Differential activation of airway eosinophils induces IL-13-mediated allergic Th2 pulmonary responses in mice.

BACKGROUND: Eosinophils are hallmark cells of allergic Th2 respiratory inflammation. However, the relative importance of eosinophil activation and the induction of effector functions such as the expression of IL-13 to allergic Th2 pulmonary disease remain to be defined. METHODS: Wild-type or cytokine-deficient (IL-13(-/-) or IL-4(-/-) ) eosinophils treated with cytokines (GM-CSF, IL-4, IL-33) were adoptively transferred into eosinophil-deficient recipient mice subjected to allergen provocation using established models of respiratory inflammation. Allergen-induced pulmonary changes were assessed. RESULTS: In contrast to the transfer of untreated blood eosinophils to the lungs of recipient eosinophil deficient mice, which induced no immune/inflammatory changes either in the lung or in the lung draining lymph nodes (LDLN), pretreatment of blood eosinophils with GM-CSF prior to transfer elicited trafficking of these eosinophils to LDLN. In turn, these LDLN eosinophils elicited the accumulation of dendritic cells and CD4(+) T cells to these same LDLNs without inducing pulmonary inflammation. However, exposure of eosinophils to GM-CSF, IL-4, and IL-33 prior to transfer induced not only immune events in the LDLN, but also allergen-mediated increases in airway Th2 cytokine/chemokine levels, the subsequent accumulation of CD4(+) T cells as well as alternatively activated (M2) macrophages, and the induction of pulmonary histopathologies. Significantly, this allergic respiratory inflammation was dependent on eosinophil-derived IL-13, whereas IL-4 expression by eosinophils had no significant role. CONCLUSION: The data demonstrate the differential activation of eosinophils as a function of cytokine exposure and suggest that eosinophil-specific IL-13 expression by activated cells is a necessary component of the subsequent allergic Th2 pulmonary pathologies.

Eosinophil activities modulate the immune/inflammatory character of allergic respiratory responses in mice.

BACKGROUND: The importance and specific role(s) of eosinophils in modulating the immune/inflammatory phenotype of allergic pulmonary disease remain to be defined. Established animal models assessing the role(s) of eosinophils as contributors and/or causative agents of disease have relied on congenitally deficient mice where the developmental consequences of eosinophil depletion are unknown. METHODS: We developed a novel conditional eosinophil-deficient strain of mice (iPHIL) through a gene knock-in strategy inserting the human diphtheria toxin (DT) receptor (DTR) into the endogenous eosinophil peroxidase genomic locus. RESULTS: Expression of DTR rendered resistant mouse eosinophil progenitors sensitive to DT without affecting any other cell types. The presence of eosinophils was shown to be unnecessary during the sensitization phase of either ovalbumin (OVA) or house dust mite (HDM) acute asthma models. However, eosinophil ablation during airway challenge led to a predominantly neutrophilic phenotype (>15% neutrophils) accompanied by allergen-induced histopathologies and airway hyper-responsiveness in response to methacholine indistinguishable from eosinophilic wild-type mice. Moreover, the iPHIL neutrophilic airway phenotype was shown to be a steroid-resistant allergic respiratory variant that was reversible upon the restoration of peripheral eosinophils. CONCLUSIONS: Eosinophil contributions to allergic immune/inflammatory responses appear to be limited to the airway challenge and not to the sensitization phase of allergen provocation models. The reversible steroid-resistant character of the iPHIL neutrophilic airway variant suggests underappreciated mechanisms by which eosinophils shape the character of allergic respiratory responses.

Trends in overweight and obesity and changes in the distribution of body mass index in schoolchildren of Jena, East Germany.

OBJECTIVE: Data of Jena children (Germany) show increases in the prevalence estimates of overweight and obesity between 1975 and 2001. Our objective was to determine if these increases contribute to changes in the distribution of body mass index (BMI) in the entire population of children. The decade 1985-1995, which includes the time of German reunification, is of particular interest because of the significant socio-economic changes in East Germany, in which Jena is located. DESIGN AND SUBJECTS: The analyses were based on data from four cross-sectional growth studies in 7- to 14-year-old children performed in Jena, Germany, in 1975 (n=2013), 1985 (n=1534), 1995 (n=1906) and 2001 (n=1918). Overweight and obesity were estimated by German reference data and the reference of Cole et al. Mean difference plots were used to investigate the changes in the BMI distributions within sexes between the studies. RESULTS: Between 1985 and 1995, the prevalence of overweight and obesity increased significantly in both sexes, whereas nonsignificant changes were found between 1975 and 1985. Although there is a tendency towards increased overweight between 1995 and 2001, the differences were nonsignificant. Comparing data from 1975 and 1985, the mean difference plots showed virtually no changes in the BMI distribution. In the plots comparing the BMI distribution for 1985 data and 1995 data, the whole distribution tended to shift upwards with a greater shift in the upper BMI range. The entire population of children in Jena gained weight during this period of time. This increase may be linked to a transition towards a more Western lifestyle, that is, usually by lower energy expenditure and nutritional transitions, caused by the process of reunification of Germany in 1989. CONCLUSIONS: Weight gain appears to be a characteristic feature of the entire population studied and does not seem to be a separate problem of the obese children. This suggests that reported changes in the prevalence may be underestimating the looming public health crisis.

Characterization of induction of protooncogene c-myc and cellular growth in human vascular smooth muscle cells by insulin and IGF-I.

Insulin and insulin-like growth factor I (IGF-I) are structurally related polypeptides that stimulate DNA synthesis and cellular proliferation, probably through a common pathway. Human arterial smooth muscle cells in culture demonstrated the presence of high-affinity receptors for both these hormones. Insulin and IGF-I both exhibited cross-reactivity to each other's receptors but with an affinity that is 100-fold less than for the homologous receptor. To examine more closely the receptor responsible for producing the growth effects, we used the polyclonal antibody against the insulin receptor, B2, and a monoclonal antibody to the IGF-I receptor, alpha IR3. We studied the growth effects of insulin and IGF-I as measured by stimulation of c-myc, DNA synthesis, and cellular proliferation in the presence and absence of these antibodies. F(ab') fragments of the anti-insulin-receptor antibody at a concentration of 10 micrograms/ml were capable of displacing greater than 90% of the bound insulin, thus establishing an effective insulin-receptor blockade. Under such blockade, insulin and IGF-I were both capable of doubling the amount of DNA synthesis and cell number in cultured human arterial smooth muscle cells. However, in the presence of a 1:2500 dilution of the monoclonal antibody alpha IR3, which caused a 90% displacement of IGF-I bound to its receptor, both the insulin and IGF-I effects on stimulating DNA synthesis or cellular proliferation were inhibited by greater than 90%. These findings demonstrate that the IGF-I receptor is the common pathway for the growth effects of both insulin and IGF-I.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin, insulin-like growth factor I and platelet-derived growth factor interact additively in the induction of the protooncogene c-myc and cellular proliferation in cultured bovine aortic smooth muscle cells.

Vascular smooth muscle cell (SMC) growth is under the influence of various growth factors. We demonstrate that platelet-derived growth factor (PDGF) stimulates DNA synthesis of cultured bovine aortic SMCs by 2.5- to 3.5-fold. PDGF also exhibits additivity with insulin and insulin-like growth factor I (IGF-I) for DNA synthesis and cellular proliferation. Insulin (2 x 10(-6) M), IGF-I (1 x 10(-8) M), and PDGF (1 x 10(-9) M) cause a 60-80% increase in cell numbers over basal, but PDGF with insulin or IGF causes a 40-150% increase over basal. No additivity between insulin and IGF-I is evident. PDGF also induces commitment to DNA synthesis earlier than insulin or IGF-I. After exposure to PDGF for 4 h, SMCs incorporate 3H-thymidine to 60% of maximum (with PDGF alone) levels (achieved after exposure of 12 h or longer). Insulin and IGF-I exposure for 4 h, on the other hand, achieves 3H-thymidine incorporation that is only a 20-30% of maximum (with insulin or IGF-I alone). Insulin, IGF-I, and PDGF increase mRNA levels of the protooncogene c-myc. This induction begins within 30 min of exposure to these growth factors which causes a 4- to 6-fold increase in c-myc mRNA levels. Additivity is also observed between PDGF with insulin or IGF-I, but not between insulin or IGF-I, in c-myc induction. C-myc mRNA levels remain elevated as long as the hormones are present, although there's a tendency for the mRNA levels to fall off with insulin and IGF-I.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth studies in Jena, Germany: Historical background and secular changes in stature and weight in children 7-14 years.

Anthropological investigations have been performed on Jena school children since 1880. The report summarizes the background of the surveys and then considers secular changes in stature and body weight since 1880. The stature of Jena school children shows a major increase over 105 years, ranging from 9.7% to 12.8% in girls and from 9.4% to 14.6% in boys. Changes in estimated growth rates are evident, especially in the preschool ages. Corresponding secular increases in weight between 1880 and 1985 range from 20.7% to 50.4%. Data during and after times of war suggest that females appear to react to changing living conditions more quickly than boys. On the other hand, the smaller variation in the stature of girls suggests more homogeneous and perhaps better buffered growth in girls. Estimated semiannual increments in stature and weight between 1880 and 1985 indicate an increase in the intensity of growth during school age in both sexes and acceleration of the pubertal growth spurt, especially in boys. The average decrease in weight in both sexes between 1932 and 1944 should be emphasized. This is the result of the poor nutritional conditions during the Second World War. Girls show a greater reduction in mean values than boys. © 1996 Wiley-Liss, Inc.

Percentile curves for skinfold thickness in 7- to 14-year-old children and adolescents from Jena, Germany.

OBJECTIVE: To present age- and sex-specific percentile curves for triceps and subscapular skinfold thickness, and to investigate long-term changes in skinfold thickness in children. SUBJECTS/METHODS: A cross-sectional study of children and adolescents was conducted in Jena/Germany in 2005/2006. The sample consisted of 2132 children (1018 girls and 1114 boys) aged 7-14 years and equated to the anthropometric characteristics of the German sample included in the reference values for body mass index (BMI). Height, weight and triceps and subscapular skinfold measurements were obtained using standardized methods. Smoothed percentile curves for triceps and subscapular skinfold thickness were derived by the LMS method. Data were compared with historical data of Jena schoolchildren from 1975. RESULTS: In both sexes, skinfold thickness increased between 7 and 14 years of age in a sex-specific pattern, with generally higher median values for triceps and subscapular skinfold in girls than boys. A comparison with skinfold thickness measured in Jena schoolchildren three decades ago showed a significant increase in subcutaneous fat. The changes in the lower range (below the tenth percentile) of the distribution exceed those in the upper range (above the 90th percentile) for both triceps and subscapular skinfold in both sexes. Furthermore, this gain in subcutaneous fat mainly occurred in underweight and normal-weight subjects, whereas skinfold thickness remained nearly unchanged in overweight subjects. CONCLUSIONS: The up-to-date percentile curves for skinfold thickness provide a basis for monitoring of individuals and evaluation of long-term trends in German children and adolescents. The changes in skinfold thickness indicate an unfavourable increase in adiposity, as well as an unfavourable change in the relationship between BMI and body fat in children and adolescents over time.

Validity of body mass index and waist circumference to detect excess fat mass in children aged 7-14 years.

BACKGROUND/OBJECTIVES: To evaluate the screening performance of body mass index (BMI) and waist circumference (WC) for excess adiposity. In addition, the diagnostic accuracy of cutoffs from different international and national reference systems based on BMI and WC was investigated. SUBJECTS/METHODS: Data from 2132 Jena children aged 7-14 years conducted in 2005/2006 were analyzed. Receiver operating characteristic (ROC) curves were constructed to assess BMI and WC, as screening measures for excess adiposity (derived from skinfolds). Sensitivity, specificity and positive predictive values (PPVs) were calculated for two BMI-based classification systems (IOTF and German reference) and sample-based WC cutoffs. RESULTS: The BMI as well as the WC performed well in detecting excess fat mass, indicated by areas under the ROC curve (AUC) close to 1.0, with slightly greater AUCs for BMI than for WC in both sexes. The specificity of all reference systems was high for both sexes (95 to 98%). However, their sensitivities were low (53-67% in boys; 51-67% in girls). PPV were higher for the German reference and the sample-based WC cutoffs than for the IOTF reference, and higher in girls than in boys. CONCLUSIONS: The setting in which the reference system should be used is important for the selection of the reference system. The results support the use of the BMI-based references for monitoring in epidemiological studies. The sample-based cutoffs for WC should be refined for clinical use on national level.

[The current status of secular acceleration]. / Zur Frage des gegenwärtigen Standes der säkularen Akzeleration.

The present paper is based upon the results of anthropological examinations of Jena schoolchildren. It gives a statement on the extent and the present level of secular changes in selected characteristics. Over long periods of time a becoming slimmer of today's population of Jena schoolchildren is documented. The secular acceleration in Jena probands has lasted up to the present time (although in part with reduced intensity).

[Dynamics of the growth intensity of Jena school children since 1880]. / Zur Dynamik der Wachstumsintensität bei Jenaer Schulkindern seit 1880.

The intensity of growth of Jena school children at the age of 7 to 14 years has been investigated between 1880 and 1985. In the regarded 105 years the intensity of growth showed little changes with the tendency of a gradual increase. The analysis differentiated for age reveals partially different results compared for the whole interval between 7 and 14 years. These differences result from a shifting of phases of intensified growth into ontogenetically earlier age stages, which can be traced back to the secular trend. The increase of the growth intensity caused by the secular trend is significantly smaller in the school age than in the preschool age.

[Results of the anthropologic studies of school children in Jena between 1880 and 1985]. / Ergebnisse Jenaer anthropologischer Schulkinderuntersuchungen zwischen 1880 und 1985.

The present report is based on the results from anthropological examinations on schoolchildren, which have been carried out in Jena since 1880. The introduction to the paper gives a survey on the goals of these inquiries, followed by remarks on secular changes in selected measurements of the body (body height, body weight, chest circumference). Besides the extent of the changes in these features, the anticipation of the pubertal growth period and--by means of the relation of body height to chest circumference--a becoming slimmer of today's population of schoolchildren is documented. The comparison of the findings of 1975 and 1985 shows that, regarding the features mentioned, the acceleration in the Jena probands (although in part with reduced intensity) has lasted up to the present time.

[100 Years of anthropological examination of school children in Jena (GDR)]. / 100 Jahre anthropologische Schulkinderuntersuchungen in Jena.

The present paper gives a review of the aims and the importance of the anthropological examinations on Jena school children, which have been carried out since 1880. It is shown that secular acceleration of stature and body weight was greater between 1964 and 1975 than the changes found in previous investigations. Special importance is attributed to a comparison of the results of the investigation made in 1880 with those of 1975.

[The phenomenon of debrachycephalization in Jena school children]. / Das Phänomen der Debrachykephalisation bei Jenaer Schulkindern.

Head measurements are performed within the anthropological investigations of school children from Jena (Germany) since more than 5 decades (1944-1995). Here we report on secular changes of the head length, the head breadth and the cephalic index. The head circumference, measured in 1985 and in 1995, is included in the analysis. Head length and head breadth show a contrary development over the whole period: the average length of the head increases between the consecutive investigations, whereas the breadth of the head decreases continuously between the separate investigations. As a consequence the cephalic index decreases in boys and girls for about 8 units since 1944. In this way a secular change of the shape of the head in the sense of debrachycephalisation can be proved in Jena school children. The head circumference, however, remains nearly constant between 1985 and 1995. Possible causes of this process of debrachycephalisation are focussed in this article.

Acute gastrointestinal haemorrhage. Experience with early panendoscopy and tranexamic acid in a rural hospital.

One hundred and fifty-nine consecutive patients admitted to a small rural hospital because of acute gastrointestinal haemorrhage were studied. Patients with haematemesis and/or melaena were treated with antacids and tranexamic acid from the very beginning and were examined by means of early panendoscopy. All patients were closely observed on a general medical ward by a staff especially trained to deal with acute gastrointestinal bleeding. Eight patients required acute surgery. The overall mortality rate was 4.4%. It is concluded that acute gastrointestinal haemorrhage can be successfully handled with modern diagnosis and treatment even in a small hospital.

[Results of the study of selected head measurements of Jena children]. / Ergebnisse der Untersuchung ausgewählter Kopfmasse bei Jenaer Kindern.

Secular changes of head measurements (frontal breadth, bizygomatic breadth, bigonial breadth, auricular height, morphological facial height, lower face height) are analysed. The data are based on the Jena anthropological investigations of school children from 1975 and 1985. The inclusion of the data of the Jena longitudinal study carried out since 1985 allows an analysis of the further secular trend. Noticeable changes are proved in most of the analysed traits (frontal breadth, bigonial breadth, auricular height, morphological facial height, lower face height) between 1975 and 1985. The vertical measurements show greater percentage differences than the horizontal measurements, which, among other things, results in a relative narrowing of the face. In some head measurements (frontal breadth, bigonial breadth, auricular height) the trends continue after 1985. The secular trends show no obvious connection with the temporal acceleration of the dentition in the probands of the longitudinal study. However, a connection seems to be possible between the accelerated puberal growth spurt of the body height and the puberal growth spurt in some head dimensions.

Prevalence of overweight and obesity among school children in Jena (Germany).

OBJECTIVES: To examine the prevalence and changes in the prevalence of overweight and obesity among school children in Jena (Germany) in the last twenty years and to identify factors associated with childhood overweight. DESIGN: Cross-sectional surveys in 1975, 1985, 1995 and a household questionnaire in 1995. SUBJECTS: Children from schools in Jena, aged 7-14 y, participated (1975 : 1002 boys and 1000 girls; 1985 : 781 boys and 753 girls; 1995 : 989 boys and 912 girls). MEASUREMENTS: Prevalence of overweight or obesity based on the 90th or 97th age- and sex-specific percentile of the body mass index (BMI) developed for French children. In 1995 factors examined in relation to overweight included birth weight, birth length, age-class, number of children in household, occupation of the father, education of the mother and size of flat (apartment). RESULTS: In boys the prevalence of overweight increased from 10.0 to 16.3% and in girls from 11.7 to 20.7% between 1975 and 1995. The prevalence of obesity increased from 5.3 to 8.2% in boys and from 4.7 to 9.9% in girls between 1975 and 1995. However, the peak in the increase of overweight as well as of obesity lie for both sexes between 1985 and 1995. Using logistic regression, statistically significant associations with overweight were found for occupation of the father, birth weight in both sexes and additionally, for size of flat in girls. CONCLUSIONS: Overweight and obesity are increasing health problems among Jena children. Further investigations are needed to explore the influence of factors such as feeding pattern, food habits and physical activity on overweight. Special attention should be paid to the further social development in the society and to the link between low social class and overweight. Through such investigations effective preventive strategies could be developed.

[Is head size modified by environmental factors?]. / Werden Kopfmasse von Umweltfaktoren beeinflusst?

In the article the development of skull measurements and head measurements (length and breadth) and of the cephalic index, calculated from these measurements, since the Neolithic period are presented. The results obtained from the historical material are compared with those of living persons. The measurements as well of the skull as of the head show secular changes. The following general trend was found: an increase of body height is connected with a debrachycephalisation and a decrease of body height is connected with a brachycephalisation. It can be emphasized that brachycephalisation/debrachycephalisation are part of the secular trend. Therefore environmental factors are responsible for the described changes of measurements of the skull and the head in a broadest sense.