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Biomedical subjects

M A Walter

Publications and source records attributed to M A Walter.

At least 19 recordsLinked to original sources
PubMed2005

[Is the Canadian CT head rule for minor head injury applicable for patients in Germany?].

PURPOSE: To evaluate the applicability of the Canadian CT Head Rule (CCHR) on head trauma patients in a German university hospital. METHODS: 122 patients (m = 74; f = 48; 40 +/- 19 years) were examined with cranial CT due to minor head trauma. The need for cranial CT according to the CCHR was evaluated retrospectively. RESULTS: With a sensitivity of 98.9 % and a specificity of 46.6 % all patients with the need for neurosurgical intervention were detected by applying the major criteria of the CCHR. Also, every patient with severe brain injury was detected by the extended criteria with a sensitivity of 99.6 % and a specificity of 34.1 %. This would have led to a reduction in the rate of cranial CT examinations by 45.1 % for the major and 22.1 % for the extended criteria. No patient with severe brain injury would have been missed by application of the criteria. CONCLUSION: The Canadian CT Head Rule for patients with minor head trauma is applicable with a very high sensitivity and the potential of significantly reducing the rate of cranial CT examinations in these patients.

Accidental Falls↗
PubMed2005

Radioiodine uptake and thyroid hormone levels on or off simultaneous carbimazole medication: a prospective paired comparison.

AIM: To allow radioiodine (RAI) treatment in patients with need for anti-thyroid drug medication and low RAI uptakes we investigated the feasibility of discontinuing carbimazole for 3 days to enhance the RAI uptake without concurrent exacerbation of hyperthyroidism. METHODS: We prospectively investigated RAI dynamics and thyroid hormone concentration in 12 patients with low RAI uptake (<30%) under simultaneous carbimazole medication and 3 days after discontinuation. At both time points fT(4), T(3) and TSH were monitored. RESULTS: Discontinuation of carbimazole for 3 days led to a significant increase of RAI uptake in all patients. We found an enhancement up to 4.9-fold compared to the measurement on carbimazole. The mean RAI uptake increased from 15.2 +/- 4.4% to 50.1 +/- 15.5% (p<0.001). The intrapersonal radioiodine half-life increased from 4.2 +/- 1.6 days to 5.4 +/- 0.7 days (p = 0.13). Mean thyroid hormone concentration was not affected by the three day withdrawal of anti-thyroid drugs and no patient suffered from an aggravation of biochemical hyperthyroidism. CONCLUSION: A withdrawal of carbimazole for 3 days is long enough to provide sufficiently high RAI uptakes for RAI treatment in patients with low RAI uptakes and short enough to avoid the risk of exacerbation of hyperthyroidism.

Adult↗
PubMed2004

Essential structural and functional determinants within the forkhead domain of FOXC1.

The forkhead domain (FHD)-containing developmental transcription factor FOXC1 is mutated in patients presenting with Axenfeld-Rieger malformations. In this paper, we report the introduction of positive, negative or neutral charged amino acids into critical positions within the forkhead domain of FOXC1 in an effort to better understand the essential structural and functional determinants within the FHD. We found that FOXC1 is intolerant of mutations at I87. Additionally, alterations of amino acids within alpha-helix 1 of the FOXC1 FHD affected both nuclear localization and transactivation. Amino acids within alpha-helix 3 were also found to be necessary for transactivation and can have roles in correct localization. Interestingly, changing amino acids within alpha-helix 3, particularly R127, resulted in altered DNA-binding specificity and granted FOXC1 the ability to bind to a novel DNA sequence. Given the limited topological variation of FHDs, due to the high conservation of residues, we anticipate that models of forkhead domain function derived from these data will be relevant to other members of the FOX family of transcription factors.

Amino Acid Sequence↗
PubMed2004

Radioiodine therapy in hyperthyroidism: inverse correlation of pretherapeutic iodine uptake level and post-therapeutic outcome.

BACKGROUND: High iodine uptake levels are widely accepted as a condition for successful treatment with radioiodine (RAI). However, the existing data are controversial and the correlation of pretherapeutic RAI uptake level and outcome of RAI therapy has not yet been quantified. The aim of this study was to analyze the influence of RAI uptake on the outcome after RAI treatment and to estimate uptake-dependent success rates. MATERIALS AND METHODS: We retrospectively analyzed 229 patients (m = 53, f = 176; age 64 +/- 14 years) suffering from toxic adenoma, multinodular goitre or Graves' disease, respectively. Clinical status and T3, fT4 and TSH levels were assessed 3, 6, 12 and 18 months after treatment. Successful treatment was defined as loss of hyperthyroidism 18 months after radioiodine therapy. Logistic regression was used to assess the relation between the maximum iodine uptake and the rate of success and hypothyroidism, respectively, after RAI treatment. RESULTS: Overall, patients presented with pretherapeutic RAI uptake values between 17% and 100%. Eighteen months after RAI treatment, an euthyroid state was achieved in 136 patients (60%), hypothyroidism occurred in 47 patients (20%) and 46 patients (20%) remained hyperthyroid. The patients with the lowest pretherapeutic RAI uptakes showed the highest success rates. The overall success rate significantly decreased from 92% at low RAI uptakes to 57% at high uptakes (P = 0.002). This effect was found in the patients suffering from multinodular goitre as well as in the patients with Graves' disease. CONCLUSION: In contrast to the current opinion, our results provide evidence that the pretherapeutic iodine uptake level and post-therapeutic outcome are inversely correlated.

Adenoma↗
PubMed2002

The complexities of ocular genetics.

The cliché 'a picture is worth a thousand words' is a testament to the power of the visual system in helping us deal with our physical environment. Rarely do perturbations to the visual system, even minor ones, go unnoticed. Major defects in eye development may occur in the absence of systemic problems which threaten health. Ocular anomalies offer a window into many developmental events which would otherwise be difficult to study.

Eye↗
PubMed2001

Functional analyses of two newly identified PITX2 mutants reveal a novel molecular mechanism for Axenfeld-Rieger syndrome.

The specific role of PITX2 in the pathogenesis of anterior segment dysgenesis has yet to be clearly defined. We provide here new insight into PITX2 pathogenesis through mutational and functional analyses. Three PITX2 mutations were found in a screen of 38 unrelated individuals affected with anterior segment anomalies (8%). All three mutations were found among the 21 individuals affected with Axenfeld-Rieger syndrome (ARS). We have identified two novel mutations, a valine-->leucine (V45L) missense mutation at position 45 within the PITX2 homeodomain, and a seven amino acid duplication (7aaDup) of residues 6-12 of the homeodomain. DNA-binding studies of the two mutant PITX2 proteins demonstrated a <10-fold reduction in the DNA-binding activity of the V45L mutant, and a >100-fold reduction in activity of the 7aaDup mutant. Luciferase reporter assays showed a >200% increase in PITX2 transactivation activity of the V45L mutant, while the 7aaDup mutant was unable to transactivate at detectable levels. Our analyses of the V45L PITX2 mutant reveal that the DNA-binding domain of PITX2 can influence transactivation activity independently of DNA binding. Furthermore, our findings expand the hypothesis that the amount of residual PITX2 activity underlies the variable severity of ocular phenotypes that result from PITX2 mutation. For the first time, we present evidence that increased PITX2 activity may underlie the severe ARS ocular phenotype. We conclude that increased activity of one PITX2 allele may be as physiologically disruptive as a mutation that nullifies a PITX2 allele, with either condition resulting in ARS.

Abnormalities, Multiple↗
PubMed2001

Genetic study of SOX9 in a case of campomelic dysplasia.

Campomelic dysplasia (CD) is a sporadic autosomal dominant syndrome that results in skeletal malformation and developmental abnormalities. Death usually occurs neonatally as a result of respiratory insufficiencies, but life expectancy varies depending on the severity of the phenotype. XY sex reversal is common in CD, and a range of genital defects is observed in males and females. CD is due to mutations in SOX9, a member of the SOX (SRY-related HMG box) gene family. SOX9 is a transcription factor involved in chondrogenesis and sex determination. We present a CD patient with a normal 46,XX karyotype and female phenotype. Single-stranded conformation polymorphism analysis of DNA from this CD patient demonstrated a single-stranded conformation polymorphism shift in the C-terminal region of SOX9. DNA sequencing showed a frameshift mutation resulting from the insertion of a single guanine residue in nucleotide region 1,453-1,456. This insertion mutation creates a mutant SOX9 open reading frame that is 201 nucleotides longer than the normal gene. It has been shown that the C-terminal region of SOX9 is responsible for the transactivating ability of the protein. The frameshift identified here affects approximately half of the protein region needed for full transactivating function. We hypothesize that residual SOX9 function may explain why this patient survived infancy.

Adult↗
PubMed2001

Isolation of a ubiquitin-like (UBL5) gene from a screen identifying highly expressed and conserved iris genes.

We have screened a human adult iris cDNA library to identify genes that are highly expressed and conserved between humans and pigs. We identified human iris cDNAs that hybridized at high stringency to a porcine choroidal ring cDNA probe. Of 1568 human iris cDNAs examined, 176 were found to have high expression in porcine choroidal rings. One of the 176 clones was identified as a previously uncharacterized cDNA that we have named the Ubiquitin-like 5 gene (UBL5). The UBL5 gene is located on chromosome 19p13.2, and its genomic structure has been examined. There is a UBL5 pseudogene on chromosome 17p11.2. We have also found homologues to the UBL5 gene in Arabidopsis thaliana, Caenorhabditis elegans, Schizosaccharomyces pombe, and Saccharomyces cerevisiae. Northern blot analysis of the Ubiquitin-like gene 5 revealed expression in every tissue tested, with the highest levels of RNA expression in heart, skeletal muscle, kidney, liver, iris, and lymphoblasts. Intracellular localization experiments in COS-7 cells showed that the recombinant UBL5 protein is cytoplasmic. Western analysis demonstrated that the recombinant UBL5 protein is approximately 9 kDa, as predicted from the cDNA. A comparison between UBL5 and its homologues with other Ubiquitin-like proteins and Ubiquitin, using the PROTDIST program, suggests that the UBL5 genes are a separate class of Ubiquitin-like genes. Further characterization of the UBL5 gene will determine the function of the encoded protein and whether it is a candidate for ocular disease.

Adult↗
PubMed2001

Analyses of the effects that disease-causing missense mutations have on the structure and function of the winged-helix protein FOXC1.

Five missense mutations of the winged-helix FOXC1 transcription factor, found in patients with Axenfeld-Rieger (AR) malformations, were investigated for their effects on FOXC1 structure and function. Molecular modeling of the FOXC1 forkhead domain predicted that the missense mutations did not alter FOXC1 structure. Biochemical analyses indicated that, whereas all mutant proteins correctly localize to the cell nucleus, the I87M mutation reduced FOXC1-protein levels. DNA-binding experiments revealed that, although the S82T and S131L mutations decreased DNA binding, the F112S and I126M mutations did not. However, the F112S and I126M mutations decrease the transactivation ability of FOXC1. All the FOXC1 mutations had the net effect of reducing FOXC1 transactivation ability. These results indicate that the FOXC1 forkhead domain contains separable DNA-binding and transactivation functions. In addition, these findings demonstrate that reduced stability, DNA binding, or transactivation, all causing a decrease in the ability of FOXC1 to transactivate genes, can underlie AR malformations.

Amino Acid Sequence↗
PubMed2001

Use of radiation hybrid panels to map genetic loci.

The mapping of genetic loci within organisms has been accelerated by the advent of Radiation Hybrid (RH) panels. These panels are available for humans and non-humans including mice, baboon, rat, and canine. This article contains a general protocol for the use of the Genebridge 4 whole genome RH panel to map a human locus. This protocol may also be adjusted to suit the other RH panels currently available.

Chromosome Mapping↗
PubMed2000

Cloning, characterization, localization, and mutational screening of the human BARX1 gene.

The Bar subclass of homeodomain proteins was first identified for its role in Drosophila eye development. The Bar subclass homolog, Barx1, has since been cloned in mouse and in chick. The expression of Barx1 in developing teeth and craniofacial mesenchyme of neural crest origin makes it a strong candidate for the related human disorders of Axenfeld-Reiger syndrome (ARS) and iridogoniodysgenesis syndrome (IGDS). Here we report the cloning and characterization of a novel human Bar class gene, human BARX1. Screening of a human fetal craniofacial library resulted in the isolation of a 1.6-kb full-length transcript. Sequence analysis indicated that human BARX1, mouse Barx1, and chick Barx1 show 100% identity at the amino acid level within their homeodomains. Human BARX1 is expressed in a number of tissues including testis and heart by Northern analysis and in iris and craniofacial tissues by PCR of cDNA libraries. BARX1 chromosomal localization to 9q12 was determined by radiation hybrid mapping. Intron/exon boundaries were established, and primers were generated to PCR amplify all four exons. A mutation screen was conducted in 55 patients affected with ARS, IGDS, or related ocular malformations. While six sequence polymorphisms were detected, no disease-causing mutations of BARX1 were observed.

Amino Acid Sequence↗