Management of patients with community-acquired pneumonia treated in hospital in Sweden

To investigate the management of patients with community-acquired pneumonia (CAP) treated in hospital in Sweden, a multicentre retrospective cohort study was performed with medical record review of 982 patients (mean age 63 y) at 17 departments of infectious diseases at hospitals in Sweden. Information on antimicrobial therapy, demographic characteristics, comorbid conditions, physical examination findings, and laboratory and microbiological test results were recorded. Outcome measures were in-hospital mortality and length of hospital stay (LOS). Cultures were obtained from blood in 80% and from sputum in 22% of the patients. A microbiological aetiology was determined for 23% of the patients, with Streptococcus pneumoniae as the dominating agent (9%). The initial antibiotic treatment was mostly given intravenously (78%). Penicillin (50%) or a cephalosporin (30%) was the most common choice. Both of these drugs were usually given as a single agent. The overall mortality was 3.5% and the mean LOS was 6.4 d. Thus, the outcome was favourable despite the empirical antibiotic treatment having a narrow spectrum compared with the broader approach recommended in most recent guidelines on the management of CAP. These findings suggest that a majority of patients who are hospitalized with moderately severe pneumonia can be treated initially with penicillin alone.     

Recombinant human megakaryocyte growth and development factor stimulates thrombocytopoiesis in normal nonhuman primates

Megakaryocyte growth and development factor (MGDF) is a novel cytokine that binds to the c-mpl receptor and stimulates megakaryocyte development in vitro and in vivo. This report describes the ability of recombinant human (r-Hu) MGDF to affect megakaryocytopoiesis in normal nonhuman primates. r-HuMGDF was administered subcutaneously to normal, male rhesus monkeys once per day for 10 consecutive days at dosages of 2.5, 25, or 250 micrograms/kg of body weight. Bone marrow and peripheral blood were assayed for clonogenic activity and peripheral blood counts were monitored. Circulating platelet counts increased significantly (P < .05) for all doses within 6 days of r-HuMGDF administration and reached maximal levels between day 12 and day 14 postcytokine administration. The 2.5, 25.0, and 250.0 micrograms/kg/d doses elicited peak mean platelet counts that were 592%, 670%, and 449% of baseline, respectively. Bone marrow-derived clonogenic data showed significant increases in the concentration of megakaryocyte (MEG)- colony-forming unit (CFU) and granulocyte-erythroid-macrophage- megakaryocyte (GEMM)-CFU, whereas that of granulocyte-macrophage (GM)- CFU and burst-forming unit-erythroid (BFU-e) remained unchanged during the administration of r-HuMGDF. These data show that r-HuMGDF is a potent stimulator of thrombocytopoiesis in the normal nonhuman primate.     

Expression of CD27 and its ligand, CD70, on chronic lymphocytic leukemia B cells

Crosslinking the CD27 antigen on T cells provides a costimulatory signal that, in concert with T-cell receptor crosslinking, can induce T- cell proliferation and cellular immune activation. We find that chronic lymphocytic leukemia (CLL) B cells from most patients coexpress both membrane-bound and soluble CD27, along with its newly identified ligand, CD70. The expression of soluble CD27 may preclude leukemic B cells from stimulating T cells via CD70, thereby potentially impairing their ability to function as effective antigen-presenting cells. We find that leukemic B-cell expression of soluble and membrane-bound CD27 can be downmodulated through a CD40-dependent signal. This signal also induces enhanced expression of CD70 on both normal and leukemic B cells. We find that tumor necrosis factor (TNF)-alpha, or the Th1 cytokine interferon (IFN)-gamma, also can induce downmodulation of CD27, whereas Th2-associated cytokines interleukin-4 (IL-4) or IL-10 can enhance leukemic B-cell expression of this accessory molecule. The modulation of CD27 induced by these conditions is accompanied by reciprocal changes in the expression levels of CD70, suggesting that these accessory molecules may be engaged in reciprocal receptor-ligand downmodulation. Consistent with this, we observe that co-culture of CLL B cells with transfected murine plasmacytoma cells that express human CD70 affects downmodulation of CD27 and enhanced expression of CD70 on leukemic B cells, but does not affect expression of CD27 mRNA. However, we find that CD40-crosslinking, in addition to reducing the level of CD27 protein, also reduces leukemic B-cell expression of CD27 mRNA. This argues that the changes in the expression levels of CD27 following CD40-signaling are not simply due to induced increases in the expression levels of CD70. Finally, we demonstrate that reciprocal changes in expression of CD27 and CD70 may contribute to the enhanced antigen-presenting capacity of CLL B cells after CD40-dependent leukemic B-cell activation. These findings expand the understanding of the regulation of costimulatory molecules important in antigen presentation and also have implications for the immunobiology of and therapy for CLL.     

Ventricular tachycardia due to sustained bundle branch reentry: Diagnostic and therapeutic considerations

We have identified bundle-branch reentry (BBR) as the mechanism of ventricular tachycardia (VT) during electrophysiologic studies in 48 patients at our institution. All but three patients had significant structural heart disease, that is, dilated ischemic or idiopathic cardiomyopathy, the most common of anatomic substrates. Syncope and sudden death were the modes of presentation in up to 70% of these patients. The critical prerequisite for the development of this arrhythmia is conduction delay in the His-Purkinje system, which was present in all patients and manifests as a nonspecific conduction delay or a left bundle-branch block (LBBB) in the surface electrocardiogram (ECG) and a prolonged HV interval in the intracardiac recordings. VT with an LBBB morphology is the most common form of BBR, present in 98% of patients. Transcatheter ablation of the right bundle branch (RBB) with the use of radiofrequency current is the treatment of choice, as it effectively eliminates BBR. During long-term follow-up, recurrent tachycardia due to BBR was not documented in any patient; however, congestive heart failure was a common cause of death in this population.     

Detection and viability of tumor cells in peripheral blood stem cell collections from breast cancer patients using immunocytochemical and clonogenic assay techniques [see comments]

Although peripheral blood stem cell collections (PBSC) are thought to have less tumor involvement than bone marrow (BM), the incidence of circulating tumor cells in patients with breast cancer has not been widely investigated. We prospectively investigated the incidence and viability of tumor cell involvement in PBSC and BM collections from breast cancer patients undergoing high-dose chemotherapy/hematopoietic stem cell transplantation. Paired samples of PBSC and BM from 48 patients were analyzed using an immunocytochemical technique that detects one epithelial-derived tumor cell per 5 x 10(5) mononuclear cells. Immunostained tumor cells were detected in 9.8% (13/133) PBSC specimens from 9/48 (18.7%) patients and in 62.3% (38/61) BM specimens from 32/48 (66.7%) patients, a significantly higher rate than in PBSC (P < .005). The geometric mean concentration of tumor cells in contaminated PBSC specimens was 0.8/10(5) mononuclear cells (range 0.33 to 2.0/10(5)) compared with 22.9/10(5) mononuclear cells in BM (range 1 to 3,000/10(5), P < .0001). In culture experiments, clonogenic tumor colonies grew in 21/26 immunocytochemically positive specimens. No tumor colony growth was detected in 30/32 immunocytochemically negative specimens. Immunocytochemical detection of tumor involvement in BM and PBSC correlated significantly with in vitro clonogenic growth (P < .0001). We conclude that PBSC contain fewer tumor cells than paired BM specimens from patients with advanced breast cancer and that these tumor cells appear to be capable of clonogenic growth in vitro.     

Vitamin D Deficiency Is Associated with Ulcerative Colitis Disease Activity

Purpose

Previous studies on experimental mouse models have suggested a role of vitamin D in immune system regulation and IBD disease severity. In this study, we examine the relationship between vitamin D levels and clinical disease activity in human subjects with ulcerative colitis (UC). We hypothesized that patients with vitamin D deficiency will display increased UC disease activity as compared to patients with normal vitamin D levels.

Methods

A cross-sectional study was performed by querying the outpatient electronic medical record of our health system for patients seen in the gastroenterology clinic from January 2007 to October 2009 who carried both a diagnosis of UC and a documented 25-OH vitamin D level within 30 days of their clinic visit. Demographic and clinical variables were collected. Clinical disease activity was calculated using the six-point partial Mayo index. Active disease was defined as a six-point index score of ≥1. Vitamin D deficiency was defined as a 25-OH D level below 30 ng/ml. Data were analyzed using the chi-square distribution test.

Results

Thirty-four patients met inclusion criteria (53 % female, mean age 45.7 ± 24.7 years). Fifteen patients had normal vitamin D levels and 19 patients were vitamin D deficient. Twelve patients had vitamin D levels <20 ng/ml. Vitamin D deficient patients were statistically more likely to have increased disease activity than patients with normal vitamin D levels (p = 0.04), with 68 % of deficient patients displaying active disease compared with 33 % in the sufficient group. There was also a statistically significant association between vitamin D status and need for treatment with steroids, with a higher percentage of vitamin D deficient patients (47 %) requiring such treatment compared with 7 % in the sufficient group (p = 0.02). There was no association between season of visit and disease activity.

Conclusion

Vitamin D deficiency is common among patients with active UC, particularly those requiring corticosteroids. Further investigation is needed to determine the clinical utility of vitamin D monitoring in patients with UC and whether there is a role for vitamin D as a treatment for UC.     

Loss of sexual differentiation of metabolism of steroids and xenobiotics in nodular hepatic tissue from male and female Wistar rats treated according to the resistant hepatocyte model

Male and female rats were treated according to the resistant hepatocyte model, i.e. initiation with diethylnitrosamine (DEN) and selection/promotion with 2-acetylaminofluorene (2-AAF) and partial hepatectomy (PH). Non-initiated controls were either treated with 2-AAF/PH or with PH only. Initiated male controls, where PH was performed, were also included. In livers obtained at PH marked effects of treatment with DEN and/or 2-AAF on several cytochrome P450-mediated microsomal reactions towards steroid and xenobiotic substrates were observed. Hepatic N,O-sulfation of N-hydroxy-2-acetylaminofluorene (N-OH-2-AAF) was decreased in rats of both sexes in response to 2-AAF treatment at the time of PH. Microsomes prepared from early male nodules, collected 39 days after initiation, exhibited levels of cytochrome P450 similar to that in liver from non-initiated male rats treated with 2-AAF/PH. The microsomal content of cytochrome P450 in nodules from both male and female rats, at 8 and 11 months after the start of the experiment respectively, was lower than that of the surrounding liver. No differences in the metabolism of 4-androstene-3,17-dione (androstenedione) were observed in early male nodules compared with 2-AAF/PH-treated controls. Eight months after initiation several sex differentiated hydroxylations of androstenedione (male greater than female) were lower in nodules than in surrounding and control liver from male rats. Female nodules obtained 11 months post-initiation exhibited a markedly lower capacity for 5 alpha-reduction of androstenedione (male greater than female) than the surrounding liver, whereas no significant differences were observed with respect to the different hydroxylation pathways. N,O-Sulfation of N-OH-2-AAF was the only reaction that was markedly decreased in preparations from early male nodules, compared with livers from non-initiated 2-AAF/PH-treated males. Also in late male nodules the sulfotransferase activity was lower than in the surrounding liver. At 11 months, N,O-sulfation in preparations from female rat liver did not reach the detection level. In conclusion, several enzyme activities are markedly less sex differentiated in nodular tissue from male and female rats than in surrounding tissue or in different kinds of control rat liver. These findings indicate that hepatocyte nodules are to some extent withdrawn from the normal endocrine regulation of rat liver.     

Sex-differentiated and growth-hormone-regulated mitoinhibition in rat liver during treatment with 2-acetylaminofluorene and partial hepatectomy in the resistant hepatocyte model

The previously observed sex difference in the growth rate of enzyme-altered foci (male greater than female) in rats treated according to the resistant hepatocyte model (RH model) occurs during selection/promotion of diethylnitrosamine-initiated cells with dietary 2-acetylaminofluorene (2-AAF) and partial hepatectomy (PH). The secretory pattern of growth hormone (GH) is sex dependent in the adult rat and is a major determinant for sex-differentiated liver functions. In the present study the capacity for liver regeneration following PH in the RH model was studied in rats of both sexes, in castrated males and in males receiving GH infusion, both treatments leading to a feminine pattern of GH secretion. Mitoinhibition during treatment with 2-AAF was shown to be more pronounced in liver from male than from female rats, both in initiated and non-initiated animals. Castration of male rats and continuous infusion of GH to males during the selection period, previously shown to decrease the focal growth rate towards that in female rats, 'feminized' also the degree of mitoinhibition. Autoradiography of sections from animals receiving continuous infusion of [3H]thymidine for 1 week, starting at the time of PH, demonstrated a lower labeling index in surrounding liver from male rats treated in the RH model than in surrounding liver from female rats. Males treated with continuous infusion of human GH during 2-AAF/PH treatment had an intermediary labeling index in the surrounding tissue. No differences in labeling index in enzyme-altered foci was observed between males, females or males plus hGH. These findings support the concept that sex-differentiated promotion in the RH model is exerted by selective mitoinhibition and that this feature is regulated by GH.     

Visual identification of bacterially contaminated red cells

There have been increasing numbers of reports of transfusion-acquired Yersinia enterocolitica bacteremia (including several fatal cases). Fifteen units of whole blood were inoculated with various concentrations of Y. enterocolitica serotype 0:3 and processed into AS-3 preserved red cells (RBCs). Consistent growth of the organism was found at inoculum concentrations greater than or equal to 10 colony-forming units per mL. In all 13 units of RBCs that supported the growth of Y. enterocolitica, a darkening in color (due to hemolysis and a decrease in pO2) was observed in the bag. The attached sample segments, which were sealed from the main unit, remained sterile and did not darken. This color change was apparent in all the contaminated units by Day 35, which was 1.5 to 2 weeks after the bacteria were first detected in cultures of the blood. Hence, by comparison of the color of the segment tubing with that of the unit itself, units grossly contaminated with Y. enterocolitica can be identified prior to transfusion. Moreover, review of photographs on file at the Centers for Disease Control revealed this dramatic color change in 2 units of blood that caused transfusion-transmitted sepsis (Enterobacter agglomerans and an unidentified gram-negative bacillus, not Yersinia sp.), which demonstrated that the color change was not limited to Y. enterocolitica. This method of visual identification of contaminated units of blood could decrease the incidence of posttransfusion bacterial sepsis.