Randomized controlled trial of pulse methyl prednisolone × placebo in treatment of pulmonary involvement associated with severe leptospirosis. [ISRCTN74625030]

Background

The lungs are involved in up to 70% of cases of leptospirosis. In the more severe forms-bleeding from the lungs and acute respiratory distress syndrome-the lethality is high. The treatment proposed for leptospirotic pneumonitis includes just care for patients in critical condition. Clinical and experimental studies point to the involvement of immunological mechanisms in the physiopathology of lung damage caused by leptospirosis. The aim of this study is to evaluate pulse treatment with methylprednisolone × placebo for leptospirotic pneumonitis.

Study design

This is a randomized double-blind clinical trial to test the efficacy of pulse treatment with methylprednisolone in patients with leptospirotic pneumonitis, compared with a placebo. The patients are recruited from three hospitals in the city of Recife, in the Brazilian State of Pernambuco. The exclusion criteria include patients aged under 15 years, a history of hypersensitivity to the use of corticosteroids, the presence of active infection of fungal, tuberculous or bacterial origin apart from the infection by leptospira itself, the presence of hemoconcentration or atypical lymphocyte count on admission to hospital, the presence of co-morbidities that could be responsible for the radiological and gasometric alterations used to diagnose leptospirotic pneumonitis, evidence of recent cranial trauma, neurosurgery, peptic ulcer, and participation in another clinical trial. The patients are followed until they are discharged from hospital or die. The intervention consists of endovenous pulse treatment with 1 g methylprednisolone for three consecutive days in the study group and a placebo in the control group. The primary end-point is mortality from leptospirotic pneumonitis. The secondary end-points are: evolution of lung disease; the occurrence of nosocomial respiratory infection; duration of mechanical ventilation; duration of intensive care unit (ICU) stay; duration of hospital stay; occurrence of other infection-related complications; other respiratory complications; and adverse effects of methylprednisolone. The study is designed to recruit 266 patients and has a statistical "power" of 80% to detect a 50% reduction in mortality.

Discussion

Lung involvement in leptospirosis is a serious manifestation, with a high and variable mortality rate. There is still no specific clearly-established treatment. Well-designed studies are needed to pave the way towards development of such a treatment.

     

Salmon calcitonin nasal spray in the prevention of corticosteroid- induced osteoporosis

The objectives were to determine the efficacy and safety of nasal salmon calcitonin 200 IU daily in the prevention of corticosteroid- induced osteoporosis. A minimized, double-blind, placebo-controlled trial was carried out in corticosteroid-treated patients with polymyalgia rheumatica. The setting was a tertiary care university- affiliated hospital and a total of 31 patients were enrolled. The primary outcome measure was the percentage change in bone mineral density of the lumbar spine in the two treatment groups from baseline to 1 yr of follow-up. The mean +/- S.D. bone mineral density of the lumbar spine in the calcitonin-treated group decreased by 1.29 +/- 6.76% and in the placebo group by 4.95 +/- 3.50% after 12 months. The observed difference of 3.65 +/- 2.10% between groups is statistically significant (P < 0.05). Nasal salmon calcitonin prevented loss of bone in the lumbar spine as measured by dual-energy X-ray absorptiometry.      

Overexpression of cyclin D1 in the Dami megakaryocytic cell line causes growth arrest

The maturation of megakaryocytes in vivo requires polyploidization or repeated duplication of DNA without cytokinesis. As DNA replication and cytokinesis are tightly regulated in somatic cells by cyclins and cyclin-dependent kinases, we sought to determine the pattern of cyclin gene expression in cells that undergo megakaryocytic differentiation and polyploidization. The Dami megakaryocytic cell line differentiates and increases ploidy in response to phorbol 12-myristate 13-acetate (PMA) stimulation in vitro. We used Northern blotting to analyze mRNA levels of cyclins A, B, C, D1, and E in PMA-induced Dami cells and found that cyclin D1 mRNA levels increased dramatically (18-fold). Similar increases in cyclin D1 mRNA were obtained for other cell lines (HEL and K562) with megakaryocytic properties, but not in HeLa cells. The increase in cyclin D1 was confirmed by Western immunoblotting of PMA-treated Dami cells. This finding suggested that cyclin D1 might participate in megakaryocyte differentiation by promoting endomitosis and/or inhibiting cell division. To address these possibilities, we constructed two stable Zn+2-inducible, cyclin D1-overexpressing Dami cell lines. Cyclin D1 expression alone was not sufficient to induce polyploidy, but in conjunction with PMA-induced differentiation, polyploidization was slightly enhanced. However, unlike other cell systems, cyclin D1 overexpression caused cessation of cell growth. Although the mechanism by which cyclin D1 may affect megakaryocyte differentiation is not clear, these data demonstrate that cyclin D1 is upregulated in differentiating megakaryocytic cells and may contribute to differentiation by arresting cell proliferation.     

Hazardous drinking is associated with an elevated aspartate aminotransferase to platelet ratio index in an urban HIV-infected clinical cohort

Objectives

The aim of the study was to determine the relationship between alcohol consumption and liver fibrosis as assessed by aspartate aminotransferase to platelet ratio index (APRI) in HIV‐infected adults and to explore the relative contributions of alcohol and hepatitis C virus (HCV) to APRI among HIV/HCV‐coinfected adults.

Methods

We performed a cross‐sectional analysis of data from an observational clinical cohort. Alcohol consumption was categorized according to National Institute on Alcohol Abuse and Alcoholism guidelines. We defined significant liver disease as APRI>1.5, and used multinomial logistic regression to identify correlates of increased APRI.

Results

Among 1358 participants, 10.4% reported hazardous drinking. It was found that 11.6% had APRI>1.5, indicating liver fibrosis. Hazardous drinking was associated with increased APRI [adjusted relative risk ratio (RRR) 2.30; 95% confidence interval (CI) 1.26–4.17]. Other factors associated with increased APRI were male gender, viral hepatitis, and HIV transmission category of injecting drug use. Among coinfected individuals, 18.3% had APRI>1.5, and hazardous drinking was not associated with APRI. Among non‐HCV‐infected individuals, 5.3% had APRI>1.5 and hazardous drinking was associated with increased APRI (adjusted RRR 3.72; 95% CI 1.40–9.87).

Conclusions

Hazardous drinking is an important modifiable risk factor for liver fibrosis, particularly among non‐HCV‐infected patients. Clinicians and researchers must address alcohol use as the burden of liver disease increases among HIV‐positive individuals.     

Association of HLA-DR with susceptibility to and clinical expression of rheumatoid arthritis: re-evaluation by means of genomic tissue typing

The clinical expression of rheumatoid arthritis (RA) varies considerably among individual patients. Genetic variations in human leucocyte antigen (HLA) may influence clinical expression. We re- examined the association of HLA-DR with susceptibility to and clinical expression of RA using genomic tissue typing, since most studies were based on (less reliable) serological techniques. Seventy-eight patients with recent-onset RA, all participating in a clinical trial on therapeutic strategies, were HLA-DR typed by means of low-resolution genomic typing. Cumulative disease activity within the first 3 yr of disease was measured. Of the RA patients, 54% expressed DR4 (DR4+) vs 26% of healthy controls. Rheumatoid factor (RF)-positive patients had a higher cumulative disease activity than RF-negative patients. Patients who were either DR1+ or DR4+ had a higher cumulative disease activity than those who expressed neither DR1 nor DR4. This association was less obvious after correction for RF status. The association of DR52+ (DR3, 5, 6) and a lower cumulative disease activity could also not be demonstrated after correction for RF status. Among RF-negative patients, DR51+ (or DR2+) was associated with a higher cumulative disease activity. Other HLA-DR types (including DR1 and DR4 separately) were not associated with the severity of RA. DR4 was associated with susceptibility to RA in our patients; HLA-DR low-resolution genomic tissue typing did not yield additional information to RF status for the clinical identification of individual patients with a poor prognosis.      

Study of constancy of hydrogen-consuming flora of human colon

The constancy of the hydrogen consuming flora of the human colon was studied in 15 healthy subjects via two measurements obtained 18 to 36 months apart. Hydrogen disappearance rate and the major products of H₂-consuming bacteria, methane and sulfide, were measured during incubation of fecal homogenates with excess hydrogen and sulfate. In 11/15, the hydrogen consumption rate and the predominant hydrogen-consuming pathway (methanogenesis, sulfate reduction, or neither) remained constant. However, major shifts in these pathways were observed in four subjects, with two losing and two gaining the ability to produce methane. Methanogenesis was associated with the highest hydrogen consumption rate. This study demonstrates that clinically unrecognizable, major alterations of the colonic flora occur in healthy subjects. Understanding of the factors responsible for these alterations might allow for therapeutic manipulation of the colonic flora.Supported in part by the Department of Veterans Affairs and NIDDKD RO1 DK 13309-25.     

A controlled trial of recombinant human erythropoietin after bone marrow transplantation

Recombinant human erythropoietin (rHuEPO) stimulates erythropoietic bone marrow cells and increases erythrocyte production. This prospective study was designed to evaluate the effects of rHuEPO on regeneration of erythropoiesis after allogeneic or autologous bone marrow transplantation (BMT). Seventeen centers participated in this randomized, double-blind, placebo-controlled multicenter trial. The randomization was performed centrally for each center and stratified according to allogeneic or autologous BMT and major ABO-blood group incompatibility. One hundred and six patients received rHuEPO after allogeneic BMT and 109 patients received placebo. After autologous BMT, 57 patients were treated with rHuEPO and 57 with placebo. Patients received either 150 IU/kg/day C127 mouse-cell-derived rHuEPO or placebo as continuous intravenous infusion. Therapy started after bone marrow infusion and lasted until independence from erythrocyte transfusions for 7 consecutive days with stable hemoglobin levels > or = 9 g/100 mL or until day 41. After allogeneic BMT, the reticulocyte counts were significantly higher with rHuEPO from day 21 to day 42 after BMT. The median time (95% confidence intervals) to erythrocyte transfusion independence was 19 days (range, 16.3 to 21.6) with rHuEPO and 27 days (range, 22.3 to > 42) with placebo (P < .003). The mean (+/- SD) numbers of erythrocyte transfusions until day 20 after BMT were 6.6 +/- 4.8 with rHuEPO and 6.0 +/- 3.8 with placebo. However, from day 21 to day 41, the rHuEPO-treated patients received 1.4 +/- 2.5 (median, 0) transfusions and the control group received 2.7 +/- 4.0 (median, 2) transfusions (P = .004). In the follow-up period from day 42 up to day 100, 2.4 +/- 5.6 transfusions were required with rHuEPO and 4.5 +/- 9.6 were required with placebo (P = .075). A multivariate analysis (ANOVA) showed that acute graft-versus-host disease (GVHD), major ABO-blood group incompatibility, age greater than 35 years, and hemorrhage significantly increased the number of transfusions. However, after day 20, rHuEPO significantly reduced the number of erythrocyte transfusions in these patient groups, as well as reducing incompatibility in the major ABO-blood group. For the whole study period, rHuEPO reduced the transfusion requirements in GVHD III and IV from 18.4 +/- 8.6 to 8.5 +/- 6.8 U (P = .05). After autologous BMT, there was no difference in the time to independence from erythrocyte transfusions and in the regeneration of reticulocytes. Marrow purging strongly increased the requirement for transfusions as well as the time to transfusion independence.     

Low incidence of red cell and HLA antibody formation by bone marrow transplant patients

BACKGROUND : Bone marrow transplant (BMT) patients, although immunosuppressed, are at risk for the development of red cell (RBC) and HLA antibodies, and they often are given filtered blood in an effort to prevent the latter complication. This study attempts to determine the rate of formation and the specificity of both RBC and HLA alloantibodies in this patient population. STUDY DESIGN AND METHODS : BMT patients (148 received autologous marrow; 45 received allogeneic marrow) from an 18-month period, including patients with leukemia (57 patients), lymphoma (54), breast cancer (68), myeloma (8), myelodysplastic syndrome (5), and aplastic anemia (1), were studied to determine the rate of alloantibody formation to RBC and HLA antigens. A total of 2,410 RBC antibody screens were performed. The patients received 3,921 packed RBCs and 5,915 single-donor platelet units; all were irradiated and administered via white cell-reduction filters. RESULTS : Seven (3.6%) of 193 patients had RBC antibodies upon hospital admission. Four (2.1%) of 193 developed RBC antibodies during the course of BMT: 3 patients had one RBC antibody and 1 patient had two RBC antibodies. RBC antibodies included anti-E (n = 2), anti-M (n = 1), anti-Jkb (n = 1), and anti-Lu14 (n = 1). Thus, 98 percent of patients (189/193) did not develop new (182/186) or additional (7/7) RBC antibodies during BMT. BMT patients were also screened weekly for HLA antibody formation (60-cell panel). Upon admission, 170 (85%) patients were negative. Of these, 8 (4.7%) developed persistent HLA antibodies (mean panel-reactive antibody score, 33 +/? 29%) and 9 (5.3%) were variably positive. Thus, in our setting and population, RBC antibody formation was 0.1 percent per unit transfused, and the HLA alloimmunization rate was 5 to 10 percent. CONCLUSION : As RBC antibody screens are done every Monday, Wednesday, and Friday on this BMT service and as RBC antibody formation is low in these patients, screening for unexpected antibodies might be possible on a more infrequent basis. Also, the rate of HLA alloimmunization in this population receiving filtered blood components is low.