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Biomedical subjects

L Hansen

Publications and source records attributed to L Hansen.

At least 109 records · Page 6Linked to original sources
PubMed1997

Hippocampal sclerosis contributes to dementia in the elderly.

OBJECTIVE: To assess the relevance of hippocampal sclerosis (HS) to dementia in the elderly. BACKGROUND: HS is a prominent pathologic finding in some demented elderly, but the anatomic substrate and cognitive profiles of this dementia have not been well established. DESIGN/METHODS: An autopsy series, including dot-immunobinding assay to estimate neocortical synaptic density, of eight patients (three men, five women) with HS on whom extensive antemortem neuropsychological testing was available. RESULTS: Mean age at onset was 72.0 (+/-9.8) (range, 59 to 89) with a mean duration of symptoms of 6.5 (+/-2.9) years. Patients were only mildly impaired with a mean MMSE of 20.9 (+/-4.9) and a mean DRS of 103.1 (+/-12.5) at presentation. Cardiovascular disease was present in 88%, with a mean Hachinski score of 3.4 (+/-2.2). No patient had a history of seizures. Sixty-three percent had depression or depressive symptoms. Neuropsychologically, most patients presented with prominent memory and language deficits and became progressively demented. Neuropathologically, isolated HS was a rare finding; many patients had either very mild or neocortical "plaque only or plaque predominant" Alzheimer's disease (AD) in addition to HS changes. Midfrontal neocortical synaptophysin counts were significantly reduced in all HS patients compared with controls (p = 0.0006). CONCLUSIONS: In the elderly, HS can be a neuropathologic substrate of dementia. Clinically, it can be associated with a course that is difficult to distinguish from AD although cardiac disease and depression are frequent concomitants. Deterioration of cognitive function in these subjects may relate to other pathologic features such as neocortical synapse loss.

Aged↗
PubMed1997

Identification of a common amino acid polymorphism in the p85alpha regulatory subunit of phosphatidylinositol 3-kinase: effects on glucose disappearance constant, glucose effectiveness, and the insulin sensitivity index.

Phosphatidylinositol 3-kinase (PI3-K) may regulate the basal plasma membrane glucose transporter recycling and the organization of the transporter intracellular pool in addition to being an insulin signal for translocation of glucose transporters to the plasma membrane. The objectives of the present study were to examine for genetic variability in the human regulatory p85alpha subunit of PI3-K, to look for an association between gene variants and NIDDM in a case-control study, and to relate identified variability to potential changes in whole-body insulin sensitivity and glucose turnover in a phenotype study. Single-strand conformational polymorphism and heteroduplex analysis of the coding region of the regulatory p85alpha subunit in cDNA isolated from human muscle tissue from 70 insulin-resistant NIDDM patients and 12 control subjects revealed three silent polymorphisms and a missense mutation at nucleotide position 1020 (G-->A), changing a Met to Ile at codon 326. Using allele-specific oligohybridization, we found a similar allelic frequency of the codon 326Met-->Ile variant in 404 NIDDM patients (0.15 [95% CI 0.13-0.17]) and 224 matched glucose tolerant control subjects (0.16 [0.13-0.19]). In a random sample of 380 unrelated healthy young Caucasians aged 18-32 years, in whom we have performed a tolbutamide modified intravenous glucose tolerance test, we identified 263 wildtype subjects, 109 heterozygous subjects, and 8 subjects homozygous for the codon 326 variant (allelic frequency = 0.16 [0.13-0.19]). No difference in glucose disappearance constant (KG), insulin sensitivity index (SI), and glucose effectiveness (SG) was observed between wildtype and heterozygous subjects. However, compared with the combined values for wildtype and heterozygous carriers, KG was reduced by 40% (P = 0.004) and SG by 23% (P = 0.03) in homozygous carriers of the p85alpha variant. Moreover, in homozygous carriers, a 32% reduction was found in SI (P = 0.08). In conclusion, a codon 326Met-->Ile variant in the gene encoding the PI3-K p85alpha regulatory subunit is found in 31% of a random sample of young healthy Caucasians. About 2% of the subjects in this population carry the gene variant in its homozygous form, and these carriers are characterized by significant reductions in whole-body glucose effectiveness and intravenous glucose disappearance constant. In itself, the gene variant does not confer an increased risk of diabetes.

Adolescent↗
PubMed1997

Amino acid polymorphisms in the ATP-regulatable inward rectifier Kir6.2 and their relationships to glucose- and tolbutamide-induced insulin secretion, the insulin sensitivity index, and NIDDM.

Kir6.2 is an inwardly rectifying potassium channel that is expressed in pancreatic beta-cells and cardiac and skeletal muscle. Expressed together with the high-affinity sulphonylurea receptor, it reconstitutes a sulphonylurea- and also ATP-sensitive potassium channel resembling the native beta-cell channel. The objective of this study was to search for mutations in the Kir6.2 gene that might be associated with NIDDM or related to altered insulin secretion, insulin action, or glucose metabolism in healthy subjects. Using polymerase chain reaction-single-strand conformation polymorphism analysis (PCR-SSCP) on genomic DNA from 69 Danish NIDDM patients and 66 matched control subjects, we report the finding of three missense polymorphisms in otherwise conserved codons and three silent polymorphisms in the gene encoding Kir6.2: codon 23 (GAG/AAG), Glu-->Lys; codon 190 (GCT/GCC), Ala-->Ala; codon 267 (CTC/CTG), Leu-->Leu; codon 270 (CTG/GTG), Leu-->Val; codon 337 (ATC/GTC), Ile-->Val; codon 381 (AAG/AAA), Lys-->Lys. The codon 23 and codon 337 amino acid polymorphisms were always coupled. The allelic frequencies of the polymorphisms were similar in NIDDM patients and control subjects. The amino acid polymorphisms were not associated with altered insulin secretion after intravenous glucose or tolbutamide injections or with altered glucose effectiveness in a phenotype study of 346 young healthy subjects. However, carriers of the maximal load of amino acid variants, the compound homozygous codon 23/337 and heterozygous codon 270, had on average a 62% higher insulin sensitivity index (P = 0.006), compared with noncarriers. We conclude that a combination of common Kir6.2 amino acid variants may contribute to the genetic background behind the large variation of the insulin sensitivity index in the general population.

Adenosine Triphosphate↗
PubMed1997

Novel MODY3 mutations in the hepatocyte nuclear factor-1alpha gene: evidence for a hyperexcitability of pancreatic beta-cells to intravenous secretagogues in a glucose-tolerant carrier of a P447L mutation.

One form of maturity-onset diabetes of the young (MODY3) results from mutations in the hepatocyte nuclear factor (HNF)-1alpha gene, located on chromosome 12q24.2. The primary objective of the present study was to search for genetic variation in the HNF-1alpha gene in nine nonrelated Danish Caucasian subjects with MODY. Direct sequencing of the coding region and intron-exon boundaries of the HNF-1alpha gene revealed 2 novel and 1 previously reported missense mutations and 2 novel frameshift mutations in five of nine MODY subjects. These five mutations were found in neither 84 NIDDM patients nor 84 control subjects. One glucose-tolerant lean male with a P447L missense mutation, which in his relatives caused MODY, underwent an oral glucose tolerance test (OGTT), a tolbutamide modified frequently sampled intravenous glucose tolerance test, and a glucagon test to examine for a possible early beta-cell abnormality. He had a low insulin secretion rate during an OGTT, but a twofold increase in pancreatic beta-cell response after intravenous glucose and a 2.5- to 4-fold increase in beta-cell response after either intravenous tolbutamide or intravenous glucagon loads. In conclusion, 1) mutations in the HNF-1alpha gene are common in Danish Caucasian MODY patients, and 2) early stages in the pathogenesis of MODY3 caused by the P447L mutation may be characterized by a hyperexcitability of beta-cells to intravenous secretagogues.

Adolescent↗
PubMed1997

Comparison of technetium-99m-ll-EC isomers in rats and humans.

UNLABELLED: Technetium-99m-L,L-ethylenedicysteine (99mTc-LL-EC) is a new renal imaging agent with pharmacokinetic properties reported to be slightly superior to those of 99mTc-mercaptoacetyltriglycine (99mTc-MAG3); however, to better define the potential of the enantiomer 99mTc-DD-EC and the diastereomer 99mTc-DL-EC as renal imaging agents, we compared the three EC stereoisomers with 131I-orthoiodohippurate (OIH) in a series of rats and humans. METHODS: Each 99mTc-EC stereoisomer was coinjected with OIH in six Sprague-Dawley rats for measurements of clearance and extraction fraction. Each stereoisomer was also coinjected with OIH in three human volunteers followed by sequential imaging, plasma clearance measurements and timed urine collections. RESULTS: Technetium-99m-DD-EC had the highest clearance and extraction efficiency in rats (p < or = 0.02). In humans, image quality was good with all three agents. The clearance ratio (EC/OIH) was 82% +/- 8% for 99mTc-DD-EC compared to 70% +/- 3% and 40% +/- 5% for 99mTc-LL-EC and 99mTc-DL-EC, respectively. Technetium-99m-DD and 99mTc-LL-EC were excreted more rapidly than 99mTc-DL-EC. CONCLUSION: Technetium-99m-DD-EC has excellent imaging properties and the data suggest that its clearance may approach that of OIH more closely than any other 99mTc renal agent. A potential limitation is the fact that both 99mTc-DD and LL-EC exist in dianionic (80%) and monoanionic (20%) forms at physiological pH and it is unlikely that these two forms have the same clearance or protein binding affinity.

Animals↗
PubMed1996

Deficient glutamate transport is associated with neurodegeneration in Alzheimer's disease.

The mechanisms of synapse damage in Alzheimer's disease (AD) are not fully understood. Deficient functioning of glutamate transporters might be involved in synaptic pathology and neurodegeneration by failing to clear excess glutamate at the synaptic cleft. In AD, glutamate transporter activity as assessed by D-[3H]aspartate binding is decreased; however, it is not clear to what extent it is associated with the neurodegenerative process and cognitive alterations. For this purpose, levels of D- and L-[3H]aspartate binding in midfrontal cortex were correlated with synaptophysin levels, brain spectrin degradation product levels, and clinical and neuropathological indicators of AD. Compared to control brains, AD brains displayed a 34% decrease in levels of D-[3H]aspartate binding, a 30% decrease in L-[3H]aspartate binding, and a 48% loss of synaptophysin immunoreactivity. Increased levels of brain spectrin degradation products correlated with a decrease in levels of D-[3H] and L-[3H]aspartate binding, and decreased levels of synaptophysin immunoreactivity. Levels of L-[3H]aspartate binding correlated with levels of synaptophysin immunoreactivity. These results suggest that decreased glutamate transporter activity in AD is associated with increased excitotoxicity and neurodegeneration, supporting the possibility that abnormal functioning of this system might be involved in the pathogenesis of synaptic damage in AD.

ATP-Binding Cassette Transporters↗
PubMed1996

Clinical and neuropathological findings in Lewy body dementias.

We compared clinical features in three groups of pathologically defined patients evaluated for dementia during life: (i) Alzheimer's disease (AD); (ii) Lewy body variant of Alzheimer's Disease (LBV), with Lewy bodies (LB) and AD; (iii) diffuse Lewy body disease (DLBD), with LB alone. All three groups had similar initial cognitive symptoms. LBV and DLBD had Parkinsonian signs, though resting tremor was extremely rare. Delusions and hallucinations were relatively more frequent in LBV and DLBD than in AD. On neuropsychological testing, the LBV group had relatively greater impairment than AD on visuospatial and executive tests. LB therefore contribute to the clinical picture of dementia.

Aged↗
PubMed1995

Insulin resistance: interactions between obesity and a common variant of insulin receptor substrate-1.

We previously discovered two aminoacid polymorphisms in codons 513 and 972 of the protein insulin receptor substrate-1 (IRS-1), which is important in cellular insulin action. We have investigated whether these polymorphisms are associated with changes in insulin sensitivity in a random sample of young healthy adults. Insulin sensitivity and secretion were measured during a combined intravenous glucose and tolbutamide tolerance test in 380 unrelated white subjects aged 18-32. IRS-1 polymorphisms were examined by single-strand conformation polymorphism and verified by restriction-enzyme digestion. No homozygous carrier of the codon-513 variant was identified, but one non-obese man had the codon-972 mutation on both alleles. He had low fasting-serum insulin and C-peptide concentrations and low insulin sensitivity and glucose effectiveness. During a 24 h dexamethasone test, he developed transient diabetes. In their heterozygous forms the codon-513 and codon-972 variants of IRS-1 were found in 3% and 9% of the subjects. Non-obese carriers of either polymorphism had similar insulin sensitivity and pancreatic beta-cell function to non-obese wild-type subjects (no known variants of IRS-1). Analysis of variance showed, however, a significant interaction between obesity (body-mass index > or = 25 kg/m2) and the heterozygous form of the codon-972 variant (p < 0.003); obese polymorphism carriers had lower insulin sensitivity than obese non-carriers (mean 6.0 [SD 3.3] vs 12.3 [9.5] x 10(-5) L min-1 pmol-1). The obese carriers of the codon-972 variant were also characterised by a clustering of metabolic cardiovascular risk factors, with raised fasting concentrations of plasma glucose, serum triglyceride, and plasma tissue-plasminogen-activator and its fast-acting inhibitor. With adjustment for known modulators of insulin sensitivity, multivariate analyses showed that the combination of obesity and the codon-972 variant was associated with a 50% reduction in insulin sensitivity (p = 0.0008). Our results suggest that the codon-972 IRS-1 gene variant may interact with obesity in the pathogenesis of common insulin-resistant disorders.

Adolescent↗
PubMed1995

The CYP2D6B allele is associated with a milder synaptic pathology in Alzheimer's disease.

Both genetic and environmental factors affect the progression of Alzheimer's disease (AD). The presence of cortical Lewy bodies in AD patients is associated with an altered presentation of AD pathology suggestive of an interaction between the pathogenesis of Lewy bodies and AD lesions. Since the CYP2D6B mutant allele is often present in patients with Lewy body diseases (Parkinson's disease and Lewy body variant of AD), we extended these prior observations by studying the neuropathology associated with the presence of the CYP2D6B mutant allele in a pure AD population without Lewy bodies. AD patients who possessed the CYP2D6B mutant allele, in comparison with those without the CYP2D6B allele, were found to have a smaller decline in two synaptic markers, choline acetyltransferase and synaptophysin, in the frontal cortex relative to normal control values. On the other hand, senile plaques and neurofibrillary tangles were not significantly affected by the presence of the CYP2D6B mutant allele in the frontal cortex of AD patients. Association of the CYP2D6B mutant allele with Lewy body formation in both Parkinson's disease and the Lewy body variant of AD and with the milder synaptic pathology in pure AD without Lewy bodies suggest that depending on the contribution of other genetic and environmental factors, this mutant allele may be involved with different aspects of neurodegeneration.

Aged↗
PubMed1995

Genetic evidence that the Lewy body variant is indeed a phenotypic variant of Alzheimer's disease.

Lewy Body Variant (LBV) patients present as Alzheimer's disease (AD) clinically; about two-thirds also have mild extrapyramidal features. At autopsy, neocortical and brain stem Lewy bodies are present in addition to changes diagnostic of AD. We have found that the Apolipoprotein E4 allele is a major genetic risk factor for LBV as it is for "pure AD," in contrast to subjects with diffuse Lewy body disease or Parkinson's disease. This genetic evidence supports the concept that LBV--the second most common neurodegenerative form of dementia--is a phenotypic variant of AD.

Aged↗
PubMed1995

Odontogenic tumours in the v-Ha-ras (TG.AC) transgenic mouse.

A line of homozygous transgenic mice (TG.AC) carrying a v-Ha-ras gene fused to the promoter of the zeta globin gene produces a variety of mesenchymal and epithelial neoplasms including odontogenic tumours. The 1-year incidence of odontogenic tumour formation in these mice was approx. 35%. Tumours formed more often in the mandible than maxilla. The various types of tumours frequently presented with: (1) primarily mesenchymal cells in a dense fibrous-like matrix, or (2) loose stroma surrounded by anastomosing cords of epithelial cells that exhibited squamous differentiation, or (3) odontomas forming mineralized tooth structures by well-differentiated odontoblasts and ameloblasts. Some tumours had areas with all three of these characteristics. Mineralized dentine and enamel in the odontomas were morphologically similar to those of normal murine teeth. Odontogenic tumours expressed the v-Ha-ras transgene that was primarily localized to the mesenchymal cells. Proliferating-cell nuclear antigen immunohistochemistry showed that the mesenchymal cells adjacent to the epithelial cords not only expressed the ras transgene but were also actively proliferating. The TG.AC mouse provides an excellent model for the study of odontogenic tumours and tooth development.

Animals↗
PubMed1995

Hemangioendothelioma of the liver in infants.

Hemangioendotheliomas are the most common type of hepatic vascular tumors that present in infancy. Eleven infants (nine boys, two girls) were referred for definitive management from 1970 through 1990. Ten were symptomatic, and the majority required intensive medical therapy because of cardiac failure. All were treated surgically. Three underwent partial hepatectomy for unilobar disease, and eight had ligation of the hepatic artery because of bilobar disease. There were two deaths (18%) in the early part of the series. Ligation of the hepatic artery was completely successful in controlling cardiac failure in six infants and was partially successful in one. There are two surgical options for treating symptomatic hepatic hemangioendotheliomata in infancy. Bilobar multifocal disease can be treated successfully by ligation of the hepatic artery; if localized, hemangioendothelioma can be resected, with rapid control of symptoms.

Blood Loss, Surgical↗
PubMed1995

Human hepatocyte isolation and transplantation into an athymic rat, using prevascularized cell polymer constructs.

Human hepatocyte viability and function in vivo in an athymic rat was assessed after transplantation on prevascularized polymer constructs with hepatotrophic stimulation. Sixteen liver biopsy specimens, weighing 5 to 12 g, were obtained from the New England Organ Bank and from the operating room after liver resection. In the laboratory they were catheterized and perfused to obtain liver cell suspensions. From eight of the 16 cell suspensions, only in vitro studies were performed. They showed 40% cell attachment 24 hours after initial cell plating. For patients aged 2, 35, and 60 years, they showed a 20% increase, a 1% decrease, and a 57% decrease (respectively) in cell number from day 2 to day 4, after cell plating. Eight cell suspensions were transplanted into athymic rats. On sections examined histologically, implanted hepatocytes were seen within the fibroblast ingrowth, in the space of the polymer device, until day 21 after cell injection. On day 9 after hepatocyte injection, reorganized hepatic parenchyma was seen on the tissue section. Implanted hepatocyte areas, quantitated through morphometric analysis on days 0, 3, and 7, showed a 36% increase in engraftment 3 days after injection, and a 42% decrease 7 days after injection. At the same time-points, immunoperoxidase staining visualized intracellular albumin, which was specific for the implanted hepatocytes. In conclusion, the authors demonstrated the feasibility of their technique (prevascularized polymer device with hepatotrophic stimulation), using human hepatocytes. Further studies are underway, before implementation of human clinical trials.

Adolescent↗
PubMed1995

A missense mutation in the glucagon receptor gene is associated with non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) affects about 5% of the world population. The disease presents a polygenic mode of inheritance, but mechanisms and genes involved in late-onset NIDDM are largely unknown. We report the association of a single heterozygous Gly to Ser missense mutation in the glucagon receptor gene with late-onset NIDDM. This mutation was highly associated with NIDDM in a pooled set of French and Sardinian patients (chi 2 = 14.4, P = 0.0001) and showed some evidence for linkage to diabetes in 18 sibships from 9 French pedigrees (chi 2 = 6.63, P < 0.01). Receptor binding studies using cultured cells expressing the Gly40Ser mutation demonstrate that this mutation results in a receptor which binds glucagon with a three-fold lower affinity compared to the wild type receptor.

DNA Primers↗