BACKGROUND

Inadequate initial treatment and delayed hemodynamic stabilization (HDS) may be associated with increased risk of death in severe sepsis patients.

METHODS

In order to compare the hemodynamic efficacy and safety of 6% HES 130/0.4 and NaCl 0.9% for HDS in patients with severe sepsis, we designed a prospective, multicenter, active-controlled, double-blind, randomized study in intensive care units.

RESULTS

174 out of 196 patients reached HDS (88 and 86 patients for HES and NaCl, respectively). Significantly less HES was used to reach HDS vs. NaCl (1,379 ± 886 ml in the HES group and 1,709 ± 1,164 ml in the NaCl group (mean difference = -331 ± 1,033, 95% CI -640 to -21, P = 0.0185). Time to reach HDS was 11.8 10.1 hours vs. 14.3 ± 11.1 hours for HES and NaCl, respectively. Total quantity of study drug infused over four consecutive days, ICU and hospital LOS, and area under the curve of SOFA score were comparable. Acute renal failure occurred in 24 (24.5%) and 19 (20%) patients for HES and NaCl, respectively (P = 0.454). There was no difference between AKIN and RIFLE criteria among groups and no difference in mortality, coagulation, or pruritus up to 90 days after treatment initiation.

CONCLUSIONS

Significantly less volume was required to achieve HDS for HES vs. NaCl in the initial phase of fluid resuscitation in severe sepsis patients without any difference for adverse events in both groups.

UNASSIGNED

NCT00464204.

This review focuses on the morphological features of atherosclerosis and the involvement of oxidative stress in the initiation and progression of this disease. There is now consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein in the vascular wall. Reactive oxygen species (ROS) are key mediators of signaling pathways that underlie vascular inflammation in atherogenesis, starting from the initiation of fatty streak development, through lesion progression, to ultimate plaque rupture. Plaque rupture and thrombosis result in the acute clinical complications of myocardial infarction and stroke. Many data support the notion that ROS released from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, myeloperoxidase (MPO), xanthine oxidase (XO), lipoxygenase (LO), nitric oxide synthase (NOS) and enhanced ROS production from dysfunctional mitochondrial respiratory chain, indeed, have a causatory role in atherosclerosis and other vascular diseases. Moreover, oxidative modifications in the arterial wall can contribute to the arteriosclerosis when the balance between oxidants and antioxidants shifts in favour of the former. Therefore, it is important to consider sources of oxidants in the context of available antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase and transferases thiol-disulfide oxidoreductases and peroxiredoxins. Here, we review also the mechanisms in which they are involved in order to accelerate the pace of the discovery and facilitate development of novel therapeutic approaches.

OBJECTIVE

The purpose of this study was to develop a valid and reliable disease-specific quality-of-life measurement tool for patients with rotator cuff disease.

METHODS

Health-related quality-of-life measurement tool development.

METHODS

Methodology for the development and evaluation of the tool included the following: 1) identification of a specific patient population, 2) generation of potential items, 3) item reduction, 4) pretesting the prototype instrument, 5) determination of reliability, and 6) validation.

RESULTS

The final instrument, the Western Ontario Rotator Cuff Index, double dagger has 21 items representing five domains, each with a Visual Analog Scale-type response option. Construct validation demonstrated that this instrument correlated predictably with other measurement tools (Disabilities of the Arm, Shoulder, and Hand outcome measure; American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form; University of California Los Angeles Shoulder Rating Scale; Constant Score; Rowe; Sickness Impact Profile; Short Form 36; and range of motion; 21 of 21 correlations within 0.19). Reliability was very high at 2 weeks, with an intraclass correlation coefficient of 0.96 and was more responsive (sensitive to change) than the other five shoulder measurement tools, global health instruments, and range of motion.

CONCLUSIONS

This measurement tool can be used as the primary outcome in clinical trials evaluating treatments in this patient population, although its features are equally attractive for monitoring patients' progress in clinical practice.

Although it is known that interleukin-7 (IL-7) and IL-15 influence the survival and turnover of CD8+ T cells, less is known about how these cytokines affect different subsets during the course of the immune response. We find that IL-7 and IL-15 differentially regulate CD8+ T-cell subsets defined by KLRG1 and CD127 expression during the contraction phase of the immune response. The provision of IL-15, or the related cytokine IL-2, during contraction led to the preferential accumulation of KLRG1(hi)CD127(lo) CD8+ T cells, whereas provision of IL-7 instead favored the accumulation of KLRG1(lo)CD127(hi) cells. While IL-7 and IL-15 both induced proliferation of KLRG1(lo) cells, KLRG1(hi) cells exhibited an extraordinarily high level of resistance to cytokine-driven proliferation in vivo despite their dramatic accumulation upon IL-15 administration. These results suggest that IL-15 and IL-2 greatly improve the survival of KLRG1(hi) CD8+ T cells, which are usually destined to perish during contraction, without inducing proliferation. As the availability of IL-15 and IL-2 is enhanced during periods of extended inflammation, our results suggest a mechanism in which a population of cytokine-dependent KLRG1(hi) CD8+ T cells is temporarily retained for improved immunity. Consideration of these findings may aid in the development of immunotherapeutic strategies against infectious disease and cancer.

OBJECTIVE

Previous research has generally found that racial/ethnic differences in breast cancer stage at diagnosis attenuate when measures of socioeconomic status are included in the analysis, although most previous research measured socioeconomic status at the contextual level. This study investigated the relation between race/ethnicity, individual socioeconomic status, and breast cancer stage at diagnosis.

METHODS

Women with stage 0 to III breast cancer were identified from population-based data from the Surveillance, Epidemiology, and End Results tumor registries in the Detroit and Los Angeles metropolitan areas. These data were combined with data from a mailed survey in a sample of White, Black, and Hispanic women (n=1700). Logistic regression identified factors associated with early-stage diagnosis.

RESULTS

Black and Hispanic women were less likely to be diagnosed with early-stage breast cancer than were White women (P< .001). After control for study site, age, and individual socioeconomic factors, the odds of early detection were still significantly less for Hispanic women (odds ratio [OR]=0.45) and Black women (OR = 0.72) than for White women. After control for the method of disease detection, the White/Black disparity attenuated to insignificance; the decreased likelihood of early detection among Hispanic women remained significant (OR=0.59).

CONCLUSIONS

The way in which racial/ethnic minority status and socioeconomic characteristics produce disparities in women's experiences with breast cancer deserves further research and policy attention.

BACKGROUND

There is concern that mastectomy is overused in the United States.

OBJECTIVE

To evaluate the association of patient-reported initial recommendations by surgeons and those given when a second opinion was sought with receipt of initial mastectomy; and to assess the use of mastectomy after attempted breast-conserving surgery (BCS).

METHODS

A survey of women aged 20 to 79 years with intraductal or stage I and II breast cancer diagnosed between June 2005 and February 2007 and reported to the National Cancer Institute's Surveillance, Epidemiology, and End Results registries for the metropolitan areas of Los Angeles, California, and Detroit, Michigan. Patients were identified using rapid case ascertainment, and Latinas and blacks were oversampled. Of 3133 patients sent surveys, 2290 responded (73.1%). A mailed survey was completed by 96.5% of respondents and 3.5% completed a telephone survey. The final sample included 1984 female patients (502 Latinas, 529 blacks, and 953 non-Hispanic white or other).

METHODS

The rate of initial mastectomy and the perceived reason for its use (surgeon recommendation, patient driven, medical contraindication) and the rate of mastectomy after attempted BCS.

RESULTS

Of the 1984 patients, 1468 had BCS as an initial surgical therapy (75.4%) and 460 had initial mastectomy, including 13.4% following surgeon recommendation and 8.8% based on patient preference. Approximately 20% of patients (n = 378) sought a second opinion; this was more common for those patients advised by their initial surgeon to undergo mastectomy (33.4%) than for those advised to have BCS (15.6%) or for those not receiving a recommendation for one procedure over another (21.2%) (P < .001). Discordance in treatment recommendations between surgeons occurred in 12.1% (n = 43) of second opinions and did not differ on the basis of patient race/ethnicity, education, or geographic site. Among the 1459 women for whom BCS was attempted, additional surgery was required in 37.9% of patients, including 358 with reexcision (26.0%) and 167 with mastectomy (11.9%). Mastectomy was most common in patients with stage II cancer (P < .001).

CONCLUSIONS

Breast-conserving surgery was recommended by surgeons and attempted in the majority of patients evaluated, with surgeon recommendation, patient decision, and failure of BCS all contributing to the mastectomy rate.

Identifying a scalable, unbiased method for discovering which members of the human gut microbiota influence specific physiologic, metabolic, and immunologic phenotypes remains a challenge. We describe a method in which a clonally arrayed collection of cultured, sequenced bacteria was generated from one of several human fecal microbiota samples found to transmit a particular phenotype to recipient germ-free mice. Ninety-four bacterial consortia of diverse size, randomly drawn from the culture collection, were introduced into germ-free animals. We identified an unanticipated range of bacterial strains that promoted accumulation of colonic regulatory T cells (T(regs)) and expansion of Nrp1(lo/-) peripheral T(regs), as well as strains that modulated mouse adiposity and cecal metabolite concentrations, using feature selection algorithms and follow-up monocolonizations. This combinatorial approach enables a systems-level understanding of microbial contributions to human biology.

The CD8⁺ memory T cell population is heterogeneous, and it is unclear which subset(s) optimally mediate the central goal of the immune system-protection against infection. Here we investigate the protective capacities of CD8⁺ T cell subsets present at the memory stage of the immune response. We show that a population of CD8⁺ T cells bearing markers associated with effector cells (KLRG1(hi), CD27(lo), T-bet(hi), Eomes(lo)) persisted to the memory phase and provided optimal control of Listeria monocytogenes and vaccinia virus, despite weak recall proliferative responses. After antigen-specific boosting, this population formed the predominant secondary memory subset and maintained superior pathogen control. The effector-like memory subset displayed a distinct pattern of tissue distribution and localization within the spleen, and their enhanced capacity to eliminate Listeria involved specialized utilization of cytolysis. Together, these data suggest that long-lived effector CD8⁺ T cells are optimal for protective immunity against certain pathogens.

A comprehensive functional assessment requires thorough and careful inquiry, which is difficult to accomplish in most busy clinical practices. This paper examines the reliability and validity of the Functional Status Questionnaire (FSQ), a brief, standardized, self-administered questionnaire designed to provide a comprehensive and feasible assessment of physical, psychological, social and role function in ambulatory patients. The FSQ can be completed and computer-scored in minutes to produce a one-page report which includes six summated-rating scale scores and six single-item scores. The clinician can use this report both to screen for and to monitor patients' functional status. In this study, the FSQ was administered to 497 regular users of Boston's Beth Israel Hospital's Healthcare Associates and 656 regular users of 76 internal medicine practices in Los Angeles. The data demonstrate that the FSQ produces reliable sub-scales with construct validity. The authors believe the FSQ addresses many of the problems behind the slow diffusion into primary care of systematic functional assessment.

OBJECTIVE

To determine the attributable cost of ventilator-associated pneumonia from a hospital-based cost perspective, after adjusting for potential confounders.

METHODS

Patients admitted between January 19, 1998, and December 31, 1999, were followed prospectively for the occurrence of ventilator-associated pneumonia. Hospital costs were defined by using the hospital cost accounting database.

METHODS

The medical and surgical intensive care units at a suburban, tertiary care hospital.

METHODS

Patients requiring >24 hrs of mechanical ventilation.

METHODS

None.

RESULTS

We measured occurrence of ventilator-associated pneumonia, in-hospital mortality rate, total intensive care unit (ICU) and hospital lengths of stay (LOS), and total hospital cost per patient. Ventilator-associated pneumonia occurred in 127 of 819 patients (15.5%). Compared with uninfected, ventilated patients, patients with ventilator-associated pneumonia had a higher Acute Physiology and Chronic Health Evaluation II score on admission (p <.001) and were more likely to require multiple intubations (p <.001), hemodialysis (p <.001), tracheostomy (p <.001), central venous catheters (p <.001), and corticosteroids (p <.001). Patients with ventilator-associated pneumonia were more likely to be bacteremic during their ICU stay (36 [28%] vs. 22 [3%]; p <.001). Patients with ventilator-associated pneumonia had significantly higher unadjusted ICU LOS (26 vs. 4 days; p <.001), hospital LOS (38 vs. 13 days; p <.001), mortality rate (64 [50%] vs. 237 [34%]; p <.001), and hospital costs (70,568 dollars vs. 21,620 dollars, p <.001). Multiple linear regression, controlling for other factors that may affect costs, estimated the attributable cost of ventilator-associated pneumonia to be 11,897 dollars (95% confidence interval = 5,265 dollars-26,214 dollars; p <.001).

CONCLUSIONS

Patients with ventilator-associated pneumonia had significantly longer ICU and hospital LOS, with higher crude hospital cost and mortality rate compared with uninfected patients. After we adjusted for underlying severity of illness, the attributable cost of ventilator-associated pneumonia was approximately 11,897 dollars.

OBJECTIVE

To determine the national incidence and risk factors for conversion from laparoscopic to open cholecystectomy.

BACKGROUND

Most series reporting the rates at which laparoscopic cholecystectomies are performed, relative to the open procedure, have come from centers specializing in laparoscopic surgery. The rates at which conversions occur from these centers may not reflect those in community practice. We sought to determine the actual, and therefore acceptable, conversion rate by examining nationally representative discharge data.

METHODS

The National Hospital Discharge database for 1998 to 2001 was acquired from the Centers for Disease Control. All gallbladder disease related admissions were extracted, and the cholecystectomies (ICD-9-CM codes 51.2X) were analyzed using the SAS package. Stepwise logistic regression was used to determine what factors were associated with the risk of conversion from laparoscopic to open cholecystectomy.

RESULTS

Approximately 25% of all cholecystectomies are performed by the open technique. Of the remaining 75%, there is an approximately 5% to 10% conversion rate. The major risk factors for conversion included male sex, obesity, and cholecystitis. Concurrent choledocholithiasis, cholelithiasis, and cholecystitis were associated with a conversion rate of 25%. Length of stay (LOS) was reduced for laparoscopic operations and although conversion added 2 to 3 days to the LOS, for most cases the LOS was still less than for primary open operations.

CONCLUSIONS

Three quarters of all cholecystectomies are performed laparoscopically, and the national conversion rate is 5% to 10%. Cholecystitis, choledocholithiasis, male sex, and obesity are major predictors for conversion. The data presented in terms of conversion rates and LOS were derived from population-adjusted hospital discharge data and represent the current U.S. experience for cholecystectomy. From these data the community experience for conversion rates, risk factors, and LOS can be derived.

T cell dysfunction is an important feature of many chronic viral infections. In particular, it was shown that programmed death-1 (PD-1) regulates T cell dysfunction during chronic lymphocytic choriomeningitis virus infection in mice, and PD-1(hi) cells exhibit an intense exhausted gene signature. These findings were extended to human chronic infections such as HIV, hepatitis C virus, and hepatitis B virus. However, it is not known if PD-1(hi) cells of healthy humans have the traits of exhausted cells. In this study, we provide a comprehensive description of phenotype, function, and gene expression profiles of PD-1(hi) versus PD-1(lo) CD8 T cells in the peripheral blood of healthy human adults as follows: 1) the percentage of naive and memory CD8 T cells varied widely in the peripheral blood cells of healthy humans, and PD-1 was expressed by the memory CD8 T cells; 2) PD-1(hi) CD8 T cells in healthy humans did not significantly correlate with the PD-1(hi) exhausted gene signature of HIV-specific human CD8 T cells or chronic lymphocytic choriomeningitis virus-specific CD8 T cells from mice; 3) PD-1 expression did not directly affect the ability of CD8 T cells to secrete cytokines in healthy adults; 4) PD-1 was expressed by the effector memory compared with terminally differentiated effector CD8 T cells; and 5) finally, an interesting inverse relationship between CD45RA and PD-1 expression was observed. In conclusion, our study shows that most PD-1(hi) CD8 T cells in healthy adult humans are effector memory cells rather than exhausted cells.

BACKGROUND

To investigate differences in pathogenesis, diagnosis and resistance pathways between HIV-1 subtypes, an accurate subtyping tool for large datasets is needed. We aimed to evaluate the performance of automated subtyping tools to classify the different subtypes and circulating recombinant forms using pol, the most sequenced region in clinical practice. We also present the upgraded version 3 of the Rega HIV subtyping tool (REGAv3).

METHODS

HIV-1 pol sequences (PR+RT) for 4674 patients retrieved from the Portuguese HIV Drug Resistance Database, and 1872 pol sequences trimmed from full-length genomes retrieved from the Los Alamos database were classified with statistical-based tools such as COMET, jpHMM and STAR; similarity-based tools such as NCBI and Stanford; and phylogenetic-based tools such as REGA version 2 (REGAv2), REGAv3, and SCUEAL. The performance of these tools, for pol, and for PR and RT separately, was compared in terms of reproducibility, sensitivity and specificity with respect to the gold standard which was manual phylogenetic analysis of the pol region.

RESULTS

The sensitivity and specificity for subtypes B and C was more than 96% for seven tools, but was variable for other subtypes such as A, D, F and G. With regard to the most common circulating recombinant forms (CRFs), the sensitivity and specificity for CRF01_AE was ~99% with statistical-based tools, with phylogenetic-based tools and with Stanford, one of the similarity based tools. CRF02_AG was correctly identified for more than 96% by COMET, REGAv3, Stanford and STAR. All the tools reached a specificity of more than 97% for most of the subtypes and the two main CRFs (CRF01_AE and CRF02_AG). Other CRFs were identified only by COMET, REGAv2, REGAv3, and SCUEAL and with variable sensitivity. When analyzing sequences for PR and RT separately, the performance for PR was generally lower and variable between the tools. Similarity and statistical-based tools were 100% reproducible, but this was lower for phylogenetic-based tools such as REGA (~99%) and SCUEAL (~96%).

CONCLUSIONS

REGAv3 had an improved performance for subtype B and CRF02_AG compared to REGAv2 and is now able to also identify all epidemiologically relevant CRFs. In general the best performing tools, in alphabetical order, were COMET, jpHMM, REGAv3, and SCUEAL when analyzing pure subtypes in the pol region, and COMET and REGAv3 when analyzing most of the CRFs. Based on this study, we recommend to confirm subtyping with 2 well performing tools, and be cautious with the interpretation of short sequences.

Large volume, low pressure endotracheal tube cuffs are claimed to have less deleterious effect on tracheal mucosa than high pressure, low volume cuffs. Low pressure cuffs, however, may easily be overinflated to yield pressures that will exceed capillary perfusion pressure. Various large volume cuffed endotracheal tubes were studied, including Portex Profile, Searle Sensiv, Mallinkrodt Hi-Lo, and Lanz. Tracheal mucosal blood flow in 40 patients undergoing surgery was assessed using an endoscopic photographic technique while varying the cuff inflation pressure. It was found that these cuffs when overpressurised impaired mucosal blood flow. This impairment of tracheal mucosal blood flow is an important factor in tracheal morbidity associated with intubation. Hence it is recommended that a cuff inflation pressure of 30 cm H2O (22 mm Hg) should not be exceeded.

In mammalian cells, eicosanoid biosynthesis is usually initiated by the activation of phospholipase A2 and the release of arachidonic acid (AA) from membrane phospholipids. The AA is subsequently transformed by cyclooxygenase (COX) and lipoxygenase (LO) pathways to prostaglandins, thromboxane and leukotrienes collectively termed eicosanoids. Eicosanoid production is considerably increased during inflammation. Both COX and LO pathways are of particular clinical relevance. The COX pathway is the major target for non-steroidal anti-inflammatory drugs (NSAIDs), the most popular medications used to treat pain, fever and inflammation. Although their anti-inflammatory effects are well known, their long-term use is associated with gastrointestinal (GI) complications such as ulceration. In 1991, it was discovered that COX exists in two distinct isozymes, COX-1 and COX-2, of which COX-2 is primarily expressed at sites of inflammation and produces pro-inflammatory eicosanoids. For this reason, COX-2 selective inhibitors (COXIBs) have been developed recently as anti-inflammatory agents to minimize the risk of GI toxicity. Recently, some COX-2 selective inhibitors have shown adverse cardiovascular side effects, resulting in the withdrawal of rofecoxib and valdecoxib from the market. Selective inhibition of COX-2 without reducing COX-1-mediated thromboxane production could alter the balance between prostacyclin and thromboxane and promote a prothrombotic state, thereby explaining the observed COX-2 cardiovascular risk. In this review, we describe mechanisms for the production of pro-inflammatory eicosanoid mediators contributing to inflammation and summarize promising options for the prevention of inflammatory mediator formation and the therapeutic inhibition of pain and inflammation.

Several inflammatory diseases, including asthma, arthritis and psoriasis are associated with the production of leukotrienes by neutrophils, mast cells and macrophages. The initial enzymatic step in the formation of leukotrienes is the oxidation of arachidonic acid by 5-lipoxygenase (5-LO) to leukotriene A4. Osteosarcoma cells transfected with 5-LO express active enzyme in broken cell preparations, but no leukotriene metabolites are produced by these cells when stimulated with the calcium ionophore A23187, indicating that an additional component is necessary for cellular 5-LO activity. A new class of indole leukotriene inhibitor has been described that inhibits the formation of cellular leukotrienes but has no direct inhibitory effect on soluble 5-LO activity. We have now used these potent agents to identify and isolate a novel membrane protein of relative molecular mass 18,000 which is necessary for cellular leukotriene synthesis.

BACKGROUND

Mechanisms involving oxidative stress and inflammation have been proposed to explain associations of ambient air pollution with cardiovascular morbidity and mortality. Experimental evidence suggests that organic components and ultrafine particles (UFP) are important.

METHODS

We conducted a panel study of 60 elderly subjects with coronary artery disease living in retirement communities within the Los Angeles, California, air basin. Weekly biomarkers of inflammation included plasma interleukin-6, tumor necrosis factor-alpha soluble receptor II (sTNF-RII), soluble platelet selectin (sP-selectin), and C-reactive protein (CRP). Biomarkers of erythrocyte antioxidant activity included glutathione peroxidase-1 and superoxide dismutase. Exposures included outdoor home daily particle mass [particulate matter < 0.25, 0.25-2.5, and 2.5-10 microm in aerodynamic diameter (PM(0.25), PM(0.25-2.5), PM(2.5-10))], and hourly elemental and black carbon (EC-BC), estimated primary and secondary organic carbon (OC(pri), SOC), particle number (PN), carbon monoxide (CO), and nitrogen oxides-nitrogen dioxide (NO(x)-NO(2)). We analyzed the relation of biomarkers to exposures with mixed effects models adjusted for potential confounders.

RESULTS

Primary combustion markers (EC-BC, OC(pri), CO, NO(x)-NO(2)), but not SOC, were positively associated with inflammatory biomarkers and inversely associated with erythrocyte anti-oxidant enzymes (n = 578). PN and PM(0.25) were more strongly associated with biomarkers than PM(0.25-2.5). Associations for all exposures were stronger during cooler periods when only OC(pri), PN, and NO(x) were higher. We found weaker associations with statin (sTNF-RII, CRP) and clopidogrel use (sP-selectin).

CONCLUSIONS

Traffic-related air pollutants are associated with increased systemic inflammation, increased platelet activation, and decreased erythrocyte antioxidant enzyme activity, which may be partly behind air pollutant-related increases in systemic inflammation. Differences in association by particle size, OC fraction, and seasonal period suggest components carried by UFP are important.

OBJECTIVE

Angiotensin II (ANG II)-induced inflammatory and oxidative stress responses contribute to the pathogenesis of hypertension. In this study, we determined whether nuclear factor-kappa B (NF-kappaB) activation in the hypothalamic paraventricular nucleus (PVN) increases oxidative stress and contributes to the ANG II-induced hypertensive response.

RESULTS

Rats were infused intravenously with ANG II (10 ng/kg per min) or saline for 4 weeks. These rats received either vehicle or losartan (LOS, 20 microg/h), an angiotensin II type 1 receptor (AT1-R) antagonist; pyrrolidine dithiocarbamate (PDTC, 5 microg/h), a NF-kappaB inhibitor; tempol (TEMP, 80 microg/h), a superoxide scavenger; LOS (20 microg/h), and PDTC (5 microg/h); or TEMP (80 microg/h) and PDTC (5 microg/h), given intracerebroventricularly (ICV) via osmotic minipump. ANG II infusion resulted in increased mean arterial pressure, renal sympathetic nerve activity, plasma proinflammatory cytokines (PIC), norepinephrine, and aldosterone. These rats also had higher levels of Fra-LI (an indicator of chronic neuronal activation), PIC, phosphorylated IKKbeta, NF-kappaB subunits, AT1-R, superoxide, and gp91phox (a subunit of NADP(H) oxidase) and lower levels of IkappaBalpha in the PVN than control animals. ICV treatment with LOS, PDTC, or TEMP attenuated these changes, and combined treatment with ICV LOS and PDTC, or ICV TEMP and PDTC prevented these ANG II-induced hypertensive responses.

CONCLUSIONS

These findings suggest that an ANG II-induced increase in the brain renin-angiotensin system activates NF-kappaB in the PVN and contributes to sympathoexcitation in hypertension. The increased superoxide in the PVN contributes to NF-kappaB activation and neurohumoral excitation in hypertension.

Human natural killer (NK) cells can be divided into two phenotypically distinct functional subsets based on their cell surface expression of CD56 (CD56(bright) and CD56(dim)). As mouse NK cells do not express CD56, comparable mouse NK cell subsets have proven difficult to identify. Recently, we have found that mouse NK cells can be subdivided by the expression of CD27. The CD27(hi) and CD27(lo) mouse NK cell subsets show some intriguing similarities to but also some distinct differences from the human CD56 NK cell subsets in terms of their function and phenotype. Extending our knowledge of mature NK cell heterogeneity between the species will be critical to further our understanding of the pathological role of NK cells in immune responses.

OBJECTIVE

Interventions based on behavioral science might reduce inappropriate antibiotic prescribing.

OBJECTIVE

To assess effects of behavioral interventions and rates of inappropriate (not guideline-concordant) antibiotic prescribing during ambulatory visits for acute respiratory tract infections.

METHODS

Cluster randomized clinical trial conducted among 47 primary care practices in Boston and Los Angeles. Participants were 248 enrolled clinicians randomized to receive 0, 1, 2, or 3 interventions for 18 months. All clinicians received education on antibiotic prescribing guidelines on enrollment. Interventions began between November 1, 2011, and October 1, 2012. Follow-up for the latest-starting sites ended on April 1, 2014. Adult patients with comorbidities and concomitant infections were excluded.

METHODS

Three behavioral interventions, implemented alone or in combination: suggested alternatives presented electronic order sets suggesting nonantibiotic treatments; accountable justification prompted clinicians to enter free-text justifications for prescribing antibiotics into patients' electronic health records; peer comparison sent emails to clinicians that compared their antibiotic prescribing rates with those of "top performers" (those with the lowest inappropriate prescribing rates).

METHODS

Antibiotic prescribing rates for visits with antibiotic-inappropriate diagnoses (nonspecific upper respiratory tract infections, acute bronchitis, and influenza) from 18 months preintervention to 18 months afterward, adjusting each intervention's effects for co-occurring interventions and preintervention trends, with random effects for practices and clinicians.

RESULTS

There were 14,753 visits (mean patient age, 47 years; 69% women) for antibiotic-inappropriate acute respiratory tract infections during the baseline period and 16,959 visits (mean patient age, 48 years; 67% women) during the intervention period. Mean antibiotic prescribing rates decreased from 24.1% at intervention start to 13.1% at intervention month 18 (absolute difference, -11.0%) for control practices; from 22.1% to 6.1% (absolute difference, -16.0%) for suggested alternatives (difference in differences, -5.0% [95% CI, -7.8% to 0.1%]; P = .66 for differences in trajectories); from 23.2% to 5.2% (absolute difference, -18.1%) for accountable justification (difference in differences, -7.0% [95% CI, -9.1% to -2.9%]; P < .001); and from 19.9% to 3.7% (absolute difference, -16.3%) for peer comparison (difference in differences, -5.2% [95% CI, -6.9% to -1.6%]; P < .001). There were no statistically significant interactions (neither synergy nor interference) between interventions.

CONCLUSIONS

Among primary care practices, the use of accountable justification and peer comparison as behavioral interventions resulted in lower rates of inappropriate antibiotic prescribing for acute respiratory tract infections.

BACKGROUND

clinicaltrials.gov Identifier: NCT01454947.

OBJECTIVE

We hypothesized that oral estrogen replacement therapy would be less common among elderly women meeting criteria for Alzheimer's disease (AD) than among nondemented elderly women. For women with AD, we hypothesized that estrogen users would perform better on a cognitive task than would nonusers.

METHODS

A case-control study of estrogen replacement therapy, in which hierarchical procedures were used to control for potentially confounding effects of age and education. When cognitive performances were compared between estrogen users and nonusers with AD, the duration of dementia symptoms was an additional control variable.

METHODS

Alzheimer's Disease Research Center at the University of Southern California, Los Angeles.

METHODS

Subjects were a volunteer sample of consecutively enrolled elderly women, recruited primarily from the community, who met clinical criteria for probable AD (n = 143) or met criteria for nondemented control status (n = 92). Seventy case patients who have subsequently died met histopathologic criteria for AD; one other demented woman who did not meet the autopsy criteria for AD was excluded from all analyses.

METHODS

Current use of estrogen replacement at the time of enrollment as reported by control subjects or by the primary caregivers of AD case patients. Among cases, performances on a brief cognitive screening instrument were compared between estrogen users (n = 10) and nonusers (n = 128) for whom this information was available.

RESULTS

Alzheimer's disease case patients were significantly less likely than control subjects to use estrogen replacement (7% vs 18%), but groups did not differ with regard to the total number of prescription medications or to the most frequently prescribed class of drug (thyroid medication). Demented case patients using estrogen did not differ significantly from those not using estrogen in terms of age, education, or symptom duration, but their mean performance on a cognitive screening instrument was significantly better (Mini-Mental State examination scores of 14.9 vs 6.5).

CONCLUSIONS

Findings are consistent with contentions that postmenopausal estrogen replacement therapy may be associated with a decreased risk of AD and that estrogen replacement may improve cognitive performance of women with this illness.

Recent findings on the clinical, electroencephalography (EEG), neuroimaging, and surgical outcomes are reviewed comparing patients with Palmini type I (mild) and type II (severe) cortical dysplasia. Resources include peer-reviewed studies on surgically treated patients and a subanalysis of the 2004 International League Against Epilepsy (ILAE) Survey of Pediatric Epilepsy Surgery. These sources were supplemented with data from University of California, Los Angeles (UCLA). Cortical dysplasia is the most frequent histopathologic substrate in children, and the second most common etiology in adult epilepsy surgery patients. Cortical dysplasia patients present with seizures at an earlier age than other surgically treated etiologies, and 33-50% have nonlocalized scalp EEG and normal magnetic resonance imaging (MRI) scans. 2-((18)F)Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is positive in 75-90% of cases. After complete resection, 80% of patients are seizure free compared with 20% with incomplete resections. Compared with type I, patients with type II cortical dysplasia present at younger ages, have higher seizure frequencies, and are extratemporal. Type I dysplasia is found more often in adult patients in the temporal lobe and is often MRI negative. These findings identify characteristics of patients with mild and severe cortical dysplasia that define surgically treated epilepsy syndromes. The authors discuss future challenges to identifying and treating medically refractory epilepsy patients with cortical dysplasia.

BACKGROUND

The present study addresses diffusion of a psychosocial-based substance abuse prevention program, including: (a) teacher adoption, implementation, and maintenance; (b) teacher characteristics associated with implementation; (c) the relationship between integrity of program delivery and program outcomes; and (d) the effectiveness of teacher training and school principal involvement in increasing implementation.

METHODS

Participants were teachers (n = 60), school principals (n = 25), and fifth-grade students (n = 1147) from four Los Angeles area school districts. Districts were randomly assigned to an intensive or brief teacher training condition. Schools were randomly assigned to a principal-intervention or a no-principal-intervention condition. Assessments included teacher and principal self-reports, classroom observations of program delivery, and evaluation of immediate program outcomes.

RESULTS

During the first year, 78% of trained teachers implemented one or more program lessons. During the second year, only 25% maintained implementation of the program. Implementors reported fewer years of teaching experience and stronger self-efficacy, enthusiasm, preparedness, teaching methods compatibility, and principal encouragement than did nonimplementors. The principal intervention increased rates of implementation, but the intensive teacher training did not. Integrity of program delivery was positively associated with immediate program outcomes.

CONCLUSIONS

Program implementation was highly variable, suggesting that widespread teacher use of psychosocial-based programs cannot be taken for granted. Strategies for increasing implementation and maintenance need to be developed.

The extent to which primary visual cues such as motion or luminance are segregated in different cortical areas is a subject of controversy. To address this issue, we examined cortical activation in the human occipital lobe using functional magnetic resonance imaging (fMRI) while subjects performed a fixed visual task, object recognition, using three different primary visual cues: motion, texture, or luminance contrast. In the first experiment, a region located on the lateral aspect of the occipital lobe (LO complex) was preferentially activated in all 11 subjects both by luminance and motion-defined object silhouettes compared to full-field moving and stationary noise (ratios, 2.00+/-0.19 and 1.86+/-0.65, respectively). In the second experiment, all subjects showed enhanced activation in the LO complex to objects defined both by luminance and texture contrast compared to full-field texture patterns (ratios, 1.43+/-0.08 and 1.32+/-0.08, respectively). An additional smaller dorsal focus that exhibited convergence of object-related cues appeared to correspond to area V3a or a region slightly anterior to it. These results show convergence of visual cues in LO and provide strong evidence for its role in object processing.