Individuals with filaggrin-related eczema and asthma have increased long-term medication and hospital admission costs.

BACKGROUND: Eczema and asthma are chronic diseases with onset usually before the age of 5 years. More than 50% of individuals with eczema will develop asthma and/or other allergic diseases. Several loss-of-function mutations in filaggrin (FLG) have been identified in patients with eczema. However, the association of FLG with healthcare use is unknown. OBJECTIVES: To determine whether FLG mutations are associated with increased prescribing for eczema and asthma and whether increased prescribing is associated with increased healthcare costs. METHODS: A secondary analysis of BREATHE, a cross-sectional study of gene-environment associations with asthma severity, was undertaken. BREATHE data was collected for 1100 participants with asthma, in Tayside and Fife, Scotland during the period 2003-2005. Through collaboration with the Health Informatics Centre in Dundee, BREATHE was linked to accident and emergency, community prescribing and Scottish morbidity records. The data linkage allowed longitudinal exploration of associations between genetic variation and prescribing. RESULTS: An association was found between FLG mutations and increased prescribing for mild and moderate eczema, asthma-reliever medicine and asthma exacerbations. A strong association was found between FLG mutations and prescribing of emollients [incidence rate ratio (IRR) 2·19, 95% confidence interval (CI) 1·36-3·52], treatment for severe eczema (IRR 2·18, 95% CI 1·22-3·91) and a combination of a long-acting ß2 -agonist and corticosteroids (IRR 3·29, 95% CI 1·68-6·43). CONCLUSIONS: The presence of FLG mutations in this cohort is associated with increased prescribing for eczema and asthma. Randomized controlled trials are required to determine if these individuals could benefit from management strategies to reduce morbidity and treatment costs.

Six-minute walk test in healthy British service personnel.

INTRODUCTION: The 6 min walk test (6MWT) is a widely used, safe and effective submaximal exercise test. The primary outcome is the distance walked, but additional physiological and patient-reported metrics can be recorded. It is used to assess function and is commonly used within UK Defence Rehabilitation. However, there are no published British military 6MWT data in a non-injured population. This study reports the 6MWT procedure and results from healthy British service personnel. METHODS: A convenience sample of 46 individuals (male n=40) undertook 95 6MWTs over three study visits throughout a year. They were performed on a 20 m straight-line route, administered by an exercise rehabilitation instructor and preceded by anthropometric measurements (height, weight). Physiological measures (HR, oxygen saturations (SpO2)) and patient-reported measures (Borg shortness of breath (SoB), rate of perceived exertion (RPE) and fatigue) were taken before and after the assessment. Statistical tests were performed between pre-test and post-test measures, and sex and body mass, and concurrent cardiopulmonary exercise tests (CPET) with 6MWT distance. RESULTS: The mean 6MWT distance was 705.5±86 m; males 709.4±86.9 m and females 685.9±81.9 m (p=0.32), with a median Borg SoB of 1 (IQR: 0-2) and RPE 9 (IQR: 7-11), and a negative correlation between body mass index and 6MWT distance, p=0.007. There were no significant differences between pre-test and post-test measures. Peak workload and VO2 Max correlated weakly with 6MWT distance (0.336, p=0.01 and 0.375, p=0.09, respectively), but submaximal CPET measures did not. CONCLUSION: These results provide a benchmark for British military 6MWT data to guide clinical and research use. However, a larger dataset is required for validation and normative values.

Organizational Leaders Perceptions of Barriers to Accessing Behavioral Health Services in a Low-Resource Community.

Little is known about how to effectively implement behavioral health programs in low-resource communities. Leaders from 20 community-serving behavioral health organizations in Flint, MI, were asked about their organizations and the barriers that they, and the populations they serve, face in providing and accessing behavioral health services. Barriers are reported using a mixed-methods analysis, reporting the number and percentage of organizations that experienced the barrier along with example quotations from the organization leaders. The most frequently reported barrier to providing services was finding adequate funding (50%) while the most frequently reported barrier for accessing services was finding adequate and reliable transportation (30%). Comparisons of these findings with barriers reported by providers in different settings and those seeking services are discussed. These comparisons may provide an important next step in identifying areas where providers perceptions and the needs of the population are misaligned and for systemic improvements more broadly.

Implantation of Bacteroides gingivalis in nonhuman primates initiates progression of periodontitis.

Although periodontitis is a bacterial disease, its multidimensional nature and its bacterial complexity have made it difficult to definitively prove that specific microorganisms initiate the disease process. The successful implantation of a rifampin-resistant strain of the putative periodontal pathogen Bacteroides gingivalis into the periodontal microbiota of monkeys (Macaca fascicularis) resulted in an increase in the systemic levels of antibody to the microorganism and rapid and significant bone loss.

Serum, uterine, and vaginal mucosal IgG antibody responses against Tritrichomonas foetus after administration of a commercial killed whole T foetus vaccine in beef cows.

The objective of this study was to determine the level and duration of IgG antibodies induced against killed whole Tritrichomonas foetus and T foetus-purified surface antigen (TF1.17) in serum, vaginal, and uterine secretions after systemic immunization of beef cows with a vaccine containing killed whole T foetus. Twenty nonpregnant beef cows were randomly assigned to vaccine or control groups as follows: Vaccine (n = 10): cows received 2 mL of a commercial vaccine containing killed whole T foetus subcutaneously and a 2-mL booster 2 weeks later. Control (n = 10): cows received 2 mL of sterile saline on the same schedule. Vaginal secretions and blood samples were collected on Days 0, 8, 15, 22, 29, 36, 43, 50, 60, 75, 89, 110, 146, and 182 relative to day of primary vaccination. Uterine flush fluid was collected on Days 0, 15, 29, and 43 after the day of primary vaccination. Samples were assayed for IgG antibodies to the killed whole T foetus and surface antigen TF1.17 using enzyme-linked immunosorbent assay. Serum whole T foetus-specific IgG levels were significantly increased (between Days 15 and 182) following vaccination with T foetus or with saline. No differences between vaccinates and controls in uterine responses to whole-cell antigen were detected. Serum anti-TF1.17 IgG responses to vaccination were significantly higher than Day 0 throughout the immunization period (P < 0.001) and were higher than responses in control animals on each day post immunization through Day 146 (P < 0.001). A significant rise in TF1.17-specific IgG levels was observed in vaginal and uterine fluids from Day 15 post vaccination compared to the Day 0 levels. These levels remained significantly elevated in vaginal and uterine fluids through Days 75 (P < 0.05) and 43 (P < 0.001) after primary vaccination, respectively. Antibody levels in serum, vaginal, and uterine secretions against TF1.17 remained low in the control group throughout the study. In conclusion, vaccination of beef cows with a commercial vaccine containing T foetus induced significant increase in the levels of IgG to the T foetus TF1.17 surface antigen in serum, vaginal secretions, and uterine fluid, which remained elevated through Days 43, 75, and 182 in uterine fluids, vaginal secretions, and serum, respectively. Since purified TF1.17 antigen has been shown to protect against experimental T foetus infection in heifers, the vaccine-induced TF1.17-specific IgG response is likely to be important in the prevention of trichomoniasis in beef cattle.

Neighborhood residence and mental health problems of 5- to 11-year-olds.

CONTEXT: Little research has investigated possible effects of neighborhood residence on mental health problems in children such as depression, anxiety, and withdrawal. OBJECTIVE: To examine whether children's mental health is associated with neighborhood structural characteristics (concentrated disadvantage, immigrant concentration, and residential stability) and whether neighborhood social processes (collective efficacy and organizational participation) underlie such effects. DESIGN AND SETTING: The Project on Human Development in Chicago Neighborhoods is a multilevel, longitudinal study of a representative sample of children aged 5 to 11 years in the late 1990s recruited from 80 neighborhoods. A community survey assessing neighborhood social processes was conducted with an independent sample of adult residents in these 80 neighborhoods and is used in conjunction with US census data to assess neighborhood conditions. PARTICIPANTS: A total of 2805 children (18.1% European American, 33.8% African American, and 48.1% Latino) and their primary caregivers were seen twice. MAIN OUTCOME MEASURES: Child Behavior Checklist total raw and clinical cutoff scores for internalizing behavior problems (depression, anxiety, withdrawal, and somatic problems). RESULTS: The percentages of children above the clinical threshold were 21.5%, 18.3%, and 11.5% in neighborhoods of low, medium, and high socioeconomic status, respectively. A substantial proportion of variance in children's total internalizing scores (intraclass correlation, 11.1%) was attributable to between-neighborhood differences. Concentrated disadvantage was associated with more mental health problems and a higher number of children in the clinical range, after accounting for family demographic characteristics, maternal depression, and earlier child mental health scores. Neighborhood collective efficacy and organizational participation were associated with better mental health, after accounting for neighborhood concentrated disadvantage. Collective efficacy mediated the effect of concentrated disadvantage. CONCLUSIONS: A large number of children in poor neighborhoods have mental health problems. The mechanism through which neighborhood economic effects operated was community social control and cohesion, which may be amenable to intervention.

Heterocyclic aromatic amines in domestically prepared chicken and fish from Singapore Chinese households.

Chicken and fish samples prepared by 42 Singapore Chinese in their homes were obtained. Researchers were present to collect data on raw sample weight, cooking time, maximum cooking surface temperature, and cooked sample weight. Each participant prepared one pan-fried fish sample and two pan-fried chicken samples, one marinated, one not marinated. The cooked samples were analyzed for five heterocyclic aromatic amine (HAA) mutagens, including MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline); 4,8-DiMeIQx (2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline); 7,8-DiMeIQx (2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline); PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), and IFP (2-amino-(1,6-dimethylfuro[3,2-e]imidazo[4,5-b])pyridine). A paired Student's t-test showed that marinated chicken had lower concentrations of PhIP (p<0.05), but higher concentrations of MeIQx (p<0.05) and 4,8-DiMeIQx (p<0.001) than non-marinated chicken, and also that weight loss due to cooking was less in marinated chicken than in non-marinated chicken (p<0.001). Interestingly, the maximum cooking surface temperature was higher for fish than for either marinated or non-marinated chicken (p<0.001), yet fish was lower in 4,8-DiMeIQx per gram than marinated or non-marinated chicken (p<0.001), lower in PhIP than non-marinated chicken (p<0.05), and lost less weight due to cooking than either marinated or non-marinated chicken (p<0.001). Fish was also lower in MeIQx and 7,8-DiMeIQx than marinated chicken (p<0.05). This study provides new information on HAA content in the Singapore Chinese diet.

Minimization of heterocyclic amines and thermal inactivation of Escherichia coli in fried ground beef.

BACKGROUND: Heterocyclic amine carcinogens are formed during the cooking of a number of foods, especially well-done meats. Lower temperatures and shorter cooking times can minimize the formation of these carcinogens, yet a major food safety concern is that pathogens in the meat must be thermally inactivated. This study investigated cooking techniques that minimize heterocyclic amine formation while simultaneously destroying contaminating bacteria. METHODS: Ground beef patties were inoculated with Escherichia coli K12 bacteria and fried to internal temperatures ranging from 35 degrees C to 70 degrees C in a skillet preheated to 160 degrees C, 180 degrees C, or 200 degrees C. Each patty was then analyzed for four common heterocyclic amines and for surviving bacteria. Additionally, the frequency of turning of the beef patty during cooking was varied (a single turn or multiple turns), length of time required for each patty to reach 70 degrees C was recorded, and heterocyclic amine levels were determined. An additional pan temperature of 250 degrees C was tested for its effect on heterocyclic amine formation but not on bacterial killing. Statistical tests were two-sided. RESULTS: Colony-forming bacteria were reduced by five orders of magnitude at internal temperatures greater than 60 degrees C, regardless of cooking method, and were completely inactivated at 70 degrees C. For patties turned just once, heterocyclic amine levels increased as the cooking temperatures increased. However, levels of heterocyclic amines were statistically significantly lower with turning every minute. For each pan temperature, patties reached 70 degrees C internal temperature sooner when they were turned every minute than when they were turned just once during cooking. CONCLUSION: Lowering the pan temperature and turning the patties frequently can greatly reduce the formation of heterocyclic amines and can simultaneously achieve bacterial inactivation with little or no increase in cooking time, ensuring a product that is safe for human consumption.

Heterocyclic amine content of cooked meat and risk of prostate cancer.

BACKGROUND: Some epidemiologic studies have described positive associations between prostate cancer risk and meat consumption, but underlying mechanisms have not been identified. Heterocyclic amines are mutagens formed during the cooking of meat. Well-done meat has been associated with increased risks of colorectal and breast cancers in humans. This study examined associations between prostate cancer risk and 1) estimated daily intake of heterocyclic amines from cooked meat and 2) level of cooked-meat doneness. METHODS: A population-based, case-control study involving 317 case patients with prostate cancer and 480 age-matched control subjects was carried out in Auckland, New Zealand. Levels of meat doneness and daily intake of heterocyclic amines were determined from self-reported dietary data and experimentally measured heterocyclic amine levels in locally sourced meat samples cooked under controlled conditions to varying degrees of doneness. RESULTS: The heterocyclic amines found in the highest concentrations in meat samples were 2-amino-1,6-dimethylfuro[3,2-e]imidazo[4,5-b]pyridine (IFP) and 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) from well-done chicken and pork and very well-done beefsteak. Meat doneness was weakly and inconsistently associated with prostate cancer risk for individual types of meat, but increased risk was observed for well-done beefsteak (relative risk = 1.68; 95% confidence interval = 1.02-2.77; two-sided P for trend =.03). A weak positive gradient of increased risk was associated with estimated daily exposure to IFP but not with the other major heterocyclic amines. CONCLUSIONS: Meat doneness and estimated intake of heterocyclic amines from cooked meat were not clearly associated with prostate cancer risk.

The capability of rat colon tissue slices to metabolize the cooked-food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.

A major target tissue for carcinogenesis from the cooked-food carcinogen 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rodents is the colon, yet the role of colon metabolism on the carcinogenicity of PhIP is not clearly understood. The mutagenic potency of PhIP is highly dependent upon cytochrome P450 N-hydroxylation. In the present study, the ability of rat colon tissue to activate PhIP to a mutagen was investigated in Salmonella typhimurium (strains TA98 and YGI024) and rat colon tissue slices. In the Ames/Salmonella assay, using rat colon S9 as the activating system, no mutations were evident from bacteria exposed to PhIP at any concentration tested. However, mutations were observed when bacteria were exposed to 2-aminoanthracene (2AA) and colon S9, indicating sufficient P450 activity in the S9 to activate 2AA but not PhIP. In rat colon slice preparations, the sulfotransferase and acetyltransferase inhibitors pentachlorophenol (PCP) and 2,6-dichloro-4-nitrophenol (DCNP) were used to modulate DNA adduct and metabolite formation. Incubations of 3-methylcholanthrene-induced colon slices dosed with 50 microMolar [(3)H]PhIP produced no detectable metabolites. However, incubations of uninduced slices exposed to 10 microMolar of the reactive intermediate, [(3)H]2-(hydroxyamino)-l-methyl-6-phenylimidazo[4,5-b]pyridine (N-hydroxy-PhIP), produced a single detectable metabolite, a glucuronide conjugate of N-hydroxy-PhIP. This metabolite decreased when PCP or DCNP was added to the incubation medium. DNA adducts were detected in colon slices exposed to N-hydroxy-PhIP at approximately 33 adducts/10(7) nucleotides. Interestingly, when PCP was added to the incubation mixture, an increase in DNA adduct levels was detected, whereas DCNP produced a decrease in adducts. Because these inhibitors are thought to have similar mechanisms with regard to sulfotransferase inhibition, the inverse relationship in DNA adduct levels due to PCP or DCNP treatment is at present unexplainable. The formation of DNA adducts and metabolites from colon slices exposed to N-hydroxy-PhIP but not PhIP implies that there is insufficient P450 activity in the rat colon to activate PhIP to hydroxylated metabolites, suggesting that the rat colon is a site of Phase II metabolism for PhIP and that the liver is the primary source for hydroxylation.

Chemical analysis, prevention, and low-level dosimetry of heterocyclic amines from cooked food.

Potent mutagenic and carcinogenic heterocyclic amines are produced from heated food derived from muscle. These compounds are present at part-per-billion levels and consist primarily of the amino-imidazoazaarene class of chemicals. Additional mutagens present in the meat are not as clearly characterized. Commercial fried-beef patties (hamburgers) have low levels of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), 0.1-0.68 ng/g meat for MeIQx and slightly lower for 4,8-DiMeIQx. The formation of these heterocyclic amines can be reduced by microwave pretreatment of meat, with the resulting liquid being poured off before frying. The Ames/Salmonella mutagenic activity was reduced to 5-10% of that of non-microwave-treated samples. MeIQx and DiMeIQx concentrations were reduced to 12% and 50% of levels in the non-microwave-treated samples, respectively. MeIQx adducts, as measured by accelerator mass spectrometry, were found to be linear with doses from 5 mg/kg to 500 ng/kg. Linear DNA binding at low doses is important for assuming linear risk estimation from the high animal-feeding doses causing cancer to the low human-dietary exposures. Extrapolating from the rodent TD50 dose to humans gives a maximum credible risk from consumption of heterocyclic amines of approximately 1/1000 exposed individuals.

Biochemical epidemiology of cervical neoplasia: measuring cigarette smoke constituents in the cervix.

In preparation for an epidemiological investigation of cigarette smoking and cervical neoplasia, we studied methods of measuring cervical exposure to tobacco smoke. The measurement of cotinine in cervical flushes by radioimmunoassay proved to be highly accurate in distinguishing smokers from nonsmokers, achieving 100% sensitivity and 97% specificity. In most subjects, quantitative levels of cervical cotinine and nicotine mirrored recent smoking intensity. Some of the apparent exceptions may have resulted from metabolic/secretory traits of the subjects. If so, the biochemical measurement of smoke constituents in the cervix might prove more valuable for epidemiological studies of cervical neoplasia than data on current smoking behavior collected by interview.

High concentrations of the carcinogen 2-amino-1-methyl-6-phenylimidazo- [4,5-b]pyridine (PhIP) occur in chicken but are dependent on the cooking method.

Heterocyclic aromatic amines (HAAs) are mutagenic and carcinogenic compounds found in meats cooked at high temperatures. Although chicken is consumed in large quantities in the United States, there is little information on its HAA content. The objective of this study was to measure the five predominant HAAs (IQ, MeIQ, MeIQx, DiMeIQx, and PhIP) in chicken cooked by various methods to different degrees of doneness. Chicken breasts were panfried, oven-broiled, or grilled/barbecued. Whole chickens were roasted or stewed. Skinless, boneless chicken breasts were cooked to three degrees of doneness: just until done, well done, or very well done. High levels of PhIP (ranging from 12 to 480 ng/g cooked meat) were found in chicken breasts when panfried, oven-broiled, and grilled/barbecued but not in while roasted or stewed chicken. PhIP concentration increased in skinless, boneless chicken breast with longer cooking time, higher internal temperature, and greater degree of surface browning. PhIP concentration was also high in chicken breasts cooked with skin and bones. MeIQx and DiMeIQx levels increased with the degree of doneness, whereas IQ and MeIQ were not detectable in any of these chicken samples. Certain cooking methods produce PhIP, a known colon and breast carcinogen in rodents and possibly a human carcinogen, at substantially higher levels in chicken than has been reported previously in red meat.

A phase II dose-ranging study of sitamaquine for the treatment of visceral leishmaniasis in India.

This randomized, open label, multicenter study assessed the dose-response and safety profile for oral sitamaquine in 120 Indian subjects with visceral leishmaniasis (VL). Patients aged 5-64 years (mean age 21.2 years) received one of four sitamaquine doses (1.5, 1.75, 2.0, or 2.5 mg kg(-1) day(-1)) daily for 28 days. At Day 180 in the intent-to-treat population, final cure (primary efficacy outcome) was achieved in 92 of 106 (87%) patients overall and 25 of 31 (81%), 24 of 27 (89%), 23 of 23 (100%), and 20 of 25 (80%) patients at doses of 1.5, 1.75, 2.0, or 2.5 mg kg(-1) day(-1) sitamaquine, respectively. Sitamaquine was generally well tolerated. The most common adverse events during the active treatment phase were vomiting (8% [10 of 120]), dyspepsia (8% [9 of 120]) and cyanosis (3% [4 of 120]). Nephrotic syndrome (3% [3 of 120]) and glomerulonephritis (2% [2 of 120]) were also reported and require further investigation. Oral sitamaquine demonstrated efficacy in Indian VL and was well tolerated.

A phase II dose-increasing study of sitamaquine for the treatment of visceral leishmaniasis in Kenya.

Sitamaquine (WR6026) is an 8-aminoquinoline in development for the oral treatment of visceral leishmaniasis (VL). This was an open-label, dose-increasing study to determine the dose-response and safety profile for sitamaquine in Kenyan patients with VL caused by Leishmania donovani. Patients (mean age 15.9 [range = 5-47] years) received sitamaquine daily for 28 days at one of four doses: 1.75 (n = 12), 2.0 (n = 61), 2.5 (n = 12), or 3.0 (n = 12) mg/kg/day. The primary efficacy outcome was cure (absence of parasites on splenic aspirate) in the intent-to-treat population at day 180. Cure was achieved in 79 (83%) of 95 patients overall, and in 11 (92%) of 12, 49 (80%) of 61, 9 (82%) of 11, and 10 (91%) of 11 patients at sitamaquine doses of 1.75, 2.0, 2.5, or 3.0 mg/kg/day, respectively. The most frequent adverse events during active treatment were abdominal pain (12 [12%] of 97) and headache (11 [11%] of 97), and one patient in each of the 2.5 mg/kg/day and 3.0 mg/kg/day dose groups had a severe renal adverse event. The effects of sitamaquine on the kidney need further investigation. Sitamaquine was efficacious and generally well tolerated in Kenyan patients with VL.

Characteristics of women by smoking status in the San Francisco Bay Area.

To better understand why smokers are more likely to develop cervical cancer than nonsmokers, we investigated laboratory and demographic differences between the two groups. Women between the ages of 18 and 49 who attended eleven community clinics in the San Francisco Bay Area were studied to investigate differences between smokers and nonsmokers. The 332 smokers and 365 nonsmokers were queried about smoking habits, sexual and reproductive history, and recent diet. Cervical mucus specimens were cultured for yeast, lactobacillus, and other microorganisms. Results showed that white Hispanic women were less likely to smoke than white non-Hispanic women. Smokers, when compared to nonsmokers, consumed larger quantities of coffee, soft drinks, liquor, and beer in the 24 h prior to the interview. Women who smoked were more likely than those who did not smoke to have had first sexual intercourse before age 16, had a greater number of lifetime sexual partners, and were more likely than nonsmokers to have been pregnant. After controlling for number of sexual partners, smokers reported a history of chlamydia, gonorrhea, and/or pelvic inflammatory disease more often than did nonsmokers, and cervical mucus of smokers was more likely than that from nonsmokers to contain greater than 8500 microorganisms/ml.

Detection of mutagens in cervical mucus in smokers and nonsmokers.

The Salmonella mutagenicity test was used to analyze cervical mucus specimens from 364 smokers and 333 nonsmokers to determine whether the association between smoking and mutagenic cervical mucus that we reported previously among women diagnosed with dysplasia would apply to a larger group of healthy women (E. A. Holly et al., J. Natl. Cancer Inst., 76: 983-986, 1986). Women smokers and nonsmokers between the ages of 18 and 49 who attended eleven clinics and physicians' offices in the San Francisco Bay area for a routine Pap smear were examined to determine whether smokers were more likely to have mutagenic substances in their cervical mucus. About 4% of smokers and 8% of nonsmokers had positive mutagenicity test results (P = 0.02). Cervical mucus with a large number of microorganisms was more likely to have a positive mutagenicity test result than that with fewer microorganisms (test for trend, P = 0.01). Mutagenicity results varied by race and clinic location but were not associated with smoking behavior, sexual behavior, gynecological diagnosis, or diet. Further work is needed to develop methods to detect mutagens in specific body fluids.