Biomedical subjects

Thomas Keil

Publications and source records attributed to Thomas Keil.

6 recordsLinked to original sources

PubMed2006

Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march.

BACKGROUND: Childhood eczema often precedes the development of asthma and allergic rhinitis in the so-called atopic march. Recently, 2 loss-of-function mutations in the gene encoding the epidermal barrier protein filaggrin were reported to be predisposing factors for eczema and concomitant asthma, suggesting a possible role in disease transition. OBJECTIVE: We aimed to assess the importance of filaggrin loss-of-function mutations in the susceptibility to eczema and associated clinical phenotypes. METHODS: The filaggrin mutations were genotyped and tested for association with allergic disorders in 2 large European populations including 1092 children with eczema. RESULTS: Highly significant association of the filaggrin null mutations with eczema and concomitant asthma was replicated. Moreover, we found that these mutations predispose to asthma, allergic rhinitis, and allergic sensitization only in the presence of eczema. We show that the presence of 2 filaggrin null alleles is an independent risk factor for asthma in children with eczema, and that the 2 investigated mutations account for about 11% of eczema cases in the German population. CONCLUSION: These results lend strong support to the role of filaggrin in the pathogenesis of eczema and in the subsequent progression along the atopic march. The fact that previous expression of eczema is a prerequisite for the manifestation of allergic airways disease and specific sensitization highlights the importance of the epidermal barrier in the pathogenesis of these disorders. CLINICAL IMPLICATIONS: Our results suggest that the maintenance and repair of the epidermal barrier in infants with eczema may prevent the subsequent development of allergic airways disease.

Asthma↗

PubMed2006

A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis.

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.

Base Sequence↗

PubMed2005

Noise burden and the risk of myocardial infarction.

AIMS: Chronic noise exposure is associated with adverse pathophysiological effects and may contribute to the progression of cardiovascular disease. We, therefore, determined the risk of noise for the incidence of myocardial infarction. METHODS AND RESULTS: In a case-control study, 4115 patients (3054 men, 56+/-9 years; 1061 women, 58+/-9 years) consecutively admitted to all 32 major hospitals in Berlin with confirmed diagnosis of acute myocardial infarction were enrolled from 1998 to 2001 in the Noise and Risk of Myocardial Infarction (NaRoMI) study. Controls were matched for gender, age, and hospital. In standardized interviews, information was obtained on environmental and work noise annoyance. The sound levels of environmental and work noise were assessed using traffic noise maps as proxy and international standards for workplaces, respectively. In multivariate logistic regression models, the adjusted odds ratios of noise variables were determined. There was a marginally increased risk of myocardial infarction associated with annoyance by environmental noise in women (adjusted odds ratio 1.47, 95% confidence interval 0.95-2.25, P=0.081) but not in men, and not associated with annoyance by work noise. Environmental sound levels were associated with increased risk in men and women (odds ratios 1.46, 1.02-2.09, P=0.040 and 3.36, 1.40-8.06, P=0.007) and work sound levels in men only (1.31, 1.01-1.70, P=0.045). CONCLUSION: Chronic noise burden is associated with the risk of myocardial infarction. The risk increase appears more closely associated with sound levels than with subjective annoyance. Further investigation of the gender-related risk of noise exposure may aid in improving prevention.

Case-Control Studies↗

PubMed2005

Outcome and costs of homoeopathic and conventional treatment strategies: a comparative cohort study in patients with chronic disorders.

OBJECTIVES: To evaluate the effectiveness of homoeopathy versus conventional treatment in routine care. DESIGN: Comparative cohort study. SETTING: Patients with selected chronic diagnoses were enrolled in medical practice. INTERVENTIONS: Conventional treatment or homeopathy. OUTCOME MEASURES: Severity of symptoms assessed by patients and physicians (visual rating scale, 0-10) at baseline, 6 and 12 months and costs. RESULTS: The analyses of 493 patients (315 adults, 178 children) indicated greater improvement in patients' assessments after homoeopathic versus conventional treatment (adults: homeopathy from 5.7 to 3.2; conventional, 5.9-4.4; p=0.002; children from 5.1 to 2.6 and from 4.5 to 3.2). Physician assessments were also more favourable for children who had received homoeopathic treatment (4.6-2.0 and 3.9-2.7; p<0.001). Overall costs showed no significant differences between both treatment groups (adults, 2155 versus 2013, p=0.856; children, 1471 versus 786, p=0.137). CONCLUSION: Patients seeking homoeopathic treatment had a better outcome overall compared with patients on conventional treatment, whereas total costs in both groups were similar.

Adolescent↗

PubMed2004

Decoding cilia function: defining specialized genes required for compartmentalized cilia biogenesis.

The evolution of the ancestral eukaryotic flagellum is an example of a cellular organelle that became dispensable in some modern eukaryotes while remaining an essential motile and sensory apparatus in others. To help define the repertoire of specialized proteins needed for the formation and function of cilia, we used comparative genomics to analyze the genomes of organisms with prototypical cilia, modified cilia, or no cilia and identified approximately 200 genes that are absent in the genomes of nonciliated eukaryotes but are conserved in ciliated organisms. Importantly, over 80% of the known ancestral proteins involved in cilia function are included in this small collection. Using Drosophila as a model system, we then characterized a novel family of proteins (OSEGs: outer segment) essential for ciliogenesis. We show that osegs encode components of a specialized transport pathway unique to the cilia compartment and are related to prototypical intracellular transport proteins.

Animals↗

PubMed2004

A tissue specific cytochrome P450 required for the structure and function of Drosophila sensory organs.

Cytochrome P450s have generally been acknowledged as broadly tuned detoxifying enzymes. However, emerging evidence argues P450s have an integral role in cell signaling and developmental processes, via their metabolism of retinoic acid, arachidonic acid, steroids, and other cellular ligands. To study the morphogenesis of Drosophila sensory organs, we examined mutants with impaired mechanosensation and discovered one, nompH, encodes the cytochrome P450 CYP303a1. We now report the characterization of nompH, a mutant defective in the function of peripheral chemo- and mechanoreceptor cells, and demonstrate CYP303a1 is essential for the development and structure of external sensory organs which mediate the reception of vital mechanosensory and chemosensory stimuli. Notably this P450 is expressed only in sensory bristles, localizing in the apical region of the socket cell. The wide diversity of the P450 family and the growing number of P450s with developmental phenotypes suggests the exquisite tissue and subcellular specificity of CYP303a1 illustrates an important aspect of P450 function; namely, a strategy to process critical developmental signals in a tissue- and cell-specific manner.

Amino Acid Sequence↗