Enabling parents who smoke to prevent their children from initiating smoking: results from a 3-year intervention evaluation

OBJECTIVE: To evaluate effects of a home-based antismoking socialization program on the initiation of smoking among children whose parents smoke. DESIGN: Three-year randomized controlled trial. PARTICIPANTS: Parents who were current smokers and had a child in the third grade who had not tried smoking were eligible; 873 parents-offspring pairs met these criteria, completed baseline interviews, and were randomly assigned to the intervention or control condition; 776 children (89%) completed an interview 3 years after baseline and were included in the study. INTERVENTION: During 3 months, the intervention group (n = 371) received 5 printed activity guides, parenting tip sheets, child newsletters, and incentives; this group also received a booster activity guide 1 year later. The control group (n = 405) received fact sheets about smoking. RESULTS: Initiation of smoking (first instance of puffing on a cigarette) was reported by 12% vs 19% of children in the intervention vs control groups. Logistic regression analysis indicated that children in the control condition had twice the odds of reporting initiation of smoking as children in the intervention condition (adjusted odds ratio, 2.16; P<.001), after adjusting for child sex, parent sex, parent race, parent educational achievement, child's best friends' smoking, parent smoking rate at baseline, and parent cessation status. CONCLUSION: Children in the pre-initiation phase of smoking who receive antismoking socialization from their parents are less likely to initiate smoking, even if their parents smoke.     

Phenytoin metabolism by human cytochrome P450: involvement of P450 3A and 2C forms in secondary metabolism and drug-protein adduct formation.

The anticonvulsant phenytoin (5,5-diphenylhydantoin) provokes a skin rash in 5 to 10% of patients, which heralds the start of an idiosyncratic reaction that may result from covalent modification of normal self proteins by reactive drug metabolites. Phenytoin is metabolized by cytochrome P450 (P450) enzymes primarily to 5-(p-hydroxyphenyl-),5-phenylhydantoin (HPPH), which may be further metabolized to a catechol that spontaneously oxidizes to semiquinone and quinone species that covalently modify proteins. The aim of this study was to determine which P450s catalyze HPPH metabolism to the catechol, proposed to be the final enzymatic step in phenytoin bioactivation. Recombinant human P450s were coexpressed with NADPH-cytochrome P450 reductase in Escherichia coli. Novel bicistronic expression vectors were constructed for P450 2C19 and the three major variants of P450 2C9, i.e., 2C9*1, 2C9*2, and 2C9*3. HPPH metabolism and covalent adduct formation were assessed in parallel. P450 2C19 was the most effective catalyst of HPPH oxidation to the catechol metabolite and was also associated with the highest levels of covalent adduct formation. P450 3A4, 3A5, 3A7, 2C9*1, and 2C9*2 also catalyzed bioactivation of HPPH, but to a lesser extent. Fluorographic analysis showed that the major targets of adduct formation in bacterial membranes were the catalytic P450 forms, as suggested from experiments with human liver microsomes. These results suggest that P450 2C19 and other forms from the 2C and 3A subfamilies may be targets as well as catalysts of drug-protein adduct formation from phenytoin.     

The contribution of blood cultures to the clinical management of adult patients admitted to the hospital with community-acquired pneumonia: a prospective observational study

STUDY OBJECTIVE: To assess the clinical usefulness of blood cultures (BCs) in the management of patients hospitalized with community-acquired pneumonia (CAP). DESIGN: A prospective, observational study to investigate the contribution of BCs to the management and outcomes of adult patients presenting with CAP. SETTING: Nineteen Canadian hospitals. PATIENTS: Adults admitted to the hospital with CAP between January 1, 1998, and July 31, 1998. INTERVENTIONS: The courses of therapy in patients for whom BC results yielded organisms considered to be clinically significant were analyzed to determine whether the BCs had contributed to management or outcome. MEASUREMENTS AND RESULTS: Forty-three of 760 patients had significantly positive BC results. Patients with CAP who had BCs performed had a 1.97% chance (15 of 760 patients) of having a change of therapy directed by BC results. Patients in whom BCs yielded positive results had a 34.8% chance (15 of 43 patients) of having a change in therapy determined by BC results, and had a 58.1% chance (25 of 43 patients) of having a course of therapy contraindicated by BC results. Severity of illness, as measured by the pneumonia severity index, correlated poorly with the yield of BCs. BC results were positive in 8.0% of patients in risk classes I and II, 6.2% of patients in risk class III, 4.6% of patients in risk class IV, and 5.2% of patients in risk class V. CONCLUSION: BCs have limited usefulness in the routine management of patients admitted to the hospital with uncomplicated CAP.     

Early prediction of outcome and response to alemtuzumab therapy in chronic lymphocytic leukemia

Alemtuzumab therapy is effective for some refractory chronic lymphocytic leukemia (CLL), but identifying responders requires at least 8 weeks of therapy. Early identification of nonresponders would minimize toxicity and/or facilitate more effective strategies. The aim of this study was to identify a minimally invasive method for early prediction of response and relapse. Flow cytometric monitoring was performed in 887 blood samples and 201 marrow samples from 43 patients undergoing intravenous alemtuzumab therapy. Although the absolute lymphocytosis was resolved in all patients by week 4, significant depletion of bone marrow tumor only occurred if circulating B-lymphocyte counts were persistently less than 0.001 x 10(9)/L, which was rare in nonresponders. The majority of patients (16/28) who did not benefit from a full course of therapy were identified with 100% positive predictive value using the following algorithm: peripheral B-cell count greater than 0.001 x 10(9)/L at week 2 with less than 1 log depletion of circulating B cells between weeks 2 and 4. Monitoring CLL levels after treatment identified patients at risk of early disease progression and could potentially improve patient management. During alemtuzumab therapy, bone marrow CLL depletion only occurs after abrogation of circulating tumor, requiring close monitoring of circulating B-cell levels. If validated in prospective studies, blood monitoring at 2 and 4 weeks may be used to optimize therapy.     

Cord blood banking: volume reduction of cord blood units using a semi-automated closed system

Clinical evidence indicates that placental/umbilical cord blood (CB) is an alternative source of haematopoietic stem cells for bone marrow reconstitution. To establish a CB bank large panels of frozen, HLA-typed CB units need to be stored. Cryopreserved, unprocessed CB units require vast storage space. This study describes a method, using the Optipress II Automated Blood Component Extractor (Opti II) from Baxter Healthcare Corporation, to reduce the volume of the CB collection, preserving the quantity and quality of the progenitor cells, in a closed system. The CB collection was transferred to a triple bag system, centrifuged to produce a buffy coat layer and processed using a standard Opti II protocol to separate the whole blood into three components: plasma, buffy coat and buffy coat-depleted red cell concentrate. The buffy coat volume was standardised to 25 ml; mean reduced volume of 24.5 ml (s.d. 1.5 ml) with 53% red cell depletion. Good recovery of cells was observed: 92%, 98%, 96% and 106% recovery of nucleated, mononuclear, CD34+ and total colony-forming cells, respectively. Using this method for processing CB units reduces storage requirement by two-thirds but preserves the quantity and quality of the progenitor cells.     

Polymorphisms of interleukin-1alpha constitute independent risk factors for chronic graft-versus-host disease after allogeneic bone marrow transplantation

The interleukin-1 (IL-1) family of cytokines is widely involved in inflammatory processes and diseases with an inflammatory component. Polymorphisms of the IL-1alpha, IL-1beta and IL-1Ra genes have been implicated in a number of autoimmune or inflammatory conditions, with polymorphism of the IL-1Ra gene showing association with severity of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). We compared the clinical outcomes (GVHD and survival) of 115 patients after human leucocyte antigen (HLA)-identical sibling allogeneic BMT with their genotype for two polymorphisms present in the IL-1alpha gene, which have been implicated in immune-related pathology. Possession of allele 2 of the IL-1alpha-889 polymorphism and allele 2 of the IL-1alpha variable number tandem repeat (VNTR) polymorphism in the donor genotype was associated with the occurrence of chronic, but not acute GVHD. A local normal population was also genotyped for these polymorphisms, and subsequent analysis identified conserved haplotypes in this gene region. Haplotypes containing allele 2 at both IL-1alpha-889 and IL-1alpha VNTR loci were extremely uncommon, suggesting that both risk alleles would be inherited independently. Both loci could therefore function as independent disease association markers. The polymorphisms of the IL-1alpha gene could be used to predict chronic GVHD in HLA-matched sibling transplants alongside clinical risk factors.     

Evaluation of indium scintigraphy in patients with active inflammatory bowel disease

Recent reports have indicated a possible role for 111Indium leucocyte scintigraphy in the management of patients with acute inflammatory bowel disease. Our experience with this technique in 15 patients (nine with ulcerative colitis, six with Crohn's disease) is described. Perfect agreement was not obtained between scintigraphic appearances and other conventional means in the assessment of extent of disease. Good correlation, however, was found between disease activity and recovery of labelled leucocytes in the faeces. While this latter finding could be used as an objective means of assessing response to therapy, it is concluded that conventional indium scintigraphy, using indium oxine-labelling of mixed leucocytes, is insufficiently reliable to replace usual methods for determining extent of disease in patients with inflammatory bowel disease.     

Effect of interleukin-5 exposure during in vitro eosinophilopiesis on MAC-1 adhesion molecule expression and function on cultured human eosinophils

We examined the selective effects of interleukin (IL-5) in regulating the maturational expression of surface adhesion molecules on human eosinophils and adhesion to endothelial cells during eosinophiiopolesis in vitro. Expression of the beta 2 integrins (CD11/CD18) and the beta 1 integrin, VLA-4 (CD49d/ CD29), was assessed during development in culture with IL-3, IL-5, and granulocyte-macrophage colony stimulating factor in cultures of human umbilical cord blood-derived eosinophil (CDE) precursor cells. Expression of both CD11b and CD18 subunits of Mac-1 was lower on CDE which were continuously (= chronically) exposed to IL-5 than on CDE which were cultured without IL-5 for the final week of culture. CD11b expression on cells grown without IL-5 was 71.3 +/- 5.92 (mean specific fluorescence value [MSF] as measured by flow cytometry) versus 52.5 +/- 4.48 MSF for Mac-1 alpha (CD11b) on CDE grown in the continued presence of 2 x 10 - 11 mol/L IL-5 (P < .01). Although expression of VLA-4 decreased as CDE matured, expression of CD29 and CD49d were similar regardless of cytokine exposure for the final week of culture. For eosinophils cultured without IL-5, acute stimulation with 10 - 8 mol/L IL-5 increased CD11b surface expression and increased the number of cells adhering to unstimulated human umbilical vein endothelial cells (HUVEC) from 4,570 +/- 780 cells (9.14 +/- 1.56% adhesion) to 8,385 +/- 515 cells (16.8 +/- 1.03% adhesion) (P < .01). Basal adhesion to unstimulated HUVEC of CDE cultured continuously with IL-5 was comparable (8.62 +/- 1.12% adhesion; P = NS), but neither CD11b expression (50.3 +/- 11.8 MSF; P = NS v control) nor adhesion to HUVEC (6.77 +/- 1.35%; P = NS) was enhanced in these eosinophils after acute stimulation with IL-5. Blockade of adhesion to IL-1-stimulated HUVEC caused by the anti-CD49d monoclonal antibody (MoAb), HP2/1, was comparable for cells cultured with IL-5 and without IL-5. However, the anti-CD18 MoAb, R15.7, caused 47.6 +/- 5.08% inhibition of adhesion of eosinophils cultured without IL-5 and only 25.8 +/- 5.20% for cells cultured continuously with IL-5 (P < .01), and failed to block significantly the adhesion of only the latter cells to IL-4-stimulated HUVEC. Our data show that continuous, chronic exposure to low concentrations of IL-5 causes decreased expression of Mac-1 and refractoriness to acute stimulation with IL-5 of adhesion to HUVEC. These data further demonstrate that CDE maturing in the continued presence of IL-5 adhere to HUVEC predominantly through VLA-4 ligation.     

Activity of the combination of fludalanine and cycloserine against mycobacteria in vitro

The initial steps in the incorporation of alanine into the bacterial cell wall include the conversion of natural to D-alanine by a racemase followed by the coupling of 2 D-alanine molecules by a synthetase to yield a dipeptide. A combination of fludalanine (3-fluoro-2-deutero-D-alanine), an analogue of D-alanine that irreversibly inactivates the racemase, and cycloserine, which inhibits the synthetase, has been found to be more active against a wide range of non-mycobacterial organisms than either fludalanine or cycloserine alone. When tested against 16 strains of slowly growing mycobacteria including M. tuberculosis, the combination was no more active than cycloserine alone. However the cycloserine minimal inhibitory concentration (MIC) of the combination against the rapidly growing species M. phlei and M. fortuitum was much lower than the MIC of cycloserine alone, particularly with low ratios of fludalanine to cycloserine, and was within the range attainable by therapeutic cycloserine plasma concentrations in man, suggesting its possible use in the treatment of disease due to M. fortuitum.     

Mortality related to after-hours discharge from intensive care in Australia and New Zealand, 2005–2012

Introduction

After-hours discharge from the intensive care unit (ICU) is associated with adverse patient outcomes including increased ICU readmissions and mortality. Since Australian and New Zealand data were last published, overall ICU patient mortality has decreased; however it is unknown whether changes in discharge practices have contributed to these improved outcomes. Our aim was to examine trends over time in discharge timing and the contemporary associations with mortality and ICU readmission.

Methods

Retrospective cohort study using data from the Australian and New Zealand Intensive Care Society Adult Patient Database (ANZICS APD) for patients admitted to Australian and New Zealand ICUs between January 2005 and December 2012. Data collected included patient characteristics, time of ICU discharge, hospital mortality and ICU readmissions.

Results

Between 1 January 2005 and 31 December 2012, there were 710,535 patients available for analysis, of whom 109,384 (15.4 %) were discharged after-hours (1800–0600 hours). There were no changes in timing of ICU discharge over the 8 years of the study. Patients discharged after-hours had a higher hospital mortality (6.4 versus 3.6 %; P < 0.001) and more ICU readmissions (5.1 versus 4.5 %; P < 0.001) than patients discharged in-hours. Although post-ICU mortality for all patients declined during the study period, the risk associated with after-hours discharge remained elevated throughout (odds ratio 1.34, 95 % confidence intervals 1.30–1.38).

Conclusions

After-hours discharge remains an important independent predictor of hospital mortality and readmission to ICU. Despite widespread dissemination this evidence has not translated into fewer after-hours discharges or reduction in risk in Australian and New Zealand hospitals.