A prime/boost vaccine platform efficiently identifies CD27 agonism and depletion of myeloid-derived suppressor cells as therapies that rationally combine with checkpoint blockade in ovarian cancer.

Cancer immunotherapies have generated remarkable clinical responses for some patients with advanced/metastatic disease, prompting exploration of rational combination therapies to bolster anti-tumor immunity in patients with limited response or those who experience tumor progression following an initial response to immunotherapy. In contrast to other tumor indications, objective response rates to single-agent PD-1/PD-L1 blockade in ovarian cancer are limited, suggesting a need to identify combinatorial approaches that lead to tumor regression in a setting where checkpoint blockade alone is ineffective. Using a pre-clinical model of aggressive intraperitoneal ovarian cancer, we have previously reported on a heterologous prime/boost cancer vaccine that elicits robust anti-tumor immunity, prolongs survival of tumor-bearing mice, and which is further improved when combined with checkpoint blockade. As tumor control in this model is CD8 + T cell dependent, we reasoned that the prime/boost vaccine platform could be used to explore additional treatment combinations intended to bolster the effects of CD8 + T cells. Using whole tumor transcriptomic data, we identified candidate therapeutic targets anticipated to rationally combine with prime/boost vaccination. In the context of a highly effective cancer vaccine, CD27 agonism or antibody-mediated depletion of granulocytic cells each modestly increased tumor control following vaccination, with anti-PD-1 therapy further improving treatment efficacy. These findings support the use of immunotherapies with well-defined mechanisms(s) of action as a valuable platform for identifying candidate combination approaches for further therapeutic testing in ovarian cancer.

Neuraxial Anesthesia in Parturients with Thrombocytopenia: A Multisite Retrospective Cohort Study.

BACKGROUND: The primary aim of this study was to estimate the risk of neuraxial hematoma associated with neuraxial anesthetic procedures in thrombocytopenic parturients. METHODS: A multicenter retrospective cohort study design was used to estimate the risk for spinal-epidural hematoma in parturients with a platelet count of <100,000/mm receiving neuraxial anesthesia and the risk of complications in thrombocytopenic parturients who receive general anesthesia. RESULTS: No cases of spinal hematoma were observed in 102 thrombocytopenic parturients receiving epidural analgesia or 71 receiving spinal anesthesia. Including data from the previous published series (total n = 499), the exact binomial 95% confidence interval for the risk of spinal-epidural hematoma was 0% to 0.6%. Given the small number of patients at each specific platelet count, the theoretical risks at individual platelet count strata are presented. Overall aggregate serious morbidity rate in women who received general anesthesia secondary to thrombocytopenia was 6.5% (95% confidence interval, 2.1%-14.5%). CONCLUSIONS: Our work supports the relative maternal safety of neuraxial anesthesia in parturients with mild thrombocytopenia and estimates the maternal complication rate associated with the avoidance of neuraxial anesthesia. Remaining uncertainties at lower platelet counts make a national "low platelet" registry critical to a more accurate assessment of the risk of epidural hematoma and would aid in standardization of anesthesia practice.

Pain in primary Sjögren's syndrome: the role of catastrophizing and negative illness perceptions.

OBJECTIVES: Pain is a major factor in health quality in Sjögren's syndrome (SS), but little is known about the factors that contribute to pain severity. Because pain perception has been linked to catastrophizing in other diseases, we assessed subjects with primary SS (pSS) to explore a possible link between pain, illness appraisal, and catastrophizing. METHOD: A total of 92 subjects who met American-European consensus criteria for the diagnosis of pSS completed a questionnaire that included health history, medication use, illness perceptions, pain severity, mood, fatigue, pain anxiety, and pain catastrophizing. Linear regression was used to test the effect of each variable on pain severity. Multivariate models were constructed using backwards elimination to assess the significant predictors of pain severity. RESULTS: From linear regression analysis, catastrophizing was more strongly predictive of pain severity than age, fatigue, depression, or anxiety in both seropositive and seronegative pSS patients. In the multivariate model identified using backwards selection, four variables (pain catastrophizing, fibromyalgia status, serological status, and the conviction that illness would have severe consequences) predicted 55% of the variance in pain severity. CONCLUSIONS: Pain catastrophizing was a significant predictor of pain severity in both seropositive and seronegative pSS patients. This study suggests that behavioural interventions designed to reduce pain catastrophizing and negative appraisal of illness could be of benefit in pSS patients. Research is needed to test the effect of psycho-educational therapies on key patient-reported outcomes, particularly pain, depression, and fatigue, in pSS.

Utility of a machine-guided tool for assessing risk behaviour associated with contracting HIV in three sites in South Africa.

Introduction: Digital data collection and the associated mobile health technologies have allowed for the recent exploration of artificial intelligence as a tool for combatting the HIV epidemic. Machine learning has been found to be useful both in HIV risk prediction and as a decision support tool for guiding pre-exposure prophylaxis (PrEP) treatment. This paper reports data from two sequential studies evaluating the viability of using machine learning to predict the susceptibility of adults to HIV infection using responses from a digital survey deployed in a high burden, low-resource setting. Methods: 1036 and 593 participants were recruited across two trials. The first trial was a cross-sectional study in one location and the second trial was a cohort study across three trial sites. The data from the studies were merged, partitioned using standard techniques, and then used to train and evaluate multiple different machine learning models and select and evaluate a final model. Variable importance estimates were calculated using the PIMP and SHAP methodologies. Results: Characteristics associated with HIV were consistent across both studies. Overall, HIV positive patients had a higher median age (34 [IQR: 29-39] vs 26 [IQR 22-33], p < 0.001), and were more likely to be female (155/703 [22%] vs 107/927 [12%], p < 0.001). HIV positive participants also had more commonly gone a year or more since their last HIV test (183/262 [70%] vs 540/1368 [39%], p < 0.001) and were less likely to report consistent condom usage (113/262 [43%] vs 758/1368 [55%], p < 0.001). Patients who reported TB symptoms were more likely to be HIV positive. The trained models had accuracy values (AUROCs) ranging from 78.5% to 82.8%. A boosted tree model performed best with a sensitivity of 84% (95% CI 72-92), specificity of 71% (95% CI 67-76), and a negative predictive value of 95% (95% CI 93-96) in a hold-out dataset. Age, duration since last HIV test, and number of male sexual partners were consistently three of the four most important variables across both variable importance estimates. Conclusions: This study has highlighted the synergies present between mobile health and machine learning in HIV. It has been demonstrated that a viable ML model can be built using digital survey data from an low-middle income setting with potential utility in directing health resources.

Oxidative stress and fatigue in systemic lupus erythematosus.

OBJECTIVE: The objective of this study is to investigate the relationship of oxidative stress to fatigue in systemic lupus erythematosus (SLE). METHODS: Patients with a confirmed diagnosis of SLE by ACR criteria and healthy controls completed validated questionnaires to assess depression and fatigue. Fatigue was measured with the Fatigue Severity Scale (FSS) and the Profile of Fatigue (Prof-F). Visual analogue scales (VAS) were also used to assess fatigue and pain. Depression was measured with the Center for Epidemiologic Studies Depression Scale (CES-D). Plasma F(2)-isoprostane was measured with gas chromatography/mass spectroscopy to assess oxidative stress. Evaluation included medical record review, physical exam and calculation of body mass index (BMI), disease activity (SLEDAI) and damage (SLICC) in the SLE patients. RESULTS: Seventy-one SLE patients with low disease activity (mean SLEDAI = 1.62 standard error (SE) 0.37, range 0-8) were compared to 51 controls. Fatigue-limiting physical activity (defined as FSS ≥ 4) was present in 56% of patients and 12% of controls. F(2)-isoprostane was higher in SLE patients with fatigue compared to not-fatigued SLE subjects (p = .0076) who were otherwise similar in ethnicity, disease activity and cardiovascular risk factors. Plasma F(2)-isoprostane was strongly correlated with FSS and Profile of Somatic Fatigue (Prof-S) (p < .0001), VAS fatigue (p = .005), CES-D (p = .008) and with BMI (p = .0001.) In a multivariate model, F(2)-isoprostane was a significant predictor of FSS after adjustment for age, BMI, pain and depression (p = .0002). CONCLUSION: Fatigue in SLE patients with low disease activity is associated with increased F(2)-isoprostane. F2-isoprostane could provide a useful biomarker to explore mitochondrial function and the regulation of oxidative pathways in patients with SLE in whom fatigue is a debilitating symptom.

Primary Sjogren's syndrome: cognitive symptoms, mood, and cognitive performance.

OBJECTIVE: To investigate the relationships between self-reported cognitive abilities, psychological symptoms and neuropsychological outcomes in PSS. METHODS: Patients with Primary Sjogren's syndrome (PSS) and healthy controls completed a comprehensive neuropsychometric battery and questionnaires: the Centers for Epidemiological Scale-Depression, the Profile of Fatigue-mental domain (Prof-M) for cognitive symptoms, Fatigue Severity Scale, and the Short-Form McGill Pain Questionnaire. RESULTS: Female patients with PSS (N = 39) were similar to controls (N = 17) in estimated premorbid intellectual function, age and education. Depression (P = 0.002), cognitive symptoms (P = 0.001), fatigue (P = 0.000003), and pain (P = 0.024) scores were greater in the patient group. Patients with PSS demonstrated inferior performance relative to controls in psychomotor processing (P = 0.027) and verbal reasoning (P = 0.007). Patients with PSS with and without depression had similar performance on multiple tests, but depressed patients had significantly lower scores for executive function (P = 0.041). Cognitive symptoms correlated with verbal memory (P = 0.048), whereas pain correlated with executive function measures (Stroop, P = 0.017) and working memory (Trails B, P = 0.036). In the regression model, depression and verbal memory were independent predictors that accounted for 61% of the variance in cognitive symptoms. CONCLUSION: The Prof-M is a simple self-report measure which could be useful in screening PSS subjects who may benefit from detailed psychometric evaluation. Our results are consistent with the hypothesis that depression and verbal memory impairment are overlapping but independent aspects of neural involvement in PSS. While pain and depression are significant confounders of cognitive function in PSS, this study suggests that impaired verbal reasoning ability in PSS is not attributable to pain or depression.

IL-12 unmasks latent autoimmune disease in resistant mice.

Inbred mice exhibit a spectrum of susceptibility to induction of experimental allergic encephalomyelitis (EAE). We have compared the immune responses of the susceptible SJL (H-2s) and resistant B10.S (H-2s) strains to determine factors other than the MHC background which control resistance/susceptibility to EAE. The resistance of the B10.S strain was found to be secondary to an antigen-specific defect in the generation of Th 1 cells that produce IFN gamma. This defect in IFN gamma production could be restored by exposure of the myelin basic protein (MBP)-reactive T cells to IL-12 with the subsequent induction of the ability to transfer EAE to naive recipients. These findings have important implications for the therapeutic use of IL-12 and IL-12 antagonists and may explain the association between relapses/exacerbation of autoimmune disease and infectious diseases.

An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease.

Cells of the innate immune system secrete cytokines early in immune responses that guide maturing T helper (Th) cells along appropriate lineages. This study investigates the role of cytokine networks, bridging the innate and acquired immune systems, in the pathogenesis of an organ specific autoimmune disease. Experimental allergic encephalomyelitis (EAE), a demyelinating disease of the central nervous system, is widely used as an animal model for multiple sclerosis. We demonstrate that interleukin (IL)-12 is essential for the generation of the autoreactive Th1 cells that induce EAE, both in the presence and absence of interferon gamma. The disease-promoting effects of IL-12 are antagonized by IL-10 produced by an antigen nonspecific CD4+ T cell which, in turn, is regulated by the endogenous production of IL-12. This unique immunoregulatory circuit appears to play a critical role in controlling Th cell differentiation and provides a mechanism by which microbial triggers of the innate immune system can modulate autoimmune disease.

Regulation of interleukin (IL)-12 receptor beta2 subunit expression by endogenous IL-12: a critical step in the differentiation of pathogenic autoreactive T cells.

The interleukin (IL)-12 receptor (R)beta2 subunit is the critical molecule involved in maintaining IL-12 responsiveness and controlling T helper cell type 1 lineage commitment. We demonstrate that IL-12 and interferon (IFN)-gamma play separate, but complementary, roles in regulating IL-12Rbeta2 expression on antigen-specific CD4(+) T cells. These results are consistent with our previous observation that IL-12 can promote autoimmune disease through IFN-gamma-independent as well as -dependent pathways. Therefore, we compared the induction of IL-12 by, and the expression of the IL-12Rbeta2 subunit on, myelin basic protein (MBP)-specific T cells from experimental allergic encephalomyelitis (EAE)-susceptible SJL (H-2(s)) mice and from EAE- resistant B10.S mice (H-2(s)). B10.S mice had an antigen-specific defect in their capacity to upregulate the IL-12Rbeta2 subunit. Defective expression was not secondary to the production of suppressive cytokines, but to a failure of B10.S MBP-specific T cells to upregulate CD40 ligand expression and to induce the production of IL-12. IL-12Rbeta2 expression as well as encephalitogenicity of these cells could be restored by the addition of IL-12. These results suggest that the development of immunotherapies that target the IL-12Rbeta2 subunit may be useful for the treatment of autoimmune diseases.

Chronic granulomatous disease.

Chronic granulomatous disease is an inherited disorder of the NADPH oxidase characterized by severe bacterial and fungal infections and disordered inflammation. We propose that NADPH oxidase has a key role in regulating acute neutrophilic and T cell responses, which in turn restrains fungal growth and calibrates the inflammatory response to minimize injury and allergy. In this model, superoxide-induced activation of indoleamine 2,3-dioxygenase (IDO) is a central mechanism by which the optimal balance of antifungal host defense and immune tolerance occurs. This model is based on studies in mice and requires correlation in humans.

Peripheral blood gene expression profiling in Sjögren's syndrome.

Sjögren's syndrome (SS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands. The affected cases commonly present with oral and ocular dryness, which is thought to be the result of inflammatory cell-mediated gland dysfunction. To identify important molecular pathways involved in SS, we used high-density microarrays to define global gene expression profiles in the peripheral blood. We first analyzed 21 SS cases and 23 controls, and identified a prominent pattern of overexpressed genes that are inducible by interferons (IFNs). These results were confirmed by evaluation of a second independent data set of 17 SS cases and 22 controls. Additional inflammatory and immune-related pathways with altered expression patterns in SS cases included B- and T-cell receptor, insulin-like growth factor-1, granulocyte macrophage-colony stimulating factor, peroxisome proliferator-activated receptor-alpha/retinoid X receptor-alpha and PI3/AKT signaling. Exploration of these data for relationships to clinical features of disease showed that expression levels for most interferon-inducible genes were positively correlated with titers of anti-Ro/SSA (P<0.001) and anti-La/SSB (P<0.001) autoantibodies. Diagnostic and therapeutic approaches targeting interferon-signaling pathway may prove most effective in the subset of SS cases that produce anti-Ro/SSA and anti-La/SSB autoantibodies. Our results strongly support innate and adaptive immune processes in the pathogenesis of SS, and provide numerous candidate disease markers for further study.

Energy and labor in the construction sector.

An energy input-output model was used to investigate energy and employment in the construction industry. The model covered nearly 400 industrial sectors and was used to determine the impact of construction activities on total national energy consumption in 1967 and to study the patterns of total energy use and employment within various construction categories. For the construction of new buildings, total energy consumption could be reduced by 20 percent by selecting less energy-intensive building materials and assemblies for fixed programmatic requirements, by expending energy in construction to minimize the total lifetime energy cost of buildings, and by energy conservation in industries that supply direct and indirect inputs to the construction sector of the economy.

Late infectious complications after cord blood stem cell transplantation.

The slower engraftment kinetics and impaired immune reconstitution of cord blood stem cell transplant recipients increase the risk of infectious complications. We retrospectively reviewed patients who underwent cord blood stem cell transplantation at Roswell Park Cancer Institute for hematological malignancies and who survived beyond day 100 for late infectious events. Among 15 patients who were included in the study, there were 18 episodes of bacteremia, 5 cases of bacterial pneumonia, 9 viral, 4 fungal, and 1 nontuberculous mycobacterial infection. Overall mortality was 60%, with infections contributing in 44% of cases. In conclusion, survival beyond day 100 following cord bloodstem cell transplantation is associated with a considerable risk of infections in our single center experience.

Critical action procedures testing: a novel method for test-enhanced learning.

CONTEXT: Human error is a leading cause of adverse events in anaesthesia. Residents' knowledge of how to respond to rare, yet potentially life-threatening events has been shown to deteriorate over time and thus cost-effective educational interventions are indicated. Previous research has shown that test-enhanced learning has the potential to strengthen both clinical knowledge and performance. We hypothesised that critical action procedures (CAPs) tests, similar to those employed by high-performance aircraft pilots, would help improve resident knowledge about how to respond to rare and potentially catastrophic events encountered during the perioperative period. METHODS: Knowledge assessments were administered to 29 first-year anaesthesiology residents over the course of 9 months. Five-minute closed-book tests were administered with fill-in-the-blank questions regarding the American Society of Anesthesiologists' difficult airway guideline, advanced cardiac life support protocols, an institutional airway fire protocol and drug dosing for malignant hyperthermia. Inter-group comparisons were evaluated using the Kruskal-Wallis test. The difference between the pre-test and final test scores for each subsection was determined with the Mann-Whitney U-test for independent samples. RESULTS: Composite subtest scores, when compared with baseline pre-test scores and subsequent scores, and when adjusted for attrition, significantly improved over the course of 9 months (20.5% versus 80%; P < or = 0.001). Likert-based survey data indicated a positive report for attainment of knowledge. CONCLUSIONS: In this longitudinal observational study of first-year anaesthesiology residents, CAPs testing helped improve knowledge about critical events. Although the study was limited by its small number of subjects, a significant attrition rate and the lack of a control group, it demonstrates a cost-effective educational intervention that improved resident knowledge. This intervention may enable residents to transfer learned skills from theoretical testing situations to real-life scenarios. We propose the use and further study of CAPs testing as a cost-effective modality to augment both simulated and actual experiential learning.

Add-on cases in the endoscopy unit: Factors that affect volume.

BACKGROUND: Although most procedures in the endoscopy clinic are elective, emergency add-on cases in hospital-based endoscopy clinics are common, frequently consuming a great deal of time and resources relative to elective endoscopy procedures. OBJECTIVE: To determine which specific factors correlate with the high volume of add-on emergency cases in a tertiary care, hospital-based endoscopy unit. METHODS: A retrospective chart review of all gastrointestinal add-on, and electively booked cases of esophagastroduodenoscopy (EGD), colonoscopy(C) and flexible sigmoidoscopy(FS)procedures from September 2006 to May 2007, was conducted. The day of the week, month, type of procedure and physician were recorded. Emergency add-on procedures performed during the weekends were not assessed. These cases were then compared with elective cases during a similar time frame to determine differences in the aspects of add-on cases versus those that were elective. RESULTS: Seven hundred twenty-one add-on cases were reviewed (mean patient age 57.4 years; 46% women) and compared with 736 elective cases (mean age 56 years; 49% women; P not significant). Of the add-on cases, 377 (52%) were EGD, 216 C (30%) and 105 (15%) were FS, with 23 combined procedures (3.2%) versus 202 (27%) EGD, 442 (60%) C and 74 (10%) FS in the elective group. Add-on cases were more likely to be EGDs than elective cases (OR 2.7; 95% CI 1.8 to 4.3; P<0.0001) and less likely to be Cs (OR 0.24; 95% CI 0.15 to 0.38; P<0.0001). There were significantly more add-on cases on Mondays (OR 1.7; 95% CI 1.0 to 2.28; P>0.03). Conversely, there were significantly fewer procedures added on Fridays (OR 0.31; 95% CI 0.16 to 0.57; P=0.0001). There were statistically fewer add-on cases in September compared with the other months that were evaluated (OR 0.31; 95% CI 0.11 to 0.78; P=0.0006). CONCLUSION: With the present system of performing only emergency cases on the weekend, Monday tends to have more add-on cases. Consistent with the fact that upper gastrointestinal bleeding is the most common emergency condition, EGD is more common in add-on cases than with elective cases. Although speculative, the reasons for Friday having fewer add-on cases may be the result of a change of physician on call that day; consequently, most cases may be performed earlier in the week. For unknown reasons, fewer cases tend to be added on in September than in the other months evaluated. These data demonstrate that even in the same institution with similar patients, variability in the number of add-on cases likely is a result of many additional factors governing add-on cases, which require appropriate resource planning to ensure adequate allocation of services to ensure ideal patient care.

Virulence of catalase-deficient aspergillus nidulans in p47(phox)-/- mice. Implications for fungal pathogenicity and host defense in chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a rare genetic disorder in which phagocytes fail to produce superoxide because of defects in one of several components of the NADPH oxidase complex. As a result, patients develop recurrent life-threatening bacterial and fungal infections. The organisms to which CGD patients are most susceptible produce catalase, regarded as an important factor for microbial pathogenicity in CGD. To test the role of pathogen-derived catalase in CGD directly, we have generated isogenic strains of Aspergillus nidulans in which one or both of the catalase genes (catA and catB), have been deleted. We hypothesized that catalase negative mutants would be less virulent than the wild-type strain in experimental animal models. CGD mice were produced by disruption of the p47(phox) gene which encodes the 47-kD subunit of the NADPH oxidase. Wild-type A. nidulans inoculated intranasally caused fatal infection in CGD mice, but did not cause disease in wild-type littermates. Surprisingly, wild-type A. nidulans and the catA, catB, and catA/catB mutants were equally virulent in CGD mice. Histopathological studies of fatally infected CGD mice showed widely distributed lesions in the lungs regardless of the presence or absence of the catA and catB genes. Similar to the CGD model, catalase-deficient A. nidulans was highly virulent in cortisone-treated BALB/c mice. Taken together, these results indicate that catalases do not play a significant role in pathogenicity of A. nidulans in p47(phox)-/- mice, and therefore raise doubt about the central role of catalases as a fungal virulence factor in CGD.

NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease.

In North America, liver disease due to alcohol consumption is an important cause of death in adults, although its pathogenesis remains obscure. Despite the fact that resident hepatic macrophages are known to contribute to early alcohol-induced liver injury via oxidative stress, the exact source of free radicals has remained a mystery. To test the hypothesis that NADPH oxidase is the major source of oxidants due to ethanol, we used p47(phox) knockout mice, which lack a critical subunit of this major source of reactive oxygen species in activated phagocytes. Mice were treated with ethanol chronically, using a Tsukamoto-French protocol, for 4 weeks. In wild-type mice, ethanol caused severe liver injury via a mechanism involving gut-derived endotoxin, CD14 receptor, production of electron spin resonance-detectable free radicals, activation of the transcription factor NF-kappaB, and release of cytotoxic TNF-alpha from activated Kupffer cells. In NADPH oxidase-deficient mice, neither an increase in free radical production, activation of NF-kappaB, an increase in TNF-alpha mRNA, nor liver pathology was observed. These data strongly support the hypothesis that free radicals from NADPH oxidase in hepatic Kupffer cells play a predominant role in the pathogenesis of early alcohol-induced hepatitis by activating NF-kappaB, which activates production of cytotoxic TNF-alpha.

A randomized, open-label, multicenter comparative study of the efficacy and safety of piperacillin-tazobactam and cefepime for the empirical treatment of febrile neutropenic episodes in patients with hematologic malignancies.

BACKGROUND: The empirical treatment of febrile, neutropenic patients with cancer requires antibacterial regimens active against both gram-positive and gram-negative pathogens. This study was performed to demonstrate the noninferiority of monotherapy with piperacillin-tazobactam, compared with cefepime. METHODS: We conducted a randomized-controlled, open-label, multicenter clinical trial among high-risk patients from 34 university-affiliated tertiary care medical centers in the United States, Canada, and Australia who were undergoing treatment for leukemia or hematopoietic stem cell transplantation and were hospitalized for empirical treatment of febrile neutropenic episodes. Patients received piperacillin-tazobactam (4.5 g every 6 h) or cefepime (2 g every 8 h) intravenously. The primary outcome was success (defined by defervescence without treatment modification) at 72 h of treatment, end of treatment, and test of cure in the modified intent-to-treat analysis. Secondary outcomes included time to defervescence, microbiological efficacy, the additional use of glycopeptide antibiotics, emergence of resistant bacteria, and safety. RESULTS: For 528 subjects (265 received piperacillin-tazobactam and 263 received cefepime), success rates were 57.7% and 48.3%, respectively (P = .04) at the 72-h time point, 39.6% and 31.6% (P = .06) at end of treatment, and 26.8% and 20.5% (P = .11) at the test-of-cure visit. The analyses demonstrated noninferiority for piperacillin-tazobactam at all time points (P< or = .0001). Treatment with piperacillin-tazobactam was independently associated with treatment success in multivariate analysis (odds ratio, 1.65; 95% confidence interval, 1.04-2.64; P = .035). Both regimens were well tolerated. CONCLUSIONS: This study demonstrates the noninferiority and safety of piperacillin-tazobactam monotherapy, compared with cefepime, for the empirical treatment of high-risk febrile neutropenic patients with cancer.

Oxidants from nicotinamide adenine dinucleotide phosphate oxidase are involved in triggering cell proliferation in the liver due to peroxisome proliferators.

It was shown that 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (Wy-14,643), a potent peroxisome proliferator, caused rapid oxidant-dependent activation of nuclear factor kappaB (NF-kappaB) in Kupffer cells in vivo and activated superoxide production by isolated Kupffer cells. Here, we tested the hypothesis that NADPH oxidase (NADPH OX) is the source of oxidants increased by Wy-14,643. Indeed, both activation of NF-kappaB and increases in cell proliferation due to a single dose of Wy-14,643 (100 mg/kg) were prevented completely when rats were pretreated with diphenyleneiodonium (1 mg/kg), an inhibitor of NADPH OX. p47phox is a critical subunit of NADPH OX; therefore, p47phox knockout mice were used to specifically address the hypothesis of NADPH OX involvement. In livers of wild-type mice, Wy-14,643 activated NF-kappaB, followed by an increase in mRNA for tumor necrosis factor a. Importantly, these changes did not occur in p47phox knockouts. Moreover, when Kupffer cells were treated with Wy-14,643 in vitro, superoxide production was increased in cells from wild-type but not p47phox-null mice. Finally, when mice were fed a Wy-14,643-containing (0.1%) diet for 7 days, the increase in liver weight and cell proliferation caused by Wy-14,643 in wild-type mice was blocked in p47phox-null mice. Combined, these results are consistent with the hypothesis that Wy-14,643 activates NADPH OX, which leads to NF-kappaB-mediated production of mitogens that causes hepatocellular proliferation characteristic of this class of nongenotoxic carcinogens.

Dexmedetomidine and ketamine show distinct patterns of cell degeneration and apoptosis in the developing rat neonatal brain.

OBJECTIVE: Early exposure to common anesthetic and sedative agents causes widespread brain cell degeneration and apoptosis in the developing rat brain, associated with persistent learning deficits in rats. This study was designed to determine whether the α2 adrenergic receptor agonist, dexmedetomidine, produces brain cell degeneration and apoptosis in postnatal day-7 rats in the same brain areas when compared to ketamine. METHODS: Systemic saline, ketamine 20 mg/kg, or dexmedetomidine at 30 or 45 µg/kg were given six times to postnatal day 7 rats (n = 6/group) every 90 min. Twenty-four hours after the initial injection, brain regions were processed and analyzed for cell degeneration using the silver stain and for apoptosis using activated caspase-3 immunohistochemistry. RESULTS: Exposure to ketamine resulted in significant cellular degeneration and apoptosis in limbic brain regions, but nonsignificant changes in primary sensory brain regions. In contrast, dexmedetomidine produced significant cellular degeneration and apoptosis in primary sensory brain regions, but nonsignificant changes in limbic regions. CONCLUSIONS: These data show that ketamine and dexmedetomidine result in anatomically distinct patterns of cell degeneration and apoptosis in the brains of 7-day-old rat pups. The meaning and the clinical significance of these findings remain to be established.