The author defines the term standardized patient (SP), the umbrella term for both a simulated patient (a well person trained to simulate a patient's illness in a standardized way) and an actual patient (who is trained to present his or her own illness in a standardized way). He first discusses the many values of simulated patients over actual patients as teaching and assessment tools in the classroom and refutes a few myths about the use of SPs. Then he recounts the origin and development of SPs over a three-decade period, beginning with his work as a neurologist at the Los Angeles County Hospital, where he trained a model from the art department to simulate a neurological patient and assist in the assessment of clinical clerks. He then describes additional roles of SPs that have developed, including: (1) their use in the Clinical Practice Examination created at Southern Illinois University School of Medicine and (2) the major use that has come into being over the last 10-15 years; facilitating the comprehensive assessment of clinical competence using multiple stations in examinations such as the objective structured clinical examination. He concludes with information about recent and current work on SPs, who are becoming more and more accepted in the assessment process, and urges skeptics not to make judgments about the value of SPs until they have experienced the technique firsthand and reviewed the literature concerning the extensive and often high-quality research about this assessment tool.

Skeletal muscle contraction increases intracellular ATP turnover, calcium flux, and mechanical stress, initiating signal transduction pathways that modulate peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha)-dependent transcriptional programmes. The purpose of this study was to determine if the intensity of exercise regulates PGC-1alpha expression in human skeletal muscle, coincident with activation of signalling cascades known to regulate PGC-1alpha transcription. Eight sedentary males expended 400 kcal (1674 kj) during a single bout of cycle ergometer exercise on two separate occasions at either 40% (LO) or 80% (HI) of . Skeletal muscle biopsies from the m. vastus lateralis were taken at rest and at +0, +3 and +19 h after exercise. Energy expenditure during exercise was similar between trials, but the high intensity bout was shorter in duration (LO, 69.9 +/- 4.0 min; HI, 36.0 +/- 2.2 min, P < 0.05) and had a higher rate of glycogen utilization (P < 0.05). PGC-1alpha mRNA abundance increased in an intensity-dependent manner +3 h after exercise (LO, 3.8-fold; HI, 10.2-fold, P < 0.05). AMP-activated protein kinase (AMPK) (2.8-fold, P < 0.05) and calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylation (84%, P < 0.05) increased immediately after HI but not LO. p38 mitogen-activated protein kinase (MAPK) phosphorylation increased after both trials (2.0-fold, P < 0.05), but phosphorylation of the downstream transcription factor, activating transcription factor-2 (ATF-2), increased only after HI (2.4-fold, P < 0.05). Cyclic-AMP response element binding protein (CREB) phosphorylation was elevated at +3 h after both trials (80%, P < 0.05) and class IIa histone deacetylase (HDAC) phosphorylation increased only after HI (2.0-fold, P < 0.05). In conclusion, exercise intensity regulates PGC-1alpha mRNA abundance in human skeletal muscle in response to a single bout of exercise. This effect is mediated by differential activation of multiple signalling pathways, with ATF-2 and HDAC phosphorylation proposed as key intensity-dependent mediators.

Although outbreaks of methicillin-resistant Staphylococcus aureus (MRSA) usually have been associated with health-care institutions, MRSA is emerging as a cause of skin infections in the community. This report summarizes several reported clusters of skin and soft tissue infections associated with MRSA among participants in competitive sports and identifies possible risk factors for infection (e.g., physical contact, skin damage, and sharing of equipment or clothing). The findings underscore 1) the potential for MRSA infections among sports participants; 2) the need for health-care providers to be aware that skin and soft tissue infections occurring in these settings might be caused by MRSA; and 3) the importance of implementing prevention measures by players, coaches, parents, and school and team administrators.

Previous reports cite optimization of O2 delivery (DO2) to 660 mL/min/m2, O2 consumption (VO2) to 170 mL/min/m2, and cardiac index (CI) of 4.5 L/min as predicting survival. We prospectively evaluated 76 consecutive patients with multiple trauma admitted directly to the ICU from the operating room or emergency department. Patients had serum lactate levels and oxygen transport measured on ICU admission and at 8, 16, 24, 36, and 48 hours. Patients were analyzed with respect to survival (S) versus nonsurvival (NS), lactate clearance to normal (< or = 2 mmol/L) by 24 and 48 hours, hemodynamic optimization as defined above, as well as Injury Severity Score (ISS), ICU stay (LOS), and admission blood pressure. All patients achieved non-flow-dependent VO2. There was no difference in CI, DO2, VO2, or ISS when S was compared with NS. All 27 patients whose lactate level normalized in 24 hours survived. If lactate levels cleared to normal between 24 and 48 hours, the survival rate was 75%. Only 3 of the 22 patients who did not clear their lactate level to normal by 48 hours survived. Ten of the 25 nonsurvivors (40%) achieved the above arbitrary optimization criteria. Fifteen of the survivors never achieved any of these criteria. Optimization alone does not predict survival. However, the time needed to normalize serum lactate levels is an important prognostic factor for survival in severely injured patients.

BACKGROUND

Hyponatremia is the most common electrolyte disorder encountered in hospitalized patients.

METHODS

We evaluated whether hospital-associated hyponatremia has an independent effect on all-cause mortality, hospital length of stay (LOS), and patient disposition. This cohort study included all adult hospitalizations at an academic medical center occurring between 2000-2007 for which an admission serum sodium concentration ([Na(+)]) was available (N = 53 236). We examined community-acquired hyponatremia (admission serum [Na(+)], <138 mEq/L [to convert to millimoles per liter, multiply by 1.0]), hospital-aggravated hyponatremia (community-acquired hyponatremia complicated by worsening in serum [Na(+)]), and hospital-acquired hyponatremia (nadir serum [Na(+)], <138 mEq/L with a normal admission serum [Na(+)]). The independent associations of these hyponatremic presentations with in-hospital mortality, LOS, and patient disposition were evaluated using generalized estimating equations adjusted for age, sex, race, admission service, and Deyo-Charlson Comorbidity Index score.

RESULTS

Community-acquired hyponatremia occurred in 37.9% of hospitalizations and was associated with adjusted odds ratios (ORs) of 1.52 (95% confidence interval [CI], 1.36-1.69) for in-hospital mortality and 1.12 (95% CI, 1.08-1.17) for discharge to a short- or long-term care facility and a 14% (95% CI, 11%-16%) adjusted increase in LOS. Hospital-acquired hyponatremia developed in 38.2% of hospitalizations longer than 1 day in which initial serum [Na(+)] was 138 to 142 mEq/L. Hospital-acquired hyponatremia was associated with adjusted ORs of 1.66 (95% CI, 1.39-1.98) for in-hospital mortality and 1.64 (95% CI, 1.55-1.74) for discharge to a facility and a 64% (95% CI, 60%-68%) adjusted increase in LOS. The strength of these associations tended to increase with hyponatremia severity.

CONCLUSIONS

Hospital-associated hyponatremia is a common occurrence. All forms of hyponatremia are independently associated with in-hospital mortality and heightened resource consumption.

The location of human area V5 (or MT) has been correlated with the intersection of the ascending limb of the inferior temporal sulcus (ALITS) and the lateral occipital sulcus (LO). This study was undertaken to attempt a replication and quantification of these observations using functional magnetic resonance imaging. V5 was significantly activated in 19 hemispheres with alternating, low contrast, random checkerboard patterns. We confirmed the stereotaxic location of V5 and were able to describe a fairly consistent sulcal pattern in the parieto-temporo-occipital cortex. V5 was usually (95%) buried within a sulcus, most commonly within the inferior temporal sulcus (ITS) (11%), the ascending limb of the ITS (ALITS) (53%) and the posterior continuation of the ITS (26%). The average distance from V5 of two identified anatomical landmarks of V5, the junctions of the LO and the ALITS, and the ITS and ALITS, were both 1 cm. However, the LO-ALITS junction often had to be determined by interpolation (47%), and was not always present even with interpolation (21%). In contrast, the ITS-ALITS junction was always present and V5 was usually (90%) located in a sulcus intersecting with this junction, making it a more reliable landmark for localizing V5 with respect to gross morphological features on individual cortical surfaces.

BACKGROUND

The earthquake that struck the Los Angeles area at 4:31 a.m. on January 17, 1994, was one of the strongest earthquakes ever recorded in a major city in North America. Once the life-threatening situation was over, the Northridge earthquake, so called because its epicenter was near Northridge, California, just north of Los Angeles, provided investigators an unusual opportunity to examine the relation between emotional stress and sudden cardiac death.

METHODS

We reviewed the records of the Department of Coroner of Los Angeles County for the week before the earthquake, the day of the earthquake, the six days after the earthquake, and corresponding control periods in 1991, 1992, and 1993.

RESULTS

On the day of the earthquake, there was a sharp increase in the number of sudden deaths from cardiac causes that were related to atherosclerotic cardiovascular disease, from a daily average (+/- SD) of 4.6 +/- 2.1 in the preceding week to 24 on the day of the earthquake (z = 4.41, P < 0.001). Sixteen victims of sudden death had symptoms, usually chest pain, or died within the first hour after the initial tremor. Only three sudden deaths occurred during or immediately after unusual physical exertion. During the six days after the earthquake, the number of sudden deaths declined to below the base-line value, to an average of 2.7 +/- 1.2 per day.

CONCLUSIONS

The Northridge earthquake was a significant trigger of sudden death due to cardiac causes, independently of physical exertion. This finding, along with the unusually low incidence of such deaths in the week after the earthquake, suggests that emotional stress may precipitate cardiac events in people who are predisposed to such events.

We studied outcomes of extended-spectrum beta-lactamase (ESBL) production in Enterobacteriaceae bacteremia. Inpatients with bacteremia caused by ESBL-producing Escherichia coli, Klebsiella spp., or Proteus spp. (cases) were compared with patients with bacteremia caused by non-ESBL producers (controls). Outcomes included mortality, mortality due to infection, length of stay (LOS), delay in appropriate therapy (DAT), discharge to a chronic care facility, and hospital cost. Ninety-nine cases and 99 controls were enrolled. Thirty-five percent of cases died, versus 18% of controls (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.3 to 4.7; P=0.01). Thirty percent of cases died due to infection, versus 16% of controls (OR, 2.3; 95% CI, 1.1 to 4.5; P=0.03). The median LOS after bacteremia for cases was 11 days (interquartile range, 5 to 21), versus 5 days for controls (interquartile range, 3 to 9) (P<0.001). DAT occurred in 66% of cases, versus 7% of controls (OR, 25.1; 95% CI, 10.5 to 60.2; P<0.001). Cases were more likely than controls to be discharged to chronic care (52% versus 21%; OR, 4.0; 95% CI, 1.9 to 8.3; P<0.001). The average hospital cost for cases was 65,509 Israeli shekels, versus 23,538 shekels for controls (P<0.001). After adjusting for differences between groups by using multivariable analysis, ESBL production remained a significant predictor of mortality (OR, 3.6; 95% CI, 1.4 to 9.5; P=0.008), increased LOS (1.56-fold; P=0.001), DAT (OR, 25.1; 95% CI, 10.5 to 60.2; P<0.001), and increased cost (1.57-fold; P=0.003). The mean increase in equivalent cost attributable to ESBL production was $9,620. ESBL production was associated with severe adverse outcomes, including higher overall and infection-related mortality, increased LOS, DAT, discharge to chronic care, and higher costs.

A longitudinal study of patients with chronic medical diseases (hypertension, diabetes, heart disease) was conducted to identify antecedents of adherence to medical recommendations. Data are from 1198 patients in three health-care provision systems in Los Angeles, Chicago, and Boston. Nonadherence at the beginning of the study was the strongest predictor of nonadherence 2 years later. Other significant predictors varied by type of adherence outcome. Patients who were younger and who relied upon avoidant coping strategies tended to be less likely to follow their doctor's specific recommendations. Patients who were distressed about their health, used avoidant coping strategies, or who reported worse physical and role functioning were less likely to adhere in general. Patient satisfaction with two features of care (interpersonal quality and financial aspects) was positively related to adherence in some models, but satisfaction with the technical quality of care was negatively associated with adherence to specific recommendations among heart disease patients. Social support contributed to specific adherence among diabetic patients. Implications of the study for medical care providers are discussed.

Previous studies have documented disparities in HIV prevalence by race among men who have sex with men (MSM), even after adjusting for traditional risk factors. In this analysis of data collected for the 1999-2000 Los Angeles Young Men's Survey, a cross-sectional venue-based survey of MSM aged 23-29, we investigated whether information on male sex-partner characteristics accounts for some of the racial/ethnic differences in HIV prevalence. In this sample of survey participants, we observed that African American MSM reported similar or lower levels of HIV risk behaviors compared with White MSM but much higher HIV prevalence (26% vs. 7.4%, respectively). In an unadjusted logistic regression model, African American participants had 4.4 times higher odds of HIV infection compared with White participants. In a multiple logistic regression model adjusting for participant behaviors, we observed elevation of the relative odds of HIV infection for African Americans compared with Whites (odds ratio [OR] = 6.9, 95% confidence limits [CL] = 2.5, 19). In a fully adjusted model, controlling for the effects of having older partners and more African American partners, we observed a 20% reduction in the relative odds of HIV for African American participants compared with White participants (OR = 5.5, 95% CL = 1.8, 17). Our findings suggest that differences in male partner types, namely older and African American partners, may account for some of the observed racial disparity in HIV infection, especially for African American MSM compared with White MSM in Los Angeles.

The concept, "quality of life" (QOL), offers a broad perspective for assessing the needs and outcomes of chronic mental patients. In this survey of Los Angeles board-and-care homes, 278 randomly selected, mentally disabled residents evaluated their QOL in structured interviews based on a general QOL model. Life areas studied included living situation, family, social relations, leisure, work, safety, finances, and health. The model performed as well among these residents as among the general population, explaining 48% to 58% of the variance in global well-being. Adding patients' subjective QOL evaluations doubled the explanatory power of a model based only on personal characteristics and objective life conditions. Global well-being was most consistently associated with personal safety, social relations, finances, leisure, and health care variables. The study identifies methodological and service issues in need of further examination.

Although regulatory T (T reg) cells are thought to develop primarily in the thymus, the peripheral events that shape the protective T reg cell population are unclear. We analyzed the peripheral CD4(+) T cell receptor (TCR) repertoire by cellular phenotype and location in mice with a fixed TCRbeta chain. We found that T reg (Foxp3(+)) cells showed a marked skewing of TCR usage by anatomical location in a manner similar to antigen-experienced (CD44(hi)Foxp3(-)) but not naive (CD44(lo)Foxp3(-)) cells, even though CD44(hi) and T reg cells used mostly dissimilar TCRs. This was likely unrelated to peripheral conversion, which we estimate generates only a small percentage of peripheral T reg cells in adults. Conversion was readily observed, however, during the immune response induced by Foxp3(-) cells in lymphopenic hosts. Interestingly, the converted Foxp3(+) and expanded Foxp3(-) TCR repertoires were different, suggesting that generation of Foxp3(+) cells is not an automatic process upon antigen activation of Foxp3(-) T cells. Retroviral expression of these TCRs in primary monoclonal T cells confirmed that conversion did not require prior cellular conditioning. Thus, these data demonstrate that TCR specificity plays a crucial role in the process of peripheral conversion and in shaping the peripheral T reg cell population to the local antigenic landscape.

During their differentiation in the mouse thymus, CD4+8- cells undergo several of the sequential changes observed upon normal activation of mature, peripheral CD4+ lymphocytes. Expression of CD69, an early activation marker, is first observed on a minority of cells at the T cell receptor (TCR)lo/med double-positive stage, is maximal (50-90%) on heat-stable antigen (HSA)hi TCRhi double-positive, HSAhi TCRmed CD4+8lo, and HSAhi TCRhi CD4+8- cells, and is downmodulated at the mature HSAlo CD4+8- stage. In contrast, CD44, a late activation marker, is selectively expressed at the HSAlo stage. The set of lymphokines that CD4+8- thymocytes can produce upon stimulation also characteristically expands from mainly interleukin 2 (IL-2) at the HSAhi stage, to IL-2 and very large amounts of IL-4, IL-5, IL-10, and interferon gamma (IFN-gamma) at the HSAlo stage. 1 in 30 HSAlo CD4+8- adult thymocytes secrete IL-4 upon stimulation through their TCR. This frequency is 25% of the frequency of IL-2 producers, about 100-fold above that of peripheral (mainly resting) CD4+ T cells. With time after their generation in organ culture, CD4+8- thymocytes lose their capacity to secrete IL-4, IL-5, and IFN-gamma, but not IL-2. Similarly, the frequency of IL-4, but not of IL-2, producers progressively decreases after emigration to the periphery as judged by direct comparison between thymic and splenic CD4+ cells in newborns, or by following the fate of intrathymically labeled CD4+8- cells in adults after their migration to the spleen. This sequence suggests that thymic selection results from an activation process rather than a simple rescue from death at the double-positive stage, and shows that the functional changes induced after intrathymic activation, although transient, are still evident after export to the periphery.

Stem cells are undifferentiated cells defined by their ability to self-renew and differentiate to progenitors and terminally differentiated cells. Stem cells have been isolated from almost all tissues, and an emerging idea is that they share common characteristics such as the presence of ATP-binding cassette transporter G2 and high telomerase and aldehyde dehydrogenase (ALDH) activity, raising the hypothesis of a set of universal stem cell markers. In the present study, we describe the isolation of primitive neural stem cells (NSCs) from adult and embryonic murine neurospheres and dissociated tissue, based on the expression of high levels of ALDH activity. Single-cell suspension was stained with a fluorescent ALDH substrate termed Aldefluor and then analyzed by flow cytometry. A population of cells with low side scatter (SSC(lo)) and bright ALDH (ALDH(br)) activity was isolated. SSC(lo)ALDH(br) cells are capable of self-renewal and are able to generate new neurospheres and neuroepithelial stem-like cells. Furthermore, these cells are multipotent, differentiating both in neurons and macroglia, as determined by immunocytochemistry and real-time reverse transcription-polymerase chain reaction analysis. To evaluate the engraftment potential of SSC(lo)ALDH(br) cells in vivo, we transplanted them into mouse brain. Donor-derived neurons with mature morphology were detected in the cortex and subcortical areas, demonstrating the capacity of this cell population to differentiate appropriately in vivo. The ALDH expression assay is an effective method for direct identification of NSCs, and improvement of the stem cell isolation protocol may be useful in the development of a cell-mediated therapeutic strategy for neurodegenerative diseases.

The major histocompatibility complex (MHC)-dependent presentation of processed tissue-specific self-antigens can contribute to either peripheral (extrathymic) tolerance or the differentiation of autoreactive T cells. Here, we have studied the MHC class II molecule presentation of gastric parietal cell (PC)-specific H(+)/K(+)-ATPase, which induces a destructive autoimmune gastritis in BALB/c mice lacking CD4(+) CD25(+) regulatory T cells. Immunofluorescence microscopy showed physical association of CD11c(+) dendritic cells (DCs) with PCs in the gastric mucosa. H(+)/K(+)-ATPase protein was found within vesicular compartments of a few CD11c(+) DCs only in the draining gastric lymph node (LN) and these antigen-containing DCs increased markedly in number with the onset of tissue destruction in autoimmune animals. Both CD8alpha(hi) and CD8alpha(lo) gastric DCs, but not peripheral or mesenteric DCs, showed evidence of constitutive in vivo processing and presentation of H(+)/K(+)-ATPase. These data provide direct support for a widely held model of local tissue antigen uptake and trafficking by DCs in normal animals and demonstrate that DCs in the draining LN can present a tissue-specific self-antigen under noninflammatory conditions without fully deleting autoreactive T cells or inducing active autoimmunity.

BACKGROUND

Heavy alcohol consumption, viral hepatitis, and diabetes are risk factors for hepatocellular carcinoma (HCC). However, to the authors' knowledge, the information concerning their interaction effect in patients with risk of HCC is sparse.

METHODS

A population-based, case-control study of HCC was conducted during 1984-2002. The study involved 295 HCC cases and 435 age-, gender-, and race-matched control subjects among Hispanic and non-Hispanic whites and blacks in Los Angeles County, California. Lifestyle risk factors were ascertained through in-person interviews. Infections with the hepatitis B and C (HCV) viruses were determined using their serologic markers.

RESULTS

Fourteen HCC cases but no control subjects tested positive for the hepatitis B surface antigen. Seropositivity for antibodies to HCV was associated with an odds ratio (OR) of 125 (95% confidence interval [95% CI], 17-909) for HCC, whereas seropositivity for antibodies to the hepatitis B core antigen was related to an OR of 2.9 (95% CI, 1.7-5.0). Heavy alcohol consumption and cigarette smoking were found to be independently associated with a statistically significant two to threefold increase in risk of HCC after adjustment for hepatitis B and C serology. Subjects with a history of diabetes had an OR of 2.7 (95% CI, 1.6-4.3) for HCC compared with nondiabetic subjects. A synergistic interaction on HCC risk was observed between heavy alcohol consumption and diabetes (OR = 4.2; 95% CI, 2.6-5.8), heavy alcohol consumption and viral hepatitis (OR = 5.5; 95% CI, 3.9-7.0), or between diabetes and viral hepatitis (OR = 4.8; 95% CI, 2.7-6.9).

CONCLUSIONS

Heavy alcohol consumption, diabetes, and viral hepatitis were found to exert independent and synergistic effects on risk of HCC in U.S. blacks and whites.

All multipotent hematopoietic progenitors in C57BL-Thy-1.1 bone marrow are divided among three subpopulations of Thy-1.1(lo) Sca-1+ Lin(-/lo) c-kit+ cells: long-term reconstituting Mac-1- CD4- c-kit+ cells and transiently reconstituting Mac-1(lo) CD4- or Mac-1(lo) CD4(lo) cells. This study shows that the same populations, with similar functional activities, exist in mice whose hematopoietic systems were reconstituted by hematopoietic stem cells after lethal irradiation. We demonstrate that these populations form a lineage of multipotent progenitors from long-term self-renewing stem cells to the most mature multipotent progenitor population. In reconstituted mice, Mac-1- CD4- c-kit+ cells gave rise to Mac-1(lo) CD4- cells, which gave rise to Mac-1(lo) CD4(lo) cells. Mac-1- CD4- c-kit+ cells had long-term self-renewal potential, with each cell being capable of giving rise to more than 10(4) functionally similar Mac-1- CD4- c-kit+ cells. At least half of Mac-1(lo) CD4- cells had transient self-renewal potential, detected in the spleen 7 days after reconstitution. Mac-1(lo) CD4(lo) cells did not have detectable self-renewal potential. The identification of a lineage of multipotent progenitors provides an important tool for identifying genes that regulate self-renewal and lineage commitment.

BACKGROUND

Evidence suggests that longer-term exposure to air pollutants over years confers higher risks of cardiovascular morbidity and mortality than shorter-term exposure. One explanation is that the cumulative adverse effects that develop over longer durations lead to the genesis of chronic disease. Preliminary epidemiological and clinical evidence suggests that air pollution may contribute to the development of hypertension and type 2 diabetes mellitus.

RESULTS

We used Cox proportional hazards models to assess incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for incident hypertension and diabetes mellitus associated with exposure to fine particulate matter (PM(2.5)) and nitrogen oxides in a cohort of black women living in Los Angeles. Pollutant levels were estimated at participants' residential addresses with land use regression models (nitrogen oxides) and interpolation from monitoring station measurements (PM(2.5)). Over follow-up from 1995 to 2005, 531 incident cases of hypertension and 183 incident cases of diabetes mellitus occurred. When pollutants were analyzed separately, the IRR for hypertension for a 10-μg/m(3) increase in PM(2.5) was 1.48 (95% CI, 0.95-2.31), and the IRR for the interquartile range (12.4 parts per billion) of nitrogen oxides was 1.14 (95% CI, 1.03-1.25). The corresponding IRRs for diabetes mellitus were 1.63 (95% CI, 0.78-3.44) and 1.25 (95% CI, 1.07-1.46). When both pollutants were included in the same model, the IRRs for PM(2.5) were attenuated and the IRRs for nitrogen oxides were essentially unchanged for both outcomes.

CONCLUSIONS

Our results suggest that exposure to air pollutants, especially traffic-related pollutants, may increase the risk of type 2 diabetes mellitus and possibly of hypertension.

We isolated hematopoietic stem cells (HSC) from mice treated with cyclophosphamide (CY) and granulocyte colony-stimulating factor (G-CSF). All mobilized multipotent progenitor activity was contained in two populations: Thy-1(lo) Sca-1+ Lin- Mac-1- CD4- c-kit+ long-term reconstituting progenitors and Thy-1(lo) Sca-1+ Lin- Mac-1(lo) CD4- transiently reconstituting progenitors. CY/G-CSF treatment drove both long-term and transient multipotent progenitors into cycle, leading to a more than 12-fold expansion in the number of long-term self-renewing HSC prior to mobilization. After CY and 2 days of G-CSF treatment the number of bone marrow HSC began to decline and the number of blood and splenic HSC increased. HSC continued to proliferate in the bone marrow and spleen through 8 days of G-CSF treatment, but HSC released into the blood tended to be in G0/G1 phase. Mobilized multipotent progenitors isolated from the spleen were less efficient than normal bone marrow multipotent progenitors in engrafting irradiated mice but did not differ in colony forming unit-spleen (CFU-S) activity or single cell in vitro assays of primitive progenitor activity. The data suggest that mobilized HSC isolated from the spleen are less efficient at homing to and engrafting the bone marrow of irradiated recipient mice.

Consistent with their role in host defense, mature dendritic cells (DCs) from central lymphoid organs preferentially prime for T helper cell type 1 (Th1)-polarized immunity. However, the "default" T helper response at mucosal surfaces demonstrates Th2 polarity, which is reflected in the cytokine profiles of activated T cells from mucosal lymph nodes. This study on rat respiratory tract DCs (RTDCs) provides an explanation for this paradox. We demonstrate that freshly isolated RTDCs are functionally immature as defined in vitro, being surface major histocompatibility complex (MHC) II lo, endocytosishi, and mixed lymphocyte reactionlo, and these cells produce mRNA encoding interleukin (IL)-10. After ovalbumin (OVA)-pulsing and adoptive transfer, freshly isolated RTDCs preferentially stimulated Th2-dependent OVA-specific immunoglobulin (Ig)G1 responses, and antigen-stimulated splenocytes from recipient animals produced IL-4 in vitro. However, preculture with granulocyte/macrophage colony stimulating factor increased their in vivo IgG priming capacity by 2-3 logs, inducing production of both Th1- and Th2-dependent IgG subclasses and high levels of IFN-gamma by antigen-stimulated splenocytes. Associated phenotypic changes included upregulation of surface MHC II and B7 expression and IL-12 p35 mRNA, and downregulation of endocytosis, MHC II processing- associated genes, and IL-10 mRNA expression. Full expression of IL-12 p40 required additional signals, such as tumor necrosis factor alpha or CD40 ligand. These results suggest that the observed Th2 polarity of the resting mucosal immune system may be an inherent property of the resident DC population, and furthermore that mobilization of Th1 immunity relies absolutely on the provision of appropriate microenvironmental costimuli.

BACKGROUND

Although the general relations between race, socioeconomic status, and mortality in the United States are well known, specific patterns of excess mortality are not well understood.

METHODS

Using standard demographic techniques, we analyzed death certificates and census data and made sex-specific population-level estimates of the 1990 death rates for people 15 to 64 years of age. We studied mortality among blacks in selected areas of New York City, Detroit, Los Angeles, and Alabama (in one area of persistent poverty and one higher-income area each) and among whites in areas of New York City, metropolitan Detroit, Kentucky, and Alabama (one area of poverty and one higher-income area each). Sixteen areas were studied in all.

RESULTS

When they were compared with the nationwide age-standardized annual death rate for whites, the death rates for both sexes in each of the poverty areas were excessive, especially among blacks (standardized mortality ratios for men and women in Harlem, 4.11 and 3.38; in Watts, 2.92 and 2.60; in central Detroit, 2.79 and 2.58; and in the Black Belt area of Alabama, 1.81 and 1.89). Boys in Harlem who reached the age of 15 had a 37 percent chance of surviving to the age of 65; for girls, the likelihood was 65 percent. Of the higher-income black areas studied, Queens--Bronx had the income level most similar to that of whites and the lowest standardized mortality ratio (men, 1.18; women, 1.08). Of the areas where poor whites were studied, Detroit had the highest standardized mortality ratios (men, 2.01; women, 1.90). On the Lower East Side of Manhattan, in Appalachia, and in Northeast Alabama, the ratios for whites were below the national average for blacks (men, 1.90; women, 1.95).

CONCLUSIONS

Although differences in mortality rates before the age of 65 between advantaged and disadvantaged groups in the United States are sometimes vast, there are important differences among impoverished communities in patterns of excess mortality.

OBJECTIVE

Compared with preterm formula (PF), mother's milk (MM) is associated with lower rates of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) among premature infants. Because not all mothers of premature infants produce sufficient milk to supply their infants throughout hospitalization, we reasoned that pasteurized donor human milk (DM) would be a suitable alternative.

METHODS

Extremely premature infants (<30 weeks of gestation) whose mothers intended to breastfeed were assigned randomly to receive either pasteurized DM or PF if the supply of their own MM became insufficient during the study (birth to 90 days of age or hospital discharge). Infection-related events (LOS, NEC, meningitis, presumed sepsis, or urinary tract infection) that occurred after the attainment of a milk intake of 50 mL/kg, dietary intake, growth, skin-to-skin contact, and duration of hospital stay were compared. The primary analysis compared groups DM and PF on an intent-to-treat basis. If no differences were noted, then these groups were combined and compared with the reference group, group MM. If differences were noted, then the subsequent analyses compared each group with group MM.

RESULTS

Of 243 infants, 70 (29%) received only MM; group DM included 81 infants and group PF included 92 infants. Because of poor weight gain, 17 infants (21%), all in group DM, were switched to PF. There were no differences in birth weight, gestational age, multiple births, and age at attainment of feeding of 50 mL/kg among groups. There were no differences between group DM and group PF in LOS and/or NEC, other infection-related events, hospital stay, or number of deaths. Group DM received a greater intake of milk and more nutritional supplements but had a slower rate of weight gain, compared with group PF. Compared with groups DM and PF, group MM had fewer episodes of LOS and/or NEC and total infection-related events and a shorter duration of hospital stay. Group MM also had fewer Gram-negative organisms isolated from blood cultures than did the other groups.

CONCLUSIONS

In this randomized, blinded trial of feeding of extremely premature infants, we found that, as a substitute for MM, DM offered little observed short-term advantage over PF for feeding extremely premature infants. Advantages to an exclusive diet of MM were observed in terms of fewer infection-related events and shorter hospital stays.

BACKGROUND

Methamphetamine-dependent gay and bisexual men (GBM) are at high risk for HIV transmission, largely due to drug-associated sexual risk behaviors. This project evaluated the efficacy of four behavioral drug abuse treatments for reducing methamphetamine use and sexual risk behaviors among this population.

METHODS

In this randomized controlled trial, 162 methamphetamine-dependent (SCID-verified) GBM in Los Angeles County were randomly assigned to one of four treatment conditions for 16 weeks: standard cognitive behavioral therapy (CBT, n=40), contingency management (CM, n=42), combined cognitive behavioral therapy and contingency management (CBT+CM, n=40), and a culturally tailored cognitive behavioral therapy (GCBT, n=40). Stimulant use was assessed thrice-weekly during treatment using urine drug screens (48 measures). Sexual risk behaviors were monitored monthly (four measures). Follow-up assessments were conducted at 6 (80.0%) and 12 months (79.9%).

RESULTS

Statistically significant differences in retention (F(3,158)=3.78, p<.02), in longest period of consecutive urine samples negative for methamphetamine metabolites (F(3,158)=11.80, p<.001), and in the Treatment Effectiveness Score were observed by condition during treatment (F(3,158)=7.35, p<.001) with post hoc analyses showing the CM and CBT+CM conditions to perform better than standard CBT. GEE modeling results showed GCBT significantly reduced unprotected receptive anal intercourse (URAI) during the first 4 weeks of treatment (X2=6.75, p<.01). During treatment between-group differences disappeared at follow-up with overall reductions in outcomes sustained to 1-year.

CONCLUSIONS

Among high-risk methamphetamine-dependent GBM, drug abuse treatments produced significant reductions in methamphetamine use and sexual risk behaviors. Drug abuse treatments merit consideration as a primary HIV prevention strategy for this population.

Leukotrienes are metabolites of arachidonic acid derived from the action of 5-LO (5-lipoxygenase). The immediate product of 5-LO is LTA4 (leukotriene A4), which is enzymatically converted into either LTB4 (leukotriene B4) by LTA4 hydrolase or LTC4 (leukotriene C4) by LTC4 synthase. The regulation of leukotriene production occurs at various levels, including expression of 5-LO, translocation of 5-LO to the perinuclear region and phosphorylation to either enhance or inhibit the activity of 5-LO. Several other proteins, including cPLA2a (cytosolic phospholipase A2a) and FLAP (5-LO-activating protein) also assemble at the perinuclear region before production of LTA4. LTC4 synthase is an integral membrane protein that is present at the nuclear envelope; however, LTA4 hydrolase remains cytosolic. Biologically active LTB4 is metabolized by w-oxidation carried out by specific cytochrome P450s (CYP4F) followed by b-oxidation from the w-carboxy position and after CoA ester formation. Other specific pathways of leukotriene metabolism include the 12-hydroxydehydrogenase/15-oxo-prostaglandin-13-reductase that forms a series of conjugated diene metabolites that have been observed to be excreted into human urine. Metabolism of LTC4 occurs by sequential peptide cleavage reactions involving a g-glutamyl transpeptidase that forms LTD4 (leukotriene D4) and a membrane-bound dipeptidase that converts LTD4 into LTE4 (leukotriene E4) before w-oxidation. These metabolic transformations of the primary leukotrienes are critical for termination of their biological activity, and defects in expression of participating enzymes may be involved in specific genetic disease.