OBJECTIVE

We assessed the usefulness of RALP in children and compared an age matched cohort undergoing OPN to RALP for safety, efficacy, operative time, blood loss, in-hospital narcotic use and LOS.

METHODS

We performed a retrospective case-control study from 2000 to 2004 of 33 patients undergoing RALP and 33 undergoing OPN. Average age of each group was not significantly different (RALP 7.8 years vs OPN 7.6 years, p = 0.75). Mean followup of RALP and OPN groups was 10 and 21 months, respectively.

RESULTS

Etiology of the obstruction was not significantly different. Mean operative time was significantly less for OPN (181 minutes vs 219 minutes for RALP, p = 0.031). As RALP experience increased, operative times improved and approached the OPN experience. RALP complications included 1 patient requiring reoperative surgery vs no complications in the OPN group (p = 0.15). Patients undergoing RALP had a mean LOS of 2.3 days compared to 3.5 days for OPN (p <0.001). Total narcotic requirements were significantly less in the RALP group (p = 0.001). All patients in the OPN and 31 in the RALP group had either resolution of hydronephrosis, improvement in drainage or relief of symptoms.

CONCLUSIONS

We documented the safety and efficacy of RALP in children. RALP showed advantages of decreased hospital stay, decreased narcotic use and operative times approaching those of open surgery. RALP is an option for pyeloplasty, and as robotic technology improves, this method of repair may become the minimally invasive treatment of choice.

15-lipoxygenase-1 (also known as 12/15-LO in mice) and 5-LO/5-LO-activating protein (FLAP) cascades play central roles in low-density lipoprotein oxidation and leukotriene biosynthesis, respectively. Several genetic and expression studies unraveling an association of the 5-LO/FLAP pathway to human cardiovascular disease have surfaced recently. Experimental studies in 12/15-LO knockout, 15-LO-1 transgenic, and 5-LO knockout mice on atherosclerotic backgrounds combined with gene expression data in human coronary artery disease have created compelling links that these pathways participate in the etiologic progression. However, a few conflicting studies and several unexplained mechanistic issues need to be resolved prior to assigning firm roles for LOs in cardiovascular disease. Development of novel pharmacologic tools to dissect the individual enzymes and receptors in the LO pathways should improve understanding of the individual components in the inflammatory aspects of atherosclerosis disease progression.

Human immunodeficiency virus type 1 (HIV-1) in the male genital tract may comprise virus produced locally in addition to virus transported from the circulation. Virus produced in the male genital tract may be genetically distinct, due to tissue-specific cellular characteristics and immunological pressures. HIV-1 env sequences derived from paired blood and semen samples from the Los Alamos HIV Sequence Database were analyzed to ascertain a male genital tract-specific viral signature. Machine learning algorithms could predict seminal tropism based on env sequences with accuracies exceeding 90%, suggesting that a strong genetic signature does exist for virus replicating in the male genital tract. Additionally, semen-derived viral populations exhibited constrained diversity (P < 0.05), decreased levels of positive selection (P < 0.025), decreased CXCR4 coreceptor utilization, and altered glycosylation patterns. Our analysis suggests that the male genital tract represents a distinct selective environment that contributes to the apparent genetic bottlenecks associated with the sexual transmission of HIV-1.

The mouse lymphoid organ-resident CD8alpha(+) dendritic cell (DC) subset is specialized in Ag presentation to CD8(+) T cells. Recent evidence shows that mouse nonlymphoid tissue CD103(+) DCs and human blood DC Ag 3(+) DCs share similarities with CD8alpha(+) DCs. We address here whether the organization of DC subsets is conserved across mammals in terms of gene expression signatures, phenotypic characteristics, and functional specialization, independently of the tissue of origin. We study the DC subsets that migrate from the skin in the ovine species that, like all domestic animals, belongs to the Laurasiatheria, a distinct phylogenetic clade from the supraprimates (human/mouse). We demonstrate that the minor sheep CD26(+) skin lymph DC subset shares significant transcriptomic similarities with mouse CD8alpha(+) and human blood DC Ag 3(+) DCs. This allowed the identification of a common set of phenotypic characteristics for CD8alpha-like DCs in the three mammalian species (i.e., SIRP(lo), CADM1(hi), CLEC9A(hi), CD205(hi), XCR1(hi)). Compared to CD26(-) DCs, the sheep CD26(+) DCs show 1) potent stimulation of allogeneic naive CD8(+) T cells with high selective induction of the Ifngamma and Il22 genes; 2) dominant efficacy in activating specific CD8(+) T cells against exogenous soluble Ag; and 3) selective expression of functional pathways associated with high capacity for Ag cross-presentation. Our results unravel a unifying definition of the CD8alpha(+)-like DCs across mammalian species and identify molecular candidates that could be used for the design of vaccines applying to mammals in general.

BACKGROUND

Current knowledge of risk assessment in survivors of myocardial infarction is largely based on data gathered before the advent of thrombolysis. It must be determined whether and to what extent available information and proposed criteria of prognostication are applicable in the thrombolytic era.

RESULTS

We reassessed risk prediction in the 10,219 survivors of myocardial infarction with follow-up data available (ie, 98% of the total) who had been enrolled in the GISSI-2 trial, relying on a set of prespecified variables. The 3.5% 6-month all-cause mortality rate of these patients compared with the higher value of 4.6% found in the corresponding GISSI-1 cohort, originally allocated to streptokinase therapy, indicates a 24% reduction in postdischarge 6-month mortality. On multivariate analysis (Cox model), the following variables were predictors of 6-month all-cause mortality: ineligibility for exercise test for both cardiac (relative risk [RR], 3.30; 95% confidence interval [CI], 2.36-4.62) and noncardiac reasons (RR, 3.28; 95% CI, 2.23-4.72), early left ventricular failure (RR, 2.41; 95% CI, 1.87-3.09), echocardiographic evidence of recovery phase left ventricular dysfunction (RR, 2.30; 95% CI, 1.78-2.98), advanced (more than 70 years) age (RR, 1.81; 95% CI, 1.43-2.30), electrical instability (ie, frequent and/or complex ventricular arrhythmias) (RR, 1.70; 95% CI, 1.32-2.19), late left ventricular failure (RR, 1.54; 95% CI, 1.17-2.03), previous myocardial infarction (RR, 1.47; 95% CI, 1.14-1.89), and a history of treated hypertension (RR, 1.32; 95% CI, 1.05-1.65). Early post-myocardial infarction angina, a positive exercise test, female sex, history of angina, history of insulin-dependent diabetes, and anterior site of myocardial infarction were not risk predictors. On further multivariate analysis, performed on 8315 patients with the echocardiographic indicator of left ventricular dysfunction available, only previous myocardial infarction was not retained as an independent risk predictor.

CONCLUSIONS

A decline in 6-month mortality of myocardial infarction survivors, seen within 6 hours of symptom onset, has been observed in recent years. Ineligibility for exercise test, early left ventricular failure, and recovery-phase left ventricular dysfunction are the most powerful (RR,>> 2) predictors of 6-month mortality among patients recovering from myocardial infarction after thrombolysis. Qualitative variables reflecting residual myocardial ischemia do not appear to be risk predictors. The lack of an independent adverse influence of early post-myocardial infarction angina on 6-month survival represents a major difference between this study and those of the prethrombolytic era.

Reactive oxygen species (ROS) are important regulatory molecules implicated in the signaling cascade triggered by tumor necrosis factor (TNF)-alpha, although the events through which TNF-alpha induces ROS generation are not yet well characterized. We therefore investigated selected candidates likely to mediate TNF-alpha-induced ROS generation. Consistent with the role of Rac in that process, stable expression of Rac(Asn-17), a dominant negative Rac1 mutant, completely blocked TNF-alpha-induced ROS generation. To understand better the mediators downstream of Rac, we investigated the involvement of cytosolic phospholipase A(2) (cPLA(2)) activation and metabolism of the resultant arachidonic acid (AA) by 5-lipoxygenase (5-LO). TNF-alpha-induced ROS generation was blocked by inhibition of cPLA(2) or 5-LO, but not cyclooxygenase, suggesting that TNF-alpha-induced ROS generation is dependent on synthesis of AA and its subsequent metabolism to leukotrienes. Consistent with that hypothesis, TNF-alpha Rac-dependently stimulated endogenous production of leukotriene B(4) (LTB(4)), while exogenous application of LTB(4) increased levels of ROS. In contrast, application of leukotrienes C(4), D(4), and E(4) or prostaglandin E(2) had little effect. Our findings suggest that LTB(4) production by 5-LO is situated downstream of the Rac-cPLA(2) cascade, and we conclude that Rac, cPLA(2), and LTB(4) play pivotal roles in the ROS-generating cascade triggered by TNF-alpha.

Protection against malaria often decays in the absence of infection, suggesting that protective immunological memory depends on stimulation. Here we have used CD4(+) T cells from a transgenic mouse carrying a T cell receptor specific for a malaria protein, Merozoite Surface Protein-1, to investigate memory in a Plasmodium chabaudi infection. CD4(+) memory T cells (CD44(hi)IL-7Rα(+)) developed during the chronic infection, and were readily distinguishable from effector (CD62L(lo)IL-7Rα(-)) cells in acute infection. On the basis of cell surface phenotype, we classified memory CD4(+) T cells into three subsets: central memory, and early and late effector memory cells, and found that early effector memory cells (CD62L(lo)CD27(+)) dominated the chronic infection. We demonstrate a linear pathway of differentiation from central memory to early and then late effector memory cells. In adoptive transfer, CD44(hi) memory cells from chronically infected mice were more effective at delaying and reducing parasitemia and pathology than memory cells from drug-treated mice without chronic infection, and contained a greater proportion of effector cells producing IFN-γ and TNFα, which may have contributed to the enhanced protection. These findings may explain the observation that in humans with chronic malaria, activated effector memory cells are best maintained in conditions of repeated exposure.

The mechanism of the age-associated decrease in CD8+ T cell response of mice to virus infection was examined in young adult (6 months) and aged (22 months) C57BL/6 mice during primary pulmonary influenza A virus infection. A significant age-associated decrease in both the percentage (P<0.0001) and number (P<0.05) of CD8+ T cells binding MHC Class I tetramers containing influenza A nucleoprotein (NP) epitope and in virus-specific CTL activity (P<0.05) was observed with pulmonary lymphocytes. The percentage of NP+CD8+ cells of individual mice strongly correlated with NP-specific cytotoxic activity (r(2)=0.77, P<0.02) and with the percentage of CD8+ cells that produced interferon-gamma (r(2)=0.86, P<0.002) in both young and aged mice. Comparable expression of the CD28, CD25, and the memory CD44(hi)/CD62L(lo) phenotype was detected on NP+CD8+ lymphocytes from mice of both age groups. There was a delay in the maximal expansion of NP+CD8+ cells in aged compared to young mice that paralleled a delay in maximal cytotoxic activity and in virus clearance. These data suggest that the age-related impairment of CD8+ lymphocyte activity during a primary influenza A infection is due to a defect in the expansion, rather than in effector activity, of influenza-specific CD8+ T cells.

There is substantial in vitro and in vivo evidence implicating tea polyphenols as chemopreventive agents against various cancers. However, epidemiologic data obtained from mainly Western populations are not supportive of a protective role of tea, mainly black tea, in the etiology of breast cancer. Much less is known about the relationship between green tea and breast cancer risk. During 1995-1998, we conducted a population-based, case-control study of breast cancer among Chinese, Japanese and Filipino women in Los Angeles County and successfully interviewed 501 breast cancer patients and 594 control subjects. Detailed information on menstrual and reproductive factors; dietary habits, including intake of black and green tea; and other lifestyle factors was collected. Risk of breast cancer was not related to black tea consumption. In contrast, green tea drinkers showed a significantly reduced risk of breast cancer, and this was maintained after adjusting for age, specific Asian ethnicity, birthplace, age at menarche, parity, menopausal status, use of menopausal hormones, body size and intake of total calories and black tea. Compared to women who did not drink green tea regularly (i.e., less than once a month), there was a significant trend of decreasing risk with increasing amount of green tea intake, adjusted odds ratios being 1.00, 0.71 (95% confidence interval [CI] 0.51-0.99) and 0.53 (95% CI 0.35-0.78), respectively, in association with no, 0-85.7 and >85.7 ml of green tea per day. The significant inverse association between risk of breast cancer and green tea intake remained after further adjustment for other potential confounders, including smoking; alcohol, coffee and black tea intake; family history of breast cancer; physical activity; and intake of soy and dark green vegetables. While both green tea and soy intake had significant, independent protective effects on breast cancer risk, the benefit of green tea was primarily observed among subjects who were low soy consumers. Similarly, the protective effect of soy was primarily observed among subjects who were nondrinkers of green tea. In summary, our results point to an important role of both green tea and soy intake in relation to breast cancer risk in Asian-American women.

Investigation of the effects of rituximab (anti-CD20) on B-cell-activating factor of the tumor necrosis factor family (BAFF) and B cells would better define the significance of B-cell homeostasis in chronic graft-versus-host disease (cGVHD) pathophysiology. We studied 20 cGVHD patients at a median of 25 months after rituximab treatment when most patients had recovered total B-cell numbers. A total of 55% of patients had stable/improved cGVHD, and total B-cell numbers in these patients were significantly higher compared with rituximab-unresponsive patients. Although total B-cell number did not differ significantly between cGVHD groups before rituximab, there was a proportional increase in B-cell precursors in patients who later had stable/improved cGVHD. After rituximab, BAFF levels increased in all patients. Coincident with B-cell recovery in the stable/improved group, BAFF/B-cell ratios and CD27(+) B-cell frequencies decreased significantly. The peripheral B-cell pool in stable/improved cGVHD patients was largely composed of naive IgD(+) B cells. By contrast, rituximab-unresponsive cGVHD patients had persistent elevation of BAFF and a predominance of circulating B cells possessing an activated BAFF-R(Lo)CD20(Lo) cell surface phenotype. Thus, naive B-cell reconstitution and decreased BAFF/B-cell ratios were associated with clinical response after rituximab in cGVHD. Our findings begin to delineate B-cell homeostatic mechanisms important for human immune tolerance.

This study evaluates associations between internalized homonegativity and demographic factors, drug use behaviors, sexual risk behaviors, and HIV status among men who have sex with men (MSM) and with men and women (MSM/W). Participants were recruited in Los Angeles County using respondent-driven sampling (RDS) and completed the Internalized Homonegativity Inventory (IHNI) and questionnaires on demographic and behavioral factors. Biological samples were tested for HIV and for recent cocaine, methamphetamine, and heroin use. The 722 MSM and MSM/W participants were predominantly African American (44%) and Hispanic (28%), unemployed (82%), homeless (50%), and HIV positive (48%) who used drugs in the past 6 months (79.5%). Total and Personal Homonegativity, Gay Affirmation, and Morality of Homosexuality IHNI scores were significantly higher for African American men than for other ethnicities, for MSM/W than for MSM, for recent cocaine users than for recent methamphetamine users, and for HIV-seronegative men than for HIV-seropositive men. Linear regression showed the Gay Affirmation scale significantly and inversely correlated with the number of sexual partners when controlling for effects of ethnicity/race and sexual identification, particularly for men who self-identified as straight. Highest IHNI scores were observed in a small group of MSM/W (n = 62) who never tested for HIV. Of these, 26% tested HIV positive. Findings describe ways in which internalized homophobia is a barrier to HIV testing and associated HIV infection and signal distinctions among participants in this sample that can inform targeted HIV prevention efforts aimed at increasing HIV testing.

Macrophages (MΦ) play an essential role in innate immune responses and can either display a pro-inflammatory, classically activated phenotype (M1) or undergo an alternative activation program (M2) promoting immune regulation. M-CSF is used to differentiate monocytes into MΦ and IFN-γ or IL-4+IL-13 to further polarize these cells towards M1 or M2, respectively. Recently, differentiation using only GM-CSF or M-CSF has been described to induce a M1- or M2-like phenotype, respectively. In this study, we combined both approaches by differentiating human MΦ in GM-CSF or M-CSF followed by polarization with either IFN-γ or IL-4+IL-13. We describe the phenotypic differences between CD14(hi) CD163(hi) CD206(int) FOLR2-expressing M-CSF MΦ and CD14(lo) CD163(lo) CD206(hi) GM-CSF MΦ but show that both macrophage populations reacted similarly to further polarization with IFN-γ or IL-4+IL-13 with up- and down-regulation of common M1 and M2 marker genes. We also show that high expression of the mannose receptor (CD206), a marker of alternative activation, is a distinct feature of GM-CSF MΦ. Changes of the chromatin structure carried out by chromatin modification enzymes (CME) have been shown to regulate myeloid differentiation. We analyzed the expression patterns of CME during MΦ polarization and show that M1 up-regulate the histone methyltransferase MLL and demethylase KDM6B, while resting and M2 MΦ were characterized by DNA methyltransferases and histone deacetylases. We demonstrate that MLL regulates CXCL10 expression and that this effect could be abrogated using a MLL-Menin inhibitor. Taken together we describe the distinct phenotypic differences of GM-CSF or M-CSF MΦ and demonstrate that MΦ polarization is regulated by specific epigenetic mechanisms. In addition, we describe a novel role for MLL as marker for classical activation. Our findings provide new insights into MΦ polarization that could be helpful to distinguish MΦ activation states.

BACKGROUND

The overall rate of mortality due to ischemic heart disease is known to increase progressively with age. We evaluated the relation between the mortality rate and age in patients with first myocardial infarctions treated with thrombolytic therapy.

METHODS

We studied 9720 patients with first infarctions who had been enrolled in the GISSI-2 trial. (This trial compared the efficacy of tissue plasminogen activator with that of streptokinase in patients with myocardial infarction.) Of these, only 35 percent had a history of angina. The relation between age and mortality during hospitalization and during the six months after discharge was determined by unadjusted and adjusted analyses.

RESULTS

The in-hospital mortality rate was 1.9 percent among patients 40 years old or younger, but it increased to 31.9 percent among those more than 80 years old; however, values for indicators of infarct size did not increase with age. Autopsies were performed in 20 percent of the 772 patients who died in the hospital; the findings showed that the frequency of cardiac rupture increased from 19 percent among patients 60 years old or younger to 86 percent among those more than 70 years old. The mortality rate for the first six months after hospital discharge also increased significantly with age. After adjustment for confounding variables, older age continued to be significantly associated with a higher risk of in-hospital and post-discharge death. When age was introduced into a multivariate model as a continuous variable, the risk of death was estimated to increase by about 6 percent per year for both in-hospital and six-month mortality rates.

CONCLUSIONS

In patients with first myocardial infarctions who received thrombolytic therapy, age was a powerful independent predictor of both in-hospital and post-discharge mortality rates. The exponential, age-related increase in the mortality rate did not appear to be explained by larger infarcts.

OBJECTIVE

To investigate the null hypothesis that an objective, noninvasive technique of measuring cardiorespiratory reserve, does not improve the preoperative assessment of patient risk of postoperative complications, when compared with a standard questionnaire-based assessment of functional capacity.

BACKGROUND

Postoperative complications may be increased in patients with reduced cardiorespiratory function. Activity questionnaires are subjective, whereas cardiopulmonary exercise testing (CPET) provides an objective definition of cardiorespiratory reserve. The use of preoperative CPET to predict postoperative complications is not fully defined.

METHODS

CPET and an algorithm-based activity assessment (Veterans Activity Questionnaire Index [VASI]) were performed on consecutive patients (n = 171) with low subjective functional capacity (metabolic equivalent score [METS] < 7), being assessed for major surgery. A morbidity survey determined postoperative day 7 complications. Logistic regression defined independent predictors of complication group. Receiver-operating curve (ROC) analysis defined the predictive value of CPET to outcome. P < 0.05 value demonstrated significance.

RESULTS

Objective cardiorespiratory reserve did not differ between operated (n = 116) and nonoperated patients (n = 55). Median complication rate on postoperative day 7 was 1. Patients with >1 complication had an increase in hospital LOS compared to the group with < or =1 complication (26 vs. 10 days; P < 0.001). Anaerobic threshold (AT) was higher in the group with < or =1 complication (11.9 vs. 9.1 mL/kg/min; P = 0.001) and demonstrated high accuracy (AUC = 0.85), sensitivity (88%), and specificity (79%), at an optimum AT of 10.1 mL/kg/min (defined by the furthest left point on the ROC curve). AT, VASI, and surgical reintervention were independent predictors of complication group. Preoperative AT significantly improved outcome prediction when compared with the use of VASI alone.

CONCLUSIONS

An objective measure of cardiorespiratory reserve was an independent predictor of a major surgical group with increased postoperative complications and hospital LOS. AT measurement significantly improved outcome prediction compared with an algorithm-based activity assessment.

BACKGROUND

Unrecognized obstructive sleep apnea (OSA) is associated with unfavorable perio-perative outcomes among patients undergoing noncardiac surgery (NCS).

METHODS

The study population was chosen from 39,771 patients who underwent internal medicine preoperative assessment between January 2002 and December 2006. Patients undergoing NCS within 3 years of polysomnography (PSG) were considered for the study, whereas those < 18 years of age, with a history of upper airway surgery, or who had had minor surgery under local or regional anesthesia were excluded. Patients with an apnea-hypopnea index (AHI) ≥ 5 were defined as OSA and those with an AHI < 5 as control subjects. For adjusting baseline differences in age, sex, race, BMI, type of anesthesia, American Society of Anesthesiology class, and medical comorbidities, the patients were classified into five quintiles according to a propensity score.

RESULTS

Out of a total of 1,759 patients who underwent both PSG and NCS, 471 met the study criteria. Of these, 282 patients had OSA, and the remaining 189 served as control subjects. The presence of OSA was associated with a higher incidence of postoperative hypoxemia (OR, 7.9; P = .009), overall complications (OR, 6.9; P = .003), and ICU transfer (OR, 4.43; P = .069), and a longer hospital length of stay (LOS), (OR, 1.65; P = .049). Neither an AHI nor use of continuous positive airway pressure at home before surgery was associated with postoperative complications (P = .3 and P = .75, respectively) or LOS (P = .97 and P = .21, respectively).

CONCLUSIONS

Patients with OSA are at higher risk of postoperative hypoxemia, ICU transfers, and longer hospital stay.

BACKGROUND

Pediatric patients with brain tumors (BT) are often excluded from health-related quality of life (HRQOL) studies even though they experience more severe disease and treatment-related sequelae than children with other types of cancer. Parent proxy assessments of HRQOL allow for greater inclusion of children who are developmentally immature, physically ill, or cognitively impaired.

METHODS

Parents of children ages 2-18 years who were diagnosed at Childrens Hospital Los Angeles and Children's Hospital San Diego with BT (n = 86) or acute lymphoblastic leukemia (ALL; n = 170) evaluated their children's HRQOL over the previous week using the parent-proxy versions of the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core scales, the PedsQL 3.0 Acute Cancer Module, and the PedsQL Multidimensional Fatigue scales. Multiple regression analyses were used to determine the independent effect of the child's diagnosis on HRQOL. Separate analyses were conducted for patients receiving treatment, patients who had not received treatment for < 12 months, and patients who had not received treatment for>> or = 12 months.

RESULTS

Patients with BT exhibited more problems than patients with ALL in the physical, social, psychosocial, school, cognitive, and fatigue domains of HRQOL. The Core Physical Health, Core Psychosocial Health, and Fatigue Total scores for patients with BT demonstrated peak improvements for children who had not received treatment for < 12 months and sharp declines for children who had not received treatment for>> or = 12 months. The Core Physical Health and Fatigue Total scores for patients with ALL were highest (better HRQOL) for those who had not received treatment for>> or = 12 months.

CONCLUSIONS

Pediatric patients and survivors of BT experienced more fatigue and HRQOL problems than patients with ALL, and HRQOL differed by treatment status.

Mounting evidence suggests that lipoxygenase (LO)-catalyzed products have a profound influence on the development and progression of human cancers. Compared with normal tissues, significantly elevated levels of LO metabolites have been found in lung, prostate, breast, colon, and skin cancer cells, as well as in cells from patients with both acute and chronic leukemias. LO-mediated products elicit diverse biological activities needed for neoplastic cell growth, influencing growth factor and transcription factor activation, oncogene induction, stimulation of tumor cell adhesion, and regulation of apoptotic cell death. Agents that block LO-catalyzed activity may be effective in preventing cancer by interfering with signaling events needed for tumor growth. In fact, in a few studies, LO inhibitors have prevented carcinogen-induced lung adenomas and rat mammary gland cancers. During the past 10 years, pharmacological agents that specifically inhibit the LO-mediated signaling pathways are now commercially available to treat inflammatory diseases such as asthma, arthritis, and psoriasis. These well-characterized agents, representing two general drug effect mechanisms, are considered good candidates for clinical chemoprevention studies. One mechanism is inhibition of LO activity (5-LO and associated enzymes, or 12-LO); the second is leukotriene receptor antagonism. Although the receptor antagonists have high potential in treating asthma and other diseases where drug effects are clearly mediated by the leukotriene receptors, enzyme activity inhibitors may be better candidates for chemopreventive intervention, because inhibition of these enzymes directly reduces fatty acid metabolite production, with concomitant damping of the associated inflammatory, proliferative, and metastatic activities that contribute to carcinogenesis. However, because receptor antagonists have aerosol formulations and possible antiproliferative activity, they may also have potential, particularly in the lung, where topical application of such formulations is feasible.

OBJECTIVE

The aim of the present study was to compare MELD score, Child-Turcotte-Pugh (CTP) score, modified Maddrey's Discriminant Function (DF) score, and the related variables in predicting in-hospital mortality of patients with alcoholic hepatitis.

METHODS

A retrospective chart review and statistical analyses were done on 202 patients consecutively admitted for alcoholic hepatitis from 1997 to 2002 at the Liver Unit at Rancho Los Amigos Medical Center.

RESULTS

Twenty-nine patients died during the hospitalization. Admission MELD score (OR 1.1, P=0.005), first week MELD score (OR 1.2, P<0.0001), and first week increase in MELD score (OR 1.3, P<0.0001) were independently associated with in-hospital mortality. The area under the receiver operating curve (AUC) for the first week increase in MELD score was higher compared to CTP score (P=0.0004) and DF score (P=0.059). Moreover, the first week MELD score>>/=20 had the best sensitivity (91%) and specificity (85%) compared with admission or first week change MELD score.

CONCLUSIONS

The present study indicates that in patients with alcoholic hepatitis, admission, first week, and first week change in MELD score are significantly independent predictors for in-hospital mortality. MELD score is a more valuable model than CTP or DF score in patients admitted with alcoholic hepatitis.

OBJECTIVE

Microvascular permeability changes and loss of blood-brain barrier integrity are important features of central nervous system (CNS) radiation injury. Expression of vascular endothelial growth factor (VEGF), an important determinant of microvascular permeability, was examined to assess its role in CNS radiation damage. Because hypoxia mediates VEGF up-regulation through hypoxia-inducible factor-1alpha (HIF1alpha) induction, we studied the relationships of hypoxia, HIF1alpha expression, and expression of VEGF in this damage pathway.

METHODS

Expression of HIF1alpha, VEGF, and another hypoxia-responsive gene, glucose transporter-1, was assessed in the irradiated rat spinal cord using immunohistochemistry and in situ hybridization. Hypoxic areas were identified using the nitroimidazole 2-(2-nitro-1H-imidazole-L-yl)-N-(2,2,3,3,3,-pentafluoropropyl) acetamide. To determine the causal importance of VEGF expression in radiation myelopathy, we studied the response of transgenic mice with greater (VEGF-A(hi/+)), reduced (VEGF-A(lo/+)), and wild-type VEGF activity to thoracolumbar irradiation.

RESULTS

In rat spinal cord, the number of cells expressing HIF1alpha and VEGF increased rapidly from 16 to 20 weeks after radiation, before white matter necrosis and forelimb paralysis. A steep dose response was observed in expression of HIF1alpha and VEGF. HIF1alpha and VEGF expressing cells were identified as astrocytes. Hypoxia was present in regions where up-regulation of VEGF and glucose transporter-1 and increased permeability was observed. VEGF-A(lo/+) mice had a longer latency to development of hindlimb weakness and paralysis compared with wild-type or VEGF-A(hi/+) mice.

CONCLUSIONS

VEGF expression appears to play an important role in CNS radiation injury. This focuses attention on VEGF and other genes induced in response to hypoxia as targets for therapy to reduce or prevent CNS radiation damage.

This study examined the use of traditional and Western health services by Chinese immigrants, as well as the cultural and socioeconomic factors affecting health-seeking behaviors and health service utilization patterns among the study population from the perspectives of consumers and Chinese health care providers. Two instruments were used for data collection. The first, a consumer instrument, was designed for interviews of service recipients; the second, a health provider instrument, was designed to elicit information from traditional and Western providers. A few topics in the former instrument were cross-examined from the perspectives of health care providers. The investigation employed a combination of qualitative and quantitative research methods for data collection. Qualitative ethnographic methods used included: (1) participant-observation, (2) face-to-face interview, and (3) case study. To complement the qualitative data, structured quantitative survey were conducted with all selected informants. A total of 105 informants participated in the study: 75 Chinese consumers and 30 Chinese health professionals. The latter group was composed of Western physicians and traditional practitioners. Results revealed several patterns of health-seeking and service utilization behaviors among the Chinese of Houston and Los Angeles. These included high rates of self-treatment and home remedies (balanced diets and other alternative medicines); medium rates of utilization of integrated Western and traditional health services, including travel to country of origin for care; and low rates of exclusive utilization of Western or traditional Chinese treatments.

A retrospective review of 37 patients (22 men and 15 women) with histologically verified heterotopic pancreas treated at the department of surgery of the University of California at Los Angeles Medical Center from 1959 to 1985 was carried out. There were 31 adults (mean age 50 years) and 6 children (mean age 2.8 years). The majority of lesions were in the stomach, duodenum, and jejunum. One was found inside a duplicated stomach. Symptomatic lesions were confined to the gastroduodenal region and were larger, with frequent mucosal ulceration. Upper gastrointestinal contrast roentgenograms were sensitive tools for detection (87.5 percent of patients) and diagnosis (71.4 percent of patients) of these lesions. Endoscopy should be performed whenever epigastric pain is the presenting symptom. Resection of the tissue-bearing segment of small intestine is advisable when encountered incidentally at operation. In the absence of endoscopic biopsy confirmation, we recommend surgical exploration and frozen section histopathologic study for all symptomatic patients. Limited local excision has been shown to be a safe and adequate procedure for patients with these congenital anomalies.

Detailed job histories and information about other suspected risk factors were obtained during interviews with 272 men aged 25-69 with a primary brain tumor first diagnosed during 1980-1984 and with 272 individually matched neighbor controls. Separate analyses were conducted for the 202 glioma pairs and the 70 meningioma pairs. Meningioma, but not glioma, was related to having a serious head injury 20 or more years before diagnosis [odds ratio (OR) = 2.3; 95% confidence interval (CI) = 1.1-5.4], and a clear dose-response effect was observed relating meningioma risk to number of serious head injuries (P for trend = 0.01; OR for greater than or equal to 3 injuries = 6.2; CI = 1.2-31.7). Frequency of full-mouth dental X-ray examinations after age 25 related to both glioma (P for trend = 0.04) and meningioma risk (P for trend = 0.06). Glioma, but not meningioma risk, related to duration of prior employment in jobs likely to involve high exposure to electric and magnetic fields (P for trend = 0.05). This risk was greatest for astrocytoma (OR for employment in such jobs for greater than 5 years = 4.3; CI = 1.2-15.6). More glioma cases had worked in the rubber industry (discordant pairs 6/1) and more worked in hot processes using plastics (9/1). More meningioma cases had jobs that involved exposure to metal dusts and fumes (discordant pairs 13/5), and six of these cases and two controls worked as machinists. Finally, there was a protective effect among glioma pairs relating to frequency of use of vitamin C and other vitamin supplements (P for trend = 0.004); the OR for use at least twice a day was 0.4 (CI = 0.2-0.8).

We present LO, NLO and NNLO sets of parton distribution functions (PDFs) of the proton determined from global analyses of the available hard scattering data. These MMHT2014 PDFs supersede the 'MSTW2008' parton sets, but they are obtained within the same basic framework. We include a variety of new data sets, from the LHC, updated Tevatron data and the HERA combined H1 and ZEUS data on the total and charm structure functions. We also improve the theoretical framework of the previous analysis. These new PDFs are compared to the 'MSTW2008' parton sets. In most cases the PDFs, and the predictions, are within one standard deviation of those of MSTW2008. The major changes are the [Formula: see text] valence quark difference at small [Formula: see text] due to an improved parameterisation and, to a lesser extent, the strange quark PDF due to the effect of certain LHC data and a better treatment of the [Formula: see text] branching ratio. We compare our MMHT PDF sets with those of other collaborations; in particular with the NNPDF3.0 sets, which are contemporary with the present analysis.

BACKGROUND

Very few data exist on risk factors for developing biofilm-forming Candida bloodstream infection (CBSI) or on variables associated with the outcome of patients treated for this infection.

RESULTS

We identified 207 patients with CBSI, from whom 84 biofilm-forming and 123 non biofilm-forming Candida isolates were recovered. A case-case-control study to identify risk factors and a cohort study to analyze outcomes were conducted. In addition, two sub-groups of case patients were analyzed after matching for age, sex, APACHE III score, and receipt of adequate antifungal therapy. Independent predictors of biofilm-forming CBSI were presence of central venous catheter (odds ratio [OR], 6.44; 95% confidence interval [95% CI], 3.21-12.92) or urinary catheter (OR, 2.40; 95% CI, 1.18-4.91), use of total parenteral nutrition (OR, 5.21; 95% CI, 2.59-10.48), and diabetes mellitus (OR, 4.47; 95% CI, 2.03-9.83). Hospital mortality, post-CBSI hospital length of stay (LOS) (calculated only among survivors), and costs of antifungal therapy were significantly greater among patients infected by biofilm-forming isolates than those infected by non-biofilm-forming isolates. Among biofilm-forming CBSI patients receiving adequate antifungal therapy, those treated with highly active anti-biofilm (HAAB) agents (e.g., caspofungin) had significantly shorter post-CBSI hospital LOS than those treated with non-HAAB antifungal agents (e.g., fluconazole); this difference was confirmed when this analysis was conducted only among survivors. After matching, all the outcomes were still favorable for patients with non-biofilm-forming CBSI. Furthermore, the biofilm-forming CBSI was significantly associated with a matched excess risk for hospital death of 1.77 compared to non-biofilm-forming CBSI.

CONCLUSIONS

Our data show that biofilm growth by Candida has an adverse impact on clinical and economic outcomes of CBSI. Of note, better outcomes were seen for those CBSI patients who received HAAB antifungal therapy.