median 6 years). Remission of proteinuria was defined as ≥70% reduction from peak ACR, sustained for ≥1 year.

Results

Only 22 of 78 patients (28%) achieved remission of proteinuria. Thirty-six (46%) had at least one major event (death, dialysis or cardiovascular). Remission of proteinuria was associated with lower incidence of ESRD/death (9% vs 36%; p = 0.02) but cardiovascular events were not reduced (32% vs 30%). A third of patients had no retinopathy when albuminuria was first recognised, suggesting that non-diabetic renal pathologies were prominent. There was a significant interaction between the severity of diabetic retinopathy and remission of proteinuria on the risk of ESRD/death (p = 0.0003).

Conclusions

Remission of proteinuria was achieved in only a third of patients despite efforts to achieve blood pressure targets <130/80 mmHg. Failure to attain remission of proteinuria was associated with increased risk of ESRD or death, a risk compounded by the presence of severe diabetic retinopathy.     

Is the metabolic syndrome, with or without diabetes, associated with progressive disability in older Mexican Americans?

BACKGROUND: The metabolic syndrome (MetS) is highly prevalent in the growing U.S. Latino population. We hypothesize that MetS, with or without diabetes, is associated with progressive disability in older Mexican Americans. METHODS: Data from Mexican Americans 60-98 years old participating in the Sacramento Area Latino Study on Aging (SALSA) were analyzed from baseline through 3 years (3 years of follow-up). Disability was assessed by self-reported limitations in activities of daily living (ADLs), instrumental ADLs (IADLs), and mobility/strength tasks. MetS (46% of sample) was defined by National Cholesterol Education Program (NCEP) Adult Treatment Panel III criteria. Diabetes (DM, 33%) was defined by fasting blood sugar>125 mg/dL, physician diagnosis, and/or medication use. Four metabolic groups were defined: MetS with diabetes (MetS+DM+, n=402); MetS without diabetes (MetS+DM-, n=330); diabetes without MetS (MetS-DM+, n=125); and neither (MetS-DM-, n=749). Generalized estimating equation (GEE) regression models were used to evaluate the effect of metabolic group on physical limitations and disability changes over time. RESULTS: Diabetes, with or without MetS, was associated with a higher percent rate of increase over 3 years in ADL and IADL disability than was no diabetes, even after controlling for demographics, body mass index (BMI), and incident disease. The mean ADL score had a 35% higher rate of increase (higher = more impairment) for the MetS+DM+ group and 68% higher for the MetS-DM+ group. Results for IADL were similar. The baseline MetS, without or with diabetes, was associated with a significantly higher rate of increase in mobility/strength limitations (8% and 36.5%, respectively). CONCLUSIONS: In older Mexican Americans, MetS is associated with progressive limitations in mobility and strength. Preventing progressive mobility/strength limitations may require assessing and treating these impairments in people with MetS regardless of the presence of diabetes. However, preventing the progression of MetS without to MetS with diabetes may be important to limit the progression of ADL and IADL disability found in people with MetS and diabetes.