Biomedical subjects

H Frederiksen

Publications and source records attributed to H Frederiksen.

At least 19 recordsLinked to original sources

PubMed2006

Octreotide scintigraphy and Chromogranin A do not predict clinical response in patients with octreotide acetate-treated hormone-refractory prostate cancer.

In this pilot study, the predictive value of Octreotide scintigraphy (Octreoscan) and/or Chromogranin-A (CgA) was investigated in patients with hormone-refractory prostate cancer treated with Octreotide acetate. In total, 20 patients with progressive disease and bone metastases entered the trial. At baseline Octreoscan, CgA, PSA, alkaline phosphates (ALP) and two self-administered questionnaires (EORTC QLQ C-30 (v3) and brief pain index) were performed and a diary of the pharmaceutical was started. The treatment consisted of Octreotide (Sandostatin LAR) acetate 30 mg intramuscular injection every month. The blood samples and questionnaires were repeated every month until 3 months. Clinical responder was defined as a patient with increased global health score more than 10 units and stable or decreased pain score without an increase in analgesic. In all, 17 patients were treated per protocol, and four were assessed as clinical responders. Six patients developed a reduction in ALP (median -26%, range -5 to -78%). All patients increased in PSA. At baseline, three patients had a negative Octreoscan and the patients with positive lesions, demonstrated uptake of low intensity. At baseline the CgA was elevated above the normal range in 15 of the patients, and during treatment five patients decreased their CgA to the normal range. Neither baseline Octreoscan nor CgA could identify the clinical reponders. A minority of patients improves their health-related quality of life. The decrease and normalization of CgA levels in five patients during therapy indicates therapeutic activity but Octreoscan and CgA could not identify clinical responders.

Aged↗

PubMed2004

High concordance for essential tremor in monozygotic twins of old age.

OBJECTIVE: To assess the relative contribution of genetic and environmental factors for the etiology of essential tremor (ET) and to explore the effect of different diagnostic criteria. METHODS: A total of 2,448 twins of the Danish twin registry aged 70 years or more were screened for ET by an interview and an Archimedes spiral test. All twin pairs (n = 162) with a positive screening test of at least one of the twins were recontacted and 218 individuals (109 pairs) were interviewed and examined by a movement disorder specialist. The consensus criteria of the Tremor Investigation Group were applied to diagnose ET. RESULTS: Twenty-nine twins fulfilled the criteria of definite, 7 of probable, and 56 of possible ET. The probandwise concordance rate for the broadest definition of ET was 77% for monozygotic twins (MZ) and 59% for dizygotic twins (DZ). However, in an analysis restricted to cases of probable and definite ET, the concordance rates were 93% and 29%. The heritability for the liability to ET ranged from 93% to 99% using a general population prevalence of 1.2% for white 70+-year-olds. The inclusion of probable and exclusion of possible cases in the diagnosis of ET produced the highest concordance rates. CONCLUSION: The high concordance among MZ twins of very old age in this first population-based twin study of ET suggests that a disease phenotype consisting of definite and probable ET has a high heritability and hence is a good candidate for a phenotype to be used in linkage studies.

Age Factors↗

PubMed2004

Excretion of metabolites in urine and faeces from rats dosed with the heterocyclic amine, 2-amino-9H-pyrido[2,3-b]indole (AalphaC).

2-amino-9H-pyrido[2,3-b]indole (AalphaC) is a mutagenic and carcinogenic heterocyclic amine formed during ordinary cooking. In model systems AalphaC can be formed by pyrolysing either tryptophan or proteins of animal or vegetable origin. In the present study, the in vivo metabolism of AalphaC in rats was investigated. Rats were dosed with tritium labelled AalphaC. Urine and faeces were collected over three days. The metabolites of AalphaC were characterised by HPLC-MS and quantified by liquid scintillation counting. Conjugated metabolites were characterised by enzymatic hydrolyses with beta-Glucuronidase or arylsulfatase. The data showed that the metabolic pattern of AalphaC was similar in all rats. About 55% of the dose was excreted in urine and faeces during 72 h and the major amount of AalphaC metabolites (31%) was excreted during the first 24 h. In addition to a small amount of unmetabolised AalphaC seven conjugated metabolites were characterised. Three minor metabolites were characterised as AalphaC-N(2)-glucuronide and glucuronic acid conjugates of 3-OH-AalphaC and 6-OH-AalphaC. Four metabolites were all characterised as sulphuric acid conjugates and accounted for the largest amount of metabolites excreted in urine. The two major sulphuric acid conjugates were identified as AalphaC-3-O-sulfate and AalphaC-6-O-sulfate, while the minor sulphuric acid conjugates were proposed to be other O-sulfonated metabolites. In faeces only AalphaC was excreted and accounted for about 12% of dose during the first 24 hours. Any activated metabolites of AalphaC were not detected in rat urine or faeces. In future accumulation or binding of AalphaC to macromolecules such as DNA and proteins has to be studied.

Administration, Oral↗

PubMed2004

Paraoxonase 1 polymorphisms and survival.

The antioxidant enzyme paraoxonase 1 (PON1) has previously been suggested to confer protection against coronary heart disease (CHD), one of the main causes of death in the Western world. Two coding polymorphisms, 55M/L and 192Q/R, and a promoter variant, -107C/T, has been extensively studied with respect to susceptibility to CHD. In this study, we have investigated the impact of these three polymorphisms on mortality using a sample of 1932 Danish individuals aged 47-93 years, previously used in gene-longevity studies. A cross-sectional study comparing the genotype distribution of the three polymorphisms separately as well as the haplotype distribution in different age groups did not reveal any difference. However, a longitudinal follow-up study on survival in the same sample indicated that 192RR homozygotes have a poorer survival compared to QQ homozygotes (hazard rate: 1.38, P = 0.04). We hereafter used an independent sample of 541 Danish individuals from the oldest cohort and confirmed the initial findings (hazard rate: 1.38, P = 0.09). In both samples, the effect was most pronounced in women. Using self-reported data on ischemic heart disease to evaluate the impact of the PON 192Q/R polymorphism on susceptibility to CHD, we found only a nonsignificant trend of 192RR homozygosity in women being a risk factor. Our results thus indicates that PON1 192RR homozygosity is associated with increased mortality in women in the second half of life and that this increased mortality is possibly related to CHD severity and survival after CHD rather than susceptibility to development of CHD.

Adult↗

PubMed2004

Identification of metabolites in urine and feces from rats dosed with the heterocyclic amine, 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C).

2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C) is a proximate mutagenic and carcinogenic heterocyclic amine formed during ordinary cooking. In model systems, MeA alpha C can be formed by pyrolyses of either tryptophan or proteins of animal or vegetable origin. In the present study, the in vivo metabolism of MeA alpha C in rats was investigated. Rats were dosed with tritium-labeled MeA alpha C, and urine and feces were collected over 3 days. The metabolites of MeA alpha C were identified by high performance liquid chromatography-mass spectrometry and quantified by liquid scintillation counting. Conjugated metabolites were characterized by enzymatic hydrolyzes with beta-glucuronidase or arylsulfatase. The data showed that the metabolic pattern of MeA alpha C was similar in all rats. About 65% of the dose was excreted in urine and feces, and the major amount of MeA alpha C-metabolites was excreted during the first 24 h. Thirty-four percent of the dose was found in the rat urine samples collected to 24 h. In addition to unmetabolized MeA alpha C and two phase I metabolites, 6-OH-MeA alpha C and 7-OH-MeA alpha C, the following conjugated metabolites were identified: MeA alpha C-N(2)-glucuronide, A alpha C-3-CH(2)O-glucuronide, 3-carboxy-A alpha C and 3-carboxy-A alpha C-glucuronide, and sulfate and glucuronide conjugates of 6-OH-MeA alpha C and 7-OH-MeA alpha C. Also, a large amount of a rather unstable compound proposed to be of MeA alpha C-N1-glucuronide was found. About 21% of the dose was excreted in feces during the first 24 h, and MeA alpha C and 7-OH-MeA alpha C were the only compounds identified in feces. Any activated metabolites of MeA alpha C were not detected in rat urine or feces.

Administration, Oral↗

PubMed2003

The influence of genetic factors on physical functioning and exercise in second half of life.

During the past decades, a number of studies of families and twins in particular have assessed the relative contribution of genetic and environmental factors to traits reflecting various aspects of physical functioning: maximal O2 uptake, muscular endurance, muscular strength, muscle cross sectional area, flexibility, and trainability. Although the estimate of the size of the genetic component differs between the various studies, they point towards a moderate to substantial genetic influence on these phenotypes. Most of the studies have used only young and healthy study subjects, although in recent years phenotypes of particular importance to the elderly and the oldest-old (e.g., activities-of-daily living abilities) have also been shown to have substantial genetic component. Furthermore, behavioural studies have also revealed a genetic contribution to the disposition to level of leisure time physical activity. At present, there is still a few association studies on specific genetic variants, and the results have either been inconsistent or failed to show an association with physical functioning. Therefore, the mechanisms through which the genetic influence is expressed, is still an enigma. Here, we summarise the evidence currently available for a genetic influence on physical functioning and disposition to leisure time physical activity with a focus on recent Danish twin data.

Aging↗

PubMed2002

2-Amino-1-methyl-6-(5-hydroxy-)phenylimidazo[4,5-b]pyridine (5-OH-PhIP), a biomarker for the genotoxic dose of the heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagenic and carcinogenic heterocyclic amine formed during ordinary cooking. PhIP is metabolically activated by CYP P450 mediated N-hydroxylation followed by phase II esterification. The ultimate mutagenic metabolite reacts with DNA resulting in formation of adducts, and with proteins and other cellular constituents resulting in unstable products which are degraded to 5-hydroxy-PhIP. Rats were dosed orally with PhIP and urine and faeces were collected to 24, 48 and 72 h. Urine and faeces samples were hydrolysed with glucuronidase/sulfatase in order to release conjugated metabolites, followed by purification on C18 columns. The rats excreted 0.88% of the dose as 5-hydroxy-PhIP with the urine to 24 h and 0.04 and 0.01% to 48 and 72 h, respectively. The amounts of 5-hydroxy-PhIP found in faeces were 0.03, 0.1 and 0% to 24, 48 and 72 h. Urinary excretion of 5-hydroxy-PhIP showed a linear dose-response relationship in rats dosed orally with PhIP. This shows that 5-hydroxy-PhIP is also formed in vivo and that 91% is excreted with the urine in 24 h, indicating the possible use of 5-hydroxy-PhIP as a urinary biomarker for the bioactive dose of PhIP. In a preliminary study, using molecular imprinted polymer a specific sorbent for purification, after enzymatic hydrolysis and purification on a C18 column, we have identified 5-OH-PhIP in a 24-h urine sample from a male volunteer who had ingested a fried beef. This indicates that urinary 5-OH-PhIP could be used as an easily obtainable marker for the genotoxic dose of PhIP in human biomonitoring studies.

Administration, Oral↗

PubMed2001

Regeneration of detrusor muscle after subtotal cystectomy in the rat: effects on contractile proteins and bladder mechanics.

The aim of the present study was to determine to what extent adult rats can produce new contracting bladder muscle and to see if such newly formed bladder tissue possesses characteristic mechanical properties or whether the ability to recover mechanically is so pronounced that the prehistory of the bladder is unimportant. Subtotal cystectomy was performed in adult female rats, leading to a pronounced decrease in total bladder weight. At 10 weeks, bladder weight had normalized. The histological appearance of such bladders was similar to that of the controls. Active and passive length-tension relations for the detrusor muscle were determined in controls and up to 10 weeks after surgery. Immediately after surgery active and passive forces showed a leftward shift and maximum active force decreased markedly. With time the length-tension curves shifted back to normal, but a decreased active force still remained at 10 weeks. Detrusor actin concentration and detrusor myosin/actin ratio were unaffected by the subtotal cystectomy. Intermediate filament protein/actin ratio showed a significant but transitory increase. We conclude that there is a remarkable recovery of detrusor muscle function after subtotal cystectomy, leading to a normalization of optimum length for active force and a net synthesis of contractile and cytoskeletal proteins. The ability to produce active force does, however, not fully recover.

Animals↗

PubMed2001

Genetic and environmental influences on self-reported reduced hearing in the old and oldest old.

OBJECTIVES: The aim of the present twin study was to estimate the relative importance of genetic and environmental factors in variation in self-reported reduced hearing among the old and the oldest old. DESIGN: Self-reported hearing abilities of older twins assessed at intake interview in a population-based longitudinal survey. SETTING: Denmark. PARTICIPANTS: Twins age 75 and older identified in the population-based Danish Twin Registry in 1995. An interview was conducted with 77% of 3,099 individuals in the study population. In 1997 and 1999, a follow-up contact to the survivors was made and an additional 2,778 twins, age 70-76, were included in the study. MEASUREMENTS: Reduced hearing was assessed by the same question in all interview waves. Heritability (proportion of the population variance attributable to genetic variation) was estimated using structural-equation analyses. RESULTS: The prevalence of self-reported reduced hearing corresponded to previous studies and showed the expected age and sex dependence. Concordance rates, odds ratios, and correlations were consistently higher for monozygotic twin pairs than for dizygotic twin pairs in all age and sex categories, indicating heritable effects. Structural-equation analyses revealed a substantial heritability for self-reported reduced hearing of 40% (95% CI = 19-53%). The remaining variation could be attributed to individuals' nonfamilial environments. CONCLUSION: We found that genetic factors play an important role in self-reported reduced hearing in both men and women age 70 and older. Because self-reports of reduced hearing involve misclassification, this estimate of the genetic influence on hearing disabilities is probably conservative. Hence, genetic and environmental factors play a substantial role in reduced hearing among the old and oldest old. This suggests that clinical epidemiological studies of age-related hearing loss should include not only information on environmental exposures but also on family history of hearing loss and, if possible, biological samples for future studies of candidate genes for hearing loss.

Aged↗

PubMed1999

The incidence of idiopathic thrombocytopenic purpura in adults increases with age.

With the aim of determining the incidence of idiopathic thrombocytopenic purpura (ITP) in adults, we searched all adult ITP patients diagnosed from April 1, 1973 to December 31, 1995 in the County of Funen in Denmark. This county comprises 9% of the total Danish adult population. A total of 221 patients fulfilled the inclusion criteria, yielding an annual standardized incidence rate of 2.68 per 100,000. The median age of the patient population was 56 years, and the female to male ratio was 1.7. Changing the platelet count cut-off point from 100 x 10(9)/L to 50 x 10(9)/L changed the incidence rate to 2.25 per 100,000. Comparing patients less and more than 60 years old, the incidence rate more than doubled and the sex difference was eliminated in the older age group. These two age groups were almost identical regarding platelet count at diagnosis and number of asymptomatic cases. The incidence rate increased in the study period. This increase in particular involved asymptomatic patients and old males who were both symptomatic or not symptomatic. Including additional patients identified by a questionnaire study of the contribution from the primary care physicians and the practicing specialists in the second half of the study period, a reliable estimate of the annual ITP incidence in Danish adults, using a platelet concentration cut-off point of 50 x 10(9)/L, is 3.2 per 100, 000 persons.

Adolescent↗

PubMed1999

Sprouting of bladder nerves into cystoplastic cecal segment in the rat.

Incorporation of bowel into the bladder (enterocystoplasty) has been widely used to increase bladder capacity. It has been reported by others that the response of smooth muscle from the cystoplastic segment of the intestine shifts from that of the intestine (relaxation to alpha-agonists and ATP) to that of the bladder (contraction to alpha-agonists and ATP). This suggests a functional integration of the intestinal muscle into the bladder; the mechanisms are unknown. The aims of the present study were (1) to elucidate if there are signs of bladder nerves sprouting across the anastomosis into the intestinal segment, and (2) to study what happens with the intrinsic innervation of the intestinal segment. As a model, we used cecocystoplasty in rats. The bladder was opened and a patch of cecum with intact vascular supply was anastomosed to the bladder. After two to 11 months the rats were sacrificed and the bladders mounted as wholemounts and stained for acetylcholinesterase-containing nerves, or embedded in paraffin for histology. A pronounced degeneration of the myenteric plexus was found in the cecal segments. In some areas, this had proceeded to the extent that the ganglia were isolated ovoid lumps of cells with no apparent connection to other ganglia. Areas lacking ganglia and nerve trunks but still with muscle could be found in all specimens. Abundant axon bundles were demonstrated sprouting from the cut bladder nerves close to the anastomosis. The bundles spread out in a fan-like pattern or were organized as fewer thicker nerves. There were many nerve bundles entering the cecal segment where they branched and the diameter decreased till they no longer became visible. Some nerves reached surviving lumps of myenteric ganglion cells. The results show that the bladder nerves sprout into the anastomosed cecal segment. It is reasonable to assume that these nerves are responsible for the changes in receptor pharmacological properties of the cecal smooth muscle towards that of bladder muscle.

Animals↗

PubMed1993

Cytogenetic analysis of 52 colorectal carcinomas--non-random aberration pattern and correlation with pathologic parameters.

Cytogenetic analysis of short-term cultures from 52 colorectal carcinomas revealed a normal karyotype in 13 and clonal chromosome aberrations in 39 tumors. In the abnormal group, 13 tumors had simple numerical changes only, whereas 26 had at least one structural rearrangement with or without concomitant numerical changes. The most common numerical abnormalities were, in order of decreasing frequency, +7, -18, -Y, +8, +13 and -14. The most common structural rearrangements affected, again in order of decreasing frequency, chromosomes 8, 1, 6, 7, 17, 3, 11, 13, 14, 16, 2 and 10. The chromosome bands most frequently involved in the structural changes were 8q10, 17p11, 11q13, 8p11, 6q21, 7p15, 7q36, 12q13, 13q10, and 16q13. The most frequent genomic imbalances brought about by the structural rearrangements were losses from chromosome arms 8p, 1p, 6q, 17p, 7p, and 16q, as well as gains of 7q, 8q, 13q, and 11q. A statistically significant (p < 0.05) correlation between the karyotypic pattern and tumor grade was found, with the poorly differentiated carcinomas generally having more massive chromosomal abnormalities.

Adult↗

PubMed1992

Recurrent chromosome aberrations in abdominal smooth muscle tumors.

Short-term cultures of four abdominal smooth muscle tumors, three leiomyosarcomas and one leiomyoma, were analyzed cytogenetically. A low-grade malignant, epithelioid leiomyosarcoma had a normal karyotype. The other two leiomyosarcomas had abnormal karyotypes; one was near-diploid, and the other was near-triploid. Structural rearrangements of the short arm of chromosome 16 and monosomies of chromosomes 14, 15, and 22 were observed in both tumors. When our cases and previously published abdominal leiomyosarcomas are viewed in conjunction, loss of chromosomes 14, 15, and 22 are the most frequent abnormalities. The leiomyoma, the second cytogenetically abnormal nonuterine leiomyoma reported to date, had a hyperdiploid karyotype with a chromosome number of 56 and structural rearrangements of chromosomes 9, 14, and 19. The only aberrations similar to those observed in the previously reported esophageal leiomyoma were trisomies of chromosomes 7 and 8.

Abdominal Neoplasms↗

PubMed1970