A multicentre, randomised, open trial with a 2 x 2 factorial design was conducted to compare the benefits and risks of two thrombolytic agents, streptokinase (SK, 1.5 MU infused intravenously over 30-60 min) and alteplase (tPA, 100 mg infused intravenously over 3 h) in patients with acute myocardial infarction admitted to coronary care units within 6 h from onset of symptoms. The patients were also randomised to receive heparin (12,500 U subcutaneously twice daily until discharge from hospital, starting 12 h after beginning the tPA or SK infusion) or usual therapy. All patients without specific contraindications were given atenolol (5-10 mg iv) and aspirin (300-325 mg a day). The end-point of the study was the combined estimate of death plus severe left ventricular damage. 12,490 patients were randomised to four treatment groups (SK alone, SK plus heparin, tPA alone, tPA plus heparin). No specific differences between the two thrombolytic agents were detected as regards the combined end-point (tPA 23.1%; SK 22.5%; relative risk 1.04, 95% Cl 0.95-1.13), nor after the addition of heparin to the aspirin treatment (hep 22.7%, no hep 22.9%; RR 0.99, 95% Cl 0.91-1.08). The outcome of patients allocated to the four treatment groups was similar with respect to baseline risk factors such as age, Killip class, hours from onset of symptoms, and site and type of infarct. The rates of major in-hospital cardiac complications (reinfarction, post-infarction angina) were also similar. The incidence of major bleeds was significantly higher in SK and heparin treated patients (respectively, tPA 0.5%, SK 1.0%, RR 0.57, 95% Cl 0.38-0.85; hep 1.0%, no hep 0.6%, RR 1.64, 95% Cl 1.09-2.45), whereas the overall incidence of stroke was similar in all groups. SK and tPA appear equally effective and safe for use in routine conditions of care, in all infarct patients who have no contraindications, with or without post-thrombolytic heparin treatment. The 8.8% hospital mortality of the study population (compared with approximately 13% in the control cohort of the GISSI-1 trial) indicates the beneficial impact of the proven acute treatments for AMI.

The 1980s witnessed an extraordinary increase in community violence in most major cities across the United States. In 1990 the homicide rate in Boston increased by 45% over the previous year; in Denver, by 29%; in Chicago, Dallas, and New Orleans, by more than 20%; in Los Angeles, by 16%; in New York, by 11%. In Washington, DC, which has the highest per capita homicide rate in the country, the 1990 murder rate set an all time record in the District's history (Escobar 1991). Across the country, 1 out of 5 teenage and young adult deaths was gun related in 1988 - the first year in which firearm death rates for both Black and White teenagers exceeded the total for all natural causes of death combined. Also in 1988, the firearm homicide rate for young Black males increased by 35%, and Black male teens were 11 times more likely than their White counterparts to be killed by guns (Christofel 1990).

BACKGROUND

Pneumonia accounts for more than 600 000 Medicare hospitalizations yearly. Guidelines have recommended antibiotic treatment within 8 hours of arrival at the hospital.

METHODS

We performed a retrospective study using medical records from a national random sample of 18 209 Medicare patients older than 65 years who were hospitalized with community-acquired pneumonia from July 1998 through March 1999. Outcomes were severity-adjusted mortality, readmission within 30 days of discharge, and length of stay (LOS).

RESULTS

Among 13 771 (75.6%) patients who had not received outpatient antibiotic agents, antibiotic administration within 4 hours of arrival at the hospital was associated with reduced in-hospital mortality (6.8% vs 7.4%; adjusted odds ratio [AOR], 0.85; 95% confidence interval [CI], 0.74-0.98), mortality within 30 days of admission (11.6% vs 12.7%; AOR, 0.85; 95% CI, 0.76-0.95), and LOS exceeding the 5-day median (42.1% vs 45.1%; AOR, 0.90; 95% CI, 0.83-0.96). Mean LOS was 0.4 days shorter with antibiotic administration within 4 hours than with later administration. Timing was not associated with readmission. Antibiotic administration within 4 hours of arrival was documented for 60.9% of all patients and for more than 50% of patients regardless of hospital characteristics.

CONCLUSIONS

Antibiotic administration within 4 hours of arrival was associated with decreased mortality and LOS among a random sample of older inpatients with community-acquired pneumonia who had not received antibiotics as outpatients. Administration within 4 hours can prevent deaths in the Medicare population, offers cost savings for hospitals, and is feasible for most inpatients.

Of 285 total hip arthroplasties (260 patients) performed for primary osteoarthritis during a six-year period, 135 were resurfaced using a Tharies prosthesis (total hip articular replacement with internal eccentric shells) and 150 were treated with the Trapezoidal-28 total hip replacement. From each of these two groups 100 hips (ninety-one patients in the Tharies group and eighty-six in the Trapezoidal-28 group) that had been followed for two to seven years were evaluated at the time of follow-up in accordance with a predetermined protocol. The patients were younger in the Tharies than in the Trapezoidal-28 group (average ages, fifty-eight and sixty-six years), included more men (sixty compared with thirty-five), and were more active postoperatively. The average follow-up was forty-seven months for the total joint-replacement group and thirty-eight months for the surface replacement group. At follow-up the ratings for pain, walking, and function according to the University of California at Los Angeles 10-point scale and the clinical results were identical in the two groups. Heterotopic ossification (Brooker grade III or IV) developed after thirteen Trapezoidal-28 and twenty-two Tharies arthroplasties. Radiographs made at six and twelve months and at final follow-up showed that the incidence of radiolucencies about the acetabular component was higher in the resurfacing group: fifty-seven with complete radiolucent lines after an average follow-up of thirty-eight months compared with thirty-six with complete lines after an average follow-up of forty-seven months. There were three failures in the joint-replacement group: a hematogenous staphylococcal deep infection that required a Girdlestone procedure, a femoral stem fracture that required revision, and loosening of an acetabular component for which revision was performed. There was also one dislocation, successfully treated by closed reduction. Similarly, in the resurfacing group there were three failures: two loose acetabular components, revised successfully, and one loose femoral component that necessitated total joint arthroplasty. Multivariate stepwise regression analysis showed that the factors that affected the final extent and width of the acetabular radiolucencies adversely after resurfacing were: any radiolucent lines that were visible at six months, a high level of physical activity after arthroplasty, and a thin superior cement mantle.(ABSTRACT TRUNCATED AT 400 WORDS)

BACKGROUND

Angiosarcomas (AS) are rare, aggressive tumors. Optimal treatment has not been well defined. The authors undertook a retrospective review of patients seen at their institution with the intent of identifying prognostic factors and optimal treatment strategies.

METHODS

Between 1955 and 1990, 67 patients with AS were seen at the University of California, at Los Angeles Medical Center. Follow-up ranged from 1 to 173 months with a median of 30 months.

RESULTS

The overall prognosis was poor. The actuarial 2- and 5-year disease free survivals (DFS) were 44% and 24%, respectively. Of 52 recurrences after primary treatment, 81% (42 of 52) had a component of local failure. Twenty-eight patients had developed distant metastases at last follow-up. Of patients who received surgery (S) and radiation therapy (RT), with or without chemotherapy (CT), 5-year actuarial DFS was 43%, compared with 17% for patients who underwent S +/- CT as initial treatment (P = 0.03). Only 9% of patients (1 of 11) treated with RT +/- CT were rendered free of disease.

CONCLUSIONS

Patients with AS usually present with high grade histology, and with multifocal disease. There is a propensity for both local recurrence and distant metastases. Our results and a review of the literature, suggest that S plus RT offers the best chance for long term control of this aggressive tumor. The role of CT remains undefined.

BACKGROUND

Exercise training is associated with improved insulin sensitivity (SI), but the potential impact of habitual, nonvigorous activity is uncertain.

OBJECTIVE

To determine whether habitual, nonvigorous physical activity, as well as vigorous and overall activity, is associated with better SI.

METHODS

A multicultural epidemiologic study.

METHODS

The Insulin Resistance Atherosclerosis Study, conducted in Oakland, Calif; Los Angeles, Calif; the San Luis Valley, Colo; and San Antonio, Tex.

METHODS

A total of 1467 men and women of African American, Hispanic, and non-Hispanic white ethnicity, aged 40 to 69 years, with glucose tolerance ranging from normal to mild non-insulin-dependent diabetes mellitus.

METHODS

Insulin sensitivity as measured by an intravenous glucose tolerance test.

RESULTS

The mean SI for individuals who participated in vigorous activity 5 or more times per week was 1.59 min(-1) x microU(-1) x mL(-1) x 10(-4) (95% confidence interval [CI], 1.39-1.79) compared with 0.90 (95% CI, 0.83-0.97) for those who rarely or never participated in vigorous activity, after adjusting for potential confounders (P<.001). When habitual physical activity (estimated energy expenditure [EEE]) was assessed by 1-year recall of activities, the correlation coefficient between SI and total EEE was 0.14 (P<.001). After adjustment for confounders, vigorous and nonvigorous levels of EEE (metabolic equivalent levels>> or = 6.0 and <6.0, respectively) were each positively and independently associated with SI (P< or =.01 for each). The association was attenuated after adjustment for the potential mediators, body mass index (a measure of weight in kilograms divided by the square of the height in meters), and waist-to-hip ratio. Results were similar for subgroups of sex, ethnicity, and diabetes.

CONCLUSIONS

Increased participation in nonvigorous as well as overall and vigorous physical activity was associated with significantly higher SI. These findings lend further support to current public health recommendations for increased moderate-intensity physical activity on most days.

BACKGROUND

No randomized controlled studies have been conducted to date on the effectiveness of psychological interventions for children with symptoms of posttraumatic stress disorder (PTSD) that has resulted from personally witnessing or being personally exposed to violence.

OBJECTIVE

To evaluate the effectiveness of a collaboratively designed school-based intervention for reducing children's symptoms of PTSD and depression that has resulted from exposure to violence.

METHODS

A randomized controlled trial conducted during the 2001-2002 academic year.

METHODS

Sixth-grade students at 2 large middle schools in Los Angeles who reported exposure to violence and had clinical levels of symptoms of PTSD.

METHODS

Students were randomly assigned to a 10-session standardized cognitive-behavioral therapy (the Cognitive-Behavioral Intervention for Trauma in Schools) early intervention group (n = 61) or to a wait-list delayed intervention comparison group (n = 65) conducted by trained school mental health clinicians.

METHODS

Students were assessed before the intervention and 3 months after the intervention on measures assessing child-reported symptoms of PTSD (Child PTSD Symptom Scale; range, 0-51 points) and depression (Child Depression Inventory; range, 0-52 points), parent-reported psychosocial dysfunction (Pediatric Symptom Checklist; range, 0-70 points), and teacher-reported classroom problems using the Teacher-Child Rating Scale (acting out, shyness/anxiousness, and learning problems; range of subscales, 6-30 points).

RESULTS

Compared with the wait-list delayed intervention group (no intervention), after 3 months of intervention students who were randomly assigned to the early intervention group had significantly lower scores on symptoms of PTSD (8.9 vs 15.5, adjusted mean difference, - 7.0; 95% confidence interval [CI], - 10.8 to - 3.2), depression (9.4 vs 12.7, adjusted mean difference, - 3.4; 95% CI, - 6.5 to - 0.4), and psychosocial dysfunction (12.5 vs 16.5, adjusted mean difference, - 6.4; 95% CI, -10.4 to -2.3). Adjusted mean differences between the 2 groups at 3 months did not show significant differences for teacher-reported classroom problems in acting out (-1.0; 95% CI, -2.5 to 0.5), shyness/anxiousness (0.1; 95% CI, -1.5 to 1.7), and learning (-1.1, 95% CI, -2.9 to 0.8). At 6 months, after both groups had received the intervention, the differences between the 2 groups were not significantly different for symptoms of PTSD and depression; showed similar ratings for psychosocial function; and teachers did not report significant differences in classroom behaviors.

CONCLUSIONS

A standardized 10-session cognitive-behavioral group intervention can significantly decrease symptoms of PTSD and depression in students who are exposed to violence and can be effectively delivered on school campuses by trained school-based mental health clinicians.

Because of the lack of data on the exposure to and toxic effects of inorganic arsenic during early human development, the transfer of arsenic to the fetus and suckling infant was studied in a native Andean population, living in the village San Antonio de los Cobres in the North west of Argentina, where the drinking water contains about 200 micrograms/liter. The concentration of arsenic in cord blood (median, 9 micrograms/liter) was almost as high as in maternal blood (median, 11 micrograms/liter), and there was a significant correlation between the two. Thus, at least in late gestation, arsenic is easily transferred to the fetus. The median concentration of arsenic in the placenta was 34 micrograms/kg, compared with 7 micrograms/kg previously reported for nonexposed women. Interestingly, essentially all arsenic in the blood plasma of both the newborns and their mothers was in the form of dimethylarsinic acid (DMA), the end product of inorganic arsenic metabolism. Similarly, about 90% of the arsenic in the urine of both the newborns and mothers in late gestation was present as DMA, compared with about 70% in nonpregnant women (p < 0.001). This may indicate that methylation of arsenic is increased during pregnancy and that DMA is the major form of arsenic transferred to the fetus. The increased methylation in late gestation was associated with lower arsenic concentrations in blood and higher concentrations in urine, compared with a few months postpartum. The arsenic concentrations in the urine of the infants decreased from about 80 micrograms/liter during the first 2 days of life to less than 30 micrograms/liter at 4.4 months (p = 0.025). This could be explained by the low concentrations of arsenic in the breast milk, about 3 micrograms/kg.

Fjorback LO, Arendt M, Ørnbøl E, Fink P, Walach H. Mindfulness-Based Stress Reduction and Mindfulness-Based Cognitive Therapy - a systematic review of randomized controlled trials.

OBJECTIVE

To systematically review the evidence for MBSR and MBCT.

METHODS

Systematic searches of Medline, PsycInfo and Embase were performed in October 2010. MBSR, MBCT and Mindfulness Meditation were key words. Only randomized controlled trials (RCT) using the standard MBSR/MBCT programme with a minimum of 33 participants were included.

RESULTS

The search produced 72 articles, of which 21 were included. MBSR improved mental health in 11 studies compared to wait list control or treatment as usual (TAU) and was as efficacious as active control group in three studies. MBCT reduced the risk of depressive relapse in two studies compared to TAU and was equally efficacious to TAU or an active control group in two studies. Overall, studies showed medium effect sizes. Among other limitations are lack of active control group and long-term follow-up in several studies.

CONCLUSIONS

Evidence supports that MBSR improves mental health and MBCT prevents depressive relapse. Future RCTs should apply optimal design including active treatment for comparison, properly trained instructors and at least one-year follow-up. Future research should primarily tackle the question of whether mindfulness itself is a decisive ingredient by controlling against other active control conditions or true treatments.

Although CD4(+) T cells have been shown to mediate protective cellular immunity against respiratory virus infections, the underlying mechanisms are poorly understood. For example, although phenotypically distinct populations of memory CD4(+) T cells have been identified in different secondary lymphoid tissues, it is not known which subpopulations mediate protective cellular immunity. In this report, we demonstrate that virus-specific CD4(+) T cells persist in the lung tissues and airways for several months after Sendai virus infection of C57BL/6 mice. A large proportion of these cells possess a highly activated phenotype (CD44(hi), CD62L(lo), CD43(hi), and CD25(hi)) and express immediate effector function as indicated by the production of interferon gamma after a 5-h restimulation in vitro. Furthermore, intratracheal adoptive transfer of lung memory cells into beta2m-deficient mice demonstrated that lung-resident virus-specific CD4(+) T cells mediated a substantial degree of protection against secondary virus infection. Taken together, these data demonstrate that activated memory CD4(+) T cells persisting at mucosal sites play a critical role in mediating protective cellular immunity.

Interleukin 1 (IL-1) plays a prominent role in immune and inflammatory reactions. Our understanding of the IL-1 family has recently expanded to include six novel members named IL-1F5 to IL-1F10. Recently, it was reported that IL-1F9 activated NF-kappaB through the orphan receptor IL-1 receptor (IL-1R)-related protein 2 (IL-1Rrp2) in Jurkat cells (Debets, R., Timans, J. C., Homey, B., Zurawski, S., Sana, T. R., Lo, S., Wagner, J., Edwards, G., Clifford, T., Menon, S., Bazan, J. F., and Kastelein, R. A. (2001) J. Immunol. 167, 1440-1446). In this study, we demonstrate that IL-1F6 and IL-1F8, in addition to IL-1F9, activate the pathway leading to NF-kappaB in an IL-1Rrp2-dependent manner in Jurkat cells as well as in multiple other human and mouse cell lines. Activation of the pathway leading to NF-kappaB by IL-1F6 and IL-1F8 follows a similar time course to activation by IL-1beta, suggesting that signaling by the novel family members occurs through a direct mechanism. In a mammary epithelial cell line, NCI/ADR-RES, which naturally expresses IL-1Rrp2, all three cytokines signal without further receptor transfection. IL-1Rrp2 antibodies block activation of the pathway leading to NF-kappaB by IL-1F6, IL-1F8, and IL-1F9 in both Jurkat and NCI/ADR-RES cells. In NCI/ADR-RES cells, the three IL-1 homologs activated the MAPKs, JNK and ERK1/2, and activated downstream targets as well, including an IL-8 promoter reporter and the secretion of IL-6. We also provide evidence that IL-1RAcP, in addition to IL-1Rrp2, is required for signaling by all three cytokines. Antibodies directed against IL-1RAcP and transfection of cytoplasmically deleted IL-1RAcP both blocked activation of the pathway leading to NF-kappaB by the three cytokines. We conclude that IL-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP.

Site-specific recombination between molecules of bacteriophage P1 DNA occurs at sites called loxP and requires the action of a protein that is the product of the P1 cre gene. Although recombination between two loxP sites is very efficient, recombination between loxP and a unique site in the bacterial chromosome (loxB) is inefficient and generates two hybrid lox sites called loxR and loxL. We present here the nucleotide sequences of all four lox sites. Analysis of these sequences indicates that (i) a region of extensive homology is not present at the loxP X loxB crossover point, in contrast to the 15-base pair common-core sequence in the bacteriophage lambda att sites, and (ii) the sites contain a region of dyad symmetry with 8- to 13-base pair inverted repeats separated by an 8- to 9-base pair sequence. The loxP X loxB crossover point falls in the sequence that separates the inverted repeats, and deletions that remove either the left or the right inverted repeat of loxP inactivate the site. These two observations are consistent with the conclusion that the region of dyad symmetry is important in los recombination. We have shown further that the loxP X loxP crossover point occurs in a 63-base pair sequence containing the loxP X loxB crossover point, suggesting that, despite the great difference in efficiencies of the two reactions, the crossover points may occur at the same place in both. Explanations for the different recombination properties of the various lox sites are discussed.

Although there is general agreement that the human middle temporal (MT)/V5+ complex corresponds to monkey area MT/V5 proper plus a number of neighboring motion-sensitive areas, the identification of human MT/V5 within the complex has proven difficult. Here, we have used functional magnetic resonance imaging and the retinotopic mapping technique, which has very recently disclosed the organization of the visual field maps within the monkey MT/V5 cluster. We observed a retinotopic organization in humans very similar to that documented in monkeys: an MT/V5 cluster that includes areas MT/V5, pMSTv (putative ventral part of the medial superior temporal area), pFST (putative fundus of the superior temporal area), and pV4t (putative V4 transitional zone), and neighbors a more ventral putative human posterior inferior temporal area (phPIT) cluster. The four areas in the MT/V5 cluster and the two areas in the phPIT cluster each represent the complete contralateral hemifield. The complete MT/V5 cluster comprises 70% of the motion localizer activation. Human MT/V5 is located in the region bound by lateral, anterior, and inferior occipital sulci and occupies only one-fifth of the motion complex. It shares the basic functional properties of its monkey homolog: receptive field size relative to other areas, response to moving and static stimuli, as well as sensitivity to three-dimensional structure from motion. Functional properties sharply distinguish the MT/V5 cluster from its immediate neighbors in the phPIT cluster and the LO (lateral occipital) regions. Together with similarities in retinotopic organization and topological neighborhood, the functional properties suggest that MT/V5 in human and macaque cortex are homologous.

BACKGROUND

Syphilitic ulcers are known to facilitate the transmission of HIV infection, but the effect of syphilis infection on HIV viral loads and CD4 cell counts is poorly understood.

METHODS

We abstracted medical records for HIV-infected male syphilis patients seen at three clinics in San Francisco and Los Angeles from January 2001 to April 2003. We compared plasma HIV-RNA levels and CD4 cell counts during syphilis infection with those before syphilis infection and after syphilis treatment, using the Wilcoxon signed rank test.

RESULTS

Fifty-two HIV-infected men with primary or secondary syphilis had HIV viral load and CD4 cell count data available for analysis; 30 (58%) were receiving antiretroviral therapy. Viral loads were higher during syphilis compared with pre-syphilis levels by a mean of 0.22 RNA log10 copies/ml (P = 0.02) and were lower by a mean of -0.10 RNA log10 copies/ml (P = 0.52) after syphilis treatment. CD4 cell counts were lower during syphilis infection than before by a mean of -62 cells/mm3 (P = 0.04), and were higher by a mean of 33 cells/mm3 (P = 0.23) after syphilis treatment. Increases in the HIV viral load and reductions in the CD4 cell count were most substantial in men with secondary syphilis and those not receiving antiretroviral therapy.

CONCLUSIONS

Syphilis infection was associated with significant increases in the HIV viral load and significant decreases in the CD4 cell count. The findings underscore the importance of preventing and promptly treating syphilis in HIV-infected individuals.

OBJECTIVE

The aim of this study was to test whether blood monocytosis in mice with atherosclerosis affects infarct healing.

BACKGROUND

Monocytes are cellular protagonists of tissue repair, and their specific subtypes regulate the healing program after myocardial infarction (MI). Inflammatory Ly-6C(hi) monocytes dominate on Day 1 to Day 4 and digest damaged tissue; reparative Ly-6C(lo) monocytes dominate on Day 5 to Day 10 and promote angiogenesis and scar formation. However, the monocyte repertoire is disturbed in atherosclerotic mice: Ly-6C(hi) monocytes expand selectively, which might disrupt the resolution of inflammation.

METHODS

Ex vivo analysis of infarcts included flow cytometric monocyte enumeration, immunoactive staining, and quantitative polymerase chain reaction. To relate inflammatory activity to left ventricular remodeling, we used a combination of noninvasive fluorescence molecular tomography (FMT-CT) and physiologic imaging (magnetic resonance imaging).

RESULTS

Five-day-old infarcts showed >10x more Ly-6C(hi) monocytes in atherosclerotic (apoE(-/-)) mice compared with wild-type mice. The injured tissue in apoE(-/-) mice also showed a more pronounced inflammatory gene expression profile (e.g., increased tumor necrosis factor-alpha and myeloperoxidase and decreased transforming growth factor-beta) and a higher abundance of proteases, which are associated with the activity of Ly-6C(hi) monocytes. The FMT-CT on Day 5 after MI showed higher proteolysis and phagocytosis in infarcts of atherosclerotic mice. Serial magnetic resonance imaging showed accelerated deterioration of ejection fraction between Day 1 and Day 21 after MI in apoE(-/-). Finally, we could recapitulate these features in wild-type mice with artificially induced Ly-6C(hi) monocytosis.

CONCLUSIONS

Ly-6C(hi) monocytosis disturbs resolution of inflammation in murine infarcts and consequently enhances left ventricular remodeling. These findings position monocyte subsets as potential therapeutic targets to augment tissue repair after infarction and to prevent post-MI heart failure.

Previous work has shown that memory-phenotype CD44(hi) CD8(+) cells are controlled by a cytokine, interleukin (IL)-15. However, the dependency of CD44(hi) CD8(+) cells on IL-15 is partial rather than complete. Here, evidence is presented that CD44(hi) CD8(+) cells comprise a mixed population of IL-15-dependent and IL-15-independent cells. The major subset of CD122(hi) CD44(hi) CD8(+) cells is heavily dependent on IL-15 by three different parameters, namely (1) "bystander" proliferation induced via IFN-induced stimulation of the innate immune system, (2) normal "background" proliferation, and (3) T cell survival; IL-15 dependency is most extreme for the Ly49(+) subset of CD122(hi) CD44(hi) CD8(+) cells. In contrast to CD122(hi) cells, the CD122(lo) subset of CD44(hi) CD8(+) cells is IL-15 independent; likewise, being CD122(lo), CD44(hi) CD4(+) cells are IL-15 independent. Thus, subsets of memory-phenotype T cells differ radically in their sensitivity to IL-15.

Functional magnetic resonance imaging was used in combined functional selectivity and retinotopic mapping tests to reveal object-related visual areas in the human occipital lobe. Subjects were tested with right, left, up, or down hemivisual field stimuli which were composed of images of natural objects (faces, animals, man-made objects) or highly scrambled (1,024 elements) versions of the same images. In a similar fashion, the horizontal and vertical meridians were mapped to define the borders of these areas. Concurrently, the same cortical sites were tested for their sensitivity to image-scrambling by varying the number of scrambled picture fragments (from 16-1,024) while controlling for the Fourier power spectrum of the pictures and their order of presentation. Our results reveal a stagewise decrease in retinotopy and an increase in sensitivity to image-scrambling. Three main distinct foci were found in the human visual object recognition pathway (Ungerleider and Haxby [1994]: Curr Opin Neurobiol 4:157-165): 1) Retinotopic primary areas V1-3 did not exhibit significant reduction in activation to scrambled images. 2) Areas V4v (Sereno et al., [1995]: Science 268:889-893) and V3A (De Yoe et al., [1996]: Proc Natl Acad Sci USA 93:2382-2386; Tootell et al., [1997]: J Neurosci 71:7060-7078) manifested both retinotopy and decreased activation to highly scrambled images. 3) The essentially nonretinotopic lateral occipital complex (LO) (Malach et al., [1995]: Proc Natl Acad Sci USA 92:8135-8139; Tootell et al., [1996]: Trends Neurosci 19:481-489) exhibited the highest sensitivity to image scrambling, and appears to be homologous to macaque the infero-temporal (IT) cortex (Tanaka [1996]: Curr Opin Neurobiol 523-529). Breaking the images into 64, 256, or 1,024 randomly scrambled blocks reduced activation in LO voxels. However, many LO voxels remained significantly activated by mildly scrambled images (16 blocks). These results suggest the existence of object-fragment representation in LO.

BACKGROUND

The stigma of HIV-infection may profoundly affect the lives of persons living with HIV/AIDS (PLHA). However few studies have examined the association of HIV stigma with multiple components of HIV treatment and care.

OBJECTIVE

To estimate the association between HIV stigma and: self-reported access to care, regular source of HIV care, and antiretroviral therapy adherence; and to test whether mental health mediates these associations.

METHODS

Cross-sectional study.

METHODS

202 PLHA living in Los Angeles County in 2007.

METHODS

Participants completed an anonymous survey, assessing internalized HIV stigma (28-items, alpha = 0.93), self-reported access to medical care (six items, alpha = 0.75), regular source of HIV care, and antiretroviral therapy (ART) adherence.

RESULTS

One-third of participants reported high levels of stigma; 77% reported poor access to care; 42.5% reported suboptimal ART adherence; and 10.5% reported no regular source of HIV care. In unadjusted analysis, those reporting a high level of stigma were more likely to report poor access to care (OR = 4.97, 95% CI 2.54-9.72), regular source of HIV care (OR = 2.48, 95% CI 1.00-6.19), and ART adherence (OR = 2.45, 95% CI 1.23-4.91). In adjusted analyses, stigma was significantly associated with poor access to care (OR = 4.42, 95% CI 1.88-10.37), but not regular source of HIV care or ART adherence. Mental health mediated the relationship between stigma and ART adherence, but not poor access to care or regular source of HIV care.

CONCLUSIONS

The association of stigma with self-reported access to care and adherence suggests that efforts to improve these components of HIV care will require a better understanding of the possible effects of stigma and its mediators.

Imiquimod (IMQ), a synthetic agonist to Toll-like receptor (TLR) 7, is being successfully used for the treatment of certain skin neoplasms, but the exact mechanisms by which this compound induces tumor regression are not yet understood. While treating basal cell carcinoma (BCC) patients with topical IMQ, we detected, by immunohistochemistry, sizable numbers of both myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs) within the inflammatory infiltrate. Surprisingly, peritumoral mDCs stained positive for perforin and granzyme B, whereas infiltrating pDCs expressed tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The biological relevance of this observation can be deduced from our further findings that peripheral blood-derived CD11c(+) mDCs acquired antiperforin and anti-granzyme B reactivity upon TLR7/8 stimulation and could use these molecules to effectively lyse major histocompatibility complex (MHC) class I(lo) cancer cell lines. The same activation protocol led pDCs to kill MHC class I-bearing Jurkat cells in a TRAIL-dependent fashion. While suggesting that mDCs and pDCs are directly involved in the IMQ-induced destruction of BCC lesions, our data also add a new facet to the functional spectrum of DCs, ascribing to them a major role not only in the initiation but also in the effector phase of the immune response.

Central tolerance is established through negative selection of self-reactive thymocytes and the induction of T-regulatory cells (T(R)s). The role of thymic dendritic cells (TDCs) in these processes has not been clearly determined. In this study, we demonstrate that in vivo, TDCs not only play a role in negative selection but in the induction of T(R)s. TDCs include two conventional dendritic cell (DC) subtypes, CD8(lo)Sirpalpha(hi/+) (CD8(lo)Sirpalpha(+)) and CD8(hi)Sirpalpha(lo/-) (CD8(hi)Sirpalpha(-)) [corrected] which have different origins. We found that the CD8(hi)Sirpalpha(+) DCs represent a conventional DC subset that originates from the blood and migrates into the thymus. Moreover, we show that the CD8(lo)Sirpalpha(+) DCs demonstrate a superior capacity to induce T(R)s in vitro. Finally, using a thymic transplantation system, we demonstrate that the DCs in the periphery can migrate into the thymus, where they efficiently induce T(R) generation and negative selection.

BACKGROUND

Biomarkers of systemic inflammation have been associated with risk of cardiovascular morbidity and mortality.

OBJECTIVE

We aimed to clarify associations of particulate matter (PM) air pollution with systemic inflammation using models based on size-fractionated PM mass and markers of primary and secondary aerosols.

METHODS

We followed a panel of 29 nonsmoking elderly subjects with a history of coronary artery disease (CAD) living in retirement communities in the Los Angeles, California, air basin. Blood plasma biomarkers were measured weekly over 12 weeks and included C-reactive protein (CRP), fibrinogen, tumor necrosis factor-alpha (TNF-alpha) and its soluble receptor-II (sTNF-RII), interleukin-6 (IL-6) and its soluble receptor (IL-6sR), fibrin D-dimer, soluble platelet selectin (sP-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1), intracellular adhesion molecule-1 (sICAM-1), and myeloperoxidase (MPO). To assess changes in antioxidant capacity, we assayed erythrocyte lysates for glutathione peroxidase-1 (GPx-1) and copper-zinc superoxide dismutase (Cu,Zn-SOD) activities. We measured indoor and outdoor home daily size-fractionated PM mass, and hourly pollutant gases, total particle number (PN), fine PM elemental carbon (EC) and organic carbon (OC), estimated secondary organic aerosol (SOA) and primary OC (OCpri) from total OC, and black carbon (BC). We analyzed data with mixed models controlling for temperature and excluding weeks with infections.

RESULTS

We found significant positive associations for CRP, IL-6, sTNF-RII, and sP-selectin with outdoor and/or indoor concentrations of quasi-ultrafine PM < or = 0.25 microm in diameter, EC, OCpri, BC, PN, carbon monoxide, and nitrogen dioxide from the current-day and multiday averages. We found consistent positive but largely nonsignificant coefficients for TNF-alpha, sVCAM-1, and sICAM-1, but not fibrinogen, IL-6sR, or D-dimer. We found inverse associations for erythrocyte Cu,Zn-SOD with these pollutants and other PM size fractions (0.25-2.5 and 2.5-10 microm). Inverse associations of GPx-1 and MPO with pollutants were largely nonsignificant. Indoor associations were often stronger for estimated indoor EC, OCpri, and PN of outdoor origin than for uncharacterized indoor measurements. There was no evidence for positive associations with SOA.

CONCLUSIONS

Results suggest that traffic emission sources of OCpri and quasi-ultrafine particles lead to increased systemic inflammation and platelet activation and decreased antioxidant enzyme activity in elderly people with CAD.

PU.1 is an Ets family transcription factor that is essential for fetal liver hematopoiesis. We have generated a PU.1(gfp) reporter strain that allowed us to examine the expression of PU.1 in all hematopoietic cell lineages and their early progenitors. Within the bone marrow progenitor compartment, PU.1 is highly expressed in the hematopoietic stem cell, the common lymphoid progenitor, and a proportion of common myeloid progenitors (CMPs). Based on Flt3 and PU.1 expression, the CMP could be divided into three subpopulations, Flt3(+) PU.1(hi), Flt3(-) PU.1(hi), and Flt3(-) PU.1(lo) CMPs. Colony-forming assays and in vivo lineage reconstitution demonstrated that the Flt3(+) PU.1(hi) and Flt3(-) PU.1(hi) CMPs were efficient precursors for granulocyte/macrophage progenitors (GMPs), whereas the Flt3(-) PU.1(lo) CMPs were highly enriched for committed megakaryocyte/erythrocyte progenitors (MEPs). CMPs have been shown to rapidly differentiate into GMPs and MEPs in vitro. Interestingly, short-term culture revealed that the Flt3(+) PU.1(hi) and Flt3(-) PU.1(hi) CMPs rapidly became CD16/32(high) (reminiscent of GMPs) in culture, whereas the Flt3(-) PU.1(lo) CMPs were the immediate precursors of the MEP. Thus, down-regulation of PU.1 expression in the CMP is the first molecularly identified event associated with the restriction of differentiation to erythroid and megakaryocyte lineages.

CD4(+) T cells differentiate into multiple effector types, but it is unclear how they form memory T cells during infection in vivo. Profiling virus-specific CD4(+) T cells revealed that effector cells with T helper 1 (Th1) or T follicular helper (Tfh) cell characteristics differentiated into memory cells, although expression of Tfh cell markers declined over time. In contrast to virus-specific effector CD8(+) T cells, increased IL-7R expression was not a reliable marker of CD4(+) memory precursor cells. However, decreased Ly6C and T-bet (Tbx21) expression distinguished a subset of Th1 cells that displayed greater longevity and proliferative responses to secondary infection. Moreover, the gene expression profile of Ly6C(lo)T-bet(int) Th1 effector cells was virtually identical to mature memory CD4(+) T cells, indicating early maturation of memory CD4(+) T cell features in this subset during acute viral infection. This study provides a framework for memory CD4(+) T cell development after acute viral infection.

Dendritic cells (DC) were cultured from mouse bone marrow (BM) progenitors in low concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF) (GM(lo) DC) by two different protocols. The phenotype and functional properties of these GM(lo) DC were compared to those of standard BM-DC cultures generated in high concentrations of GM-CSF (GM(hi) DC) or in low GM-CSF plus IL-4 (GM(lo)/IL-4 DC). An effect of IL-4 on maturation was observed only at low but not high doses of GM-CSF. Compared to mature DC, GM(lo) DC were phenotypically immature, weak stimulators of allogeneic and peptide-specific T cell responses, but substantially more potent in presentation of native protein. Immature GM(lo) DC were resistant to maturation by lipopolysaccharide, TNF-alpha or anti-CD40 monoclonal antibodies, as the expression of co-stimulatory molecules was not increased, and stimulatory activity in oxidative mitogenesis was not enhanced. These maturation-resistant immature GM(lo) DC induced T cell unresponsiveness in vitro and in vivo. GM(lo) DC also prolonged haplotype-specific cardiac allograft survival (from 8 days to >100 days median survival time) when they were administered 7 days (but not 3, 14 or 28 days) before transplantation. Our findings may have important implications for future studies in T cell tolerance induction in vivo.