Macrophages are a heterogeneous cell population involved in tissue homeostasis, inflammation, and various pathologies. Although the major tissue-resident macrophage populations have been extensively studied, interstitial macrophages (IMs) residing within the tissue parenchyma remain poorly defined. Here we studied IMs from murine lung, fat, heart, and dermis. We identified two independent IM subpopulations that are conserved across tissues: Lyve1^loMHCII^hiCX3CR1^hi (Lyve1^loMHCII^hi) and Lyve1^hiMHCII^loCX3CR1^lo (Lyve1^hiMHCII^lo) monocyte-derived IMs, with distinct gene expression profiles, phenotypes, functions, and localizations. Using a new mouse model of inducible macrophage depletion (Slco2b1^flox/DTR), we found that the absence of Lyve1^hiMHCII^lo IMs exacerbated experimental lung fibrosis. Thus, we demonstrate that two independent populations of IMs coexist across tissues and exhibit conserved niche-dependent functional programming.

BACKGROUND

Patients with acute neurologic symptoms may have other causes simulating ischemic stroke, called stroke mimics (SM), but they may also have averted strokes that do not appear as infarcts on neuroimaging, which we call neuroimaging-negative cerebral ischemia (NNCI). We determined the safety and outcome of IV thrombolysis within 3 hours of symptom onset in patients with SM and NNCI.

METHODS

Patients treated with IV tissue plasminogen activator (tPA) within 3 hours of symptom onset were identified from our stroke registry from June 2004 to October 2008. We collected admission NIH Stroke Scale (NIHSS) score, modified Rankin score (mRS), length of stay (LOS), symptomatic intracerebral hemorrhage (sICH), and discharge diagnosis.

RESULTS

Among 512 treated patients, 21% were found not to have an infarct on follow-up imaging. In the SM group (14%), average age was 55 years, median admission NIHSS was 7, median discharge NIHSS was 0, median LOS was 3 days, and there were no instances of sICH. The most common etiologies were seizure, complicated migraine, and conversion disorder. In the NNCI group (7%), average age was 61 years, median admission NIHSS was 7, median discharge NIHSS was 0, median LOS was 3 days, and there were no instances of sICH. Nearly all SM (87%) and NNCI (91%) patients were functionally independent on discharge (mRS 0-1).

CONCLUSIONS

Our data support the safety of administering IV tissue plasminogen activator to patients with suspected acute cerebral ischemia within 3 hours of symptom onset, even when the diagnosis ultimately is found not to be stroke or imaging does not show an infarct.

The authors studied 2,950 population-based colon cancer cases in males in Los Angeles County, California, that were diagnosed between 1972 and 1981. To determine if colon cancer risk is reduced by physical activity on the job in males aged 20-64 years, the authors first rated each occupation by judging the activity level as high, moderate, or sedentary. Men with sedentary jobs had a colon cancer risk at least 1.6 times that of men whose jobs required a high level of activity. Risk increased in a stepwise manner as activity level decreased. This gradient was consistently seen within each socioeconomic stratum, among whites, blacks, immigrant and native Hispanics, and for each subsection of the colon from the hepatic flexure to the sigmoid. The protective effect of physical activity was very strong in the descending colon and diminished in a gradient both proximally and distally. There was no such relationship between physical activity and risk for rectal cancer. Physical activity may play a major, previously unrecognized role in colon cancer etiology. Such a role is consistent with the known pattern of colon cancer occurrence and with our understanding of colon physiology and colon cancer pathogenesis. In addition to the implications for prevention, understanding the effects of physical activity on colon cancer risk may allow future studies to evaluate more accurately the role played by diet.

BACKGROUND

Most acute pancreatitis risk scoring systems use total white blood cell counts (WBC) as one of the risk factors. The value of the neutrophil-lymphocyte ratio (NLR) to predict the severity of acute pancreatitis has not been previously evaluated.

METHODS

This observational study included 283 patients admitted to a tertiary center between 2004 and 2007. The patients were arranged into tertiles according to NLR and WBC values. The primary outcomes were intensive care unit (ICU) admission and length of stay (LOS) in the hospital.

RESULTS

According to NLR tertiles, patients in the 3rd tertile (NLR ≥7.6) had significantly more ICU admissions (17 vs. 2.2%, p < 0.0001) and longer average LOS (6.2 vs. 4.2 days, p < 0.002) compared with those in the 1st tertile (NLR <3.6). According to WBC tertiles, patients in the 3rd tertile had more ICU admissions (12.6 vs. 6.2%, p = 0.12) and a longer average LOS (5.8 vs. 4.4 days, p = 0.059) compared to patients in the 1st WBC tertile, but this did not reach statistical significance. In the multivariate model including NLR, WBC and other predictors, only NLR tertiles (p < 0.0262) and modified early warning scores (p < 0.0025) were significant predictors of ICU admission. Likewise, in the multivariate model of LOS, only NLR and glucose level were significant predictors of longer LOS (p < 0.0161 and p < 0.0053, respectively).

CONCLUSIONS

NLR is superior to total WBC in predicting adverse outcomes of acute pancreatitis. According to our data, we suggest using the NLR cutoff value of >4.7 as a simple indicator of severity in patients presenting with acute pancreatitis. and IAP.

OBJECTIVE

To examine the relationship between type 2 diabetes mellitus (T2DM) and the risk of having open-angle glaucoma (OAG) in an adult Latino population.

METHODS

Population-based cross-sectional study.

METHODS

Latinos 40 years and older (n = 5894) from 6 census tracts in Los Angeles, California.

METHODS

Participants from the Los Angeles Latino Eye Study (LALES), a large population-based study of self-identified adult Latinos, answered an interviewer-administered questionnaire and underwent a clinical and complete ocular examination, including visual field (VF) testing and stereo fundus photography. A participant was defined as having diabetes mellitus (DM) if she or he had a history of being treated for DM, the participant's glycosylated hemoglobin was measured at 7.0% or higher, or the participant had random blood glucose of 200 mg% or higher. Type 2 DM was defined if the participant was 30 years or older when diagnosed with DM. Open-angle glaucoma was defined as the presence of an open angle and a glaucomatous VF abnormality and/or evidence of glaucomatous optic disc damage in at least one eye. Logistic regression analysis was used to identify the risk of having OAG in persons with T2DM.

METHODS

Prevalence of OAG.

RESULTS

Of the 5894 participants with complete data, 1157 (19.6%) had T2DM and 288 (4.9%) had OAG. The prevalence of OAG was 40% higher in participants with T2DM than in those without T2DM (age/gender/intraocular pressure-adjusted odds ratio, 1.4; 95% confidence interval, 1.03-1.8; P = 0.03). Trend analysis revealed that a longer duration of T2DM (stratified into 5-year increments) was associated with a higher prevalence of OAG (P<0.0001).

CONCLUSIONS

The presence of T2DM and a longer duration of T2DM were independently associated with a higher risk of having OAG in the LALES cohort. The high prevalences of T2DM and OAG and their association in this fastest growing segment of the United States population have significant implications for designing screening programs targeting Latinos.

5-Lipoxygenase (5-LO) catalyzes the conversion of arachidonic acid (AA) into leukotriene (LT) A(4) and 5-hydroperoxyeicosatetraenoic acid. LTA(4) can then be converted into LTB(4) by LTA(4) hydrolase or into LTC(4) by LTC(4) synthase and the LTC(4) synthase isoenzymes MGST2 and MGST3. LTB(4) is a potent chemoattractant for neutrophils, eosinophils and monocytes leading to adherence of phagocytes to vessel walls, neutrophil degranulation and release of superoxide anions. LTC(4) and its metabolite, LTD(4), are potent bronchoconstrictors that increase vascular permeability and stimulate mucus secretion from airways. Recent data also suggest that LT have an immunomodulatory role. Due to these properties, the increased biosynthesis of LT in asthma, and based upon clinical data obtained with CysLT(1) receptor antagonists in asthma patients, there is a consensus that CysLT play a prominent role in asthma. In this review, we summarize the knowledge on possible functions of the 5-LO pathway in various diseases like asthma, cancer and cardiovascular events and review the corresponding potential therapeutic roles of 5-LO inhibitors.

OBJECTIVE

An accurate system for predicting survival for patients with solid tumors will allow for better patient selection for both established and novel therapies. We propose a staging system for clear cell variants of renal cell carcinoma (RCC) that includes molecular predictors and standard clinical predictors such as tumor-node-metastasis (TNM) stage, histological grade, and performance status (PS).

METHODS

A custom tissue array was constructed using clear cell RCC from 318 patients, representing all stages of localized and metastatic RCC, and immunohistochemically stained for molecular markers Ki67, p53, gelsolin, CA9, CA12, PTEN, EpCAM, and vimentin. We present a strategy for evaluating individual candidate markers for prognostic information and integrating informative markers into a multivariate prognostic system.

RESULTS

The overall median follow-up and the median follow-up for surviving patients were 28 and 55 months, respectively. A prognostic model based primarily on molecular markers included metastasis status, p53, CA9, gelsolin, and vimentin as predictors and had high discriminatory power: its statistically validated concordance index (C-index) was found to be 0.75. A prognostic model based on a combination of clinical and molecular predictors included metastasis status, T stage, Eastern Cooperative Oncology Group PS, p53, CA9, and vimentin as predictors and had a C-index of 0.79, which was significantly higher (P < 0.05) than that of prognostic models based on grade alone (C = 0.65), TNM stage alone (C = 0.73), or the University of California Los Angeles integrated staging system (C = 0.76).

CONCLUSIONS

Protein expressions obtained using widely available technology can complement standard clinical predictors such as TNM stage, histological grade, and PS.

Importance: Coronavirus disease 2019 (COVID-19) has infected more than 8.1 million US residents and killed more than 221 000. There is a dearth of research on epidemiology and clinical outcomes in US patients with COVID-19.

Objectives: To characterize patients with COVID-19 treated in US hospitals and to examine risk factors associated with in-hospital mortality.

Design, setting, and participants: This cohort study was conducted using Premier Healthcare Database, a large geographically diverse all-payer hospital administrative database including 592 acute care hospitals in the United States. Inpatient and hospital-based outpatient visits with a principal or secondary discharge diagnosis of COVID-19 (International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis code, U07.1) between April 1 and May 31, 2020, were included.

Exposures: Characteristics of patients were reported by inpatient/outpatient and survival status. Risk factors associated with death examined included patient characteristics, acute complications, comorbidities, and medications.

Main outcomes and measures: In-hospital mortality, intensive care unit (ICU) admission, use of invasive mechanical ventilation, total hospital length of stay (LOS), ICU LOS, acute complications, and treatment patterns.

Results: Overall, 64 781 patients with COVID-19 (29 479 [45.5%] outpatients; 35 302 [54.5%] inpatients) were analyzed. The median (interquartile range [IQR]) age was 46 (33-59) years for outpatients and 65 (52-77) years for inpatients; 31 968 (49.3%) were men, 25 841 (39.9%) were White US residents, and 14 340 (22.1%) were Black US residents. In-hospital mortality was 20.3% among inpatients (7164 patients). A total of 5625 inpatients (15.9%) received invasive mechanical ventilation, and 6849 (19.4%) were admitted to the ICU. Median (IQR) inpatient LOS was 6 (3-10) days. Median (IQR) ICU LOS was 5 (2-10) days. Common acute complications among inpatients included acute respiratory failure (19 706 [55.8%]), acute kidney failure (11 971 [33.9%]), and sepsis (11 910 [33.7%]). Older age was the risk factor most strongly associated with death (eg, age ≥80 years vs 18-34 years: odds ratio [OR], 16.20; 95% CI, 11.58-22.67; P < .001). Receipt of statins (OR, 0.60; 95% CI, 0.56-0.65; P < .001), angiotensin-converting enzyme inhibitors (OR, 0.53; 95% CI, 0.46-0.60; P < .001), and calcium channel blockers (OR, 0.73; 95% CI, 0.68-0.79; P < .001) was associated with decreased odds of death. Compared with patients with no hydroxychloroquine or azithromycin, patients with both azithromycin and hydroxychloroquine had increased odds of death (OR, 1.21; 95% CI, 1.11-1.31; P < .001).

Conclusions and relevance: In this cohort study of patients with COVID-19 infection in US acute care hospitals, COVID-19 was associated with high ICU admission and in-hospital mortality rates. Use of statins, angiotensin-converting enzyme inhibitors, and calcium channel blockers were associated with decreased odds of death. Understanding the potential benefits of unproven treatments will require future randomized trials.

Screening mammography is underutilized, even for women older than 50 years for whom there is a general consensus that regular annual screening is appropriate and necessary. To evaluate reasons for this underutilization, we studied a random sample of 517 women in Los Angeles, Calif who were older than 50 years. All women were found to be underscreened, especially women older than 65 years. For example, approximately 35% of women 50 to 64 years old and 47% of women aged 65 years and older never had had even one mammogram. Analyses revealed that the most important factor that predicted whether a women ever had had a mammogram was whether her physician had talked to her about mammography. Women were between four and 12 times more likely, depending on their age group, to have had a mammogram at some time if their physicians discussed it with them. The discussions did not need to be lengthy or complex. These results indicate that physicians need to know that discussing screening mammography with their patients has a major impact on breast cancer screening behaviors.

Despite evidence that oxygen regulates neural precursor fate, the effects of changing oxygen tensions on distinct stages in precursor differentiation are poorly understood. We found that 5% oxygen permitted clonal and long-term expansion of mouse fetal cortical precursors. In contrast, 20% oxygen caused a rapid decrease in hypoxia-inducible factor 1alpha and nucleophosmin, followed by the induction of p53 and apoptosis of cells. This led to a decrease in overall cell number and particularly a loss of astrocytes and oligodendrocytes. Clonal analysis revealed that apoptosis in 20% oxygen was due to a complete loss of CD133(lo)CD24(lo) multipotent precursors, a substantial loss of CD133(hi)CD24(lo) multipotent precursors, and a failure of remaining CD133(hi)CD24(lo) cells to generate glia. In contrast, committed neuronal progenitors were not significantly affected. Switching clones from 5% to 20% oxygen only after mitogen withdrawal led to a decrease in total clone numbers but an even greater decrease in oligodendrocyte-containing clones. During this late exposure to 20% oxygen, bipotent glial (A2B5+) and early (platelet-derived growth factor receptor alpha) oligodendrocyte progenitors appeared and disappeared more quickly, relative to 5% oxygen, and late stage O4+ oligodendrocyte progenitors never appeared. These results indicate that multipotent cells and oligodendrocyte progenitors are more susceptible to apoptosis at 20% oxygen than committed neuronal progenitors. This has important implications for optimizing ex vivo production methods for cell replacement therapies.

Discussed here are conceptual and methodologic issues that bear on the role of behaviorally evoked cardiovascular reactivity in cardiovascular disease. It is argued that recent criticisms concerning the validity of cardiovascular reactivity as a stable dimension of individual differences arise from inadequacies of measurement prevalent in prior literature. With standardization of test stimuli and application of psychometric principles lo protocol development, assessment of reactivity are found to be highly reliable and, in turn, to demonstrate the dispositional nature of this construct. Recent studies also document an underlying heterogeneity of hemodynamic reactions to stress, with distinct cardiac and vascular components. Because hemodynamic adjustments show some plasticity under differing task conditions, responses seen in particular contexts reflect influences of both an individual-specific response potential and response-eliciting properties of the stimulus. On the question of disease relevance, it is concluded that cardiovascular reactivity cannot yet be considered an established risk factor for either coronary heart disease or hypertension. However, the preponderance of existing clinical, experimental. and epidemiologic evidence is consistent with such an association and warrants further study in the context or population-based, prospective investigation.

To study the possible role of the human lipid-oxidizing enzyme 15-lipoxygenase (15-LO) in atherosclerosis, we overexpressed it specifically in the vascular wall of C57B6/SJL mice by using the murine preproendothelin-1 promoter. The mice overexpressing 15-LO were crossbred with low density lipoprotein (LDL) receptor-deficient mice to investigate atherogenesis. High levels of 15-LO were expressed in the atherosclerotic lesion in the double-transgenic mice as assessed by immunohistochemistry. The double-transgenic, 15-LO-overexpressing, LDL receptor-deficient mice (LDLR-/-/15LO) developed significantly larger atherosclerotic lesions at the aortic sinus compared with lesions in the LDL receptor-deficient (LDLR-/-) mice after 3 and 6 weeks (107,000 versus 28,000 microm(2) [P:<0.001] and 121,000 versus 87,000 microm(2) [P:<0.05], respectively) of an atherogenic diet. LDL from the LDLR-/-/15LO mice was more susceptible to oxidation than was the LDL from the control LDLR-/- mice, as shown by a shorter lag period for copper-induced conjugated diene formation. On the other hand, no differences were found in the levels of serum anti-oxidized LDL antibodies between the study groups. There were also no differences with respect to the density of macrophages and T lymphocytes infiltrating the lesions in both experimental groups. Taken together, these results support the hypothesis that 15-LO overexpression in the vessel wall is associated with enhanced atherogenesis.

Daily asthma attack diaries of 16 panels of asthmatics residing in the Los Angeles area were collected by the Environmental Protection Agency for 34-week periods during the years 1972-1975. There data are examined here for the relationship between daily attack occurrence and daily levels of photochemical oxidant, total suspended particulates, minimum temperature, relative humidity, and average wind speed. A separate multiple logistic regression is used for each panelist's attack data. Variables representing the presence or absence of attack on the preceding day, as well as day of week and time since the start of the study, are included in the regressions. The most significant predictor of attacks was the presence of an attack on the preceding day. On the average, the panelists tended to have increased attacks on days with high oxidant and particulate pollution, on cool days, and during the first two months of the study. Panelists' attack propensity also differed by day of week; in particular they had more attacks on Saturdays (the last day of the weekly reporting period) than on Sundays. Each panelist's regression coefficients are classified according to age, sex, hay fever status, and self-assessed attack precursors; this classification is used to examine subgroups among the panelists with high coefficients corresponding to the above factors.

Patients with lesions in the primary visual cortex (V1) may show processing of visual stimuli presented in their field of cortical blindness even when they report being unaware of the stimuli. To elucidate the neuroanatomical basis of their residual visual functions, we used functional magnetic resonance imaging in two hemianopic patients, FS and GY. In the first experiment, a rotating spiral stimulus was used to assess the responsiveness of dorsal stream areas. Although no response was detectable within denervated or destroyed early visual cortex, motion-sensitive areas (hMT+/V5) ipsilateral to the lesion showed a strong sustained hemodynamic response. In GY, this activation was at least as strong as that of his contralesional hMT+/V5 to the stimulus in the normal hemifield. In the second experiment, coloured images of natural objects were used to assess the responsiveness of ventral stream areas. Again, no activity was detectable in ipsilesional early visual areas, but extrastriate areas in the lateral occipital cortex (hMT+/V5 and LO) and within the posterior fusiform gyrus (V4/V8) showed a robust sustained hemodynamic response. In both experiments, we observed that ipsilesional areas responded to stimuli presented in either hemifield, whereas the normal hemisphere responded preferentially to stimuli in the sighted hemifield. As only one subject occasionally noticed the onset of stimulation in the impaired field, the unexpectedly strong sustained activity in ipsilesional dorsal and ventral cortical areas appears to be insufficient to generate conscious vision.

Campylobacter jejuni strains exhibit significant variation in the genetic content of the lipooligosaccharide (LOS) biosynthesis loci with concomitant differences in LOS structure. The C. jejuni LOS loci have been grouped into six classes based on gene content and organization. Utilizing PCR amplifications of genes from these loci, we were able to classify a majority (80%) of the LOS biosynthesis loci from 123 strains of C. jejuni that included 39 of the Penner serotype reference strains. We found that a particular LOS class was not always associated with a specific Penner serotype, and 14 of 16 Guillain-Barré syndrome-associated isolates tested in this study shared the same LOS class. The remaining isolates that could not be classified were often distinguishable from each other based on the results of gene-specific PCR and the lengths of their LOS biosynthesis loci as determined by long (XL) PCR. Sequence analysis of two of these unique XL PCR products demonstrated two new LOS classes. These results support the hypothesis that the LOS locus is a hot spot for genetic exchange and rearrangements. Analysis of the LOS biosynthesis genes by PCR assays can be used for typing C. jejuni and offers the advantage of inferring potential LOS structures.

The HIV-1 integrase, responsible for the chromosomal integration of the newly synthesized double-stranded viral DNA into the host genomic DNA, represents a new and important target of potential clinical relevance. For instance, two integrase inhibitors, raltegravir and elvitegravir, have been shown to be promising in clinical trials, and the first has been recently made available for clinical practice. As is the case for other antiviral drugs, drug resistance to integrase inhibitors occurs both in vitro and/or in vivo through the selection of mutations within the HIV genome. Indeed, many integrase mutations have already been associated with resistance to all the different integrase inhibitors tested in in vitro and/or in vivo studies. Among them, about 40 substitutions have been specifically associated with the development of resistance to raltegravir and/or elvitegravir; some of them were also found in vivo in patients failing such integrase inhibitors. The relevance of integrase mutations in clinical practice has yet to be defined, in light of the lack of long-term follow-up of treated patients and the limited data about the prevalence of integrase inhibitor-associated mutations in integrase inhibitor-naive patients (either untreated, or treated with antiretrovirals not containing integrase inhibitors). Therefore, by structural analysis elaboration and literature discussion, the aim of this review is to characterize the conserved residues and regions of HIV-1 integrase and the prevalence of mutations associated with integrase inhibitor resistance, by matching data originated from a well-defined cohort of HIV-1 B subtype-infected individuals (untreated and antiretroviral-treated) and data originated from the public Los Alamos Database available in the literature (all patients integrase inhibitor-naive by definition). In integrase inhibitor-naive patients, 180 out of 288 HIV-1 integrase residues (62.5%) are conserved (< 1% variability). Residues involved in protein stability, multimerization, DNA binding, catalytic activity, and in the binding with the human cellular cofactor LEDGF/p75 are fully conserved. Some of these residues clustered into large defined regions of consecutive invariant amino acids, suggesting that consecutive residues in specific structural domains are required for the correct performance of HIV-1 integrase functions. All primary signature mutations emerging in patients failing raltegravir (Y143R, Q148H/K/R, N155H) or elvitegravir (T66I, E92Q, S147G, Q148H/K/R, N155H), as well as secondary mutations (H51Y, T66A/K, E138K, G140S/A/C, Y143C/H, K160N, R166S, E170A, S230R, D232N, R263K) were completely absent or highly infrequent (< 0.5%) in integrase inhibitor-naive patients, either infected with HIV-1 B subtype (drug-naive or antiretroviral-treated), or non-B subtypes/group N and O. Differently, other mutations (L74M, T97A, S119G/R, V151I, K156N, E157Q, G163K/R, V165I, I203M, T206S, S230N) occurred as natural polymorphisms with a different prevalence according to different HIV-1 subtype/circulating recombinant form/group. In conclusion, the HIV-1 integrase in vivo is an enzyme requiring the full preservation of almost two-thirds of its amino acids in the absence of specific integrase inhibitor pressure. Primary mutations associated with resistance to integrase inhibitors clinically relevant today are absent or highly infrequent in integrase inhibitor-naive patients. The characterization of the highly conserved residues (involved in protein stability, multimerization, DNA binding, catalytic activity, LEDGF binding, and some with still poorly understood function) could help in the rational design of new HIV-1 inhibitors with alternative mechanisms of action and more favorable resistance profiles.

Eating away from home and particularly fast food consumption have been shown to contribute to weight gain. Increased geographic access to fast food outlets and other restaurants may contribute to higher levels of obesity, especially in individuals who rely largely on the local environment for their food purchases. We examined whether fast food and restaurant concentrations are associated with body mass index and whether car ownership might moderate this association. We linked the 2000 US Census data and information on locations of fast food and other restaurants with the Los Angeles Family and Neighborhood Study database, which consists of 2,156 adults sampled from 63 neighborhoods in Los Angeles County. Multilevel modeling was used to estimate associations between body mass index (BMI), fast food and restaurant concentration, and car ownership after adjustment for individual-level factors and socioeconomic characteristics of residential neighborhoods. A high concentration of local restaurants is associated with BMI. Car owners have higher BMIs than non-car owners; however, individuals who do not own cars and reside in areas with a high concentration of fast food outlets have higher BMIs than non-car owners who live in areas with no fast food outlets, approximately 12 lb more (p = 0.02) for an individual with a height of 5 ft. 5 in. Higher restaurant density is associated with higher BMI among local residents. The local fast food environment has a stronger association with BMI for local residents who do not have access to cars.

OBJECTIVE

Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of DSM-IV-TR ADHD.

METHODS

Families were ascertained at Massachusetts General Hospital (MGH; N = 309 trios), Washington University at St. Louis (WASH-U; N = 272 trios), and University of California at Los Angeles (UCLA; N = 156 trios). Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. After applying quality control filters, association with ADHD was tested with 835,136 SNPs in 735 DSM-IV ADHD trios from 732 families.

RESULTS

Our smallest p value (6.7E-07) did not reach the threshold for genome-wide statistical significance (5.0E-08), but one of the 20 most significant associations was located in a candidate gene of interest for ADHD (SLC9A9, rs9810857, p = 6.4E-6). We also conducted gene-based tests of candidate genes identified in the literature and found additional evidence of association with SLC9A9.

CONCLUSIONS

We and our colleagues in the Psychiatric GWAS Consortium are working to pool together GWAS samples to establish the large data sets needed to follow-up on these results and to identify genes for ADHD and other disorders.

Virus-specific cytotoxic T lymphocytes (CTL) exert intense selection pressure on replicating simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) in infected individuals. The immunodominant Mamu-A(*)01-restricted Gag p11C, C-M epitope is highly conserved among all sequenced isolates of SIV and therefore likely is structurally constrained. The strategies used by virus isolates to mutate away from an immunodominant epitope-specific CTL response are not well defined. Here we demonstrate that the emergence of a position 2 p11C, C-M epitope substitution (T47I) in a simian-human immunodeficiency virus (SHIV) strain 89.6P-infected Mamu-A(*)01(+) monkey is temporally correlated with the emergence of a flanking isoleucine-to-valine substitution at position 71 (I71V) of the capsid protein. An analysis of the SIV and HIV-2 sequences from the Los Alamos HIV Sequence Database revealed a significant association between any position 2 p11C, C-M epitope mutation and the I71V mutation. The T47I mutation alone is associated with significant decreases in viral protein expression, infectivity, and replication, and these deficiencies are restored to wild-type levels with the introduction of the flanking I71V mutation. Together, these data suggest that a compensatory mutation is selected for in SHIV strain 89.6P to facilitate the escape of that virus from CTL recognition of the dominant p11C, C-M epitope.

OBJECTIVE

To determine if INH-A21, an intravenous immune globulin (IGIV) derived from donors with high titers of antibody to surface adhesins of Staphylococcus epidermidis and S. aureus prevents late-onset sepsis (LOS) in very low birth weight (VLBW) infants.

METHODS

In this double-blind, placebo-controlled study, infants with birth weights 500 to 1250 g were randomized to receive up to four doses of INH-A21 (Veronate) or placebo. The primary objective was to determine the safety and efficacy of INH-A21 versus placebo for prevention of S. aureus LOS in VLBW infants.

RESULTS

A total of 1983 infants from 95 neonatal intensive care units were randomized, and received at least one dose of study drug. S. aureus LOS developed in 50 of 989 (5%) and 60 of 994 (6%) infants who received placebo or INH-A21, respectively (P = .34). No differences were found in the frequencies of LOS caused by coagulase-negative staphylococci (CoNS), Candida spp, or overall mortality. No adverse events were statistically significantly associated with INH-A21 infusions compared with placebo.

CONCLUSIONS

INH-A21 failed to reduce the incidence of staphylococcal LOS or candidemia in premature infants.

BACKGROUND

Leiomyosarcoma of the inferior vena cava (IVC) is an uncommon tumor that many believe portends a poor prognosis compared with leiomyosarcoma with similar histology at other anatomic sites. Because of the limited international experience with this disease, the optimal management of these patients is unknown.

METHODS

From October 1978 to January 1997, 14 patients with leiomyosarcoma of the IVC were treated at the University of California-Los Angeles Medical Center. Wide resection was attempted in all patients. The characteristics of each patient were documented and compared with those of patients with leiomyosarcoma of the stomach (n = 13), small intestine (n = 18), retroperitoneum (n = 19), and uterus (n = 10) who were treated during the same time period.

RESULTS

Age, gender, tumor size, tumor grade, and lymph node status did not impact survival of patients with leiomyosarcoma of the IVC. Patients with positive surgical margins fared significantly worse (P < 0.03) compared with those who underwent complete resection. Radiation therapy diminished local recurrence and may improve median survival (6 months [n = 2] vs. 51 months [n = 12]) in this patient population. Patients who received combined chemotherapy and radiation lived longer than those who did not (P < 0.05). The 5-year cumulative survival rate (Kaplan-Meier method) was 53% for patients with leiomyosarcoma of the IVC, 47% for those with leiomyosarcoma of the stomach, 43% for those with leiomyosarcoma of the small intestine, 56% for those with leiomyosarcoma of the retroperitoneum, and 65% for those with leiomyosarcoma of the uterus.

CONCLUSIONS

Despite having a tumor that originates from the IVC, patients with this tumor type can enjoy reasonably long term survival. It appears that these patients benefit from radiation therapy to control local disease. Survival of these patients is no worse than of patients with leiomyosarcomatous lesions of other origin. Aggressive surgical management combined with adjuvant therapy offers the best treatment for patients with leiomyosarcoma of the IVC.

Potent TLR4-dependent cell activation by gram-negative bacterial endotoxins depends on sequential endotoxin-protein and protein-protein interactions with LPS-binding protein, CD14, myeloid differentiation protein 2 (MD-2), and TLR4. Previous studies have suggested that reduced agonist potency of underacylated endotoxins (i.e., tetra- or penta- vs hexa-acylated) is determined by post-CD14 interactions. To better define the molecular basis of the differences in agonist potency of endotoxins differing in fatty acid acylation, we compared endotoxins (lipooligosaccharides (LOS)) from hexa-acylated wild-type (wt), penta-acylated mutant msbB meningococcal strains as well as tetra-acylated LOS generated by treatment of wt LOS with the deacylating enzyme, acyloxyacylhydrolase. To facilitate assay of endotoxin:protein and endotoxin:cell interactions, the endotoxins were purified after metabolic labeling with [3H]- or [14C]acetate. All LOS species tested formed monomeric complexes with MD-2 in an LPS-binding protein- and CD14-dependent manner with similar efficiency. However, msbB LOS:MD-2 and acyloxyacylhydrolase-treated LOS:MD-2 were at least 10-fold less potent in inducing TLR4-dependent cell activation than wt LOS:MD-2 and partially antagonized the action of wt LOS:MD-2. These findings suggest that underacylated endotoxins produce decreased TLR4-dependent cell activation by altering the interaction of the endotoxin:MD-2 complex with TLR4 in a way that reduces receptor activation. Differences in potency among these endotoxin species is determined not by different aggregate properties, but by different properties of monomeric endotoxin:MD-2 complexes.

Significant increases in asthma morbidity and mortality in the United States have occurred since the 1970s, particularly among African-Americans. Exposure to various environmental factors, including air pollutants and allergens, has been suggested as a partial explanation of these trends. To examine relations between several air pollutants and asthma exacerbation in African-Americans, we recruited a panel of 138 children in central Los Angeles. We recorded daily data on respiratory symptoms and medication use for 13 weeks and examined these data in conjunction with data on ozone (O3) nitrogen dioxide (NO2), particulate matter (PM10 and PM2.5), meteorological variables, pollens, and molds. Using generalized estimating equations, we found associations between respiratory symptom occurrence and several environmental factors. For example, new episodes of cough were associated with exposure to PM10 (OR = 1.25; 95% CI = 1.12-1.39; interquartile range [IQR] = 17 microg/m3, 24-hour average), PM2.5 (OR = 1.10; 95% CI = 1.03-1.18; IQR = 30 microg/m3, 12-hour average), NO2, and the molds Cladosporium and Alternaria, but not with exposure to O3 or pollen. The factors PM10 and O3 were associated with the use of extra asthma medication. For this population several bioaerosols and air pollutants had effects that may be clinically significant.

The prevalence of MRSA in the nosocomial setting has been well studied, and its control remains a challenge for infection control professionals. Complicating this problem is the increasing number of reports on the spread of community-acquired MRSA (CA-MRSA). CA-MRSA strains differ from hospital-acquired MRSA (HA-MRSA) strains in that they are generally susceptible to most antibiotics. These strains share the presence of staphylococcal cassette chromosome mec (SCCmec) type IV in their genomes, are frequently virulent, and predominantly cause skin and soft tissue infections. The genome sequence of the prototypic CA-MRSA strain, MW2, revealed the presence of additional virulence factors not commonly present in other S. aureus strains. We determined the genetic relatedness of 30 geographically diverse CA-MRSA isolates clustered based on SCCmec type IV by sequence analysis of the polymorphic repeat region of the protein A gene (spa typing). These results indicated that most strains shared a common spa type (131), identical to MW2. Because this group tends to infect healthy individuals with no known risk factors for nosocomial acquisition of MRSA, we refer to it as CA-MRSA without risk factors. A second group, CA-MRSA with risk factors, consists of two related genotypes, spa types 1 and 7, which differ by one nucleotide change. These strains have caused severe infections in HIV-positive patients in Los Angeles and New York. Although CA-MRSA strains share genetic determinants, they are not clonal but rather are derived from different genetic backgrounds. The genetic characteristics and the epidemiology of CA-MRSA with and without risk factors are discussed.