Infections caused by Escherichia coli resistant to norfloxacin in hospitalized cirrhotic patients

Selective intestinal decontamination with norfloxacin is useful to prevent bacterial infections in several groups of cirrhotic patients at high risk of infection. However, the emergence of infections caused by Escherichia coli resistant to quinolones has recently been observed in cirrhotic patients undergoing prophylactic norfloxacin. Our aim is to determine the characteristics of the infections caused by E. coli resistant to norfloxacin in hospitalized cirrhotic patients. One hundred and six infections caused by E. coli in 99 hospitalized cirrhotic patients were analyzed and distributed into two groups: group I (n = 67), infections caused by E. coli sensitive to norfloxacin, and group II (n = 39), infections caused by E. coli resistant to norfloxacin. The clinical and analytical characteristics at diagnosis of the infection were similar in both groups. Previous prophylaxis with norfloxacin was more frequent in group II (15/67, 22.4% vs. 32/39, 82%, P <.0001), as a result of a higher number of patients submitted to continuous long-term prophylaxis in this group, whereas previous short-term prophylaxis was similar in both groups. Infections were more frequently nosocomial-acquired in group II than in group I (17/67, 25.3% vs. 20/39, 51.2%, P =.01). The type of infections was similar in both groups: urinary tract infections 38 in group I and 24 in group II, spontaneous bacterial peritonitis 8 and 2, spontaneous bacteremia 4 and 4, and bacterascites 1 and 0, respectively (pNS). Mortality during hospitalization was similar in the two groups (4/67, 5.9% vs. 5/39, 12.8%, pNS). None of the E. coli resistant to norfloxacin were also resistant to cefotaxime and only one of them was resistant to amoxicillin-clavulanic acid. Prophylaxis with norfloxacin, usually continuous long-term prophylaxis, favors the development of infections caused by norfloxacin-resistant E. coli. Long-term antibiotic prophylaxis should therefore be restricted to highly selected groups of cirrhotic patients at high-risk of infection. Infections caused by E. coli resistant to norfloxacin show a severity similar to those caused by sensitive E. coli. No significant associated resistance between norfloxacin and the antibiotics most frequently used in the treatment of bacterial infections in cirrhotic patients has been observed.     

Saporin, a ribosome-inactivating protein used to prepare immunotoxins, induces cell death via apoptosis

The plant toxin saporin is a ribosome-inactivating protein which inhibits protein synthesis and growth of both normal and tumour cells. Its cytotoxic activity can be increased by coupling with antibodies recognizing cell surface antigens. In this work we performed experiments to test the hypothesis that saporin induces cell death via apoptosis. Exposure to saporin induced apoptosis in different cellular models, such as human peripheral blood B lymphocytes and neutrophils, in the Daudi B-cell line, and in the haemopoietic cell lines HL-60 and TF-1. This was indicated by: (a) the appearance of typical morphological features such as chromatin condensation, nuclear fragmentation and blebbing of plasma membranes; (b) DNA degradation into oligonucleosomal fragments; (c) the appearance of apoptotic cells on DNA flow cytometry as a cell population with reduced DNA content (A₀ region). The fraction of cells showing features of apoptosis ranged from 19 ± 5% for TF-1 cells to 35 ± 8% for neutrophils. In experiments with normal peripheral blood B lymphocytes or with Daudi cells, we compared the activity of native saporin with that of an immunotoxin hybrid molecule obtained by binding the toxin to two bispecific antibodies recognizing both saporin and the B lymphocyte-specific antigen CD22 (Sap/BsAb complexes). Saporin bound to the antibodies was 2–3 logs more effective than native saporin in inducing apoptosis, with maximal inhibitions being observed at concentrations of 10^?6 M for native saporin and 10^?9–10^?8 M for the hybrid molecules. These findings indicate that treatment with saporin results in apoptosis of target cells and suggest that this may be relevant to the therapeutic use of saporin-containing immunotoxins. In fact, if used in vivo as an immunotoxin, its cytotoxic activity could be devoid of more extensive and non-specific tissue damaging effects as would be the case if saporin induced necrosis of target cells.     

A randomized controlled trial of acarbose in hepatic encephalopathy.

BACKGROUND & AIMS: Hepatic encephalopathy in cirrhosis is contributed to by toxic products deriving from the proteolytic bacterial flora-related degradation of dietary nitrogen substances. Acarbose is a novel hypoglycemic agent acting through the inhibition of glucose absorption in the gut and the promotion of intestinal saccharolytic bacterial flora at the expense of proteolytic flora. We assessed whether acarbose exerts a beneficial effect on hepatic encephalopathy and on postprandial hyperglycemia in cirrhotic patients with low-grade hepatic encephalopathy and type 2 diabetes mellitus. METHODS: One hundred seven cirrhotic patients with grade 1-2 hepatic encephalopathy and type 2 diabetes mellitus were randomized to acarbose 100 mg 3 times daily or placebo for 8 weeks; after a 2-week washout period, treatments were switched, and patients were followed for 8 more weeks. Ammonia blood levels, Reitan's number connection test, intellectual function, fasting and postprandial glucose levels, glycated hemoglobin values, and C peptide values were determined 2 weeks before and 4, 8, 11, 14, and 18 weeks after treatment. RESULTS: (1) Acarbose significantly decreased ammonia blood levels and improved Reitan's test score and intellectual function score compared with placebo (P < .01). (2) Acarbose caused a 33% decrease in fasting glucose level and an approximately 50% decrease in postprandial glucose level compared with placebo (P < .01). (3) Acarbose significantly lowered glycated hemoglobin values and postprandial C peptide compared with baseline values, whereas placebo did not. (4) No change in biochemical parameters of liver function was observed after acarbose treatment. CONCLUSIONS: Acarbose is a safe and effective drug in cirrhotic patients with low-grade hepatic encephalopathy and type 2 diabetes mellitus.     

Molecular histogenesis of plasmablastic lymphoma of the oral cavity

Plasmablastic lymphoma (PBL) of the oral cavity is an aggressive B-cell lymphoma associated with human immunodeficiency virus infection. Although the lymphoma phenotype is consistent with late B-cell maturation, the molecular histogenesis of PBL is unknown. We investigated PBL of the oral cavity (n = 12) for mutations of immunoglobulin variable heavy chain (IgVH) and BCL-6 genes, which are acquired by B cells at the time of germinal centre (GC) transit, and for expression of BCL-6, MUM-1 and CD138, which distinguish GC B cells from post-GC B cells. Somatic IgVH hypermutation occurred in 4/10 PBL whereas 6/10 PBL displayed germline IgVH genes. Among PBL carrying hypermutated IgVH genes, the pattern of IgVH mutations was consistent with antigen stimulation in two cases. Mutations of the BCL-6 gene were restricted to 1/12 patients with PBL of the oral cavity. All cases of PBL of the oral cavity displayed the BCL-6-/MUM-1+/CD138+ phenotype that is consistent with late stage of B-cell differentiation. Overall, these data indicate that, despite a common phenotype and an apparently similar degree of differentiation, PBL of the oral cavity are characterized by histogenetic heterogeneity. A subset of PBL of the oral cavity carried the molecular clues of GC transit and conceivably originated from a B-cell subset corresponding to post-GC B cells. Conversely, another fraction of these lymphomas were devoid of somatic IgVH mutations and appeared to originate from naive B cells that have undergone preterminal differentiation independent of GC transit.     

Thrombophilic genotypes,natural anticoagulants,and plasma homocysteine in myeloproliferative disorders: relationship with splanchnic vein thrombosis and arterial disease

The contribution of pro-thrombotic factors towards the development of arterial disease (AD) and splanchnic vein thrombosis (SVT) was retrospectively evaluated in 79 patients (39M, 40F, mean age 55 +/- 16 years) with myeloproliferative disorders (MPD) (essential thrombocythemia [n = 26], primary proliferative polycythemia [n = 27], and idiopathic myelofibrosis [n = 26]). Of these, 18 had AD and 17 SVT, the remaining 44 were non-thrombotic (NT). Plasma concentrations of natural anticoagulants, plasma homocysteine (HC), IgG anticardiolipin antibodies (aCL), and thrombophilic genotypes (methylenetetrahydrofolate reductase C(677)T, factor V Leiden, prothrombin G(20210)-->A) were determined. Isolated protein C deficiency was found in 23% of patients from the SVT group, in 5% from the AD group, in 6.8% from the NT group, and in 1% of historical controls (P = 0.0001). The prevalence of thrombophilic genotypes and that of the other natural anticoagulants did not differ across the groups. The proportion of patients with elevated plasma HC was 66% in the AD group, 27% in the non-thrombotic group, 12% in the SVT group and 4.5% in the control group (P < 0.0001). Patients with AD had higher plasma HC (24.4 +/- 23 micromol/L) than NT patients (12.3 +/- 7.7 micromol/L), SVT patients (9 +/- 4.9 micromol/L), and healthy controls (7.9 +/- 3 micromol/L) (P < 0.0001). In a logistic regression model lower protein C was independently associated with SVT, whereas elevated plasma HC was independently associated with AD. Measurement of plasma HC and protein C in MPD may identify patients more likely to suffer arterial disease and splanchnic vein thrombosis and who may require plasma HC lowering in the former case.     

De novo acute myeloid leukemia with multilineage dysplasia: treatment results and prognostic evaluation from a series of 44 patients treated with fludarabine,cytarabine and G-CSF (FLAG)

OBJECTIVES: To evaluate therapeutic results and prognostic factors from a series of 44 patients affected by de novo acute myeloid leukemia with multilineage dysplasia (MD-AML), treated with the combination of fludarabine, cytarabine and G-CSF (FLAG). METHODS: Forty-four patients with de novo MD-AML were treated with the FLAG regimen. The median age was 61 yr (range 31-75 yr). Induction therapy consisted of the FLAG regimen; consolidation included idarubicin plus cytarabine. Patients with a compatible donor and aged less than 55 yr were programmed to receive allogeneic bone marrow transplantation (BMT), while in those without a donor and aged less than 65 yr autologous transplantation with peripheral blood stem cells mobilized by a consolidation regimen plus G-CSF was planned. Bone marrow harvest was performed in poor mobilizers. RESULTS: Complete remission (CR) was achieved in 28 out of 44 patients (64%). Death in induction occurred in four patients (9%), while 12 patients (27%) were resistant to FLAG. Toxicity of consolidation was negligible. Most patients aged less than 60 yr and achieving CR were eligible for transplantation procedures, the main reason of exclusion being early relapse. Median overall survival and disease free survival were 16 and 22 months, respectively. Unfavorable cytogenetics was the only parameter significantly related to inferior clinical outcome following multivariate analysis. CONCLUSION: Multilineage dysplasia per se is not an adverse prognostic factor in AML patients treated with the FLAG regimen. Favorable results are obtained in patients with intermediate karyotype, while in those with adverse cytogenetics new approaches are clearly needed. The toxicity of the regimen is also acceptable in the elderly, and following induction/consolidation, most patients may be submitted to transplantation procedures.