This population epidemiology study investigates the prevalence of IgG and IgM antibodies to SARS-CoV-2 in Los Angeles County, California, as a marker of both active and past infections.

Ferroptosis is a form of programmed cell death that is pathogenic to several acute and chronic diseases and executed via oxygenation of polyunsaturated phosphatidylethanolamines (PE) by 15-lipoxygenases (15-LO) that normally use free polyunsaturated fatty acids as substrates. Mechanisms of the altered 15-LO substrate specificity are enigmatic. We sought a common ferroptosis regulator for 15LO. We discovered that PEBP1, a scaffold protein inhibitor of protein kinase cascades, complexes with two 15LO isoforms, 15LOLOLO complexes represent a new target for drug discovery.

This article evaluates the behavior of an adaptation of the Charlson Index (CHI) applied to administrative databases to measure the relationship between chronic comorbidity and the hospital care outcomes of length of stay (LOS), in-hospital mortality, and emergency readmissions at 30 and 365 days. These outcomes were analyzed in 106,673 hospitalization episodes whose records are registered in a minimum basic data set maintained by the public health authorities of the community of Valencia, Spain. The highest comorbidity measured by the CHI was associated with greater LOS and in-hospital mortality and increased readmission at 30 and 365 days. The rate of readmissions at 1 year dropped, however, in the group with the greatest comorbidity, probably owing to an increase in mortality after hospitalization. While comorbidity does appear to increase the risk of adverse outcomes in general and mortality and readmission specifically, the second outcome is only possible if the first has not occurred. For this reason, information and selection biases derived from administrative databases, or from the CHI itself, should be taken into account when using and interpreting the index.

Aldehyde dehydrogenase (ALDH) activity has been implicated in multiple biological and biochemical pathways and has been used to identify potential cancer stem cells. Our main hypothesis is that ALDH activity may be a lung cancer stem cell marker. Using flow cytometry, we sorted cells with bright (ALDH(br)) and dim (ALDH(lo)) ALDH activity found in H522 lung cancer cell line. We used in vitro proliferation and colony assays as well as a xenograft animal model to test our hypothesis. Cytogenetic analysis demonstrated that the ALDH(br) cells are indeed a different clone, but when left in normal culture conditions will give rise to ALDH(lo) cells. Furthermore, the ALDH(br) cells grow slower, have low clonal efficiency, and give rise to morphologically distinct colonies. The ability to form primary xenografts in NOD/SCID mice by ALDH(br) and ALDH(lo) cells was tested by injecting single cell suspension under the skin in each flank of same animal. Tumor size was calculated weekly. ALDH1A1 and ALDH3A1 immunohistochemistry (IHC) was performed on excised tumors. These tumors were also used to re-establish cell suspension, measure ALDH activity, and re-injection for secondary and tertiary transplants. The results indicate that both cell types can form tumors but the ones from ALDH(br) cells grew much slower in primary recipient mice. Histologically, there was no significant difference in the expression of ALDH in primary tumors originating from ALDH(br) or ALDH(lo) cells. Secondary and tertiary xenografts originating from ALDH(br) grew faster and bigger than those formed by ALDH(lo) cells. In conclusion, ALDH(br) cells may have some of the traditional features of stem cells in terms of being mostly dormant and slow to divide, but require support of other cells (ALDH(lo)) to sustain tumor growth. These observations and the known role of ALDH in drug resistance may have significant therapeutic implications in the treatment of lung cancer.

We used mouse monoclonal antibodies (MAbs) to characterize Neisseria gonorrhoeae lipooligosaccharide (LOS). LOSs that bound two or more MAbs in a solid-phase radioimmunoassay usually bound them to different LOS components, as separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE); strains with multiple LOS components on SDS-PAGE usually bound more than one MAb. However, the LOS of some strains bound the same MAb to two LOS components with different relative molecular weights, and some individual LOS components bound more than one MAb. LOSs from different strains bound different amounts of the same MAb at saturation, reflecting differences in the quantitative expression of individual LOS components. Not all components recognized by MAbs were stained by silver after periodate oxidation. Treatment with NaOH variously affected epitopes defined by different MAbs. MAb 3F11 completely inhibited and MAb 2-1-L8 partially inhibited the binding of 125I-labeled 06B4 MAb to WR220 LOS and WR220 outer membranes in competitive binding studies. Other MAbs did not compete with the binding of 125I-labeled 06B4 to either antigen. We conclude that a strain of N. gonorrhoeae elaborates multiple LOSs that can be separated by SDS-PAGE and that are antigenically distinct. Epitope expression within these glycolipids is complex.

Preterm birth may be affected by the interaction of residential air pollution with neighborhood economic hardship. The authors examined variations in traffic-related pollution exposure--measured by distance-weighted traffic density--using a framework reflecting the social and physical environments. An adverse social environment was conceptualized as low socioeconomic status (SES) neighborhoods--census tracts with concentrated poverty, unemployment, and dependence on public assistance. An adverse physical environment was depicted by the winter season, when thermal inversions trap motor vehicle pollutants, thereby increasing traffic-related air pollution. Los Angeles County, California, birth records from 1994 to 1996 were linked to traffic counts, census data, and ambient air pollution measures. The authors fit multivariate logistic models of preterm birth, stratified by neighborhood SES and third pregnancy trimester season. Traffic-related air pollution exposure disproportionately affected low SES neighborhoods in the winter. Further, in these poorer neighborhoods, the winter season evidenced increased susceptibility among women with known risk factors. Health insurance was most beneficial to women residing in neighborhoods exposed to economic hardship and an adverse physical environment. Reducing preterm births warrants a concerted effort of social, economic, and environmental policies, focused on not only individual risk factors but also the reduction of localized air pollution, expansion of health-care coverage, and improvement of neighborhood resources.

One major hallmark of Alzheimer's disease (AD) is the massive loss of synapses that occurs at an early clinical stage of the disease. In this study, we characterize alterations in spine density and the expression of synapse-associated immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the hippocampal CA1 regions of two different amyloid precursor protein (APP) transgenic mouse lines before plaque development and their connection to performance in hippocampus-dependent memory tests. The density of mushroom-type spines was reduced by 34% in the basal dendrites proximal to the soma of CA1 pyramidal neurons in 5.5-month-old Tg2576 mice, carrying the Swedish mutation, compared with wild-type littermates. A similar reduction of 42% was confirmed in the same region of 8-month-old APP/Lo mice, carrying the London mutation. In this strain, the reduction extended to the distal dendritic spines (28%), although no differences were found in apical dendrites in either transgenic mouse line. Both transgenic mice lines presented a significant increase in Arc protein expression in CA1 compared with controls, suggesting rather an overactivity and increased spine turnover that was supported by a significant decrease in number of somatostatin-immunopositive inhibitory interneurons in the stratum oriens of CA1. Behaviorally, the transgenic mice showed decrease freezing in the fear contextual conditioning test and impairment in spatial memory assessed by Morris water maze test. These data indicate that cognitive impairment in APP transgenic mice is correlated with impairment of synaptic connectivity in hippocampal CA1, probably attributable to loss of inhibitory interneurons and subsequent hyperactivity.

Expression of lipooligosaccharide (LOS) antigenic determinants during human gonococcal infection was studied in secretions from seven men with gonococcal urethritis. Five monoclonal antibodies with distinct gonococcal LOS specificities and an H.8 lipoprotein monoclonal antibody were used in combination with immunogold electron microscopic analysis. The LOS epitope defined by antibody 6B7 was present on all seven strains in secretions and after in vitro growth. Gonococci from six of seven patients, when grown in vitro, expressed the 6B4 LOS epitope. The 6B4 epitope is a Gal beta 1-4-GlcNAc residue, which is immunochemically similar to the precursor of the human erythrocyte i antigen. This epitope was found unmodified on gonococcal LOS in urethral secretions from two patients. The unmodified epitope could not be demonstrated on organisms in five secretions. Neuraminidase digestion exposed the 6B4 epitope on organisms in these secretions and increased the 6B4 epitope density in the two secretions, which contained the unmodified epitope. These studies indicate that in vivo modification by sialylation of gonococcal LOS Gal beta 1-4-GlcNAc residue occurs during human infection.

Natural IgM antibodies secreted in the absence of antigenic challenge are important contributors to antimicrobial immunity and tissue homeostasis. Early studies identified BM and, to a lesser extent the spleen, as main tissue sources of this spontaneously secreted IgM. However, the responsible B-cell subset has never been identified. Using multicolor flow cytometry, cell sorting and chimeric mice in which B-1 and B-2 cells and their secreted antibodies are distinguished by their Ig-allotype, we unequivocally identify the natural IgM-secreting cells in spleen and, for the first time, in the BM as IgM(+) IgD(lo/-) CD19(hi) CD43(+) CD5(+/-) B-1 cells. The newly identified population of BM B-1 cells shows many of the phenotypic characteristics of splenic B-1 cells but is distinct from B-1 cells in the peritoneal cavity, which generate at best very small amounts of IgM. Antibody-secreting spleen and BM B-1 cells are distinct also from terminally differentiated plasma cells generated from antigen-induced conventional B cells, as they express high levels of surface IgM and CD19 and lack expression of CD138. Overall, these data identify populations of non-terminally differentiated B-1 cells in spleen and BM as the most significant producers of natural IgM.

Genome-wide association studies (GWASs) are commonly used for the mapping of genetic loci that influence complex traits. A problem that is often encountered in both population-based and family-based GWASs is that of identifying cryptic relatedness and population stratification because it is well known that failure to appropriately account for both pedigree and population structure can lead to spurious association. A number of methods have been proposed for identifying relatives in samples from homogeneous populations. A strong assumption of population homogeneity, however, is often untenable, and many GWASs include samples from structured populations. Here, we consider the problem of estimating relatedness in structured populations with admixed ancestry. We propose a method, REAP (relatedness estimation in admixed populations), for robust estimation of identity by descent (IBD)-sharing probabilities and kinship coefficients in admixed populations. REAP appropriately accounts for population structure and ancestry-related assortative mating by using individual-specific allele frequencies at SNPs that are calculated on the basis of ancestry derived from whole-genome analysis. In simulation studies with related individuals and admixture from highly divergent populations, we demonstrate that REAP gives accurate IBD-sharing probabilities and kinship coefficients. We apply REAP to the Mexican Americans in Los Angeles, California (MXL) population sample of release 3 of phase III of the International Haplotype Map Project; in this sample, we identify third- and fourth-degree relatives who have not previously been reported. We also apply REAP to the African American and Hispanic samples from the Women's Health Initiative SNP Health Association Resource (WHI-SHARe) study, in which hundreds of pairs of cryptically related individuals have been identified.

BACKGROUND

We sought to analyze the prognostic significance of the new International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) lung adenocarcinoma (ADC) classification for patients undergoing resection for small (≤2cm) lung ADC and to investigate whether histologic subtyping can predict recurrence after limited resection (LR) vs lobectomy (LO).

METHODS

Comprehensive histologic subtyping was performed according to the IASLC/ATS/ERS classification on all consecutive patients who underwent LR or LO for small lung ADC between 1995 and 2009 at Memorial Sloan-Kettering Cancer Center. Clinical characteristics and pathologic data were retrospectively evaluated for 734 consecutive patients (LR: 258; LO: 476). Cumulative incidence of recurrence (CIR) was calculated using competing risks analysis and compared across groups using Grey's test. All statistical tests were two-sided.

RESULTS

Application of IASLC/ATS/ERS lung ADC histologic subtyping to predict recurrence demonstrates that, in the LR group but not in the LO group, micropapillary (MIP) component of 5% or greater was associated with an increased risk of recurrence, compared with MIP component of less than 5% (LR: 5-year CIR = 34.2%, 95% confidence interval [CI] = 23.5% to 49.7% vs 5-year CIR = 12.4%, 95% CI = 6.9% to 22.1%, P < .001; LO: 5-year CIR = 19.1%, 95% CI = 12.0% to 30.5% vs 15-year CIR = 12.9%, 95% CI = 7.6% to 21.9%, P = .13). In the LR group, among patients with tumors with an MIP component of 5% or greater, most recurrences (63.4%) were locoregional; MIP component of 5% or greater was statistically significantly associated with increased risk of local recurrence when the surgical margin was less than 1cm (5-year CIR = 32.0%, 95% CI = 18.6% to 46.0% for MIP ≥ 5% vs 5-year CIR = 7.6%, 95% CI = 2.3% to 15.6% for MIP < 5%; P = .007) but not when surgical margin was 1cm or greater (5-year CIR = 13.0%, 95% CI = 4.1% to 22.1% for MIP ≥ 5% vs 5-year CIR = 3.4%, 95% CI = 0% to 7.7% for MIP < 5%; P = .10).

CONCLUSIONS

Application of the IASLC/ATS/ERS classification identifies the presence of an MIP component of 5% or greater as independently associated with the risk of recurrence in patients treated with LR.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta (Aβ) that is assumed to result from impaired elimination of this neurotoxic peptide. Most patients with AD also exhibit cerebral amyloid angiopathy, which consists of Aβ deposition within the cerebral vasculature. The contribution of monocytes in AD has so far been limited to macrophage precursors. In this study, we aimed to investigate whether circulating monocytes could play a role in the elimination of Aβ. With live intravital two-photon microscopy, we demonstrate that patrolling monocytes are attracted to and crawl onto the luminal walls of Aβ-positive veins, but not on Aβ-positive arteries or Aβ-free blood vessels. Additionally, we report the presence of crawling monocytes carrying Aβ in veins and their ability to circulate back into the bloodstream. Selective removal of Ly6C(lo) monocytes in APP/PS1 mice induced a significant increase of Aβ load in the cortex and hippocampus. These data uncover the ability of Ly6C(lo) monocytes to naturally target and eliminate Aβ within the lumen of veins and constitute a potential therapeutic target in AD.

BACKGROUND

Circulating 25 hydroxyvitamin D (25 (OH)D), an accurate measure of vitamin D status, is markedly greater in individuals with increased exposure to ultraviolet B (UVB) light via sunlight or the use of artificial UV light. Aside from the known relationship between vitamin D and bone, vitamin D has also been implicated in immune function and inflammation. Furthermore, a mass of evidence is accumulating that vitamin D deficiency could lead to immune malfunction. Our overall objective was to study the relationship between vitamin D status (as determined by serum 25(OH) D concentrations) and inflammatory markers in healthy women.

METHODS

This observational study included 69 healthy women, age 25-82 years. Women with high UVB exposure and women with minimal UVB exposure were specifically recruited to obtain a wide-range of serum 25(OH)D concentrations. Health, sun exposure and habitual dietary intake information were obtained from all subjects. Body composition was determined by dual-energy-x-ray absorptiometry. A fasting blood sample was collected in the morning and analyzed for serum 25(OH)D, parathyroid hormone (iPTH), estradiol (E2), cortisol, and inflammatory markers [tumor necrosis factor -alpha (TNF-alpha), interleukin-6 and -10 (IL-6, IL-10), and C-reactive protein (CRP)].

RESULTS

Women with regular UVB exposure (Hi-D) had serum 25(OH)D concentrations that were significantly higher (p < 0.0001) and iPTH concentrations that were significantly lower (p < 0.0001) than women without regular UVB exposure (Lo-D). Although IL-6, IL-10, and CRP did not have a statistically significant relationship with 25(OH)D concentrations, linear regression models revealed a significant inverse relationship between serum 25(OH)D and TNF-alpha concentrations. This relationship remained significant after controlling for potential covariates such as body fat mass, menopausal status, age, or hormonal contraceptive use.

CONCLUSIONS

Serum 25(OH)D status is inversely related to TNF-alpha concentrations in healthy women, which may in part explain this vitamin's role in the prevention and treatment of inflammatory diseases. Results gleaned from this investigation also support the need to re-examine the biological basis for determining optimal vitamin D status.

Severe Plasmodium falciparum malaria is a major cause of global mortality, yet the immunological factors underlying progression to severe disease remain unclear. CD4(+)CD25(+) regulatory T cells (Treg cells) are associated with impaired T cell control of Plasmodium spp infection. We investigated the relationship between Treg cells, parasite biomass, and P. falciparum malaria disease severity in adults living in a malaria-endemic region of Indonesia. CD4(+)CD25(+)Foxp3(+)CD127(lo) Treg cells were significantly elevated in patients with uncomplicated (UM; n = 17) and severe malaria (SM; n = 16) relative to exposed asymptomatic controls (AC; n = 10). In patients with SM, Treg cell frequency correlated positively with parasitemia (r = 0.79, p = 0.0003) and total parasite biomass (r = 0.87, p<0.001), both major determinants for the development of severe and fatal malaria, and Treg cells were significantly increased in hyperparasitemia. There was a further significant correlation between Treg cell frequency and plasma concentrations of soluble tumor necrosis factor receptor II (TNFRII) in SM. A subset of TNFRII(+) Treg cells with high expression of Foxp3 was increased in severe relative to uncomplicated malaria. In vitro, P. falciparum-infected red blood cells dose dependently induced TNFRII(+)Foxp3(hi) Treg cells in PBMC from malaria-unexposed donors which showed greater suppressive activity than TNFRII(-) Treg cells. The selective enrichment of the Treg cell compartment for a maximally suppressive TNFRII(+)Foxp3(hi) Treg subset in severe malaria provides a potential link between immune suppression, increased parasite biomass, and malaria disease severity. The findings caution against the induction of TNFRII(+)Foxp3(hi) Treg cells when developing effective malaria vaccines.

We compared the five- to seven-year clinical and radiological results of the metal-on-metal Birmingham hip resurfacing with a hybrid total hip arthroplasty in two groups of 54 hips, matched for gender, age, body mass index and activity level. Function was excellent in both groups, as measured by the Oxford hip score, but the Birmingham hip resurfacings had higher University of California at Los Angeles activity scores and better EuroQol quality of life scores. The total hip arthroplasties had a revision or intention-to-revise rate of 8%, and the Birmingham hip resurfacings of 6%. Both groups demonstrated impending failure on surrogate end-points. Of the total hip arthroplasties, 12% had polyethylene wear and osteolysis under observation, and 8% of Birmingham hip resurfacings showed migration of the femoral component. Polyethylene wear was present in 48% of the hybrid hips without osteolysis. Of the femoral components in the Birmingham hip resurfacing group which had not migrated, 66% had radiological changes of unknown significance.

A case-control study of children of ages 10 years and under in Los Angeles County was conducted to investigate the causes of leukemia. The mothers and fathers of acute leukemia cases and their individually matched controls were interviewed regarding specific occupational and home exposures as well as other potential risk factors associated with leukemia. Analysis of the information from the 123 matched pairs showed an increased risk of leukemia for children whose fathers had occupational exposure after the birth of the child to chlorinated solvents [odds ratio (OR) = 3.5, P = .01], spray paint (OR = 2.0, P = .02), dyes or pigments (OR = 4.5, P = .03), methyl ethyl ketone (CAS: 78-93-3; OR = 3.0, P = .05), and cutting oil (OR = 1.7, P = .05) or whose fathers were exposed during the mother's pregnancy with the child to spray paint (OR = 2.2, P = .03). For all of these, the risk associated with frequent use was greater than for infrequent use. There was an increased risk of leukemia for the child if the father worked in industries manufacturing transportation equipment (mostly aircraft) (OR = 2.5, P = .03) or machinery (OR = 3.0, P = .02). An increased risk was found for children whose parents used pesticides in the home (OR = 3.8, P = .004) or garden (OR = 6.5, P = .007) or who burned incense in the home (OR = 2.7, P = .007). The risk was greater for frequent use. Risk of leukemia was related to mothers' employment in personal service industries (OR = 2.7, P = .04) but not to specified occupational exposures. Risk related to fathers' exposure to chlorinated solvents, employment in the transportation equipment-manufacturing industry, and parents' exposure to household or garden pesticides and incense remains statistically significant after adjusting for the other significant findings.

A key role of the thymic medulla is to negatively select autoreactive CD4(+) and CD8(+) thymocytes, a process important for T cell tolerance induction. However, the involvement of the thymic medulla in other aspects of αβ T cell development, including the generation of Foxp3(+) natural regulatory T cells (nTreg cells) and the continued maturation of positively selected conventional αβ T cells, is unclear. We show that newly generated conventional CD69(+)Qa2(-) CD4 single-positive thymocytes mature to the late CD69(-)Qa2(+) stage in the absence of RelB-dependent medullary thymic epithelial cells (mTECs). Furthermore, an increasing ability to continue maturation extrathymically is observed within the CD69(+)CCR7(-/lo)CCR9(+) subset of conventional SP4 thymocytes, providing evidence for an independence from medullary support by the earliest stages after positive selection. In contrast, Foxp3(+) nTreg cell development is medullary dependent, with mTECs fostering the generation of Foxp3(-)CD25(+) nTreg cell precursors at the CD69(+)CCR7(+)CCR9(-) stage. Our results demonstrate a differential requirement for the thymic medulla in relation to CD4 conventional and Foxp3(+) thymocyte lineages, in which an intact mTEC compartment is a prerequisite for Foxp3(+) nTreg cell development through the generation of Foxp3(-)CD25(+) nTreg cell precursors.

BACKGROUND

This study compared the experience and cost of the DaVinci Robotic system and laparoscopy for colon resections.

METHODS

For this study, 30 consecutive robotic and 27 consecutive laparoscopic colectomies were divided into right and sigmoid colectomies for analysis. Comparisons included indications for surgery, gender, age, body mass index (BMI), estimated blood loss (EBL), length of operation, length of hospital stay (LOS), complications, operating room (OR) cost, OR personnel cost, OR supply cost, OR time cost, and total hospital cost.

RESULTS

The comparison groups were similar in indications for surgery, gender, age, BMI, EBL, and LOS. The right colectomies included 17 robotic and 15 laparoscopic procedures. An intracorporeal anastomosis was performed in the robotic cases, and an extracorporeal anastomosis was performed in the laparoscopic cases. The total case time was 218.9 min for the robotic and 169.2 min for the laparoscopic procedures (p = 0.002). The total hospital cost was $9,255 for the robotic and $8,073 for the laparoscopic procedures (p = 0.430). The total OR cost was $5,823 for the robotic and $4,339 for the laparoscopic procedures (p < 0.000). The sigmoid colectomies included 13 robotic and 12 laparoscopic procedures. The robotic and laparoscopic cases were managed in similar sequence. The total case time was 225.2 min for the robotic and 199.4 min for the laparoscopic procedures (p = 0.128). The total hospital cost was $12,335 for the robotic and $10,697 for the laparoscopic procedures (p = 0.735). The total OR cost was $6,059 for the robotic and $4,974 for the laparoscopic procedures (p = 0.068). The complications in the robotic groups were more numerous, but were not attributable to equipment.

CONCLUSIONS

The comparison groups were similar. The robotic cases were significantly longer for right colectomies because of the intracorporeal anastomosis instead of the extracorporeal anastomosis performed in the laparoscopy cases. Every cost category was higher for the robotic cases. The right colectomies showed significant increases in total OR cost, OR personnel cost, OR supply cost, and OR time cost. The sigmoid colectomies had significant increases in OR personnel cost and OR supply cost. The total hospital cost was higher for the robotic groups, but the difference was not statistically significant.

OBJECTIVE

To examine hepatitis C virus (HCV) seroprevalence among injection drug users in 4 US cities from 1994 through 2004.

METHODS

Demographic characteristics, behaviors, and prevalence of HCV antibody among 5088 injection drug users aged 18-40 years from Baltimore, Maryland; Chicago, Illinois; Los Angeles, California; and New York, New York, enrolled in 3 related studies--Collaborative Injection Drug User Study (CIDUS) I (1994-1996), CIDUS II (1997-1999), and CIDUS III/Drug User Intervention Trial (2002-2004)--were compared using the chi(2) and Mantel-Haenszel tests of significance. Trends over time were assessed by logistic regression.

RESULTS

Prevalence of HCV infection was 65%, 35%, and 35% in CIDUS I, CIDUS II, and CIDUS III, respectively. The adjusted prevalence odds ratio (OR) of being HCV antibody positive increased with the number of years of injection drug use (OR, 1.93 [95% confidence interval {CI}, 1.68-2.21] for each year of injecting within the first 2 years; OR, 1.09 [95% CI, 1.07-1.11] for each year of injecting beyond the first 2 years). Significant decreases were observed in the prevalence of HCV antibody between CIDUS I and CIDUS III in Baltimore (OR, 0.30; 95% CI, 0.20-0.43) and Los Angeles (OR, 0.17; 95% CI, 0.09-0.31) and among people of races other than black in Chicago (OR, 0.12; 95% CI, 0.08-0.17). No decrease in prevalence was seen in New York (OR, 1.04; 95% CI, 0.69-1.58) or among blacks in Chicago (OR, 0.55; 95% CI, 0.16-1.90).

CONCLUSIONS

Although regional differences exist, our data suggest that the incidence of HCV infection among injection drug users in the United States decreased from 1994 through 2004.

Inflammation is a key pathological process in the progression of atherosclerosis and type 2 diabetes. 12/15-lipoxygenase (12-LO), an enzyme involved in fatty acid metabolism, may contribute to inflammatory damage triggered by stressors such as obesity and insulin resistance. We hypothesized that mice lacking 12-LO are protected against inflammatory-mediated damage associated with a "western" diet. To test this hypothesis, age-matched male 12-LO knockout (12-LOKO) and wild-type C57BL/6 (B6) mice were fed either a standard chow or western diet and assessed for several inflammatory markers. Western-fed B6 mice showed expected reductions in glucose and insulin tolerance compared with chow-fed mice. In contrast, western-fed 12-LOKO mice maintained glucose and insulin tolerance similar to chow-fed mice. Circulating proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-6, were increased in western B6 mice but not 12-LOKO mice, whereas the reported protective adipokine, adiponectin, was decreased only in western B6 mice. 12-LO activity was significantly elevated by western diet in islets from B6 mice. Islets from 12-LOKO mice did not show western-diet-induced islet hyperplasia or increases in caspase-3 apoptotic staining observed in western-fed B6 mice. Islets from 12-LOKO mice were also protected from reduced glucose-stimulated insulin secretion observed in islets from western-fed B6 mice. In visceral fat, macrophage numbers and monocyte chemoattractant protein-1 expression were elevated in western B6 mice but not 12-LOKO mice. These data suggest that 12-LO activation plays a role in western-diet-induced damage in visceral fat and islets. Inhibiting 12-LO may provide a new therapeutic approach to prevent inflammation-mediated metabolic consequences of excess fat intake.

The magnitude of future climate change depends substantially on the greenhouse gas emission pathways we choose. Here we explore the implications of the highest and lowest Intergovernmental Panel on Climate Change emissions pathways for climate change and associated impacts in California. Based on climate projections from two state-of-the-art climate models with low and medium sensitivity (Parallel Climate Model and Hadley Centre Climate Model, version 3, respectively), we find that annual temperature increases nearly double from the lower B1 to the higher A1fi emissions scenario before 2100. Three of four simulations also show greater increases in summer temperatures as compared with winter. Extreme heat and the associated impacts on a range of temperature-sensitive sectors are substantially greater under the higher emissions scenario, with some interscenario differences apparent before midcentury. By the end of the century under the B1 scenario, heatwaves and extreme heat in Los Angeles quadruple in frequency while heat-related mortality increases two to three times; alpine/subalpine forests are reduced by 50-75%; and Sierra snowpack is reduced 30-70%. Under A1fi, heatwaves in Los Angeles are six to eight times more frequent, with heat-related excess mortality increasing five to seven times; alpine/subalpine forests are reduced by 75-90%; and snowpack declines 73-90%, with cascading impacts on runoff and streamflow that, combined with projected modest declines in winter precipitation, could fundamentally disrupt California's water rights system. Although interscenario differences in climate impacts and costs of adaptation emerge mainly in the second half of the century, they are strongly dependent on emissions from preceding decades.

Expression of Thy-1 on hematopoietic cells from human fetal liver (FL), cord blood (CB), and bone marrow (BM) was studied with a novel anti-Thy-1 antibody, 5E10. Specificity of 5E10 for human Thy-1 was demonstrated by immunoprecipitation of a 25-35-kD molecule, and the sequence of a cDNA that was cloned by immunoselection of COS cells transfected with a cDNA library derived from a 5E10+ cell line. Two- and three-color immunofluorescence staining experiments revealed that the Thy-1 expression is restricted to, an average, 1-4% of FL, CB, and BM cells, and binding to these cell types is essentially restricted to a very small subset of lymphoid cells and approximately 25% of CD34+ cells. Thy-1+ CD34+ cells were further characterized as CD38lo/CD45RO+/CD45RA-/CD71lo/c-kit(lo) and rhodamine 123dull. When CD34+ cells were sorted on the basis of Thy-1 expression, the majority of clonogenic cells were recovered in the CD34+Thy-1- fraction, whereas the majority of cells capable of producing myeloid colonies after 5-8 wk of long-term culture (long-term culture initiating cells) were recovered in the Thy-1+CD34+ fraction. In addition to CD34+ cells, Thy-1 was found to be expressed on a variable, very small number (< 1%) of CD34- mononuclear cells in BM, CB, and peripheral blood that were further characterized as CD3+ CD4+ lymphocytes. The restricted expression of Thy-1 on primitive hematopoietic cells is in agreement with a previous report (Baum et al., 1992. Proc. Natl. Acad. Sci. USA. 89:2804) in which Thy-1 expression was used to enrich for primitive hematopoietic cells from fetal tissue. Compared with those previous studies, we found Thy-1 expression on a larger proportion of CD34+ cells (25% in our study vs. 5% in Baum et al.) and furthermore performed studies on Thy-1 expression on CD34+ cells from CB, FL, and BM in relation to markers that are known to be differentially expressed on hematopoietic cells. Taken together our results indicate that Thy-1-specific antibody 5E10 is an attractive tool for further studies on the biology and purification of human stem cells.

Hematopoietic stem cells (HSCs) are characterized by their ability to differentiate into all hematopoietic cell lineages while retaining their capacity for self renewal. One of the predictions of this model is the existence of a heterogeneous pool of HSCs, some members of which are destined to become lineage restricted progenitor cells while others function to renew the stem cell pool. To test whether HSCs are heterogeneous with respect to cell cycle status, we determined the fraction of phenotypically defined murine HSCs (Thy1.1lo Lin-/lo Sca-1+) that contain>> 2n amount of DNA as measured by propidium iodide staining, Hoechst dye uptake and [3H]thymidine labeling; that fraction is 18-22%. In contrast, in the developing fetal liver, 40% of HSCs are in the S/G2/M phases of the cell cycle. Those HSCs which exhibit a low level of staining with rhodamine 123 are almost exclusively in G0/G1 (97%) whereas only 70% of HSCs which stain brightly for rhodamine 123 are in G0/G1. The injection of 100 G0/G1 HSCs rescued 90% of lethally irradiated mice in contrast to 100 S/G2/M HSCs, which protected only 25% of lethally irradiated recipients. Enhanced long-term donor-derived multilineage reconstitution of the peripheral blood was observed in recipients of 100 G0/G1 HSCs compared to recipients of 100 S/G2/M cells. These data indicate that a significant proportion of HSCs are actively proliferating during steady state hematopoiesis and that this subpopulation of cells exhibits reduced stem cell activity.