HMGB1 acts as an agent of host defense at the gut mucosal barrier.

Mucosal barriers provide the first line of defense between internal body surfaces and microbial threats from the outside world. 1 In the colon, the barrier consists of two layers of mucus and a single layer of tightly interconnected epithelial cells supported by connective tissue and immune cells. 2 Microbes colonize the loose, outer layer of colonic mucus, but are essentially excluded from the tight, epithelial-associated layer by host defenses. 3 The amount and composition of the mucus is calibrated based on microbial signals and loss of even a single component of this mixture can destabilize microbial biogeography and increase the risk of disease. 4-7 However, the specific components of mucus, their molecular microbial targets, and how they work to contain the gut microbiota are still largely unknown. Here we show that high mobility group box 1 (HMGB1), the prototypical damage-associated molecular pattern molecule (DAMP), acts as an agent of host mucosal defense in the colon. HMGB1 in colonic mucus targets an evolutionarily conserved amino acid sequence found in bacterial adhesins, including the well-characterized Enterobacteriaceae adhesin FimH. HMGB1 aggregates bacteria and blocks adhesin-carbohydrate interactions, inhibiting invasion through colonic mucus and adhesion to host cells. Exposure to HMGB1 also suppresses bacterial expression of FimH. In ulcerative colitis, HMGB1 mucosal defense is compromised, leading to tissue-adherent bacteria expressing FimH. Our results demonstrate a new, physiologic role for extracellular HMGB1 that refines its functions as a DAMP to include direct, virulence limiting effects on bacteria. The amino acid sequence targeted by HMGB1 appears to be broadly utilized by bacterial adhesins, critical for virulence, and differentially expressed by bacteria in commensal versus pathogenic states. These characteristics suggest that this amino acid sequence is a novel microbial virulence determinant and could be used to develop new approaches to diagnosis and treatment of bacterial disease that precisely identify and target virulent microbes.

The role of hippocampal estradiol in synaptic plasticity and memory: A systematic review.

The consolidation of long-term memory is influenced by various neuromodulators. One of these is estradiol, a steroid hormone that is synthesized both in peripheral endocrine tissue and in the brain, including the hippocampus. Here, we examine the evidence regarding the role of estradiol in the hippocampus, specifically, in memory formation and its effects on the molecular mechanisms underlying synaptic plasticity. We conclude that estradiol improves memory consolidation and, thereby, long-term memory. Previous studies have shown that it does this in three, interconnected ways: (1) via functional changes in excitatory activity, (2) signaling changes in calcium dynamics, protein phosphorylation and protein expression, and (3) structural changes to synaptic morphology. Through a functional network analysis of proteins affected by estradiol, we identify potential protein-protein interactions that further support a role for estradiol in modulating synaptic plasticity as well as highlight signaling pathways that may be involved in these changes within the hippocampus.

The effect of standard laboratory diets on estrogen signaling and spatial memory in male and female rats.

Phytoestrogens are plant-derived compounds that can modulate estrogen activity in the brain and periphery. Laboratory rodent diets are typically high in soy-based phytoestrogens and therefore may influence neurophysiological and behavioural measures that are sensitive to estrogen signaling. Here we assessed such measures in rats (males and females) fed Australian made diets that varied in their soy levels. We found that a low-soy diet promoted greater weight, and lower levels of plasma estradiol, particularly in male rats. It also produced sex-specific effects on estrogen receptor gene expression in the brain, increasing ESR2 expression in the hippocampus and prefrontal cortex in female rats, and decreasing dopamine D1 receptor gene expression in the striatum of both male and female rats. We also found a dietary effect on short-term place recognition memory, but this was independent of soy levels in the diet. These results demonstrate that the choice of rodent laboratory diet can influence physiology, neurobiology and behavior, particularly on measures related to estrogen signaling.

Cognitive ability, social desirability, body mass index and socioeconomic status as correlates of fourth-grade children's dietary-reporting accuracy.

BACKGROUND/OBJECTIVES: To investigate the relationship of reporting accuracy in 24-h dietary recalls to child-respondent characteristics-cognitive ability, social desirability, body mass index (BMI) percentile and socioeconomic status (SES). SUBJECTS/METHODS: Fourth-grade children (mean age 10.1 years) were observed eating two school meals and interviewed about dietary intake for 24 h that included those meals. (Eight multiple-pass interview protocols operationalized the conditions of an experiment that crossed two retention intervals-short and long-with four prompts (ways of eliciting reports in the first pass)). Academic achievement-test scores indexed cognitive ability; social desirability was assessed by questionnaire; height and weight were measured to calculate BMI; nutrition-assistance program eligibility information was obtained to index SES. Reported intake was compared to observed intake to calculate measures of reporting accuracy for school meals at the food-item (omission rate; intrusion rate) and energy (correspondence rate; inflation ratio) levels. Complete data were available for 425 of 480 validation-study participants. RESULTS: Controlling for manipulated variables and other measured respondent characteristics, for one or more of the outcome variables, reporting accuracy increased with cognitive ability (omission rate, intrusion rate, correspondence rate, P<0.001), decreased with social desirability (correspondence rate, P<0.0004), decreased with BMI percentile (correspondence rate, P=0.001) and was better by higher- than by lower-SES children (intrusion rate, P=0.001). Some of these effects were moderated by interactions with retention interval and sex. CONCLUSIONS: Children's dietary-reporting accuracy is systematically related to such respondent characteristics as cognitive ability, social desirability, BMI percentile and SES.

Characterizing dilute combustion instabilities in a multi-cylinder spark-ignited engine using symbolic analysis.

Spark-ignited internal combustion engines have evolved considerably in recent years in response to increasingly stringent regulations for emissions and fuel economy. One new advanced engine strategy ustilizes high levels of exhaust gas recirculation (EGR) to reduce combustion temperatures, thereby increasing thermodynamic efficiency and reducing nitrogen oxide emissions. While this strategy can be highly effective, it also poses major control and design challenges due to the large combustion oscillations that develop at sufficiently high EGR levels. Previous research has documented that combustion instabilities can propagate between successive engine cycles in individual cylinders via self-generated feedback of reactive species and thermal energy in the retained residual exhaust gases. In this work, we use symbolic analysis to characterize multi-cylinder combustion oscillations in an experimental engine operating with external EGR. At low levels of EGR, intra-cylinder oscillations are clearly visible and appear to be associated with brief, intermittent coupling among cylinders. As EGR is increased further, a point is reached where all four cylinders lock almost completely in phase and alternate simultaneously between two distinct bi-stable combustion states. From a practical perspective, it is important to understand the causes of this phenomenon and develop diagnostics that might be applied to ameliorate its effects. We demonstrate here that two approaches for symbolizing the engine combustion measurements can provide useful probes for characterizing these instabilities.

Urban/rural residence moderates effect of race on receipt of surgery in patients with nonmetastatic breast cancer: a report from the South Carolina central cancer registry.

BACKGROUND: Surgical resection is the cornerstone of therapy in patients with nonmetastatic breast cancer. Previous studies have reported underuse of adjuvant therapy among African Americans (AA). This study explores the independent effect of race on surgical resection in a recent, population-based sample of breast cancer patients. METHODS: All cases of nonmetastatic breast cancer reported to the our state Cancer Registry between 1996 and 2002 were identified and linked to the state Inpatient/Outpatient Surgery Files and the 2000 Census. Characteristics between Caucasian and AA patients were compared using Student's t and chi-square tests. Odds ratios (OR) of resection and 95% confidence intervals (CI) were calculated using logistic regression. RESULTS: We identified 12,404 Caucasian and 3,411 AA women. AA patients were more likely to be younger, non-married, have greater comorbidity, reside in rural communities, be less educated, live in poverty, and be uninsured or covered by Medicaid (all P < 0.0001). AA patients were slightly less likely to undergo resection compared to Caucasian patients (94.9% versus 96.4%, P < 0.0001). An interaction effect between race and urban/rural patient residence was observed (P = 0.003). After controlling for other factors, the adjusted OR for resection for urban AA patients was 0.58 (95% CI 0.41-0.82). In contrast, race had no effect on resection among rural patients (OR = 1.02; 95% CI 0.70-1.47). CONCLUSIONS: AA race is an independent predictor of underuse of surgery among urban patients with breast cancer, while rural residence is associated with underuse of surgery, irrespective of race. Interventions designed to optimize surgical cancer care should target these vulnerable populations.

Optical measurement of isolated canine lung filtration coefficients after alloxan infusion.

In this study, lung filtration coefficient (Kfc) was measured in eight isolated canine lung preparations by using three methods: standard gravimetric (Std), blood-corrected gravimetric (BC), and optical. The lungs were held in zone III conditions and were subjected to an average venous pressure increase of 8.79 +/- 0.93 (mean +/- SD) cmH2O. The permeability of the lungs was increased with an infusion of alloxan (75 mg/kg). The resulting Kfc values (in milliliters . min-1 . cmH2O-1 . 100 g dry lung weight-1) measured by using Std and BC gravimetric techniques before vs. after alloxan infusion were statistically different: Std, 0.527 +/- 0.290 vs. 1. 966 +/- 0.283; BC, 0.313 +/- 0.290 vs. 1.384 +/- 0.290. However, the optical technique did not show any statistical difference between pre- and postinjury with alloxan, 0.280 +/- 0.305 vs. 0.483 +/- 0. 297, respectively. The alloxan injury, quantified by using multiple-indicator techniques, showed an increase in permeability and a corresponding decrease in reflection coefficient for albumin (sigmaf). Because the optical method measures the product of Kfc and sigmaf, this study shows that albumin should not be used as an intravascular optical filtration marker when permeability is elevated. However, the optical technique, along with another means of measuring Kfc (such as BC), can be used to calculate the sigmaf of a tracer (in this study, sigmaf of 0.894 at baseline and 0.348 after injury). Another important finding of this study was that the ratio of baseline-to-injury Kfc values was not statistically different for Std and BC techniques, indicating that the percent contribution of slow blood-volume increases does not change because of injury.

Optical measurement of isolated canine lung filtration coefficients at normal hematocrits.

In this study, lung filtration coefficient (Kfc) values were measured in eight isolated canine lung preparations at normal hematocrit values using three methods: gravimetric, blood-corrected gravimetric, and optical. The lungs were kept in zone 3 conditions and subjected to an average venous pressure increase of 10.24 +/- 0.27 (SE) cmH2O. The resulting Kfc (ml . min-1 . cmH2O-1 . 100 g dry lung wt-1) measured with the gravimetric technique was 0.420 +/- 0.017, which was statistically different from the Kfc measured by the blood-corrected gravimetric method (0.273 +/- 0.018) or the product of the reflection coefficient (sigmaf) and Kfc measured optically (0. 272 +/- 0.018). The optical method involved the use of a Cellco filter cartridge to separate red blood cells from plasma, which allowed measurement of the concentration of the tracer in plasma at normal hematocrits (34 +/- 1.5). The permeability-surface area product was measured using radioactive multiple indicator-dilution methods before, during, and after venous pressure elevations. Results showed that the surface area of the lung did not change significantly during the measurement of Kfc. These studies suggest that sigmafKfc can be measured optically at normal hematocrits, that this measurement is not influenced by blood volume changes that occur during the measurement, and that the optical sigmafKfc agrees with the Kfc obtained via the blood-corrected gravimetric method.

The effect of fasting status on the determination of low-density and high-density lipoprotein cholesterol.

PURPOSE: To determine the effect of a self-selected meal on concentrations of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in a screening setting and to determine the effect of using nonfasting values to classify individuals according to National Cholesterol Education Program guidelines. SUBJECTS AND METHODS: Study subjects were 115 employees who had previously participated in worksite total cholesterol screening, selected by stratified random sampling for sex and total cholesterol levels. Total cholesterol, triglycerides, HDL-C, and estimated LDL-C were determined before subjects ate a self-selected breakfast and 3 and 5 hours after eating it. RESULTS: LDL-C values determined 3 and 5 hours following breakfast were approximately 7% and 2.5% lower, respectively, than fasting values. Use of 3-hour and 5-hour LDL-C determinations to classify individuals with elevated fasting levels (> or = 3.36 mmol/L) resulted in false-negative rates of 20% and 14%, respectively. Three- and 5-hour HDL-C values were approximately 4% and 1.5% lower, respectively, than fasting levels. Use of 3-hour HDL-C values to classify individuals with low fasting levels (< 0.91 mmol/L) resulted in no false-negatives, whereas 1 of 7 individuals with low fasting HDL-C was misclassified when 5-hour values were used. CONCLUSIONS: These results support the 1993 National Cholesterol Education Program guidelines that LDL-C levels should be determined only in fasting persons, and that nonfasting HDL-C values may be acceptable for screening purposes.

An evaluation of the efficacy of postoperative blood salvage after total joint arthroplasty. A prospective randomized trial.

The efficacy of a postoperative blood salvage system was assessed in 239 consecutive patients undergoing total knee or total hip arthroplasty. Patients were randomly allocated to either a control group using a standard drainage system or to the study group using the Solcotrans blood salvage canister. The median amount of homologous blood required after operation by the study group was reduced by 74% from the amount required by the control group (mean, 67 ml vs 256 ml, respectively; P less than .0001). Thirteen percent (13%) of the study group required postoperative homologous blood transfusions, as compared to 39% of the control group (P less than .0001). Additionally, patients in the study group had higher hemoglobin levels beginning on the first postoperative day. This study indicates that a postoperative blood salvage system safely and effectively reduces the amount of homologous blood required and sustains higher hemoglobin levels after operation.

Lipoprotein-cholesterol analysis during screening: accuracy and reliability.

OBJECTIVE: To evaluate the accuracy and reliability of lipoprotein-cholesterol measurements obtained during screening. DESIGN: Cross-sectional study. PARTICIPANTS: From November 1989 to January 1990, 154 adults were screened. MEASUREMENTS: Split venous samples from fasting participants were analyzed for total cholesterol, triglyceride, and high-density-lipoprotein (HDL) cholesterol with screening and standardized laboratory methods. Low-density-lipoprotein (LDL)-cholesterol levels were calculated using the Friedewald equation. Split venous samples from nonfasting participants were analyzed for total cholesterol. Capillary blood samples were analyzed for total cholesterol with the screening method. MAIN RESULTS: Total cholesterol measurements in screening venous blood samples were 5.4% and 3.8% lower than the laboratory values in samples from fasting and nonfasting participants, respectively. Triglyceride and HDL-cholesterol values in venous samples obtained from fasting participants were, on average, 9.8% and 11.2% lower than the respective laboratory measurements. Screening HDL-cholesterol values varied, differing from the laboratory values by as much as 40% in 95% of participants. In fasting participants, total cholesterol in capillary samples averaged 5.5% higher than in venous samples; in nonfasting participants the capillary samples were 3.1% higher. Screening for either total cholesterol or LDL cholesterol identified 93% of the persons with LDL-cholesterol values of 3.36 mmol/L (130 mg/dL) or higher. CONCLUSIONS: Total cholesterol can be reliably measured in samples from fasting or nonfasting persons. The values in capillary blood samples were slightly higher than those in venous samples. Screening HDL-cholesterol values were too variable to establish the HDL-cholesterol level reliably. Participants with high LDL-cholesterol levels were identified as accurately by measuring total cholesterol only when compared with calculating the LDL-cholesterol level from total cholesterol, triglyceride, and HDL-cholesterol concentrations.

The yield of cholesterol screening in an urban black community.

BACKGROUND: While the distribution of cholesterol levels have been well studied in the general population, little is known about cholesterol and other cardiovascular disease risk factors in screenings held in an urban Black community. This study was designed to determine the yield of cholesterol screening in this community. METHODS: Screening took place in eight community sites. Serum total cholesterol was measured using a rapid capillary technique. Blood pressure was taken according to national guidelines and the average of two to three measurements were used. Standard interviews were used to determine the presence of cardiovascular risk factors by history. RESULTS: Of the 562 individuals screened, 44.9 percent had cholesterol levels requiring referral for follow-up care. Of those with total cholesterol greater than or equal to 6.21 mmol/L, 66.4 percent were previously undetected and more than half also had blood pressure levels greater than or equal to 140/90 mmHg on screening; 45 percent of all participants had blood pressure greater than or equal to 140/90 on screenings. Of those with a history of elevated total cholesterol levels, none had levels below 5.17 mmol/L at the time of screening. CONCLUSIONS: Multiple risk factors are highly prevalent in the urban Black community during cholesterol screening programs. Findings suggest the need for cholesterol programs incorporating blood pressure screening in the urban Black community.

Measurement issues in cholesterol screening: an overview for nurses.

The detection of elevated cholesterol levels in more than 60% of adults in the United States has prompted widespread mass cholesterol screening to identify this modifiable risk factor for coronary disease. As nurses begin to assume more responsibility for these screenings, additional training in this area may be warranted. National screening guidelines are reviewed in reference to measurement issues, including potential sources of variation in cholesterol measurement, precision and accuracy testing, and the importance of rigorous quality control measures and staff training programs, all of which ensure the standardization of cholesterol measurements. The role of nurses in cholesterol screening is presented.

Reevaluation of serum-plasma differences in total cholesterol concentration.

We measured total cholesterol levels in serum and disodium ethylenediaminetetraacetate (EDTA) plasma samples obtained from 84 healthy medical students during their entrance physical examinations and 48 adults from a cholesterol screening program who were resampled because they had initial values of 5.17 mmol/L (200 mg/dL) or higher. Plasma cholesterol concentrations were 4.7% lower than those in serum samples. The plasma and serum values were highly correlated (r = .994), however, suggesting that measurements in EDTA plasma can be converted readily to equivalent serum concentrations. Thus, the negative bias in EDTA plasma was greater than the 3% value cited in the National Cholesterol Education Program Guidelines, probably because the amount of EDTA now provided in evacuated blood collection tubes is 50% greater than in those used when the 3% value was established. These findings are relevant to the interpretation of both cholesterol screening measurements and follow-up lipoprotein analyses.