The determinants of mortality and morbidity after multiple-valve operations

The factors predictive of hospital mortality and morbidity after contemporary multiple-valve surgical procedures were identified to develop strategies to improve the results of such procedures. Preoperative, intraoperative, and postoperative information was collected prospectively on 90 consecutive patients undergoing surgical procedures between 1982 and 1984. The operative mortality was 5.6%, and the incidence of postoperative low-output syndrome was 16.7%. Multivariate logistic regression analysis identified tricuspid regurgitation (p less than .03, improvement-of-fit chi square) and the aortic valve lesion (p less than .03) as the independent predictors of postoperative complications (mortality or low-output syndrome). Patients with tricuspid regurgitation and right ventricular decompensation and those with aortic stenosis and left ventricular hypertrophy had limited ventricular functional reserve and faced an increased risk. Improved methods of myocardial protection may reduce the risk in these patients.     

Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial

OBJECTIVE: Tumor necrosis factor (TNF) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti-TNF monoclonal antibody, to inhibit the progression of structural joint damage, reduce the signs and symptoms, and improve physical function in patients with active RA receiving concomitant treatment with methotrexate (MTX). METHODS: In this multicenter, 52-week, double-blind, placebo-controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to receive adalimumab 40 mg subcutaneously every other week (n = 207), adalimumab 20 mg subcutaneously every week (n = 212), or placebo (n = 200) plus concomitant MTX. The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]). RESULTS: At week 52, there was statistically significantly less radiographic progression, as measured by the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean +/- SD change 0.1 +/- 4.8) or 20 mg weekly (0.8 +/- 4.9) as compared with that in the placebo group (2.7 +/- 6.8) (P < or = 0.001 for each comparison). In addition, there were statistically significant changes in the components of the TSS. At week 24, ACR20 responses were achieved by 63% and 61% of patients in the adalimumab 40 mg every other week and 20 mg weekly groups, respectively, versus 30% of patients in the placebo group (P < or = 0.001 for each comparison). At week 52, ACR20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg every other week and 20 mg weekly, respectively, versus 24% of patients taking placebo (P < or = 0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo (mean change in HAQ score -0.59 and -0.61, respectively, versus -0.25; P < or = 0.001 for each comparison). A total of 467 patients (75.4%) completed 52 weeks of treatment. Adalimumab was generally well tolerated. Discontinuations occurred in 22.0% of adalimumab-treated patients and in 30.0% of placebo-treated patients. The rate of adverse events (both serious and nonserious) was comparable in the adalimumab and placebo groups, although the proportion of patients reporting serious infections was higher in patients receiving adalimumab (3.8%) than in those receiving placebo (0.5%) (P < or = 0.02), and was highest in the patients receiving 40 mg every other week. CONCLUSION: In this 52-week trial, adalimumab was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX.     

Epidemiology, clinical characteristics and antimicrobial resistance patterns of community-acquired pneumonia in 1702 hospitalized children in Singapore

OBJECTIVE AND BACKGROUND: Childhood community-acquired pneumonia (CAP) remains a leading cause of morbidity and mortality worldwide. The features of childhood CAP vary between countries. The aim of this study was to delineate the clinical characteristics, complications, spectrum of pathogens and patterns of antimicrobial resistance associated with hospitalized cases of childhood CAP in Singapore. METHODS: A retrospective study was conducted of patients discharged from Singapore's only children's hospital over a 3-year period with a principal diagnosis of CAP. RESULTS: A total of 1702 children, with a median age of 4.2 years (range: 1 month-16.3 years) were enrolled. A pathogen was identifiable in 38.4% of cases, including Mycoplasma pneumoniae in 20.3%, typical respiratory bacteria in 10.3% (64.6%Streptococcus pneumoniae; 21.7% non-typeable Haemophilus influenzae), viruses in 5.5% and mixed bacterial/viral infections in 2%. The majority of M. pneumoniae infections were in school-aged children (>5 years). Severity of infection was greater in CAP caused by typical bacteria, as reflected by length of hospital stay, CRP level, white cell and absolute neutrophil counts. Mortality from typical bacterial infections (8.9%) exceeded that from M. pneumoniae (0.3%) and viral pneumonias (0%) (P < 0.001). Aminopenicillins were often prescribed empirically for suspected S. pneumoniae and H. influenzae infections; however, resistance to these agents was frequently documented among S. pneumoniae (58.5%) and H. influenzae isolates (51%). CONCLUSION: In Singaporean children hospitalized with CAP, M. pneumoniae is the most commonly identified causative organism, followed by common respiratory viruses, S. pneumoniae and H. influenzae. Streptococcus pneumoniae and H. influenzae are associated with greater severity of infection than other organisms, and have high levels of resistance to commonly prescribed antibiotics.     

CD40 activation mediates p53-dependent cell cycle regulation in human multiple myeloma cell lines

It has been reported that the activation of multiple myeloma (MM) cells by CD40 induces proliferation, growth arrest, and apoptosis. To determine whether the biologic sequelae of CD40 activation in MM cells depends on p53 function, we identified temperature-sensitive p53 mutations in the RPMI 8226 (tsp53E285K) and the HS Sultan (tsp53Y163H) MM cell lines. These cells were then used as a model system of inducible wtp53-like function because wild-type-like p53 is induced at permissive (30 degrees C) but not at restrictive (37 degrees C) temperatures. Using p21-luciferase reporter assays, we confirmed that CD40 induces p53 transactivation in RPMI 8226 and HS Sultan cells cultured under permissive, but not restrictive, conditions. Furthermore, CD40 activation of these MM cells under permissive, but not restrictive, temperatures increased the expression of p53 and p21 mRNA and protein. Importantly, CD40 activation induced the proliferation of RPMI 8226 and HS Sultan cells at restrictive temperatures and growth arrest and increased subG1 phase cells at permissive temperatures. These data confirmed that CD40 activation might have distinct biologic sequelae in MM cells, depending on their p53 status.     

Interleukin-6 is a key mediator of the hepatoprotective and pro-proliferative effects of ischaemic preconditioning in mice

BACKGROUND/AIMS: The biological effects of ischaemic preconditioning include NF-kappaB activation, increased TNF synthesis, stimulation of cell cycle entry and hepatoprotection against ischaemia-reperfusion (IR) injury. Low dose TNF initiates the priming phase of liver regeneration via NF-kappaB and IL-6. To determine whether (1) IL-6 is released during preconditioning and confers protection against hepatic IR injury, and (2) IL-6 could mediate the biological effects of preconditioning. METHODS: Wildtype (wt) and TNF-/- C57BL6 mice were subjected to 90 min partial hepatic ischaemia and 2-44 h reperfusion with or without prior 10 min ischaemic preconditioning. To restitute liver injury, TNF-/- mice were administered murine TNF 5 microg/kg iv 1 min prior to IR. Murine recombinant IL-6 (500 ng/kg iv) was administered 30 min prior to IR, either to wt mice or to TNF-/--repleted mice; in the latter case, 1 min before preconditioning. RESULTS: In wt mice, IL-6 attenuated hepatic IR injury and stimulated cell cycle entry. IR injury in TNF-repleted TNF-/- mice was not ameliorated by preconditioning. However, prior IL-6 administration conferred hepatoprotection (IL-6/preconditioned: 349+/-169 U/L vs vehicle/preconditioned: 1250+/-608 U/L, P<0.01). CONCLUSIONS: IL-6 is one likely mediator of the hepatoprotective and pro-proliferative effects of ischaemic preconditioning.