Biomedical subjects

H B Rasmussen

Publications and source records attributed to H B Rasmussen.

At least 19 recordsLinked to original sources

PubMed2006

Links between cardiovascular disease and osteoporosis in postmenopausal women: serum lipids or atherosclerosis per se?

INTRODUCTION AND HYPOTHESIS: Epidemiological observations suggest links between osteoporosis and risk of acute cardiovascular events and vice versa. Whether the two clinical conditions are linked by common pathogenic factors or atherosclerosis per se remains incompletely understood. We investigated whether serum lipids and polymorphism in the ApoE gene modifying serum lipids could be a biological linkage. METHODS: This was an observational study including 1176 elderly women 60-85 years old. Women were genotyped for epsilon (epsilon) allelic variants of the ApoE gene, and data concerning serum lipids (total cholesterol, triglycerides, HDL-C, LDL-C, apoA1, ApoB, Lp(a)), hip and spine BMD, aorta calcification (AC), radiographic vertebral fracture and self-reported wrist and hip fractures, cardiovascular events together with a wide array of demographic and lifestyle characteristics were collected. RESULTS: Presence of the ApoE epsilon 4 allele had a significant impact on serum lipid profile, yet no association with spine/hip BMD or AC could be established. In multiple regression models, apoA1 was a significant independent contributor to the variation in AC. However, none of the lipid components were independent contributors to the variation in spine or hip BMD. When comparing the women with or without vertebral fractures, serum triglycerides showed significant differences. This finding was however not applicable to hip or wrist fractures. After adjustment for age, severe AC score (>or=6) and/or manifest cardiovascular disease increased the risk of hip but not vertebral or wrist fractures. CONCLUSION: The contribution of serum lipids to the modulators of BMD does not seem to be direct but rather indirect via promotion of atherosclerosis, which in turn can affect bone metabolism locally, especially when skeletal sites supplied by end-arteries are concerned. Further studies are needed to explore the genetic or environmental risk factors underlying the association of low triglyceride levels to vertebral fractures.

Aged↗

PubMed2006

Identification and evaluation of Peruvian plants used to treat malaria and leishmaniasis.

Households in eleven geographically and ethnically distinct areas in Loreto, Peru, were interviewed about their knowledge and use of plants, for the treatment of malaria and leishmaniasis. The survey resulted in 988 use records representing 118 plant-taxa for malaria and 289 use-records representing 85 plant-taxa for leishmaniasis. In both cases the 10 most frequently reported taxa accounted for about half of all the use-records. Plant material was collected and extracts were screened for in vitro inhibition of Plasmodium and Leishmania parasites. In the case of Plasmodium, extracts of 11 of the 13 most frequently reported plants showed significant growth inhibitory activity, while only a few plant extracts inhibited the growth of Leishmania parasites.

Animals↗

PubMed2005

Noninvasive genotyping and Mendelian analysis of microsatellites in African savannah elephants.

We obtained fresh dung samples from 202 (133 mother-offspring pairs) savannah elephants (Loxodonta africana) in Samburu, Kenya, and genotyped them at 20 microsatellite loci to assess genotyping success and errors. A total of 98.6% consensus genotypes was successfully obtained, with allelic dropout and false allele rates at 1.6% (n = 46) and 0.9% (n = 37) of heterozygous and total consensus genotypes, respectively, and an overall genotyping error rate of 2.5% based on repeat typing. Mendelian analysis revealed consistent inheritance in all but 38 allelic pairs from mother-offspring, giving an average mismatch error rate of 2.06%, a possible result of null alleles, mutations, genotyping errors, or inaccuracy in maternity assignment. We detected no evidence for large allele dropout, stuttering, or scoring error in the dataset and significant Hardy-Weinberg deviations at only two loci due to heterozygosity deficiency. Across loci, null allele frequencies were low (range: 0.000-0.042) and below the 0.20 threshold that would significantly bias individual-based studies. The high genotyping success and low errors observed in this study demonstrate reliability of the method employed and underscore the application of simple pedigrees in noninvasive studies. Since none of the sires were included in this study, the error rates presented are just estimates.

Animals↗

PubMed2003

Localization of KCNQ5 in the normal and epileptic human temporal neocortex and hippocampal formation.

The KCNQ family of voltage-dependent non-inactivating K+ channels is composed of five members, four of which (KCNQ2-5) are expressed in the CNS and are responsible for the M-current. Mutations in either KCNQ2 or KCNQ3 lead to a hereditary form of dominant generalized epilepsy. Using specific antisera to the KCNQ2, KCNQ3 and KCNQ5 subunits, we found that KCNQ3 co-immunoprecipitated with KCNQ2 and KCNQ5 subunits, but no association was detected between KCNQ2 and KCNQ5. Intense KCNQ5 immunoreactivity was found to be widely distributed throughout the temporal neocortex and the hippocampal formation. In these structures, both pyramidal and non-pyramidal neurons and a population of glial cells in the white matter expressed the KCNQ5 subunit. In the sclerotic areas of the CA fields of epileptic patients, a marked loss of KCNQ5 immunoreactive pyramidal neurons was found in relation with the loss of neurons in these regions. However, in the regions adjacent to the sclerotic areas, the distribution and intensity of KCNQ5 immunostaining was apparently normal. The widespread distribution of KCNQ5 subunits, its persistence in pharmacoresistant epilepsy, along with the significant role of the M-current in the control of neuronal excitability, makes this protein a possible target for the development of anticonvulsant drugs.

Adolescent↗

PubMed2003

Cebus apella, a nonhuman primate highly susceptible to neuroleptic side effects, carries the GLY9 dopamine receptor D3 associated with tardive dyskinesia in humans.

Tardive dyskinesia (TD) is a severe side effect of traditional neuroleptics affecting a considerable number of schizophrenic patients. Accumulating evidence suggests the existence of a genetic disposition to TD and other extra pyramidal symptoms (EPS) most strongly linked to a ser/gly polymorphism in position 9 of the D3 dopamine receptor gene (DRD3). The Cebus apella monkey is the favored animal model to study TD and other EPS because of its high susceptibility to side effects of neuroleptics. We therefore determined the sequence of the DRD3 gene in this species and compared it with that of humans. We found that the highly TD susceptible C. apella monkey (n=21) carries the gly9/gly9 DRD3 genotype that has been associated with TD in humans. Contrarily, C. apella did not carry the ser23 5HT2C allele that has been reported to increase TD susceptibility in humans.

Amino Acid Substitution↗

PubMed2003

Plant stress signalling: understanding and exploiting plant-plant interactions.

When plants are attacked by insects, volatile chemical signals can be released, not only from the damaged parts, but also systemically from other parts of the plant and this continues after cessation of feeding by the insect. These signals are perceived by olfactory sensory mechanisms in both the herbivorous insects and their parasites. Molecular structures involved can be characterized by means of electrophysiological assays, using the insect sensory system linked to chemical analysis. Evidence is mounting that such signals can also affect neighbouring intact plants, which initiate defence by the induction of further signalling systems, such as those that increase parasitoid foraging. Furthermore, insect electrophysiology can be used in the identification of plant compounds having effects on the plants themselves. It has been found recently that certain plants can release stress signals even when undamaged, and that these can cause defence responses in intact plants. These discoveries provide the basis for new crop protection strategies, that are either delivered by genetic modification of plants or by conventionally produced plants to which the signal is externally applied. Delivery can also be made by means of mixed seed strategies in which the provoking and recipient plants are grown together. Related signalling discoveries within the rhizosphere seem set to extend these approaches into new ways of controlling weeds, by exploiting the elusive potential of allelopathy, but through signalling rather than by direct physiological effects.

Animals↗

PubMed2001

CTLA4 in multiple sclerosis. Lack of genetic association in a European Caucasian population but evidence of interaction with HLA-DR2 among Shanghai Chinese.

In the present study we searched for an association between multiple sclerosis (MS) and the gene encoding the cytotoxic T lymphocyte antigen 4 (CTLA4). Our experimental approach involved amplification of DNA fragments of the promoter and exon 1 of this gene containing single nucleotide polymorphisms followed by treatment of the amplified fragments with restriction enzymes for allele determination. Included in the study were 84 MS patients and 125 healthy control subjects from a population of white Caucasians. We also examined 42 MS patients and 86 healthy control subjects of Shanghai Chinese origin. Significant differences in the distribution of genotypes or haplotypes of the CTLA4 gene were not observed between MS patients and control subjects in either of the two populations (P>0.05). Moreover, we were not able to confirm a previous finding of an association between relapsing-remitting MS and the heterozygous genotype A/G of CTLA4 exon 1. There was no evidence to suggest that interaction between HLA-DR2 and CTLA4 is involved in the development of MS among European Caucasians (P>0.05). Opposed to this, analysis of the Shanghai Chinese suggested presence of such interaction (P=0.02). Our results do not support the assumption that CTLA4 influences susceptibility to MS in European Caucasians. On the other hand, they raise the possibility that the development of MS in other ethnic groups involves interaction between CTLA4 and DR2.

Abatacept↗

PubMed2001

Genetic susceptibility to multiple sclerosis: detection of polymorphic nucleotides and an intron in the 3' untranslated region of the major histocompatibility complex class II transactivator gene.

The master player in the transcriptional regulation of major histocompatibility (MHC) class II genes is a factor known as the MHC class II transactivator (CIITA). In this study we searched for polymorphisms in the 5' and 3' ends of the human CIITA gene to assess whether or not there is an association between alleles of this gene and multiple sclerosis (MS). Polymorphism screening based upon detection of single strand conformational changes (SSCP analysis) followed by sequencing revealed six single nucleotide variations, namely one in the promoter utilized by B cells and five in the 3' untranslated region (UTR) of the gene. Determination of alleles at these polymorphic sites was facilitated by treatment of amplified DNA fragments with a panel of appropriate restriction enzymes. The distributions of CIITA alleles did not differ between MS patients and control subjects (p > 0.05). After subgrouping of the patients into relapsing-remitting MS and primary progressive MS we found that the distribution of promoter alleles in the latter of these two patient groups differed from that of healthy control subjects (p = 0.04). There was no evidence of linkage disequilibrium between the polymorphic site in the B cell specific promoter and those in the 3' UTR. Based upon the polymorphic sites in the 3' UTR we identified two common CIITA haplotypes which were present at similar frequencies in patients and control subjects. Assuming that susceptibility to MS depends upon type of MHC class II molecule as well as the amounts of expressed class II molecules we tested for interaction between DR15 status and CIITA alleles. No such interaction was detected. Unexpectedly, we identified an intron in the 3' UTR of the human as well as the mouse CIITA gene. Due to the proximity of these introns to the termination codon in both the human and mouse CIITA gene, the mechanism for regulation of transcript stability known as nonsense-mediated decay is probably not involved in the posttranscriptional control of the expression of these genes. So far, the function and significance of the intron in the human and mouse CIITA genes are unknown.

3' Untranslated Regions↗

PubMed2001

Additive effect of the HLA-DR15 haplotype on susceptibility to multiple sclerosis.

Multiple sclerosis (MS) has been associated with the human leukocyte antigen DR15 allele in Caucasians of North and Central European origin. However, the relative effect of the DR15 homozygous and the DR15 heterozygous genotypes on the disease susceptibility is unclear. Based upon results from three North European studies we have examined this by meta-analysis. Our results suggested that the effect of the DRB1*1501,DQA1*0102,DQB1*0602 haplotype on the susceptibility to MS is additive, perhaps reflecting that development of the disease is facilitated by a high density surface expression of the antigen presenting molecules encoded by this haplotype. Possible implications of our finding to future studies of the genetic background of MS is discussed.

Genetic Predisposition to Disease↗

PubMed2000

A gene for hypotrichosis simplex of the scalp maps to chromosome 6p21.3.

Hypotrichosis simplex of the scalp (HSS) is an autosomal dominant form of isolated alopecia causing almost complete loss of scalp hair, with onset in childhood. After exclusion of candidate regions previously associated with hair-loss disorders, we performed a genomewide linkage analysis in two Danish families and localized the gene to chromosome 6p21.3. This was confirmed in a Spanish family, with a total LOD score of 11.97 for marker D6S1701 in all families. The combined haplotype data identify a critical interval of 14.9 cM between markers D6S276 and D6S1607. Localization of the locus for HSS to 6p21.3 is a first step toward identification of the gene. The gene will give important insights into the molecular and cellular basis of hair growth on the scalp.

Adolescent↗

PubMed2000

2-(oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases.

Protein-tyrosine phosphatases (PTPs) are critically involved in regulation of signal transduction processes. Members of this class of enzymes are considered attractive therapeutic targets in several disease states, e.g. diabetes, cancer, and inflammation. However, most reported PTP inhibitors have been phosphorus-containing compounds, tight binding inhibitors, and/or inhibitors that covalently modify the enzymes. We therefore embarked on identifying a general, reversible, competitive PTP inhibitor that could be used as a common scaffold for lead optimization for specific PTPs. We here report the identification of 2-(oxalylamino)-benzoic acid (OBA) as a classical competitive inhibitor of several PTPs. X-ray crystallography of PTP1B complexed with OBA and related non-phosphate low molecular weight derivatives reveals that the binding mode of these molecules to a large extent mimics that of the natural substrate including hydrogen bonding to the PTP signature motif. In addition, binding of OBA to the active site of PTP1B creates a unique arrangement involving Asp(181), Lys(120), and Tyr(46). PTP inhibitors are essential tools in elucidating the biological function of specific PTPs and they may eventually be developed into selective drug candidates. The unique enzyme kinetic features and the low molecular weight of OBA makes it an ideal starting point for further optimization.

Binding Sites↗

PubMed2000

Absolute configuration and antiprotozoal activity of minquartynoic acid.

Minquartynoic acid (1) was isolated as an antimalarial and antileishmanial constituent of the Peruvian tree Minquartia guianensis and its absolute configuration at C-17 established to be (+)-S through conversion to the known (+)-(S)-17-hydroxystearic acid (2) and confirmed using Mosher's method.

Alkynes↗

PubMed2000

A simple and efficient separation of the curcumins, the antiprotozoal constituents of Curcuma longa.

A simple and efficient method for the separation of the three phenolic diketones, curcumin 1, demethoxycurcumin 2, and bis-demethoxycurcumin 3, isolated from the rhizomes of Curcuma longa has been developed. The method is of general applicability for the separation of compounds containing acidic and chelating groups and is amenable to large scale separations. The curcumins 1-3 show moderate activity against Plasmodium falciparum (IC50: 3.5, 4.2 and 3.0 micrograms/ml) and Leishmania major (IC50: 7.8, 14.1 and 21.5 micrograms/ml) respectively.

Animals↗

PubMed2000

Association between the endogenous retrovirus HRES-1 and multiple sclerosis in the United Kingdom--evidence of genetically different disease subsets?

In the present study we determined the frequencies of four haplotypes of the human T-cell lymphotropic virus-related endogenous sequence, HRES-1, in 110 multiple sclerosis (MS) patients and 100 healthy control subjects from the United Kingdom. We found evidence of an association between this endogenous retrovirus and MS (p < 0.01), in particular reflecting an increased frequency of HRES-1 haplotype 1 in the group of patients. There was no significant difference in the distribution of HRES-1 haplotypes between relapsing-remitting MS and the primary progressive form of the disease. The odds ratio for HRES-1 haplotype 1 and MS did not differ significantly between individuals positive for HLA-DR2 and DR2-negative individuals. Comparison of the observations from the present study with previous results implicated HRES-1 as a marker of genetic heterogeneity in MS.

DNA, Viral↗

PubMed2000

Genetic risk factors in multiple sclerosis and approaches to their identification.

Development of multiple sclerosis (MS) is believed to involve genetic as well as environmental factors. A complicating aspect to the study of aetiological factors in MS concerns the possible existence of genetically different subtypes of the disease. In addition, a relatively large number of susceptibility genes could be involved. Most likely, the contribution of the single genes to the susceptibility to MS is modest. However, interactions between different genes could result in a dramatic increase in disease susceptibility (synergistic gene effects). In this short review we focus upon genetic heterogeneity and gene interactions in MS. We also outline approaches to the genetic analysis of complex disease traits such as MS.

Genetic Heterogeneity↗

PubMed2000

Endogenous retroviruses and multiple sclerosis.

Endogenous retroviruses are normal constituents in vertebrate genomes. They have been associated with various diseases of presumed autoimmune etiology. However, conclusive evidence of their significance as susceptibility factors in these diseases is still lacking. In our laboratory we have focused attention upon endogenous retroviruses as candidate genes in multiple sclerosis. In this communication we describe general properties of endogenous retroviruses and we present observations from some of our studies.

Endogenous Retroviruses↗

PubMed1999

Fetal antigen 1, a member of the epidermal growth factor superfamily, in neurofibromas and serum from patients with neurofibromatosis type 1.

Fetal antigen 1 (FA1) is a 26-32 kDa glycoprotein containing six epidermal growth factor-like repeats closely related to the delta/notch/serrate proteins in Drosophila. FA1 has been shown to be involved in cell differentiation in a juxtacrine/paracrine manner. As neurofibromatosis type 1 (NF-1), also called von Recklinghausen disease, involves aberrant growth of tissues derived from the neural crest, the expression of FA1 was examined in neurofibroma skin biopsies and serum from patients with NF-1. FA1 was found in the spindle cells of all (n = 10) skin tumour specimens from adult NF-1 patients, whereas normal dermis was FA1 negative. In adults, the serum FA1 levels were significantly higher in NF-1 patients (n = 13) than in normal healthy controls (n = 177) (P = 0.037). In the group of children with NF-1 (n = 9), significantly higher serum FA1 levels were observed in those known to have complications with cerebral or spinal involvement (n = 4) (P = 0.014). The presence of FA1 in neurofibroma specimens and the elevated serum levels in patients with NF-1 suggests that FA1 may be involved in the pathogenesis of NF-1, perhaps acting as a growth promoting factor.

Adolescent↗

PubMed1999

A novel haplotype of the endogenous retrovirus, HRES-1, in patients with multiple sclerosis and healthy individuals.

In this study we searched for genetic variation in a segment of the human endogenous retrovirus, HRES-1, which encodes a potential autoantigen of 28 kDa. The purpose was to further investigate a possible association between this endogenous retrovirus and multiple sclerosis (MS). Fragments amplified from the HRES-1 region in question were subjected to single strand conformational analysis (SSCP analysis) and sequencing if the SSCP migration pattern suggested presence of polymorphisms. Using this approach a synonymous G --> C substitution, creating an NciI site, was found. Our sequence data also revealed an additional nucleotide in the region encoding the 28-kDa protein, i.e. a nucleotide not present in the first published sequence. This finding has implications for future studies of the 28-kDa HRES-1 protein since the additional nucleotide changes the reading frame of this protein. The detection of the Nci polymorphism allowed us to define a novel haplotype of HRES-1 distinct from the three previously known HRES-1 haplotypes. On comparison of the distribution of these four haplotypes in MS patients and healthy individuals we found a statistically significant difference (P = 0.03) but the contribution from the novel haplotype to this was modest.

Alleles↗