BACKGROUND

Emergency departments (EDs) are traditionally designed to provide rapid evaluation and stabilization and are neither staffed nor equipped to provide prolonged care. Longer ED length of stay (LOS) may compromise quality of care and contribute to delays in the emergency evaluation of other patients.

OBJECTIVE

The objective was to determine whether ED LOS increased between 2001 and 2005 and whether trends varied by patient and hospital factors.

METHODS

This was a retrospective analysis of a nationally representative sample of 138,569 adult ED visits from the National Hospital Ambulatory Medical Care Survey (NHAMCS), 2001 to 2005. ED LOS was measured from registration to discharge.

RESULTS

Median ED LOS increased 3.5% per year from 132 minutes in 2001 to 154 minutes in 2005 (p-value for trend < 0.001). There was a larger increase among critically ill patients for whom ED LOS increased 7.0% annually from 185 minutes in 2001 to 254 minutes in 2005 (p-value for trend < 0.01). ED LOS was persistently longer for black/African American, non-Hispanic patients (10.6% longer) and Hispanic patients (13.9% longer) than for non-Hispanic white patients, and these differences did not diminish over time. Among factors potentially associated with increasing ED LOS, a large increase was found (60.1%, p-value for trend < 0.001) in the use of advanced diagnostic imaging (computed tomography [CT], magnetic resonance imaging [MR], and ultrasound [US]) and in the proportion of ED visits at which five or more diagnostic or screening tests were ordered (17.6% increase, p-value for trend = 0.001). The proportion of uninsured patients was stable throughout the study period, and EDs with predominately privately insured patients experienced significant increases in ED LOS (4.0% per year from 2001 to 2005, p-value for trend < 0.01).

CONCLUSIONS

Emergency department LOS in the United States is increasing, especially for critically ill patients for whom time-sensitive interventions are most important. The disparity of longer ED LOS for African Americans and Hispanics is not improving.

While experiments in animals demonstrate neurotoxic effects of particulate matter (PM) and ozone (O3), epidemiologic evidence is sparse regarding the relationship between different constituencies of air pollution mixtures and cognitive function in adults. We examined cross-sectional associations between various ambient air pollutants [O3, PM2.5 and nitrogen dioxide (NO2)] and six measures of cognitive function and global cognition among healthy, cognitively intact individuals (n=1496, mean age 60.5 years) residing in the Los Angeles Basin. Air pollution exposures were assigned to each residential address in 2000-06 using a geographic information system that included monitoring data. A neuropsychological battery was used to assess cognitive function; a principal components analysis defined six domain-specific functions and a measure of global cognitive function was created. Regression models estimated effects of air pollutants on cognitive function, adjusting for age, gender, race, education, income, study and mood. Increasing exposure to PM2.5 was associated with lower verbal learning (β=-0.32 per 10 μg/m(3) PM2.5, 95% CI=-0.63, 0.00; p=0.05). Ambient exposure to NO2 >20 ppb tended to be associated with lower logical memory. Compared to the lowest level of exposure to ambient O3, exposure above 49 ppb was associated with lower executive function. Including carotid artery intima-media thickness, a measure of subclinical atherosclerosis, in models as a possible mediator did not attenuate effect estimates. This study provides support for cross-sectional associations between increasing levels of ambient O3, PM2.5 and NO2 and measures of domain-specific cognitive abilities.

Differentiation of proinflammatory CD4⁺ conventional T cells (T_conv) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4⁺ T_conv, but then fail to support antitumor CD4⁺ T_conv differentiation. Regulatory T cell (T_reg) depletion enhanced their capacity to elicit strong CD4⁺ T_conv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to T_reg predicts protective ICOS⁺ PD-1^lo CD4⁺ T_conv phenotypes and survival. Further, in melanoma patients with low T_reg abundance, intratumoral cDC2 density alone correlates with abundant CD4⁺ T_conv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4⁺ T_conv abundance and controls tumor growth.

OBJECTIVE

The primary purpose of this article is to report 12-month prevalence rates and predictors of alcohol abuse and dependence among Mexican Americans, Cuban Americans, Puerto Ricans, and South/Central Americans living in the United States.

METHODS

Using a multistage cluster sample design, a total of 5,224 individuals 18 years of age and older were selected from the household population in five metropolitan areas of the United States: Miami, New York, Philadelphia, Houston, and Los Angeles. The survey weighted response rate was 76%. Personal interviews lasting an average of 1 hour were conducted in respondents' homes either in English or Spanish.

RESULTS

There is considerable heterogeneity in rates of abuse and dependence across these national groups, with Mexican American and Puerto Rican men having higher rates than Cuban American and South/Central American men. The rates of dependence for Mexican American and Puerto Rican men are also higher than those for men in the U.S. general population. Further, although the highest rates of abuse and dependence are among those in their 20s, the rate decline with age is not as strong as in the U.S. population. Thus, Hispanics at older ages (40-49, 50-59) are at considerably more risk of dependence and its health consequences than the U.S. general population. This is particularly true of Puerto Rican and Mexican American men.

CONCLUSIONS

Future analysis must take this heterogeneity into consideration by conducting national group-specific analysis. Prevention efforts must also be guided by these findings, which suggest that Puerto Ricans and Mexican Americans are at higher risk for abuse, dependence, and the associated consequences than the other two groups of U.S. Hispanics.

Although overproduction of proinflammatory 5-lipoxygenase (5-LO)-derived leukotrienes (LTs) has been demonstrated in the lungs of patients with pulmonary fibrosis, their causal involvement in this condition has not been established. Bleomycin-induced pulmonary fibrosis was studied in mice rendered LT deficient by knockout of the 5-LO gene (KO) and in wild-type (WT) control mice. Following administration of bleomycin, lung lavage fluid of WT mice demonstrated an approximately 5-fold increase in levels of cysteinyl-LTs over baseline levels at Day 1, with persistent elevation up to Day 21. As compared with WT mice, 5-LO KO mice demonstrated reduced amounts of histologically evident collagen as well as an approximately 60% reduction in lung hydroxyproline levels postbleomycin. Unlike WT mice, KO mice showed no increases in the numbers of lung inflammatory cells postbleomycin. Furthermore, in situ expression and stimulated production by mixed lung leukocytes of the antifibrotic cytokine interferon-gamma were significantly greater in cells from the 5-LO KO mice. Finally, lavage levels of the antiinflammatory and antifibrotic molecule, prostaglandin E(2), were significantly greater in the KO animals. These results provide strong evidence that LTs may participate in the pathogenesis of pulmonary fibrosis, and they may do so by direct effects as well as indirect effects occurring via their modulation of the synthesis of other inflammatory mediators.

NIDDM is usually characterized by beta-cell failure and decreased insulin sensitivity. It has been reported that a high proportion of African-American NIDDM subjects are insulin sensitive. To examine this issue, we determined insulin sensitivity (S(I)) in 479 NIDDM subjects by minimal model analyses of frequently sampled intravenous glucose tolerance (FSIGT) from the Insulin Resistance Atherosclerosis Study (IRAS), a large multicenter study of insulin sensitivity and cardiovascular risk in African-Americans, Hispanics, and non-Hispanic whites. The African-Americans and non-Hispanic whites were sampled in Los Angeles and Oakland, California. The non-Hispanic whites and Hispanics were sampled in San Antonio, Texas, and San Luis Valley, Colorado. We defined the proportion of insulin-sensitive (S(I)) subjects as>> or =1.61 min-1 x microU-1 x ml-1, which is above the median for nondiabetic subjects of all ethnic groups in the IRAS. Using this definition, the proportion of insulin-sensitive diabetic subjects was very low in all ethnic groups (non-Hispanic whites [14.3%] vs. African-Americans [6.5%], P = 0.039 in Los Angeles and Oakland; non-Hispanic whites [6.8%] vs. Hispanics [4.9%], P = 0.737 in San Luis Valley and San Antonio). These results were also similar in newly diagnosed mildly hyperglycemic diabetic subjects. In addition, these results were not affected by the adjustment for differences in obesity, body fat distribution, and severity of hyperglycemia. Even in nonobese subjects (with BMI <30 kg/m2), the proportion of insulin-sensitive subjects (S(I)>> or =1.61 min-1 x microU-1 x ml-1) was low (3.6-9.7%). The acute insulin response (AIR) was significantly higher in African-Americans than in non-Hispanic whites; there were no ethnic differences in AIR between Hispanics and non-Hispanic whites. There were no significant ethnic differences for non-insulin-mediated glucose disposal (S(G)). We conclude that the number of insulin-sensitive NIDDM subjects is low and similar among non-Hispanic whites, Hispanics, and African-Americans in the U.S.

OBJECTIVE

We tested a theory of syndemic production among men who have sex with men (MSM) using data from a large cohort study.

METHODS

Participants were 1551 men from the Multicenter AIDS Cohort Study enrolled at 4 study sites: Baltimore, Maryland-Washington, DC; Chicago, Illinois; Los Angeles, California; and Pittsburgh, Pennsylvania. Participants who attended semiannual visits from April 1, 2008, to March 31, 2009, completed an additional survey that captured data about events throughout their life course thought to be related to syndemic production.

RESULTS

Using multivariate analysis, we found that the majority of life-course predictor variables (e.g., victimization, internalized homophobia) were significantly associated with both the syndemic condition and the component psychosocial health outcomes (depressive symptoms, stress, stimulant use, sexual compulsivity, intimate partner violence). A nested negative binomial analysis showed that the overall life course significantly explained variability in the syndemic outcomes (χ(2) = 247.94; P < .001; df = 22).

CONCLUSIONS

We identified life-course events and conditions related to syndemic production that may help to inform innovative interventions that will effectively disentangle interconnecting health problems and promote health among MSM.

Frog sartorius muscles tetanized isometrically were released at a constant velocity from lengths lL to lS (delta l = lL -lS; Ls greater than lO). The tension PS redeveloped after the release was lower than the isometric tension PS at LS, and higher than the isometric tension PL at lL. The tension deficit D is defined as the difference PS-PS. The timing of the release during the tetanus did not influence D. D/PO was proportional to delta l/lO. The proportionality constant k was equal to 1.35 +/- 0.19 (n = 8) when the velocity of release was 2.5 mm/s. When the muscles were released the same delta l, D was found to be an exponential decreasing function of the velocity. The tension deficit was also found in experiments performed in the region lS less than lO. The proportionality constant k was smaller, but the influence of the velocity of the release on D was not modified. When the velocity of the release was changed during the release, D changed accordingly, showing that the effects of delta l and V are multiplicative. These facts suggest a working hypothesis based on the concept that the actin filaments which enter the overlap region during a release are strained by the tetanic stress and therefore unable to make normal cross-bridges.

T follicular helper (Tfh) cells represent a Th subset engaged in the help of B-cell responses in germinal centers (GCs). Tfh cells abundantly express the transcription repressor B-cell lymphoma 6 (Bcl6), a factor that is necessary and sufficient for their development in vivo. Whether Tfh or Tfh-committed cells are involved in the help of B cells outside GCs remains unclear, particularly in humans. In this study, we identified a previously undefined BCL6-expressing CD4(+) T-cell subset in human tonsils. This subset expressed IL-7 receptor and chemokine receptor 5 (CXCR5) and inducible costimulator (ICOS) at low levels (CXCR5(lo)ICOS(lo)), and it was found exclusively outside GCs. CXCR5(lo)ICOS(lo) CD4(+) T cells secreted larger amounts of IL-21 and IL-10 than CXCR5(hi)ICOS(hi) GC-Tfh cells upon activation, and they induced proliferation and differentiation of naïve B cells into Ig-producing cells more efficiently than GC-Tfh cells. However, this subset lacked the capacity to help GC-B cells because of the induction of apoptosis of GC-B cells through the FAS/FAS-ligand interaction. CXCR5(lo)ICOS(lo) CD4(+) T cells expressed equivalent amounts of BCL6 transcript with CXCR5(hi)ICOS(hi) GC-Tfh cells, but they expressed less Bcl6 protein. Collectively, our study indicates that CXCR5(lo)ICOS(lo) CD4(+) T cells in human tonsils represent Tfh lineage-committed cells that provide help to naïve and memory B cells outside GCs.

Prior research has identified the lateral occipital complex (LOC) as a critical cortical region for the representation of object shape in humans. However, little is known about the nature of the representations contained in the LOC and their relationship to the perceptual experience of shape. We used human functional MRI to measure the physical, behavioral, and neural similarity between pairs of novel shapes to ask whether the representations of shape contained in subregions of the LOC more closely reflect the physical stimuli themselves, or the perceptual experience of those stimuli. Perceptual similarity measures for each pair of shapes were obtained from a psychophysical same-different task; physical similarity measures were based on stimulus parameters; and neural similarity measures were obtained from multivoxel pattern analysis methods applied to anterior LOC (pFs) and posterior LOC (LO). We found that the pattern of pairwise shape similarities in LO most closely matched physical shape similarities, whereas shape similarities in pFs most closely matched perceptual shape similarities. Further, shape representations were similar across participants in LO but highly variable across participants in pFs. Together, these findings indicate that activation patterns in subregions of object-selective cortex encode objects according to a hierarchy, with stimulus-based representations in posterior regions and subjective and observer-specific representations in anterior regions.

OBJECTIVE

Previous studies demonstrated that inhibition of P glycoprotein (P-gp) by Pluronic P85 (P85) block copolymer increases apical (AP) to basolateral (BL) transport of rhodamine 123 (R123) in the polarized monolayers of bovine brain microvessel endothelial cells (BBMEC) and Caco-2 cells. The present work examines the effects of P85 on the transport of fluorescein (Flu), doxorubicin (Dox), etoposide (Et), taxol (Tax), 3'-azido-3'-deoxythymidine (AZT), valproic acid (VPA) and loperamide (Lo) using BBMEC and Caco-2 monolayers as in vitro models of the blood brain barrier and intestinal epithelium respectively.

METHODS

Drug permeability studies were performed on the confluent BBMEC and Caco-2 cell monolayers mounted in Side-Bi-Side diffusion cells.

RESULTS

Exposure of the cells to P85 significantly enhanced AP to BL permeability coefficients of Flu, Tax, Dox and AZT in both cell models. Further, P85 enhanced AP to BL transport of Et, VPA and Lo in Caco-2 monolayers. No changes in the permeability coefficients of the paracellular marker mannitol were observed in the presence of the copolymer.

CONCLUSIONS

P85 increases AP to BL permeability in BBMEC and Caco-2 monolayers with respect to a broad panel of structurally diverse compounds, that were previously shown to be affected by P-gp and/ or multidrug resistance associated protein (MRP) efflux systems. Broad specificity of the block copolymer effects with respect to drugs and efflux systems appears to be a valuable property in view of developing pharmaceutical formulations to increase drug accumulation in selected organs and overcome both acquired and intrinsic drug resistance that limits the effectiveness of many chemotherapeutic agents.

This article describes psychiatric and substance dependence comorbidities, lifetime rates of infectious disease, and reported high-risk sexual behaviors for methamphetamine-dependent, gay and bisexual men at entry to outpatient drug abuse treatment in Los Angeles. Participants' self-reports of high-risk sexual and drug use behaviors and of history of infectious disease status were correlated with diagnostic information from 155 Structured Clinical Interviews for the DSM-IV (SCID). A total of 82 participants met criteria for lifetime depressive disorders; 44 participants met criteria for lifetime anxiety disorders. Compared to those without psychiatric diagnoses, significant differences were observed in lifetime prevalence of sexually transmitted infections among those who have generalized anxiety disorder (higher rates of genital gonorrhea), specific phobia and major depressive disorder (higher rates of oral gonorrhea), social phobia (higher rates of syphilis) and bipolar disorder, type I (higher rates of HIV). Differences in infectious disease prevalence did not correspond to significantly different rates of high-risk sexual behaviors. Findings indicate that gay and bisexual men seeking outpatient treatment for methamphetamine dependence are likely to experience psychiatric comorbidity and to have high rates of infectious disease, including HIV, syphilis and gonorrhea.

Thirty-five patients with documented absence of the anterior cruciate ligament were tested on the University of California, Los Angeles, instrumented clinical knee-testing apparatus and we measured the response curves for the following testing modes: anterior-posterior force versus displacement at full extension and at 20 and 90 degrees of flexion; varus-valgus moment versus angulation at full extension and 20 degrees of flexion; and tibial torque versus rotation at 20 degrees of flexion. Absolute values of stiffness and laxity and right-left differences for these injured knees were compared with identical quantities measured previously for a control population of forty-nine normal subjects with no history of treatment for injury to the knee. For both the uninjured knees and the knees without an anterior cruciate ligament, at 20 and 90 degrees of flexion the anterior-posterior laxity was greatest at approximately 15 degrees of external rotation of the foot. The injured knees demonstrated significantly increased total anterior-posterior laxity and decreased anterior stiffness when compared with the uninjured knees in all tested positions of the foot and knee. The mean increase in paired anterior-posterior laxity for the injured knees in this group of patients at +/- 200 newtons of applied anterior-posterior force was 3.1 millimeters (+39 per cent) at full extension, 5.5 millimeters (+57 per cent) at 20 degrees of flexion, and 2.5 millimeters (+34 per cent) at 90 degrees of flexion. The mean reduction in anterior stiffness for injured knees was also greatest (-54 per cent) at 20 degrees of knee flexion. Only slight reduction in posterior stiffness (-16 per cent) was measured at 20 degrees of flexion, and this probably reflected the presence of associated capsular and meniscal injuries. In the group of anterior cruciate-deficient knees, the patients with an absent medial meniscus showed greater total anterior-posterior laxity in all three positions of knee flexion than did the patients with an intact or torn meniscus. Varus-valgus laxity at full extension increased an average of 1.7 degrees (+36 per cent) for the injured knees, while varus and valgus stiffness decreased 21 per cent and 24 per cent. Absence of the medial meniscus (in a knee with absence of the anterior cruciate ligament) increased varus-valgus laxity at zero and 20 degrees of flexion.(ABSTRACT TRUNCATED AT 400 WORDS)

Associations of reproductive factors with ovarian cancer may differ by histologic type. Data from a multiethnic, population-based, case-control study, conducted in Hawaii and Los Angeles, California, between 1993 and 1999, were used to assess this hypothesis. A structured questionnaire was administered to 558 histologically confirmed epithelial ovarian cancer cases and 607 population controls. Factors suppressing ovulation, including pregnancy and oral contraceptive use, were inversely associated with the risk of all histologic types. Nonmucinous but not mucinous tumors were significantly associated with menstruation years (odds ratio = 1.5 for the highest vs. the lowest quartile) and lifetime ovulatory cycles (odds ratio = 2.8 for the highest vs. the lowest quartile). Duration of breastfeeding (odds ratio = 0.4 for the highest vs. the lowest quartile) was significantly and inversely related to nonmucinous tumors but not to mucinous tumors. Among all tumor types, endometrioid tumors were the most strongly related to pregnancy and tubal ligation, while clear cell tumors were the only type that was associated with noncontraceptive hormone use. The risk factors were similar for borderline and invasive tumors, except for age at diagnosis. Mucinous tumors, both borderline and invasive, were more common in Asian women than in Caucasian and other women. Our data suggest that histologic types of epithelial ovarian cancer are etiologically distinct.

Neisseria gonorrhoeae lipooligosaccharide (LOS) undergoes antigenic variation at a high rate, and this variation can be monitored by changes in a strain's ability to bind LOS-specific monoclonal antibodies. We report here the cloning and identification of a gene, lsi-2, that can mediate this variation. The DNA sequence of lsi-2 has been determined for N. gonorrhoeae 1291, a strain that expresses a high-molecular-mass LOS, and a derivative of this strain, RS132L, that produces a truncated LOS. In the parental strain, lsi-2 contains a string of 12 guanines in the middle of its coding sequence. In cells that had antigenically varied to produce a truncated LOS, the number of guanines in lsi-2 was altered. Site-specific deletions were constructed to verify that expression of a 3.6-kDa LOS is due to alterations in lsi-2.

The role of Treg in patients with late-stage HIV disease, who commence combination antiretroviral therapy (cART) and develop pathogen-specific immunopathology manifesting as immune restoration disease (IRD) remains unclear. We hypothesised that Treg could be defective in either numbers and/or function and therefore unable to ensure the physiological equilibrium of the immune system in patients with IRD. Phenotypic and functional CD4(+) T-cell subsets of eight late-stage HIV patients with nadir CD4 count <50 cells/microL, who developed mycobacterial IRD upon commencing cART were compared with six therapy naive HIV(+) patients (nadir CD4 count <50 cells/microL), who did not develop an IRD after cART. Mycobacterium-avium-specific CD4(+) T cells from IRD patients produced high levels of IFN-gamma and IL-2 compared with controls (p<0.001). Surprisingly, we found a significant expansion of CD127(lo)Foxp3(+)CD25(+) Treg in IRD patients and a higher ratio of Treg to effector/memory subsets (p<0.001). In vitro suppression assays demonstrated reduced functional capacity of suppressor cells and diminished IL-10 secretion in IRD patients. Plasma levels of IL-7 were increased in patients and, interestingly, exogenous IL-7 and other cytokines strongly inhibited Treg suppression. These data suggest that despite substantial Treg expansion in IRD, their ability to induce suppression, and thereby downregulate aberrant immune responses, is compromised.

Efforts to assess health risks associated with exposures to multiple urban air toxics have been hampered by the lack of exposure data for people living in urban areas. The TEACH (Toxic Exposure Assessment, a Columbia/Harvard) study was designed to characterize levels of and factors influencing personal exposures to urban air toxics among high school students living in inner-city neighborhoods of New York City and <em>Los</em> Angeles, California. This present article reports methods and data for the New York City phase of TEACH, focusing on the relationships between personal, indoor, and outdoor concentrations in winter and summer among a group of 46 high school students from the A. Philip Randolph Academy, a public high school located in the West Central Harlem section of New York City. Air pollutants monitored included a suite of 17 volatile organic compounds (VOCs) and aldehydes, particulate matter with a mass median aerodynamic diameter <or= 2.5 microm (PM2.5), black carbon, and a suite of 28 particle-associated trace elements. Sequential 48-hr ambient samples also were collected over 8 weeks in each season at an urban fixed site and an upwind, nonurban fixed site. Personal, indoor, and outdoor concentrations of particle elements were generally similar, suggesting that ambient sources may have driven indoor and personal exposures for most elements. More varied relationships among personal, home indoor, and home outdoor concentrations were observed for VOCs and aldehydes. For formaldehyde and acetaldehyde, and several VOCs, indoor concentrations far exceeded outdoor levels and appeared to dominate personal exposures. Strong seasonal differences in indoor to outdoor concentration ratios were observed for these compounds, reflecting the influence of home air exchange rates. For other VOCs, especially those related to motor vehicle exhaust, more consistent indoor, outdoor, and personal concentrations were observed, suggesting that ambient concentrations may have been the driving force for personal exposures to some VOCs. These results demonstrate exposures to a wide range of air toxic pollutants among young people attending school in inner-city New York.

Recent studies by Dorshkind, Yoder, and colleagues show that embryonic (E9) B-cell progenitors located in the yolk sac and intraembryonic hemogenic endothelium before the initiation of circulation give rise to B-1 and marginal zone B cells but do not give rise to B-2 cells. In studies here, we confirm and extend these findings by showing that distinct progenitors for B-1 and B-2 cells are present in the adult spleen. Furthermore, we show that the splenic B-cell progenitor population (lin(-)CD19(+)/B220(lo/-)/CD43(-)) that gives rise to B-1 cells is likely to be heterogeneous because, in some recipients, it also gives rise to B cells expressing the marginal zone phenotype (B220(hi)IgM(hi)IgD(lo)CD21(hi)) and to some (CD19(-)CD5(hi)) T cells. In addition to the well-known function differences between B-1 and B-2, our studies demonstrate that substantial developmental differences separate these B-cell lineages. Thus, consistent with the known dependence of B-2 development on IL-7, all B-2 progenitors express IL-7R. However, >30% of the B-1 progenitors do not express this marker, enabling the known IL-7 independent development of B-1 cells in IL-7(-/-) mice. In addition, marker expression on cells in the early stages of the B-2 development pathway (CD19(-)/c-Kit(lo/-)/Sca-1(lo/-)) in adult bone marrow distinguish it from the early stages of B-1 development (CD19(hi)/c-Kit(+)/Sca-1(+)), which occur constitutively in neonates. In adults, in vivo inflammatory stimulation (LPS) triggers B-1 progenitors in spleen to expand and initiate development along this B-1 developmental pathway.

Eicosanoids derived from lipoxygenase (LO)-catalyzed reactions play important roles in pulmonary inflammation. Here, we examined formation of LO-derived products by human alveolar macrophages (HAM). HAM converted [1-14C]-arachidonic acid to a product carrying 14C-radiolabel that was identified as 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid (15-HETE) by physical methods. 15-LO mRNA was demonstrated in HAM by reverse transcription-polymerase chain reaction. Incubation of HAM for 3 d with interleukin 4(IL-4) before exposure to [1-14C]arachidonic acid led to both increased mRNA for 15-LO and a 4-fold increase in 15-HETE formation. In contrast, 5(S)-hydroxy-6-trans-8,11,14-cis-eicosatetraenoic acid generation was not significantly altered by prior exposure to IL-4. Additionally, lipoxins (LXA4 and LXB4) were detected from endogenous substrate, albeit in lower levels than leukotriene B4 (LTB4), in electrochemical detection/high performance liquid chromatography profiles from HAM incubated in the presence and absence of the chemotactic peptide (FMLP) or the calcium ionophore (A23187). Exposure of HAM to leukotriene A4 (LTA4) resulted in a 2-fold increase in LXA4 and 10-fold increase in LXB4. These results demonstrate the presence of 15-LO mRNA and enzyme activity in HAM and the production of LXA4 and LXB4 by these cells. Along with 5-LO-derived products, the biosynthesis of 15-LO-derived eicosanoids by HAM may also be relevant in modulating inflammatory responses in the lung.

The initial steps in the biosynthesis of leukotrienes from arachidonic acid are carried out by the enzyme 5-lipoxygenase (5-LO). In intact cells, the helper protein 5-LO activating protein (FLAP) is necessary for efficient enzyme utilization of endogenous substrate. The last decade has witnessed remarkable progress in our understanding of these two proteins. Here we review the molecular and cellular aspects of the expression, function, and regulation of 5-LO and FLAP.

SAMP1/YitFc mice develop discontinuous, transmural inflammatory lesions in the terminal ileum, similar to what is found in human Crohn disease. Compared with the mesenteric lymph nodes (MLNs) of AKR control mice, SAMP1/YitFc MLNs contain a 4.3-fold expansion in total B cell number and a 2.5-fold increased percentage of CD4(+) T cells expressing the alpha(E)beta(7) integrin. Although alpha(E)beta(7)(+)CD4(+) T cells possess a regulatory phenotype (CD25(+), L-selectin(lo), and CD45RB(lo)), express IL-10, and suppress effector T cell proliferation in vitro, they cannot prevent ileitis development in SCID mice adoptively transferred with effector CD4(+) T cells, although the CD4(+)CD25(+) subset, which overlaps with the alpha(E)beta(7)(+)CD4(+) subset, prevents colitis. The alpha(E)beta(7)(+)CD4(+) T cells express high levels of ICOS, a costimulatory molecule that augments B cell function, suggesting their involvement in the increase in B cells, IgA(+) cells, and soluble IgA found within the MLNs and ileum of SAMP1/YitFc mice. MLN B cell numbers correlate with ileitis severity in SAMP1/YitFc mice, and cotransfer of SAMP1/YitFc MLN B cells along with CD4(+) T cells increases ileitis severity in SCID mice compared with transfer of CD4(+) T cells alone. SAMP1/YitFc B cells prevent alpha(E)beta(7)(+)CD4(+) T cells from suppressing effector T cell proliferation. We conclude that SAMP1/YitFc MLN B cells contribute to the development of SAMP1/YitFc ileitis.

BACKGROUND

Little is known about vitamin D status in breast cancer survivors. This issue is important because vitamin D influences pathways related to carcinogenesis.

OBJECTIVE

The objective of this report was to describe and understand vitamin D status in a breast cancer survivor cohort.

METHODS

Data are from the Health, Eating, Activity, and Lifestyle study. With the use of a cross-sectional design, we examined serum concentrations of 25-hydroxyvitamin D [25(OH)D] in 790 breast cancer survivors from western Washington state, New Mexico, and Los Angeles County. Cancer treatment data were obtained from Surveillance, Epidemiology, and End Results registries and medical records. Fasting blood, anthropometry, and lifestyle habits were collected after diagnosis and treatment. We examined distributions of 25(OH)D by race-ethnicity, season, geography, and clinical characteristics. Multivariate regression tested associations between 25(OH)D and stage of disease.

RESULTS

Five hundred ninety-seven (75.6%) of the women had low serum 25(OH)D, suggesting vitamin D insufficiency or frank deficiency. The overall mean (+/-SD) was 24.8 +/- 10.4 ng/mL, but it was lower for African Americans (18.1 +/- 8.7 ng/mL) and Hispanics (22.1 +/- 9.2 ng/mL). Women with localized (n = 424) or regional (n = 182) breast cancer had lower serum 25(OH)D than did women with in situ disease (n = 184) (P = 0.05 and P = 0.03, respectively). Multivariate regression models controlled for age, body mass index (in kg/m(2)), race-ethnicity, geography, season, physical activity, diet, and cancer treatments showed that stage of disease independently predicted serum 25(OH)D (P = 0.02).

CONCLUSIONS

In these breast cancer survivors, the prevalence of vitamin D insufficiency was high. Clinicians might consider monitoring vitamin D status in breast cancer patients, together with appropriate treatments, if necessary.

BACKGROUND

Histology is generally considered as a tool of limited value in the diagnosis of gastro-esophageal reflux disease (GERD).

OBJECTIVE

To reevaluate the diagnostic role of histological alterations in GERD, using multiple biopsy sites and an appropriate control group.

METHODS

We studied 135 patients with typical and atypical symptoms of GERD. They underwent upper GI endoscopy and Los Angeles classification was used for grading cases with mucosal breaks. Biopsies were taken at the Z-line, 2 and 4 cm above it. Microscopic esophagitis was identified by necrosis/erosion, neutrophil/eosinophil intraepithelial infiltration, basal cell hyperplasia, elongation of papillae, dilation of intercellular spaces and a score (range: 0-2) was given for each lesion. Twenty-four-hour esophageal pH monitoring was performed in each patient. Twenty subjects without reflux symptoms, and with normal endoscopy and pH testing were considered as controls.

RESULTS

Histological alterations were found in 100 of 119 GERD patients (84%) and in 3 of 20 controls (15%) with a significant difference (p < 0.00001). Histology was abnormal in 96% of patients with erosive esophagitis and in 76% of patients with nonerosive reflux disease (NERD). The sum of scores of microscopic lesions found in all biopsy sites ranged from 0 to 22 and we identified a cut-off value (score 2) that distinguished efficiently controls from GERD patients.

CONCLUSIONS

In contrast with previous reports on the marginal role of histology in patients with GERD, our study shows that this technique can be a useful diagnostic tool, particularly in patients with NERD, when biopsies are taken at two sites including Z-line and 2 cm above it.

We present the results of arthroscopic repair of full-thickness tears of the rotator cuff in seventy-three patients (thirty-nine men and thirty-four women). The average age of the patients at the time of the operation was 60.7 years (range, thirty-one to eighty-two years). All of the patients were followed for at least two years (average, thirty months; range, twenty-four to forty months). The shoulders were evaluated with the rating scale of the University of California at Los Angeles, the shoulder index of the American Shoulder and Elbow Surgeons, and the functional rating scale of Constant and Murley. In addition, the patients completed the Short-Form 36 Health Survey (SF-36) preoperatively and at the yearly follow-up evaluations. Eleven tears were small (less than one centimeter in length), forty-five were medium (one to three centimeters), eleven were large (more than three to five centimeters), and six were massive (more than five centimeters). The average length of the tear was twelve millimeters, and the average width was twenty-seven millimeters. Sixty-nine tendons were repaired anatomically, and four were repaired an average of three millimeters (range, two to eight millimeters) medial to the anatomical insertion of the tendon. An average of 2.3 (range, one to four) suture anchors were used in the repair. Sixty-three glenohumeral joints were normal, and ten had an intra-articular lesion. Seven patients had a concomitant resection of the acromioclavicular joint. The average duration of the operation was fifty-six minutes (range, thirty-five to ninety minutes). The active and passive ranges of motion improved significantly after the procedure (p = 0.0001). The strength of resisted elevation improved from 7.5 to 14.0 pounds (3.4 to 6.3 kilograms) (p = 0.0001). The average total score according to the rating scale of the University of California at Los Angeles improved from 12.4 to 31.1 points; the average total score according to the shoulder index of the American Shoulder and Elbow Surgeons, from 30.7 to 87.6 points; and the average absolute score according to the rating system of Constant and Murley, from 41.7 to 83.6 points (p = 0.0001 for all comparisons). The average score for the pain component of the rating scale of the University of California at Los Angeles improved from 2.4 to 8.6 points; fifty-seven (78 per cent) of the seventy-three patients rated the relief of pain as good or excellent on the visual-analog scale. The average score for satisfaction improved from 0.4 to 4.6 points; sixty-six patients (90 per cent) rated their satisfaction as good or excellent at the time of the most recent examination. None of the shoulders were rated as good or excellent before the operation, whereas sixty-one (84 per cent) were so rated at the most recent follow-up evaluation after the index procedure. In addition, significant improvements (p = 0.0015) were noted in the scales and summary measures of the SF-36. Arthroscopic repair of full-thickness tears of the rotator cuff produced satisfactory results with regard to traditional orthopaedic criteria as well as with regard to patient-assessed criteria such as satisfaction, pain relief, and general health. The arthroscopic method offers several advantages, including smaller incisions, access to the glenohumeral joint for the inspection and treatment of intra-articular lesions, no need for detachment of the deltoid, and less soft-tissue dissection. However, these advantages must be considered against the technical difficulty of the method, which limits its application to surgeons who are skilled in both open and arthroscopic procedures on the shoulder.