Structural polymorphism of glycophorins demonstrated by immunoblotting techniques

We have explored the polymorphism of the glycophorin system in the human erythrocyte membrane using the immunoblotting techniques and examining 52 individuals selected without prior bias as to their serologic state and ten documented serologic variants of M, N, S, s blood group system. Polyclonal antisera to alpha glycophorin and to alpha glycophorin CNBr carboxyl terminal fragment C (residues 82-131) and M and N specific monoclonal antibodies (MoAbs) were used. The first two reagents detect specific regions of the alpha glycophorin molecule and all electrophoretically resolved species of glycophorins immunologically related to alpha and delta glycophorins (delta glycophorin, [alpha-delta] hybrids and other glycophorins with an alteration in the carboxyl terminal segment); the M and N MoAbs identified the glycophorin species containing or lacking the M or N determinant in the amino terminal octapeptide structures. We find that immunoblotting confirmed in all cases the serologically determined phenotype; we also find that polymorphic forms of the glycophorin system are relatively infrequent; immunoblotting, independent from serologic testing, was capable of detecting five mutants, two most likely S-s-U-phenotypes; a new glycophorin species was detected in normal red cells with both antiglycophorin and antipeptide C sera, which is not evident with MoAbs; immunoblots of known glycophorin variants (En(a-), U-, Mg, Mi I, II, III, V, and Sta) confirmed but also extended our knowledge of the abnormal glycophorins involved; and the He+ and Wrb(-) cells showed normal patterns.     

Cytogenetic and histologic correlations in malignant lymphoma

Although a number of studies have indicated correlations between histologic subtypes of tumors and certain nonrandom chromosome changes, cytogenetic studies of lymphoma are in an early stage compared to those of leukemia. No comprehensive analysis of available data has so far been attempted in the literature either. Here we present an analysis of chromosome changes and their correlation with subtypes of lymphoma studied by conventional histology and cell surface markers, as observed in two sets of data: a group of 65 karyotypically abnormal tumors sequentially ascertained and studied by us during the period January 1, 1984 to April 30, 1985, and a larger data set derived by combining our data with those from two published series from the University of Minnesota that are comparable to our data. These combined data, which comprise the largest data set on the cytogenetics of lymphomas assembled so far, enabled a comprehensive analysis of correlation between chromosome change and tumor histology and the patterns of chromosome instability in these tumors. We found several significant associations, some previously described and others now recognized, between nonrandom chromosome gains, breaks, translocations, and deletions and histologic subtypes of tumors that characterize lymphomas. The data indicate that finding of chromosome breaks at certain sites (eg, 8q24, 14q32, 18q21) is of diagnostic value in dealing with cases of unusual lymphoma. Furthermore, nonrandom chromosome breakage exhibited three distinct patterns that reflected three levels of etiologically relevant genetic change.     

Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma

Hemorrhagic tumor necrosis is an inflammatory event that leads to selective destruction of malignant tissues, with both potentially toxic and beneficial consequences. A pilot clinical trial was undertaken combining tumor necrosis factor-alpha (TNF-alpha) with the monoclonal antibody R24 (MoAb R24) against GD3 ganglioside in patients with metastatic melanoma. Patients received MoAb R24 to recruit leukocytes to the tumor followed by low doses of recombinant TNF-alpha to activate leukocytes. Eight patients were treated and seven patients had mild toxicity. One patient with extensive metastatic melanoma developed tumor lysis syndrome within hours after treatment with almost complete necrosis of bulky tumors in multiple visceral sites. To our knowledge, this is the first documented case of hemorrhagic tumor necrosis in a patient with metastatic cancer in multiple visceral sites.     

Efficacy and acceptability of rilmenidine for mild to moderate systemic hypertension

A double-blind multicenter trial compared rilmenidine with placebo in the treatment of 126 patients with mild to moderate hypertension after a 4-week placebo run-in period. Patients with mild hypertension (study 1) with mean supine diastolic blood pressure (BP) between 95 and 104 mm Hg received either rilmenidine 1 mg/day (n = 31) or placebo (n = 35) for 4 weeks. In study 2, patients with moderate hypertension (mean supine diastolic BP between 105 and 115 mm Hg) received either rilmenidine 1 mg twice a day (n = 30) or placebo twice a day (n = 30) for 4 weeks. All 61 patients taking rilmenidine completed the study; 8 of the 65 patients taking placebo were withdrawn because of an increase in BP. Rilmenidine significantly reduced mean systolic and diastolic BP compared with placebo in both studies. BP was normalized (systolic less than 160 mm Hg and diastolic less than or equal to 90 mm Hg in 61% of the patients taking rilmenidine as opposed to 23% of those taking placebo (p less than 0.001). There was no significant difference in the incidence of either dry mouth or daytime drowsiness between rilmenidine, 1 mg/day, and placebo. Dry mouth was significantly more frequent with rilmenidine, 2 mg/day, than with placebo, but this difference was transient and no longer significant at the end of the study. No unexpected adverse effects occurred. Rilmenidine as single therapy appears to be effective and well accepted in the management of mild to moderate hypertension, in particular at the 1-mg/day dose, which normalized 84% of mild hypertensive patients and did not induce any significant adverse effects compared with placebo.     

Hospital readmission after transvenous cardioverter/defibrillator implantation; a single centre study.

AIMS: Hospital readmission after implantation of cardioverter/defibrillators has a major impact on quality of life and cost-effectiveness in defibrillator patients. Rehospitalization has not been studied in large patient populations with modern transvenous defibrillation systems. METHODS AND RESULTS: We report on incidence, reasons, time in follow-up, duration and predictors of hospital readmission in 180 patients after transvenous implantation of a cardioverter/defibrillator during a follow-up period of 25+/-18 months. There were 156 readmissions in 79 patients with a 0.87 readmission rate per patient during the time followed, a 0.46 readmission rate per patient-year of follow-up and a 0.38 readmission rate per patient-year of follow-up for cardiac reasons. The majority of readmissions was caused by multiple appropriate shock interventions (26%), battery depletion (19%) and lead- and device-related complications (14%). The time to first hospital readmission was 12+/-9 months for arrhythmia-related and 20+/-16 months for other cardiac-related reasons (P<0.05), and could not be predicted by clinical variables, respectively. The duration of rehospitalization was 14+/-15 days for cardiac-related reasons and 12+/-17 days for arrhythmia-related reasons. Age >60 years was an independent predictor of rehospitalization time per patient-year of follow-up for both cardiac-related (P<0.005) and arrhythmia-related reasons (P<0.05). CONCLUSION: The rate of hospital readmission per patient-year of follow-up is as high as 0.46 after implantation of a modern cardioverter/defibrillator. Rehospitalization time in such patients is significantly longer in the patient cohort >60 years. The majority of readmissions is caused by multiple appropriate shock treatments. Further studies are needed to systematically investigate strategies for the prevention of rehospitalization in modern ICD therapy.     

Platelets modulate the proteolysis of factor VIII:C protein by plasmin

Factor VIII coagulant protein (VIII:C) functions as a critical cofactor with factor IXa, calcium ions, and phospholipid during the activation of factor X. In the course of this reaction, the activity of VIII:C is first increased and then is destroyed by one or more serine proteases that are part of the coagulation sequence. In this study, we have investigated the influence of platelets on the inactivation of VIII:C by plasmin. Platelets were separated from plasma proteins in the presence of granule release inhibitors and were incubated with plasmin and isolated VIII:C or the complex of purified VIII:C/von Willebrand factor (vWF); VIII:C activity and antigen levels were assessed over time. In the presence of platelets, the isolated VIII:C showed an initial increase in VIII:C activity that was not present when platelets were absent, and the VIII:C/vWF showed an increase in VIII:C activity over that seen when platelets were absent. In addition, platelets stabilized VIII:C activity over a one-hour time course when compared with buffer. The VIII:C antigen did not increase and decreased slowly whether platelets were present or absent. Preincubating the platelets with ristocetin, collagen, or plasmin did not alter the results, and experiments using platelets from a patient with severe von Willebrand's disease also showed a pattern similar to that seen with normal platelets. Experiments using fixed platelets or phospholipid vesicles showed that they did not support the activation reaction or delay the inactivation reaction. These studies demonstrate that platelets modulate the activation and inactivation of VIII:C by plasmin, apparently by a mechanism that is independent of the platelet release reaction.     

Bodily Maps of Emotion in Major Depressive Disorder

Cognitive Therapy and Research - Emotions play a central role in mental disorder and especially in depression. They are sensed in the body, and it has recently been shown in healthy participants...     

Current management of patients hospitalized with complicated skin and soft tissue infections across Europe (2010–2011): assessment of clinical practice patterns and real-life effectiveness of antibiotics from the REACH study

Complicated skin and soft tissue infections (cSSTI) are common and frequently require treatment in hospital. Comprehensive current data on management practices in patients hospitalized with cSSTI are limited. REACH was a retrospective, observational cohort study designed to provide data on current clinical management of moderate to severe cSSTI in European hospitals. Data were collected via an electronic case report form from 129 sites in ten European countries. The study population comprised patients ≥18 years, hospitalized between March 2010 and February 2011 with cSSTI who received intravenous antibiotic treatment. Presented here is an analysis of the disease characteristics, treatment patterns during hospitalization and clinical outcomes identified by the study. The total population included 1995 patients (mean age 60.6 years; 57.7% male). Initial antibiotic treatment modification was reported in 39.6% (n = 791) of patients; it was more common in patients with co-morbidities (42.6%), those requiring surgical intervention (43.4%), those with more severe infections such as bacteraemia (51.6%) or with fascia affected (49.0%), those admitted to the intensive care unit (56.2%) and those with lesions > 50 cm² (44.3%). A switch to narrower-spectrum antibiotic treatment (streamlining) occurred in 5.6% of patients. Mean length of hospital stay was 18.5 days (±19.9; median 12.0) and the total mortality rate was 3.4%. The data collected in REACH give a comprehensive and current view of real-life clinical management of cSSTI in European hospitals and provide evidence of a high rate of initial antibiotic treatment modification.     

Hematopoietic growth factor expression and ATRA sensitivity in acute promyelocytic blast cells

Acute promyelocytic leukemia (APL) is a homogeneous subgroup of acute myeloid leukemias (AMLs) characterized by the presence of the t(15,17) translocation and the resulting promyelocytic myeloid leukemia/retinoic acid receptor alpha (PML/RAR alpha) fusion proteins. To date APL is the only AML that is sufficiently sensitive to all-trans retinoic acid's (ATRA) differentiating effect. In vivo ATRA alone achieves complete remission in most APL patients. However, failure or partial responses are observed and the molecular basis of the absence of ATRA response in these patients has not been determined. To gain insights in the cell growth and differentiation of APL cells, expression of hematopoietic growth factors (HGF) shown to be produced by leukemic cells (interleukin-1 beta [IL-1 beta], IL-6, tumor necrosis factor alpha (TNF alpha), granulocyte colony-stimulating factor [G-CSF], granulocyte- macrophage colony-stimulating factor [GM-CSF], and IL-3) was studied in 16 APL samples. Twelve APL cases expressed IL-1 beta, IL-6, and TNF alpha, but not G-CSF, GM-CSF, and IL-3. These cases achieved complete remission with ATRA therapy. The four remaining patients (either TNF alpha negative or G-CSF, GM-CSF or IL-3 positive) did not achieve complete remission with ATRA. In all cases, in vivo response to ATRA therapy was correlated to the in vitro differentiation effect of all- trans retinoic acid 10(-6) mol/L. Thus, ATRA differentiation induction was strongly correlated to the HGF expression (P < .0001). These results suggest that the presence or absence of HGF's expression by APL cells may contribute to the therapeutic effect of ATRA in this disease.