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Biomedical subjects

S Weiland

Publications and source records attributed to S Weiland.

At least 19 recordsLinked to original sources
PubMed2006

Do respiratory symptoms predict job choices in teenagers?

Existing guidelines advise adolescents with asthma and allergies against high-risk occupations. The aim of the current authors' analyses was to investigate the resulting self-selection in a prospective cohort study. The participants of Phase II of the International Study of Asthma and Allergies in Childhood in Germany (aged 9-11 yrs at baseline) were re-contacted after 7 yrs (response rate was 77%) and were asked to complete a questionnaire, which included items on atopic diseases. The subjects were also asked about the type of job they would like to have in the future (preferred job choice). Exposure to agents with potential asthma risk was evaluated using a job exposure matrix. The analyses were restricted to those in school-based vocational training programmes without occupational exposures. A total of 33% of subjects chose jobs with high asthma risk, 23% selected low asthma risk jobs and the remaining adolescents indicated jobs without known asthma risk (reference category). There were no statistically significant associations between asthma, allergic rhinitis or atopic dermatitis and selecting jobs with asthma risk. Participants with allergic rhinitis tended to select high risk jobs less frequently. In conclusion, self-selection into low risk jobs seems to play a minor role in teenagers with asthma or allergies.

Adolescent↗
PubMed2005

Atopic dermatitis, extrinsic atopic dermatitis and the hygiene hypothesis: results from a cross-sectional study.

BACKGROUND: Atopic Dermatitis (AD), hayfever and asthma are commonly summarized as atopic diseases. The spatial distribution of AD differs from that of asthma and hayfever, suggesting that AD might follow a different risk pattern than these diseases. AD can be differentiated into an allergic extrinsic form (EAD) and a non-allergic intrinsic form (IAD). Only EAD might follow the distribution and risk pattern that have been ascribed to asthma and hayfever. OBJECTIVE: To investigate the distribution and risk factor profile of AD and EAD focusing on environmental factors relating to the hygiene hypothesis. METHODS: Population-based cross-sectional study on 12,601 children aged 5-7 and 9-11 years from Dresden (Eastern Germany) and Munich (Western Germany). Information was obtained by International Study of Asthma and Allergic Childhood questionnaires, dermatological examinations and skin prick testing. AD-diagnosis ever, current AD-symptoms and visible eczema were investigated with their respective extrinsic forms. RESULTS: Maternal and paternal history of AD were equally strong determinants of the child's AD status. Factors related to the hygiene hypothesis like day-care attendance and number of older siblings were not associated with a decreased risk of AD. The proportion of EAD within AD was higher in Eastern than in Western Germany. The determinants of the diseases appeared to be similar for both EAD and IAD. CONCLUSIONS: There was no evidence of the hygiene hypothesis holding true for AD or EAD. AD might be a separate entity than respiratory atopic diseases. Little is known about the risk factors of AD and factors different from those of respiratory allergic diseases should be considered in future research.

Child↗
PubMed2002

How mutations in the nAChRs can cause ADNFLE epilepsy.

PURPOSE: The linkage between autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and neuronal nicotinic acetylcholine receptor has been strongly reinforced by the report of five distinct mutations in the two genes coding for the major brain alpha4beta2 nicotinic acetylcholine (ACh) receptors. As a first step toward understanding the basic mechanisms underlying this genetically transmissible neurologic disorder, we examined the similarities and differences of the functional properties displayed by naturally occurring mutant forms of this ligand-gated channel. METHODS: Functional studies of neuronal nicotinic ACh receptors reconstituted in Xenopus oocytes were designed to analyze the common traits displayed by the different mutations associated with ADNFLE. RESULTS: Coexpression of the control and mutated alleles harboring the alpha4S248F mutation obtained from patient DNAs yielded ACh-evoked currents of amplitude comparable to the control responses but with a higher sensitivity and desensitization to the natural agonist. Alternatively, the other mutants (alpha4L776ins3, alpha4S252L, and beta2V287M) displayed an increased ACh sensitivity without pronounced desensitization. In addition, whereas a reduction of calcium permeability was observed for the mutants (alpha4S248F and alpha4L776ins3), no significant modification of ionic selectivity could be detected in the alpha4S252L mutation. Hence increase in ACh sensitivity is the only common characteristic so far observed between the four naturally occurring mutant receptors investigated. CONCLUSIONS: Analyses of functional properties of four nAChR mutants associated with ADNFLE indicate that a gain of function of these mutant receptors may be at the origin of the neuronal network dysfunction that causes the epileptic seizures. These data are discussed in the context of our latest knowledge of the pyramidal cell function.

Acetylcholine↗
PubMed2001

Ion channel variation causes epilepsies.

The discovery of genetically transmissible form of epilepsy associated with a mutation in a gene that codes for a subunit of a ligand-gated channel shined a new light in this field of neurological diseases. Because this gene (CHRNA4) codes for a neuronal nicotinic acetylcholine receptor subunit, functional studies could be designed to evaluate the alterations caused by this mutation. Since this initial observation, five mutations were identified and determination of their functional properties initiated. These experiments were extended to pairwise expression of the control and mutated allele to mimic the heterozygote human genotype. The first common functional trait identified so far, in four of these mutants, is an increased sensitivity to the acetylcholine, suggesting that these mutations may cause a gain of function. An alternative possibility that cannot be excluded is that conditions in the brain are such that these higher responding receptors may be more prone to desensitization. The importance of ionic channels as cause of epilepsies was further demonstrated with the identification of the association between the benign neonatal epilepsy and mutations in genes coding for potassium channel subunits (KCNQ2, KCNQ3). Additional evidences were brought by the identification of mutations in voltage-dependent sodium channels (SCN1A, SCN1B) in a form of generalized epilepsy with febrile seizures.

Acetylcholine↗
PubMed2000

Assembly of Trp1 in a signaling complex associated with caveolin-scaffolding lipid raft domains.

Trp1 has been proposed as a component of the store-operated Ca(2+) entry (SOC) channel. However, neither the molecular mechanism of SOC nor the role of Trp in this process is yet understood. We have examined possible molecular interactions involved in the regulation of SOC and Trp1 and report here for the first time that Trp1 is assembled in signaling complex associated with caveolin-scaffolding lipid raft domains. Endogenous hTrp1 and caveolin-1 were present in low density fractions of Triton X-100-extracted human submandibular gland cell membranes. Depletion of plasma membrane cholesterol increased Triton X-100 solubility of Trp1 and inhibited carbachol-stimulated Ca(2+) signaling. Importantly, thapsigargin stimulated Ca(2+) influx, but not internal Ca(2+) release, and inositol 1,4,5-triphosphate (IP(3))-stimulated I(soc) were also attenuated. Furthermore, both anti-Trp1 and anti-caveolin-1 antibodies co-immunoprecipitated hTrp1, caveolin-1, Galpha(q/11), and IP(3) receptor-type 3 (IP(3)R3). These results demonstrate that caveolar microdomains provide a scaffold for (i) assembly of key Ca(2+) signaling proteins into a complex and (ii) coordination of the molecular interactions leading to the activation of SOC. Importantly, we have shown that Trp1 is also localized in this microdomain where it interacts with one or more components of this complex, including IP(3)R3. This finding is potentially important in elucidating the physiological function of Trp.

Calcium↗
PubMed2000

Neuronal nicotinic acetylcholine receptors: from the gene to the disease.

The neuronal nicotinic acetylcholine receptors are excitatory ligand-gated channels. Widely expressed throughout the peripheral and central nervous system, their properties depend upon their subunit composition. Furthermore, genetic studies have revealed a high degree of variation at the genomic level and alternative splicing of the mRNAs coding for these integral membrane proteins. In particular, genes coding for alpha4 and alpha7 subunits harbour a high degree of polymorphisms. Although well characterised at their molecular and functional level, the role of these receptors in the central nervous system remains obscure. Despite accumulating evidence for the participation of nicotinic receptors in disorders of the central nervous system including nicotinic addiction, Parkinson's disease, Alzheimer's disease and Tourette's syndrome, the exact role of these receptors is still speculative. Because most of these phenotypes are complex and genetically heterogeneous, the investigation is difficult. However, in the past few years, significant progress has been made in understanding the contribution of nicotinic acetylcholine receptors to the origin of epilepsies and schizophrenia. By concentrating on the latest results gained for these diseases, we discuss in this review the possible relationships between neuronal nicotinic receptors and neurological and psychiatric disorders.

Alleles↗
PubMed2000

International patterns of tuberculosis and the prevalence of symptoms of asthma, rhinitis, and eczema.

BACKGROUND: An ecological analysis was conducted of the relationship between tuberculosis notification rates and the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema in 85 centres from 23 countries in which standardised data are available. These essentially comprised countries in Europe as well as the USA, Canada, Australia, and New Zealand. METHODS: Tuberculosis notification rates were obtained from the World Health Organization. Data on the prevalence of symptoms of asthma, rhinitis, and eczema in 235 477 children aged 13-14 years were based on the responses to the written and video questionnaires from the International Study of Asthma and Allergies in Childhood (ISAAC). The analysis was adjusted for gross national product (GNP) as an estimate of the level of affluence. RESULTS: Tuberculosis notification rates were significantly inversely associated with the lifetime prevalence of wheeze and asthma and the 12 month period prevalence of wheeze at rest as assessed by the video questionnaire. An increase in the tuberculosis notification rates of 25 per 100 000 was associated with an absolute decrease in the prevalence of wheeze ever of 4.7%. Symptoms of allergic rhinoconjunctivitis in the past 12 months were inversely associated with tuberculosis notification rates, but there were no other significant associations with other ISAAC questions on allergic rhinoconjunctivitis or atopic eczema. CONCLUSIONS: These findings are consistent with recent experimental evidence which suggests that exposure to Mycobacterium tuberculosis may reduce the risk of developing asthma.

Adolescent↗
PubMed1999

Elevated mortality from nonalcohol-related chronic liver disease among female rubber workers: is it associated with exposure to nitrosamines?

BACKGROUND: Despite several case reports describing liver toxicity of nitrosamines and the fact that some N-nitroso compounds are used to induce cirrhosis of the liver in animal models, this association has not been investigated in epidemiological studies. METHODS: A cohort of 2,875 female rubber workers who were active on January 1, 1976, or hired thereafter, and who had been employed for at least 1 year in one of five plants producing tires or technical rubber goods was followed for mortality from January, 1976, through December, 1991. Work histories were reconstructed using routinely documented "cost center codes" and classified into six work areas. Age and calendar year standardized mortality ratios (SMR) and 95% confidence intervals (95% CI) were calculated and stratified by plant, work area, year of hire, and years of employment in the respective work area. RESULTS: The excess mortality from cirrhosis of the liver was most pronounced for nonalcohol-related cirrhosis of the liver (ICD-9 571.4-571.9: 10 deaths, SMR 202; 95% CI 97-372). Mortality from alcohol-related cirrhosis of the liver (ICD-9 571.0-571.3: 3 deaths, SMR 153; 95% CI 31-446) and from other alcohol-related diseases (organic psychoses, injury, and poisoning) was not statistically significantly elevated. All 10 cases of nonalcohol-related cirrhosis had worked in production of technical rubber goods (SMR 279; 95% CI 134-514) and risks increased with earlier years of hire and with longer duration of employment in this work area. DISCUSSION: Although our results must be interpreted with caution, they suggest that the observed excess deaths from cirrhosis of the liver are associated with occupational risk factors. In light of additional evidence from case reports and animal data, exposure to nitrosamines may be a plausible risk factor for the observed excess mortality.

Adult↗
PubMed1998

Properties of neuronal nicotinic acetylcholine receptor mutants from humans suffering from autosomal dominant nocturnal frontal lobe epilepsy.

1. Physiological and pharmacological properties of the human neuronal alpha4beta2 nicotinic AChR and mutants found in patients suffering from autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) were studied. 2. Investigations of nicotinic AChRs reconstituted in Xenopus oocytes with the control or mutated alpha4 subunits revealed that both mutation S248F as well as the Leucine insertion (776ins3) result in major but different changes in the physiological and pharmacological properties of the receptors. 3. Mutation S248F causes a decrease in apparent affinity to ACh of about 7 fold. In addition, this receptor already desensitizes during exposure to agonist concentration 3000 times lower than the control. 4. 776ins3 provokes a 10 fold increase of apparent ACh affinity, an increase in the IC50 caused by prolonged ACh exposures and a slowing down of the response decay. 5. At saturating ACh concentration cells expressing the S248F mutant display average currents that are about five times smaller than control. 6. When measured at very low concentration, agonist sensitivities of the control and mutated receptors to ACh, nicotine and epibatidine exhibit differences that match those observed for higher agonist concentrations. 7. Mutation 776ins3 increases the apparent efficacy to cytisine. 8. Data presented herein suggest that mutation S248F mainly affects the desensitization properties of the receptor while the leucine insertion (776ins3) increases the probability of transition to the active state. Although these mutations differentially affect the receptor properties they both result in reduced permeability to calcium and enhanced desensitization sensitivity that might account for the ADNFLE phenotype.

Animals↗
PubMed1997

An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy.

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is the first, and to date only, idiopathic epilepsy for which a specific mutation has been found. A missense mutation in the critical M2 domain of the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4) has been recently identified in one large Australian pedigree. Here we describe a novel mutation in the M2 domain of the CHRNA4 gene in a Norwegian family. Three nucleotides (GCT) were inserted at nucleotide position 776 into the coding region for the C-terminal end of the M2 domain. Physiological investigations of the receptor reconstituted with the mutated CHRNA4 subunit reveal that this insertion does not prevent the receptor function but increases its apparent affinity for ACh. In addition, this mutant receptor shows a significantly lower calcium permeability that, at the cellular level, may correspond to a loss of function. Comparison of the two mutations identified so far in families with ADNFLE illustrates that different mutations can result in similar phenotypes.

Amino Acid Sequence↗
PubMed1997

Worldwide variations in prevalence of symptoms of allergic rhinoconjunctivitis in children: the International Study of Asthma and Allergies in Childhood (ISAAC).

BACKGROUND: As part of the International Study of Asthma and Allergies in Childhood (ISAAC), prevalence surveys were conducted among representative samples of school children from locations in Europe, Asia, Africa, Australia, North and South America. SUBJECTS: 257,800 children aged 6-7 years from 91 centres in 38 countries, and 463,801 children aged 13-14 years from 155 centres in 56 countries. METHODS: Written symptom questionnaires were translated from English into the local language for self-completion by the 13-14-year-olds and completion by the parents of the 6-7-year-olds. Rhinitis was described as a problem with sneezing, or a runny, or blocked nose when you (your child) DID NOT have a cold or the flu. Additional questions were asked about rhinitis associated with itchy-watery eyes, interference with activities and a history of hay fever ever. RESULTS: The prevalence of rhinitis with itchy-watery eyes ("rhinoconjunctivitis") in the past year varied across centres from 0.8% to 14.9% in the 6-7-year-olds and from 1.4% to 39.7% in the 13-14-year-olds. Within each age group, the global pattern was broadly consistent across each of the symptom categories. In centres of higher prevalence there was great variability in the proportion of rhinoconjunctivitis labelled as hay fever. The lowest prevalences of rhinoconjunctivitis were found in parts of eastern Europe, south and central Asia. High prevalences were reported from centres in several regions. CONCLUSION: These results suggest substantial worldwide variations in the prevalence and labelling of symptoms of allergic rhinoconjunctivitis which require further study. These differences, if real, may offer important clues to environmental influences on allergy.

Adolescent↗
PubMed1996

An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics.

The alpha4 subunit of the neuronal nicotinic acetylcholine receptor is the first gene shown to be involved in a human idiopathic epileptic disease. A missense mutation, leading to the replacement of serine 248 by phenylalanine in the second transmembrane segment, had been detected in patients with autosomal dominant nocturnal frontal lobe epilepsy. The properties of the wild type receptor composed of alpha4 and beta2 subunits and the mutant receptor where alpha4 subunits carried the mutation at serine 248 were compared by means of cDNA manipulation and expression in Xenopus oocytes. The mutant receptor exhibited faster desensitization upon activation by acetylcholine and recovery from the desensitized state was much slower than in the wild type receptor. We conclude that the reported mutation causes seizures via a diminution of the activity of the alpha4beta2 neuronal nicotinic acetylcholine receptor.

Acetylcholine↗
PubMed1996

Complex regulation of the DNA-binding activity of p53 by phosphorylation: differential effects of individual phosphorylation sites on the interaction with different binding motifs.

The tumor suppressor protein p53 exists in different phosphorylation states depending on the cellular environment and perhaps the stage of the cell cycle. These different phosphorylation states can be mimicked in the baculovirus expression system by employing the phosphatase inhibitor okadaic acid. Hyperphosphorylation of p53, particularly of Ser313 and/or Ser309, stimulated its DNA binding activity (Fuchs, Hecker and Scheidtmann, Eur. J. Biochem. 228, 625, 1995). Here we show that hyperphosphorylation of p53 has different effects on its DNA-binding activity, depending on the phosphorylation sites and the binding motif: (i) Phosphorylation of amino-terminal sites appeared to reduce binding to the RGC consensus motif, whereas additional phosphorylation of both, Ser313 and Ser309 led to enhanced binding. (ii) Upon hyperphosphorylation, binding to the RGC motif was enhanced whereas binding to the p53 response element of the bax1 gene promoter was diminished. (iii) DNA binding was also greatly enhanced by antibodies Pab 122 and 421 directed against the carboxyl terminus, but this latter effect was superimposed by the phosphorylation state of p53. Thus, the DNA binding activity of p53 appears to be regulated in a complex way in that (i) binding to a given sequence motif may be regulated by differential phosphorylation and/or by interaction with other factors; (ii) binding to different motifs may be modulated in opposite ways. Thus, the different genes that are regulated by p53 may be differently affected by these parameters.

Animals↗
PubMed1996

Exon-intron structure of the human neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4).

The human neuronal nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4) is located in the candidate region for three different phenotypes: benign familial neonatal convulsions, autosomal dominant nocturnal frontal lobe epilepsy, and low-voltage EEG. Recently, a missense mutation in transmembrane domain 2 of CHRNA4 was found to be associated with autosomal dominant nocturnal frontal lobe epilepsy in one extended pedigree. We have determined the genomic organization of CHRNA4, which consists of six exons distributed over approximately 17 kb of genomic DNA. The nucleotide sequence obtained from the genomic regions adjacent to the exon boundaries enabled us to develop a set of primer pairs for PCR amplification of the complete coding region. The sequence analysis provides the basis for a comprehensive mutation screening of CHRNA4 in the above-mentioned phenotypes and possibly in other types of idiopathic epilepsies.

Amino Acid Sequence↗
PubMed1993

Self-reported prevalence of asthma symptoms in children in Australia, England, Germany and New Zealand: an international comparison using the ISAAC protocol.

There is a need for a standardized approach to international and regional comparisons of the prevalence and severity of asthma, and for the monitoring of asthma morbidity over time. In 1991, standardized written and video questionnaires were developed and administered in surveys of schoolchildren, aged 12-15 yrs, in five regions in four countries: Adelaide, Australia (n = 1,428); Sydney, Australia (n = 1519); West Sussex, England (n = 2,097); Bochum, Germany (n = 1928); and Wellington, New Zealand (n = 1863). The self-reported prevalence of wheezing during the previous 12 months was similar in West Sussex (29% using the written questionnaire and 30% using the video questionnaire), Wellington (28 and 36%), Adelaide (29 and 37%), and Sydney (30 and 40%), but was lower in Bochum (20 and 27%). The one year prevalence of severe wheezing limiting speech was greater in Wellington (11%), Adelaide (10%) and Sydney (13%), than in West Sussex (7%) and Bochum (6%). The self-reported one year prevalences of frequent attacks, frequent nocturnal wheezing, and doctor diagnosed asthma, were also higher in the Australasian centres than in the European centres. We conclude, that an international comparison of asthma symptom prevalence in childhood, using simple standardized instruments, is feasible. Possible explanations for the differences in reported asthma severity between the Australasian and European centres include differences in exposure to risk factors and differences in the management of asthma.

Adolescent↗
PubMed1989

Aging according to biography.

Aging can no longer be considered an afterthought in biographies. How scholarly biographers treat their subjects is considered in the context of the work of Erik H. Erikson. Readers of biographies can discover in accounts of the subject's last years the same interest in developmental values typical of biographical attention to youth. Developmental theorists can observe in biography representations of the life cycle that add meaning to aging.

Aging↗