Indoor heat exposure in Baltimore: does outdoor temperature matter?

Heat exposure of a population is often estimated by applying temperatures from outdoor monitoring stations. However, this can lead to exposure misclassification if residents do not live close to the monitoring station and temperature varies over small spatial scales due to land use/built environment variability, or if residents generally spend more time indoors than outdoors. Here, we compare summertime temperatures measured inside 145 homes in low-income households in Baltimore city with temperatures from the National Weather Service weather station in Baltimore. There is a large variation in indoor temperatures, with daily-mean indoor temperatures varying from 10 °C lower to 10 °C higher than outdoor temperatures. Furthermore, there is only a weak association between the indoor and outdoor temperatures across all houses, indicating that the outdoor temperature is not a good predictor of the indoor temperature for the residences sampled. It is shown that much of the variation is due to differences in the availability of air conditioning (AC). Houses with central AC are generally cooler than outdoors (median difference of - 3.4 °C) while those with no AC are generally warmer (median difference of 1.4 °C). For the collection of houses with central or room AC, there is essentially no relationship between indoor and outdoor temperatures, but for the subset of houses with no AC, there is a weak relationship (correlation coefficient of 0.36). The results presented here suggest future epidemiological studies of indoor exposure to heat would benefit from information on the availability of AC within the population.

Endotypes of difficult-to-control asthma in inner-city African American children.

African Americans have higher rates of asthma prevalence, morbidity, and mortality in comparison with other racial groups. We sought to characterize endotypes of childhood asthma severity in African American patients in an inner-city pediatric asthma population. Baseline blood neutrophils, blood eosinophils, and 38 serum cytokine levels were measured in a sample of 235 asthmatic children (6-17 years) enrolled in the NIAID (National Institute of Allergy and Infectious Diseases)-sponsored Asthma Phenotypes in the Inner City (APIC) study (ICAC (Inner City Asthma Consortium)-19). Cytokines were quantified using a MILLIPLEX panel and analyzed on a Luminex analyzer. Patients were classified as Easy-to-Control or Difficult-to-Control based on the required dose of controller medications over one year of prospective management. A multivariate variable selection procedure was used to select cytokines associated with Difficult-to-Control versus Easy-to-Control asthma, adjusting for age, sex, blood eosinophils, and blood neutrophils. In inner-city African American children, 12 cytokines were significant predictors of Difficult-to-Control asthma (n = 235). CXCL-1, IL-5, IL-8, and IL-17A were positively associated with Difficult-to-Control asthma, while IL-4 and IL-13 were positively associated with Easy-to-Control asthma. Using likelihood ratio testing, it was observed that in addition to blood eosinophils and neutrophils, serum cytokines improved the fit of the model. In an inner-city pediatric population, serum cytokines significantly contributed to the definition of Difficult-to-Control asthma endotypes in African American children. Mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Difficult-to-Control asthma. Collectively, these data may contribute to risk stratification of Difficult-to-Control asthma in the African American population.

Environmental exposures and asthma morbidity in children living in urban neighborhoods.

A substantial disparity in asthma prevalence and morbidity among urban children compared with their nonurban counterparts has been recognized for more than two decades. Because of the nature of urban neighborhoods, pest allergens, such as cockroach and mouse, are present in high concentrations in US urban housing and have both repeatedly been linked to asthma morbidity in sensitized children. In addition, there is a growing body of evidence demonstrating that concentrations of many pollutants are higher indoors than outdoors in both US and European urban communities and that exposures to indoor pollutants such as particulate matter (PM) and nitrogen dioxide (NO2 ) are independently associated with symptoms in children with asthma. Although environmental interventions are challenging to implement, when they reduce relevant indoor allergen and pollutant exposures, they are associated with clear improvements in asthma. Other modifiable risk factors in urban childhood asthma that have emerged include dietary and nutritional factors. Overweight and obese children, for example, may be more susceptible to the pulmonary effects of pollutant exposure. Insufficiency of vitamin D and folate has also emerged as modifiable risk factors for asthma morbidity in children. The identification of these modifiable risk factors for urban childhood asthma morbidity offers a ripe opportunity for intervention.

Home interventions are effective at decreasing indoor nitrogen dioxide concentrations.

UNLABELLED: Nitrogen dioxide (NO2 ), a by-product of combustion produced by indoor gas appliances such as cooking stoves, is associated with respiratory symptoms in those with obstructive airways disease. We conducted a three-armed randomized trial to evaluate the efficacy of interventions aimed at reducing indoor NO2 concentrations in homes with unvented gas stoves: (i) replacement of existing gas stove with electric stove; (ii) installation of ventilation hood over existing gas stove; and (iii) placement of air purifiers with high-efficiency particulate air (HEPA) and carbon filters. Home inspection and NO2 monitoring were conducted at 1 week pre-intervention and at 1 week and 3 months post-intervention. Stove replacement resulted in a 51% and 42% decrease in median NO2 concentration at 3 months of follow-up in the kitchen and bedroom, respectively (P = 0.01, P = 0.01); air purifier placement resulted in an immediate decrease in median NO2 concentration in the kitchen (27%, P < 0.01) and bedroom (22%, P = 0.02), but at 3 months, a significant reduction was seen only in the kitchen (20%, P = 0.05). NO2 concentrations in the kitchen and bedroom did not significantly change following ventilation hood installation. Replacing unvented gas stoves with electric stoves or placement of air purifiers with HEPA and carbon filters can decrease indoor NO2 concentrations in urban homes. PRACTICAL IMPLICATIONS: Several combustion sources unique to the residential indoor environment, including gas stoves, produce nitrogen dioxide (NO2), and higher NO2 concentrations, are associated with worse respiratory morbidity in people with obstructive lung disease. A handful of studies have modified the indoor environment by replacing unvented gas heaters; this study, to our knowledge, is the first randomized study to target unvented gas stoves. The results of this study show that simple home interventions, including replacement of an unvented gas stove with an electric stove or placement of HEPA air purifiers with carbon filters, can significantly decrease indoor NO2 concentrations.

Dose-response relationships between mouse allergen exposure and asthma morbidity among urban children and adolescents.

Home mouse allergen exposure is associated with asthma morbidity, but little is known about the shape of the dose-response relationship or the relevance of location of exposure within the home. Asthma outcome and allergen exposure data were collected every 3 months for 1 year in 150 urban children with asthma. Participants were stratified by mouse sensitization, and relationships between continuous measures of mouse allergen exposure and outcomes of interest were analyzed. Every tenfold increase in the bed mouse allergen level was associated with an 87% increase in the odds of any asthma-related health care use among mouse-sensitized [Odds Ratio (95% CI): 1.87 (1.21-2.88)], but not non-mouse-sensitized participants. Similar relationships were observed for emergency department visit and unscheduled doctor visit among mouse-sensitized participants. Kitchen floor and bedroom air mouse allergen concentrations were also associated with greater odds of asthma-related healthcare utilization; however, the magnitude of the association was less than that observed for bed mouse allergen concentrations. In this population of urban children with asthma, there is a linear dose-response relationship between mouse allergen concentrations and asthma morbidity among mouse-sensitized asthmatics. Bed and bedroom air mouse allergen exposure compartments may have a greater impact on asthma morbidity than other compartments.

Risk factors for infantile atopic dermatitis and recurrent wheezing.

BACKGROUND: The pathogenic mechanisms of atopic dermatitis (AD) and recurrent wheezing (RW) during infancy are not fully understood. OBJECTIVE: We evaluated immunological markers associated with AD and RW during infancy. METHODS: We followed a cohort (n = 314) from birth to 14 months of age. Some of the participants underwent a physical examination and blood test at 6 and 14 months of age. Univariate and multivariate logistic regression analysis and receiver operating characteristic curve analysis were performed to find which immunological markers could be risk factors for AD and RW. RESULTS: Of 16 immunological markers found in cord blood, only immunoglobulin (Ig) E was associated with AD at 6 months of age (adjusted OR [aOR], 1.607). None of the markers was associated with AD or RW at 14 months of age. Of 23 immunological markers at 6 months of age, total IgE (aOR, 1.018) and sensitization to egg white (aOR, 23.246) were associated with AD at 14 months of age. Phytohemagglutinin (PHA)-induced production of interleukin (IL) 4 from peripheral blood mononuclear cells (PBMCs) (aOR, 1.043) was associated with RW at 14 months of age. CONCLUSION: Cord blood IgE was a risk factor for AD at 6 months of age. Total IgE and sensitization to egg white at 6 months of age were risk factors for AD at 14 months of age. PHA-induced IL-4 production in PBMCs at 6 months of age was a risk factor for RW at 14 months of age.

Potential mechanisms for the association between fall birth and food allergy.

BACKGROUND: Season of birth has been reported as a risk factor for food allergy, but the mechanisms by which it acts are unknown. METHODS: Two populations were studied: 5862 children from the National Health and Nutrition Examination Survey (NHANES) III and 1514 well-characterized food allergic children from the Johns Hopkins Pediatric Allergy Clinic (JHPAC). Food allergy was defined as self-report of an acute reaction to a food (NHANES), or as milk, egg, and peanut allergy. Logistic regression compared fall or nonfall birth between (i) food allergic and nonallergic subjects in NHANES, adjusted for ethnicity, age, income, and sex, and (ii) JHPAC subjects and the general Maryland population. For NHANES, stratification by ethnicity and for JHPAC, eczema were examined. RESULTS: Fall birth was more common among food allergic subjects in both NHANES (OR, 1.91; 95% CI, 1.31-2.77) and JHPAC/Maryland (OR, 1.31; 95% CI, 1.18-1.47). Ethnicity interacted with season (OR, 2.34; 95% CI, 1.43-3.82 for Caucasians; OR, 1.19; 95% CI, 0.77-1.86 for non-Caucasians; P = 0.04 for interaction), as did eczema (OR, 1.47; 95% CI, 1.29-1.67 with eczema; OR, 1.00; 95% CI, 0.80-1.23 without eczema; P = 0.002 for interaction). CONCLUSIONS: Fall birth is associated with increased risk of food allergy, and this risk is greatest among those most likely to have seasonal variation in vitamin D during infancy (Caucasians) and those at risk for skin barrier dysfunction (subjects with a history of eczema), suggesting that vitamin D and the skin barrier may be implicated in seasonal associations with food allergy.

A multi-allergen standard for the calibration of immunoassays: CREATE principles applied to eight purified allergens.

BACKGROUND: Allergen measurements are widely used for environmental exposure assessments and for determining the potency of allergen vaccines, yet few purified allergen standards have been developed. The aim of the study was to develop a single standard containing multiple purified allergens that could be used in enzyme immunoassays and in multiplex arrays for the standardization of allergen measurements. METHODS: Eight purified allergens were formulated into a single multi-allergen, or 'universal', standard based on amino acid analysis. Dose-response curves were compared with previous individual ELISA standards and allergen measurements of house dust extracts to obtain correction factors. Measured allergen concentrations were also modeled using linear regression, and the predictive accuracy was determined. RESULTS: Parallel dose-response curves were obtained between the universal allergen standard and the individual ELISA standards, with close agreement between curves for 5/8 allergens. Quantitative differences of greater than twofold were observed for Fel d 1, Can f 1, and Der f 1, which were confirmed by the analysis of house dust extracts. Correction factors were developed that allowed ELISA data to be expressed in terms of the universal standard. Linear regression data confirmed the predictive accuracy of the universal standard. CONCLUSION: This study shows that a single standard of eight purified allergens can be used to compare allergen measurements by immunoassay. This approach will improve the continuity of environmental exposure assessments and provide improved standardization of allergy diagnostics and vaccines used for immunotherapy.

Predictors of airborne endotoxin concentrations in inner city homes.

Few studies have assessed in home factors which contribute to airborne endotoxin concentrations. In 85 inner city Baltimore homes, we found no significant correlation between settled dust and airborne endotoxin concentrations. Certain household activities and characteristics, including frequency of dusting, air conditioner use and type of flooring, explained 36-42% of the variability of airborne concentrations. Measurements of both airborne and settled dust endotoxin concentrations may be needed to fully characterize domestic exposure in epidemiologic investigations.

Allergen-specific IgE as a biomarker of exposure plus sensitization in inner-city adolescents with asthma.

BACKGROUND: Relationships among allergen-specific IgE levels, allergen exposure and asthma severity are poorly understood since sensitization has previously been evaluated as a dichotomous, rather than continuous characteristic. METHODS: Five hundred and forty-six inner-city adolescents enrolled in the Asthma Control Evaluation study underwent exhaled nitric oxide (FE(NO)) measurement, lung function testing, and completion of a questionnaire. Allergen-specific IgE levels and blood eosinophils were quantified. Dust samples were collected from the participants' bedrooms for quantification of allergen concentrations. Participants were followed for 12 months and clinical outcomes were tracked. RESULTS: Among sensitized participants, allergen-specific IgE levels were correlated with the corresponding settled dust allergen levels for cockroach, dust mite, and mouse (r = 0.38, 0.34, 0.19, respectively; P < 0.0001 for cockroach and dust mite and P = 0.03 for mouse), but not cat (r = -0.02, P = 0.71). Higher cockroach-, mite-, mouse-, and cat-specific IgE levels were associated with higher FE(NO) concentrations, poorer lung function, and higher blood eosinophils. Higher cat, dust mite, and mouse allergen-specific IgE levels were also associated with an increasing risk of exacerbations or hospitalization. CONCLUSIONS: Allergen-specific IgE levels were correlated with allergen exposure among sensitized participants, except for cat. Allergen-specific IgE levels were also associated with more severe asthma across a range of clinical and biologic markers. Adjusting for exposure did not provide additional predictive value, suggesting that higher allergen-specific IgE levels may be indicative of both higher exposure and a greater degree of sensitization, which in turn may result in greater asthma severity.

Mouse allergen-specific immunoglobulin G4 and risk of mouse skin test sensitivity.

BACKGROUND: High serum levels of cat-specific IgG and IgG4 are associated with protection against allergic sensitization to cat, but whether this association applies to other animal allergens remains unclear. OBJECTIVE: To determine if high levels of mouse-specific IgG and IgG4 are associated with a decreased risk of mouse skin test sensitivity. METHODS: Two hundred and sixty workers of a mouse facility underwent skin prick testing and completed a questionnaire. Serum levels of mouse-specific IgG and IgG4 were quantified by solid-phase antigen binding assays. Room air samples were collected and airborne Mus m 1 was quantified by ELISA. RESULTS: Forty-nine participants had a positive skin prick test to mouse. Mouse-specific IgG was detected in 219 (84%) participants and IgG4 was detected in 72 (28%) participants. A detectable mouse-specific IgG4 level was associated with an increased risk of mouse skin test sensitivity (odds ratios (OR) 6.4, 95% confidence intervals (CI) 3.3-12.4). Mouse-specific IgG and IgG4 were both positively correlated with mouse allergen exposure (r(s)=0.31, P=0.0001, and r(s)=0.27, P=0.0006, respectively). The odds of skin test sensitivity peaked at moderate levels of IgG4, but decreased at the highest levels of mouse-specific IgG4. In contrast, the odds of skin test sensitivity increased monotonically with IgG levels. CONCLUSIONS: A detectable level of mouse-specific IgG4 is associated with an increased risk of skin test sensitivity to mouse. However, the highest IgG4 levels appear to be associated with an attenuated risk of mouse skin test sensitivity, suggesting that induction of high levels of IgG4 through natural exposure may protect against the development of allergic sensitization.

Mouse allergen-specific immunoglobulin G and immunoglobulin G4 and allergic symptoms in immunoglobulin E-sensitized laboratory animal workers.

BACKGROUND: High levels of allergen-specific IgG have been associated with clinical efficacy in immunotherapy studies, but whether this antibody isotype is associated with clinical tolerance in the setting of environmental exposure remains unclear. OBJECTIVE: To determine if mouse allergen-specific IgG (mIgG) and IgG4 (mIgG4) levels are associated with mouse-related symptoms among IgE-sensitized laboratory workers. METHODS: Fifty-eight workers with either skin test or serologic evidence of IgE-mediated mouse sensitization were studied. Symptom data were obtained by a questionnaire. Serum levels of mouse-specific IgG, IgG4, and IgE were quantified by a solid-phase antigen-binding assay (IgG) and RAST (IgG4 and IgE), and the relationships between mouse-specific serologic responses and mouse-related symptoms were analysed. RESULTS: Twenty-three (39.7%) participants reported mouse-related symptoms. Mouse-specific IgG and IgG4 levels were not associated with mouse-related symptoms among the study population as a whole. Among the 29 (50%) participants with detectable mouse-specific IgE (mIgE), higher mouse-specific IgG and IgG4 levels were associated with a decreased risk of symptoms, after adjusting for mIgE level (odds ratio (OR) 0.3, 95% confidence interval (CI): 0.1-1.4, and OR 0.3, 95% CI: 0.04-2.6, respectively). Higher levels of mIgG and mIgG4 remained associated with a decreased risk of symptoms after additional adjustment for sex and handling of mice (OR 0.1, 95% CI: 0.02-0.7, and OR 0.2, 95% CI: 0.02-2.1, respectively). Higher mIgG : IgE and mIgG4 : IgE ratios were also associated with a decreased risk of symptoms after adjusting for these confounders (OR 0.1, 95% CI: 0.02-0.7, and OR 0.2, 95% CI: 0.02-0.92, respectively). CONCLUSION: Among workers with detectable mIgE, higher mIgG and mIgG4 levels are associated with a decreased risk of mouse-related symptoms. High serum levels of mIgG or mIgG4 may be markers for clinical tolerance among laboratory mouse workers with detectable mIgE, but these findings need to be confirmed in larger, prospective studies.

Leaky phenotype of X-linked agammaglobulinaemia in a Japanese family.

X-linked agammaglobulinaemia (XLA) is an inherited immunodeficiency that is caused by a block in early B-cell differentiation. Whereas early B precursors in the bone marrow are present in substantial numbers, XLA-affected individuals have dramatically reduced numbers of circulating mature B cells, plasma cells and immunoglobulins of all isotypes. We report on a Japanese family with 3 XLA patients, in whom the serum immunoglobulin levels and number of B cells showed a significant difference among them in spite of harbouring the same splice donor site mutation in the BTK gene. We developed concise method for detection of this mutation, which is helpful for discovering the carrier. Patient 2 showed a significant serum immunoglobulin levels of all isotypes, including allergen-specific IgE. Expression of a normal and truncated size BTK gene was detected in patient 2's peripheral blood mononuclear cells (PBMCs). Expression of BTK protein was also detected in some B cells. These results suggest that the leaky phenotype in patient 2 was caused in part by the expression of a normal BTK gene transcript. The increased frequency of infection with age expanded the number of B cells with normal BTK gene expression and produced the serum immunoglobulin, including IgE.

Identification of somatic and germline mosaicism for a keratin 5 mutation in epidermolysis bullosa simplex in a family of which the proband was previously regarded as a sporadic case.

Epidermolysis bullosa simplex (EBS) is an autosomal-dominant inherited blistering skin disease characterized by intraepidermal blistering due to mechanical stress-induced degeneration of basal keratinocytes. EBS is caused by mutations in either keratin 5 or keratin 14, the major keratins expressed in the basal layer of the epidermis. We experienced a unique EBS-affected family. The proband had a heterozygous 1649delG mutation in the keratin 5 gene and had been reported as a case of de novo mutation, because the mutations were not detected in the parents' DNA from blood samples. However, the proband's younger sister was revealed to have the same disease at birth and we found the same mutation in her. We reinvestigated the familial segregation of the 1649delG mutation and it was shown that the mother's DNA from hair bulb and buccal cell samples had the 1649delG mutation heterozygously, but her DNA from blood samples did not. A careful check on the mother's history disclosed that she had migratory circinate pigmentation in her skin in childhood, which means maternal somatic and germline mosaicism. The demonstration of somatic and gonadal mosaicism in the keratin 5 gene is important for accurate genetic counselling of families with sporadic cases of EBS.

Subunit interaction and regulation of activity through terminal domains of the family D DNA polymerase from Pyrococcus horikoshii.

Family D DNA polymerase (PolD) has recently been found in the Euryarchaeota subdomain of Archaea. Its genes are adjacent to several other genes related to DNA replication, repair and recombination in the genome, suggesting that this enzyme may be the major DNA replicase in Euryarchaeota. We successfully cloned, expressed, and purified the family D DNA polymerase from Pyrococcus horikoshii (PolDPho). By site-directed mutagenesis, we identified amino acid residues Asp-1122 and Asp-1124 of a large subunit as the essential residues responsible for DNA-polymerizing activity. We analysed the domain structure using proteins truncated at the N- and C-termini of both small and large subunits (DP1Pho and DP2Pho), and identified putative regions responsible for subunit interaction, oligomerization and regulation of the 3'-5' exonuclease activity in PolDPho. It was also found that the internal region of the putative zinc finger motif (cysteine cluster II) at the C-terminal of DP2Pho is involved in the 3'-5' exonuclease activity. Using gel filtration analysis, we determined the molecular masses of the recombinant PolDPho and the N-terminal putative dimerization domain of the large subunit, and proposed that PolD from P. horikoshii probably forms a heterotetrameric structure in solution. Based on these results, a model regarding the subunit interaction and regulation of activity of PolDPho is proposed.

RNA editing of interleukin-12 receptor beta2, 2451 C-to-U (Ala 604 Val) conversion, associated with atopy.

BACKGROUND: The production of IgE in B lymphocytes is down-regulated by IFN-gamma. IL-12 induces IFN-gamma production by T lymphocytes and natural killer cells by binding to its specific receptor. RNA editing is a post-transcriptional modification. OBJECTIVE: Here we show that the RNA editing of IL-12 receptor (R) beta2 is associated with atopy. METHODS: Atopic patients and non-atopic healthy controls were studied. Fragments of IL-12R beta2 cDNA and genomic DNA were amplified and sequenced. Furthermore, the function of the IL-12R beta2 chain was investigated. RESULTS: Sequence analysis of the cDNA clones representing IL-12R beta2 mRNA transcripts revealed a C-to-U conversion at nucleotide 2451 (Ala 604 Val) on exon 13 in some atopic patients. Surprisingly, sequence analysis of their genomic DNA showed no 2451 C-to-T (Ala 604 Val) mutation. We concluded that the observed C-to-U mismatch in the cDNA clone is due to a post-transcriptional modification, RNA editing. The C-to-U conversion was observed in 21 (20.6%) of 102 atopic patients, whereas this conversion was observed in only 4 (3.8%) of 104 non-atopic subjects (P<0.001). IFN-gamma production by peripheral blood mononuclear cells (PBMCs) stimulated with IL-12 in the subjects with the C-to-U conversion was significantly lower than that in the subjects without the C-to-U conversion. In atopic patients with the C-to-U conversion, PBMCs faintly showed the tyrosine phosphorylation of Stat4, and the IgE production by PBMCs was not suppressed by IL-12 whereas it was suppressed by IFN-gamma. CONCLUSIONS: The RNA editing of IL-12R beta2, 2451 C-to-U (Ala 604 Val) conversion causes impairment of the IL-12 signal cascade and the subsequent reduction in IFN-gamma production, resulting in the impaired down-regulation of IgE production. This is the first report indicating that atopy is associated with RNA editing.

Association between interleukin-18 gene polymorphism 105A/C and asthma.

BACKGROUND: IL-18 has been shown to exert anti-allergic or allergy-promoting activities, but the existence of genetic polymorphisms in the coding regions of IL-18 gene has not been demonstrated. OBJECTIVE: The aim of this study was to investigate whether polymorphism is present in the coding regions of the IL-18 gene and, if so, to further analyse the association between polymorphism and asthma in a case-control study. METHODS: We screened the coding regions of the IL-18 gene for polymorphisms by using PCRsingle-stranded conformation polymorphism and direct sequencing of PCR products, followed by analysis of the association between polymorphism and asthma. RESULTS: We identified one polymorphism (105A/C) in the coding regions. The frequency of the 105A allele was significantly higher in asthmatic patients than in controls (P<0.01; odds ratio (OR)=1.83 (1.37-2.26)). Significant linkage disequilibrium was observed between the 105A/C and -137G/C polymorphisms in the 5' flanking region of the IL-18 gene (D=0.58, P<0.0001). However, in asthmatic patients the 105A allele was not associated with either total serum IgE or IL-18 levels. CONCLUSION: The 105A/C polymorphism of the IL-18 gene may be associated with the pathogenesis of asthma.

[QOL questionnaire version 2001 for pediatric patients with bronchial asthma and their parents or caregivers--preparation and evaluation].

We already reported that the QOL questionnaire for pediatric patients with bronchial asthma and their parents or caregivers reflects reliability (including test retest), factorial validity, and changes in paroxysmal attacks of asthma. In this study, we revised the questionnaire for use in routine medical care. We investigated the importance of questions for affected children and their parents or caregivers and selected and discarded questions on the basis of average ranks of the importance and medical standpoint so that the questionnaire might have physical and emotional domains. The QOL questionnaire version 2001 for pediatric patients with bronchial asthma and their parents or caregivers (hereafter to be abbreviated as the version 2001) includes 15 questions for patients under the age of 4 years and 20 questions for patients over the age of 4 years and 4 year-old. The "present" and "absent" groups, which were categorized with respect to the events (e.g., attack) that developed in 2 weeks prior to the QOL investigation, showed a significant difference (Mann-Whitney U-test) in terms of the total score of replies which constitute each domain, i.e., physical domain (p = 0.0052) in patients under the age of 4 years and physical domain (p < 0.0001) and emotional domain (p < 0.0001) in patients over the age of 4 years and 4 year-old. Regarding the average value of each reply which constitutes the domain as well, the physical domain showed a decrease in symptom instability and the "> or = 4 years" group showed a decrease in exertional load and mental load. Therefore, a QOL investigation like ours which investigates disorders in which attacks develop suddenly, e.g., asthma, should examine the presence or absence of all events prior to the investigation. The version 2001 was considered useful for affected children and their parents or caregivers to comprehend the content and severity of impairments which were provoked by asthma.

Biosynthesis and secretion of adrenomedullin and proadrenomedullin N-terminal 20 peptide in a rat model of endotoxin shock.

To study the biosyntheses and pathophysiological roles of adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) in septic shock, we compared the time course of plasma concentrations of these peptides and blood pressure in rats injected with either 0.9% saline (control group) or lipopolysaccharide (LPS group). The plasma AM concentration in the LPS group did not increase 30 and 60 min after LPS injection, at which time points the blood pressure remained low. Thereafter, AM rapidly increased, and it amounted to 35 times the basal value 4 h after injection, when the blood pressure returned to the basal level. The increment of plasma PAMP in the LPS group was lower than that of AM. We also examined the tissue concentration of AM and PAMP--as well as the tissue expression of proadrenomedullin (proAM) mRNA--in the LPS and control groups. LPS significantly increased the tissue concentrations of AM and PAMP in the lung, but decreased them in the adrenal gland and cardiac atrium. The LPS injection augmented proAM gene transcription in the lung, adrenal gland and aorta. In an immunohistochemical examination, AM staining was intense in alveolar endothelial cells of the lung in the LPS group. Thus, this septic shock model had high plasma levels of PAMP as well as AM, while the biosynthesis and secretion of the two peptides may have been differentially regulated in various tissues of rats injected with LPS. The present results suggest that these two bioactive peptides may play different roles in the pathophysiology of septic shock.