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Biomedical subjects

Lars Hansen

Publications and source records attributed to Lars Hansen.

At least 19 recordsLinked to original sources
PubMed2007

The functional Pro129Thr variant of the FAAH gene is not associated with various fat accumulation phenotypes in a population-based cohort of 5,801 whites.

Food intake and weight gain are influenced by endocannabinoids whose actions are regulated by the fatty acid amide hydrolase (FAAH) enzyme. The homozygous Thr/Thr genotype of the functional Pro129Thr variant (rs324420) in the gene encoding FAAH was recently reported to associate with overweight and obesity in white and black populations. We investigated the Pro129Thr variant in relation to overweight and obesity in a relatively large population-based study sample of Danish whites (n=5,801). In case-control studies of obesity, a borderline association with the major Pro allele was identified; however, after correction for multiple testing, no association was found. Furthermore, a possible association between the major Pro allele and obesity was not supported by studies of obesity-related quantitative traits. In conclusion, in a large study sample, we were unable to find robust evidence of an association of the Pro129Thr FAAH variant with overweight, obesity, and any related quantitative traits among the examined whites.

Adult↗
PubMed2006

[Fructose 1,6-bisphosphatase deficiency as a cause of recessive serious hypoglycaemia].

Fructose 1,6-bisphosphatase (FBPase) deficiency is an autosomal recessive disorder of gluconeogenesis. Here we describe a family from Morocco with parental consanguinity with three affected children. All were homozygous for a novel mutation in exon 5: 685 C-->T of the gene coding for the liver isoform of fructose 1,6-bisphosphatase (FBP1). The mutation changed the amino acid codon (Q229X) from a glutamine (CAG) in position 229 to a stop codon (TAG), which caused a shortening of the protein from the normal 338 amino acids to 228. The shortened protein lacks a major part of the active site and is therefore probably without enzymatic activity.

Consanguinity↗
PubMed2006

The congenital "ant-egg" cataract phenotype is caused by a missense mutation in connexin46.

PURPOSE: "Ant-egg" cataract is a rare, distinct variety of congenital/infantile cataract that was reported in a large Danish family in 1967. This cataract phenotype is characterized by ant-egg-like bodies embedded in the lens in a laminar configuration and is inherited as an autosomal dominant trait. We retrieved the family and performed linkage analysis to determine the disease locus and identify the mutated gene. METHODS: The family (CC00103) was identified in a National Register of Hereditary Eye Diseases and updated based on The Danish Civil Register System. Genome wide linkage analysis and haplotyping using STS marker systems were carried out to achieve a LOD score above 3. The disease-causing candidate gene was sequenced and the mutation was identified and verified by restriction enzyme digestion of genomic DNA from all individuals in family CC00103 and 60 healthy controls. RESULTS: Linkage analysis resulted in a LOD score of 3.91 for marker D13S1275 located close to the known cataract gene GJA3. A novel missense mutation c.32T > C (L11S), was found by sequencing DNA from two affected members. The mutation was present in all affected individuals and was neither found in unaffected family members nor in 60 healthy individuals by restriction enzyme digests. CONCLUSIONS: The congenital "ant-egg" cataract phenotype is caused by a L11S mutation in connexin46 (Cx46) located in the signal peptide domain. Further studies are needed to unravel the mechanism leading to the formation of the "ant-eggs".

Amino Acid Sequence↗
PubMed2006

The Pro12Ala variant of the PPARG gene is a risk factor for peroxisome proliferator-activated receptor-gamma/alpha agonist-induced edema in type 2 diabetic patients.

CONTEXT: Activation of peroxisome proliferator-activated receptors (PPARs)-gamma by thiazolidinediones (pioglitazone, rosiglitazone) and dual-acting PPARalpha/gamma agonists (pargluva, ragaglitazar) is a widely used pharmacological principle to treat insulin resistance and type 2 diabetes. Clinically, however, fluid retention and edema are worrying side effects with these drugs. OBJECTIVE: The objective of the present study was to investigate any variation in the PPARG and PPARA genes associated with the risk of fluid retention and development of peripheral edema in patients with type 2 diabetes treated with the dual-acting PPARalpha/gamma agonist ragaglitazar. DESIGN: Single-nucleotide polymorphism and haplotype analyses of the PPARA and PPARG genes were performed on DNA obtained from 345 type 2 diabetic patients randomized to 26-wk monotherapy with the dual-acting PPARalpha/gamma agonist ragaglitazar. RESULTS: At 26 wk, edema was recorded in 48 of the patients (14%) treated with ragaglitazar, and Cox regression analyses identified the common Pro12Ala variant of the PPARG gene as biologically the most important risk factor (hazard ratio 4.42, P = 0.0081) for edema. Other risk factors included female gender (hazard ratio 3.34, P = 0.0005) and weight change during treatment (hazard ratio 1.20, P = 0.0017). CONCLUSIONS: A population-attributable risk of approximately 50% for the Pro12Pro genotype indicates that testing for the Pro12Ala of the PPARG gene in addition to the already identified clinical risk factors may become a useful tool to further reduce the risk of PPARgamma agonist-induced fluid retention and edema in patients with type 2 diabetes.

DNA↗
PubMed2006

A novel primate specific gene, CEI, is located in the homeobox gene IRXA2 promoter in Homo sapiens.

The Iroquois (IRX) homeobox gene family consists of six highly conserved transcription factors that are of importance for normal embryonic development. They are organized in two gene clusters in human, one on 5p15.33 and the other one on 16q12.2, respectively, and both the organization and the structure of the genes are highly conserved. An open reading frame coding for an unknown protein is identified in the promoter of IRXA2 on chromosome 5p. This new gene is composed of four exons and it is orientated in a head-to-head manner to IRXA2. Only a short 851 bp segment separates the two translation start codons and the two genes may share a bi-directional promoter. This bi-directional promoter is embedded in a large CpG-island, that also continues into both genes. RT-PCR analysis of the new gene reveals two alternative mRNA transcripts and a third mRNA transcript can be predicted from EST clones. The expression profile of the gene analysed in 9 different human tissues reveals that it is expressed in a coordinated fashion with IRXA2, which has led to the name CEI (Coordinated Expression to IRXA2). The CEI protein lacks homology to any known protein or protein domain in public databases, and a putative amino terminal signal peptide suggests the protein is secreted or ER compartment located. The gene is only found in the human and the chimpanzee genome, but not in the mouse or the rat genome, which suggests that CEI is unique for higher primates. As the identified bi-directional promoter not being a relic of an ancient compact genome, CEI may play an important role in the evolution of higher primates in coordination with the IRX genes.

Amino Acid Sequence↗
PubMed2006

Plane orientation for standardization in 3-dimensional cephalometric analysis with computerized tomography imaging.

INTRODUCTION: The purpose of this study was to propose certain landmarks and planes to standardize 3-dimensional image orientation. METHODS: Cone-beam computerized tomographic images were obtained from 10 adolescent patients and analyzed with AMIRA software (AMIRA, Mercury Computer Systems, Berlin, Germany). RESULTS: Four points (ELSA, right superior external auditory meatus, left superior external auditory meatus, and mid-dorsum foramen magnum) were located on each image. The axial-horizontal plane (x-y plane) was then determined by using both superior external auditory meatus and ELSA; the sagittal-vertical plane (z-y plane) was formed by ELSA and mid-dorsum foramen magnum perpendicular to the x-y plane. CONCLUSIONS: All points had high intrareliability and were adequate for standardizing the orientation of 3-dimensional images.

Adolescent↗
PubMed2006

Rating suicidality in schizophrenia: items on global scales (HoNOS and CPRS) correlate with a validated suicidality rating scale (InterSePT).

The use of general scales such as the Health of the Nation Outcome Scale (HoNOS) and the Comprehensive Psychopathological Rating Scale (CPRS) are widespread. Both scales contain non-validated items on suicidality. This study aimed to establish whether an association between these suicidality items and the validated scale, InterSePT exists. Forty patients with a diagnosis of schizophrenia or schizo-affective disorder were assessed using the three scales. A highly significant association between the two items and the validated scale was found. The suicidality items from HoNOS and CPRS appear to be strong indicators of suicidality in this patient population. The findings allow for use of the suicidality items in clinical assessments and re-investigation of suicidality of other studies where these general rating scales have been used.

Humans↗
PubMed2005

A 72-year-old Danish puzzle resolved--comparative analysis of phenotypes in families with different-sized HOXD13 polyalanine expansions.

A phenotype-genotype correlation was previously described for carriers of different sized of polyalanine expansions in HOXD13. We report on a detailed comparison of 55 members (approximately 220 limbs) from 4 Danish families with duplications of 21 or 27 bp, expanding the polyalanine repeat from 15 to 22 and 24 residues, respectively. Two of these were previously described by Danish pioneers of human genetics, Tage Kemp and Oluf Thomsen. A clinical score was assigned to each limb based on manifestations assumed to represent different degrees of a duplication defect in hand rays 3-4 and foot rays 4-5. The length of metacarpals and phalangeal bones in rays 1, 2, and 5 was measured on hand radiographs and converted to Z-scores. The relative difference between corresponding right and left bones and directional, total, and fluctuating asymmetry was calculated for each individual. All of these parameters were compared between carriers of the +9 alanine expansion, the +7 alanine expansion, and non-mutation carriers with affected parents from the two families. Upper limb scores and the rate of abnormal bones (>2SD) were significantly higher in the first group than in the others. The first metacarpal and the middle phalanx of the little finger were significantly shorter, and the proximal phalanx of the index finger was significantly longer in this group than in the others. An increased level of total and fluctuating asymmetry was observed in long expansion carriers. Thus, our data have added evidence to the phenotype-genotype correlation previously reported, which was further extended to include lesser involvement of bones in ray 1, 2, and 5.

Base Sequence↗
PubMed2005

Male-to-male transmission in Laurin-Sandrow syndrome and exclusion of RARB and RARG.

We report on a father and a son with nasal and limb defects characteristic of Laurin-Sandrow syndrome (LSS) excluding for the first time X-linked inheritance in this rare condition. Based on a search for genes expressed late during nose formation and early in limb formation we identified retinoic acid receptor B (RARB) and retinoic acid receptor G (RARG) as possible candidate genes and sequenced bidirectionally including all exons and intron-exon bounders. We identified a single nucleotide substitution in intron 2 of RARB, which is conserved in human, chimp, dog, mouse, rat, and chicken. However, it was located 83 bp from exon 2, suggesting it is a rare polymorphism which does not account for the phenotype. No other mutations were found. This suggests that another yet unknown gene is responsible for the condition.

Abnormalities, Multiple↗
PubMed2005

Studies of variations of the cyclin-dependent kinase inhibitor 1C and the cyclin-dependent kinase 4 genes in relation to type 2 diabetes mellitus and related quantitative traits.

CDK4 is involved in the regulation of body weight, pancreatic beta-cell proliferation, insulin responsiveness, and diabetes pathogenesis. CDK4 activity is inhibited by CDKN1C, which is regulated by insulin. In addition, CDKN1C plays an important role in beta-cell proliferation and is involved in the pathogenesis of the Beckwith-Wiedemann syndrome, a disorder characterized by neonatal hyperinsulinaemic hypoglycaemia and pre- and post-natal overgrowth. The aim of this study was to investigate if variations in the proximal promoter and the coding region of the CDKN1C and CDK4 genes are associated with type 2 diabetes or changes in related quantitative phenotypes among glucose-tolerant subjects. Mutation analyses of the two genes in 62 type 2 diabetic patients resulted in the discovery of seven variants of CDKN1C and two variants of CDK4. In a case-control study comprising 717 type 2 diabetic patients and 518 glucose-tolerant subjects the most frequent variants did not show any difference in allele frequencies between the type 2 diabetic patients and the control subjects. However, in two genotype-quantitative trait correlation studies involving 206 glucose-tolerant offspring of type 2 diabetic patients and 359 young, healthy subjects the CDKN1C del171APVA variant associated with increased birth weight (P=0.05 and P=0.05). Furthermore, the same variant tended to be associated with decreased basal glucose oxidation among 16 genotypically discordant dizygotic twins (P=0.03). In a genotype-quantitative trait study involving 500 middle-aged glucose-tolerant subjects the CDK4 IVS2-31G-->A variant was associated with an increased waist circumference (P=0.03) and waist-to-hip ratio (P=0.02) and altered fasting plasma glucose (P=0.03). However, these later findings could not be replicated in additional studies. In conclusion, variants in CDKN1C may contribute to the inter-individual variation in birth weight.

Aged↗
PubMed2005

Mapping of hereditary trichilemmal cyst (TRICY1) to chromosome 3p24-p21.2 and exclusion of beta-CATENIN and MLH1.

Trichilemmal cysts (also named pilar cyst) derived from the outer root sheath of the deeper parts of the hair follicle can segregate dominantly, and are caused by a yet unknown gene. In order to identify candidate genes for this trait we have ascertained a Danish family with 38 persons (11 affected), and carried out a genome wide scan with 580 DNA micro-satellite markers to identify the locus for a gene, which we termed TRICY1 (for trichilemmal cysts). We found tight linkage to D3S1277 (Z = 4.63; theta(M = F) = 0.00), with flanking markers D3S2432 (Z = 1.59; theta(M = F) = 0.08), and D3S3685 (Z = 2.69; theta(M = F) = 0.08) spanning 10.3 Mb on chromosome 3p24-p21.2. We sequenced two candidate genes previously reported in inherited hair defects, CTNNB1 and MLH1 but failed to detect mutations in exons and intron-exon bounders.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Comparison of suicide in people aged 65-74 and 75+ by gender in England and Wales and the major Western countries 1979-1999.

BACKGROUND: The factors most strongly associated with suicide are age and gender--more men than women, and, more people over 65 kill themselves. As a number of Governments have targets to reduce suicide levels we compare elderly suicide rates over a 20-year period in England and Wales. And the major Western countries focusing upon age and gender. METHOD: WHO mortality data were used to calculate three-year average General Population Suicide Rates (GPSR) for 1979-1981 to 1997-1999 and rates of people aged 65-74 and 75+ suicide by gender to provide ratios of change and a statistical comparison of England and Wales and the Major Western countries over the period. RESULTS: Male GSPR: '65-74' suicide ratios fell significantly in six countries and in three for the '75+'. Female GSPR: '65-74' suicide ratios fell in every country except Spain. Proportionately, there were more suicides in the over 65s in countries with an 'extended family' tradition, Spain, Italy, Germany, France and Japan, than in the five 'secular' countries. England and Wales male '65-74' suicide fell significantly more than Canada, France, Germany, Italy, Japan, Spain, Netherlands and the USA, and did significantly better than the other countries for all female senior citizen suicides. CONCLUSION: Suicide of the over-65s has improved in seven countries, especially in England and Wales, who had the greatest proportional reduction, which reflects well upon the psycho-geriatric and community services. However, in all countries, male 65-74 rates did not match the female out so extra efforts are needed to improve male rates.

Age Distribution↗
PubMed2005

Significant difference in knowledge between English and Danish psychiatrists.

PURPOSE: The purpose of the study was to investigate if differences in levels of knowledge existed between Danish and English training and specialist psychiatrists. This is important in the context of the free (and growing) movement of the medical workforce across European Union (EU) countries' borders. METHODS: A complete balanced two-way factorial study design was used. Ten training and ten specialist psychiatrists were recruited in each country from reputable, university hospitals. They answered 50 multiple choice questions (MCQs), translated into the appropriate language, consisting of four subcategories of questions: psychology (15 MCQs), psychopharmacology (10 MCQs), neuroscience (five MCQs) and psychopathology (20 MCQs). No memory or other types of aids were allowed at the knowledge test. A two-way analysis of variance was used to analyse the total knowledge score (number of correct answers) and the component subscores. Levene's test of equality of error variances was used to test for variance homogeneity. RESULTS: There were significant differences in total knowledge and psychology knowledge by country and level of training. UK doctors scored 3.10 points higher than Danish doctors, with 95% confidence interval (0.97, 5.23). The knowledge of the specialists was also significantly superior to that of the training psychiatrists, with 2.30 higher score, 95% confidence interval (0.17, 4.43). In the sub-categories only the scores in the psychology section were significantly different. UK doctors scored 2.30 higher than Danish doctors, with 95% confidence interval (1.15, 3.45). Specialists scored 1.20 higher than non-specialists with 95% confidence interval (0.05, 2.35). CONCLUSIONS: The results indicate that there is a significant difference in level of knowledge between psychiatrists in these two EU-countries, England and Denmark. This difference seemed to be chiefly the result of different knowledge of psychology. The disparity could be a result of the fundamentally different post-graduate training system in psychiatry in the two countries. Surprisingly, the differences in total knowledge and psychology knowledge between countries were larger than the differences between levels of training. The difference in knowledge is worrying taking into consideration that there is free movement of the workforce, including doctors, across the EU. The results here need further confirmation in future studies with greater numbers, more countries involved and perhaps additional measurements to MCQs.

Culture↗
PubMed2005

A systematic review of suicide rating scales in schizophrenia.

In spite of a substantial number of suicides in patients with schizophrenia, this area of research has until very recently been the Cinderella of schizophrenia research. Both clinical and research practices have been hampered by a lack of assessment tolls specifically designed to measure suicidality in patients with schizophrenia. This has partly been because of uncertainty about what constitutes reliable risk factors for suicide in schizophrenia. A literature search following evidence-based guidelines was carried out. A number of relevant articles were found, which were then critically reviewed. The majority of rating scales used for patients with schizophrenia were actually based--at least partly--on patients with other diagnoses than schizophrenia (affective conditions, schizoaffective disorder). This procedure could result in misleading conclusions as a result of the heterogeneity of the different mental illnesses. We conclude that, at present, only one rating scale measuring suicidality specifically designed for patients with schizophrenia (the InterSePT-scale) is based on both sound methodology and has clinical relevance. Suicide in patients with schizophrenia remains a pressing problem in the treatment of this high-risk group.

Humans↗
PubMed2005

Determination of the 'critical region' for cat-like cry of Cri-du-chat syndrome and analysis of candidate genes by quantitative PCR.

Cri-du-chat (CDC, OMIM 123450) is a chromosomal syndrome that results from partial deletions on the short arm of chromosome 5. The clinical features of CDC normally include high-pitched cat-like cry, mental retardation, microcephaly, hypertelorism and epicanthic folds. The cat-like cry is the most prominent clinical characteristic in newborn children and is usually considered as diagnostic for the CDC syndrome. Using a strategy of 'phenotype dissection', the critical region for cat-like cry was mapped to the chromosomal segment 5p15.3-5p15.2 in previous reports. In this study, the distal breakpoints of two interstitial deletions in two clinical distinctive CDC patients are analysed, one with and one without the cat-like cry. Using PCR, the critical region for the cat-like cry is mapped to a short 640 kbp region on chromosome 5p. Genome analysis of this critical region reveals a gene-rich sequence containing five known genes, five putative genes and three spliced EST sequences, altogether 71 predicted exons. Three genes, FLJ25076, a homolog to a ubiquitin-conjugating enzyme UBC-E2, FLJ20303, a nucleolar protein NOP2, which may play a role in the regulation of the cell cycle and MGC5309, a protein with similarity to Nut2, a Drosophila transcriptional coactivator, have been characterized and expression profiles determined by quantitative PCR. These results suggest that one candidate gene, FLJ25076, encodes a ubiquitin-conjugated enzyme E2 type, which is locally expressed in thoracic and scalp tissues. The other two genes are expressed uniformly in all tissues tested, which suggest that they are housekeeping genes.

Animals↗
PubMed2005

Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified.

Wolfram syndrome (WS) is a neuro-degenerative autosomal recessive (AR) disorder (OMIM #222300) caused by mutations in the WFS1 gene on 4p16.1. More than 120 mutations have been identified in WFS1 associated with AR WS, as well as autosomal dominant nonsyndromic low-frequency sensorineural hearing loss (LFSNHL). WFS1 variants were identified in eight subjects from seven families with WS, leading to the identification of four novel mutations, Q194X (nonsense), H313Y (missense), L313fsX360 (duplication frame shift) and F883fsX951 (deletion frame shift), and four previously reported mutations, A133T and L543R (missense), V415del (in frame triple deletion) and F883fsX950 (deletion frame shift). A mutation was found in 11/14 disease chromosomes, two subjects were homozygous for one mutation, one subject was compound heterozygous for two nucleotide substitutions (missense), one subject was compound heterozygous for a duplication and a deletion (frame shift), and in three families only one mutation was detected (Q194X and H313Y). All affected individuals shared clinically early-onset diabetes mellitus and progressive optic atrophy with onset in the first and second decades, respectively. In contrast, diabetes insipidus was present in two subjects only. Various degrees and types of hearing impairment were diagnosed in six individuals and cataract was observed in five subjects.

Adolescent↗