bluuebunny/crossref_metadata_2025 huggingface dataset:
Linkage Disequilibrium and Haplotype Analysis in German Friedreich Ataxia Families
Authors: Zühlke Christine , Gehlken Ulrike , Purmann Sabine , Kunisch Markus , Müller-Myhsok Bertram , Kreuz Friedmar , Laccone Franco
Published: April 2003

The main mutation causing Friedreich ataxia (FRDA) is the expansion of a GAA repeat localized within the intron between exon 1 and exon 2 of the gene X25. This expansion has been observed in 98% of FRDA chromosomes. To analyze frequencies of markers tightly linked to the Friedreich ataxia gene and to investigate wheter a limited number of ancestral chromosomes are shared by German FRDA families, a detailed analysis employing nine polymorphic markers was performed. We found strong linkage disequilibria and association of FRDA expansions with a few haplotypes. FRDA haplotypes differ significantly from control haplotypes. Our results confirm that GAA repeat expansions in intron 1 of the frataxin gene are limited to a few chromosomes and indicate an obvious founder effect in German patients. Based on these analyses, we estimate a minimum age of the mutation of 107 generations.
A Principal-Components Approach Based on Heritability for Combining Phenotype Information
Authors: Ott Jürg , Rabinowitz Daniel
Published: April 2003

For many traits, genetically relevant disease definition is unclear. For this reason, researchers applying linkage analysis often obtain information on a variety of items. With a large number of items, however, the test statistic from a multivariate analysis may require a prohibitively expensive correction for the multiple comparisons. The researcher is faced, therefore, with the issue of choosing which variables or combinations of variables to use in the linkage analysis. One approach to combining items is to first subject the data to a principal components analysis, and then perform the linkage analysis of the first few principal components. However, principal-components analyses do not take family structure into account. Here, an approach is developed in which family structure is taken into account when combining the data. The essence of the approach is to define principal components of heritability as the scores with maximum heritability in the data set, subject to being uncorrelated with each other. The principal components of heritability may be calculated as the solutions to a generalized eigensystem problem. Four simulation experiments are used to compare the power of linkage analyses based on the principal components of heritability and the usual principal components. The first of the experiments corresponds to the null hypothesis of no linkage. The second corresponds to a setting where the two kinds of principal components coincide. The third corresponds to a setting in which they are quite different and where the first of the usual principal components is not expected to have any power beyond the type I error rate. The fourth set of experiments corresponds to a setting where the usual principal components and the principal components of heritability differ, but where the first of the usual principal components is not without power. The results of the simulation experiments indicate that the principal components of heritability can be substantially different from the standard principal components and that when they are different, substantial gains in power can result by using the principal components of heritability in place of the standard principal components in linkage analyses.
Mutation Analysis in Patients with Congenital Adrenal Hyperplasia in the Spanish Population: Identification of Putative Novel Steroid 21-Hydroxylase Deficiency Alleles Associated with the Classic Form of the Disease
Authors: Lobato M. Natividad , Ordóñez-Sánchez M. Luisa , Tusié-Luna M. Teresa , Meseguer Anna
Published: April 2003

Steroid 21-hydroxylase deficiency, due to the genetic impairment of the CYP21 gene, is a major cause of congenital adrenal hyperplasia (CAH). In about 80% of the cases, the defect is related with the transfer of deleterious point mutations from the CYP21P pseudogene to the active CYP21 gene. Sixteen different point mutations have been searched for in 60 Spanish patients with the classic form of CAH and 171 unaffected family members, using selective amplification of the CYP21 gene followed by allele-specific oligonucleotide hybridization (PCR-ASOH) and sequencing analysis. While 31.9% of the disease alleles carry CYP21 deletions or large gene conversions, around 58% of the alleles carry single point mutations. Corresponding segregation of mutations was found in every case indicating that none of them has apparently appeared de novo. The most frequent mutations found in our sample are i2G, V281L, R356W, Q318X, P453S and F306+t, with rates of 30, 14.2, 10, 9.2, 9.2 and 7.5%, respectively. We found similar frequencies for the A and C polymorphism at position 656 (40 and 31.5%, respectively) in wild-type alleles for the i2G mutation. Around 10% of the alleles, for which no mutations were identified by searching for the sixteen previously known mutations, are currently being sequenced and new possible mutations and polymorphisms have been identified.
Gln → Arg 191 Polymorphism of Paraoxonase and Parkinson’s Disease
Authors: Akhmedova S. , Anisimov S. , Yakimovsky A. , Schwartz E.
Published: April 2003

We investigated the Gln → Arg 191 polymorphism in paraoxonase (PON1) in St. Petersburg population, in three clinically differentiated groups of patients with Parkinson’s disease (PD) and in the symptomatic tremor group. A new approach for Gln → Arg 191 PON1 polymorphism genotyping is suggested. No significant differences in the groups studies as compared to the controls was observed.
Genetic Maternal Effects on HumanLife Span through the Inh eritance of Mitochondrial DNA
Authors: Korpelainen Helena
Published: April 2003

Ageing consists of an accumulation of changes with time both at the molecular and cellular levels, accompanying an increased susceptibility to diseases and death. If maternally inherited mitochondrial genes are involved in defining the nature and timing of ageing, and if there are genetic differences in their susceptibility to damage, a maternal contribution could be found in the inheritance of life span. The present study explores the inheritance pattern of longevity and discovers a significant genetic maternal component in human life span.
Ethnic Variation in the Mitochondrial Targeting Sequence Polymorphism of MnSOD
Authors: van Landeghem G.F. , Tabatabaie P. , Kučinskas V. , Saha N. , Beckman G.
Published: April 2003

In contrast to CuZn superoxide dismutase (SOD), only a very limited number of mutations have been described in MnSOD. One interesting example is a polymorphism (Ala-9Val) in the mitochondrial targeting sequence of this radical-scavenging enzyme. We have studied the Ala-9Val polymorphism in various ethnic groups by means of the oligonucleotide ligation assay. There were significant variations in this unique polymorphism between three different language groups: Baltic (Lithuanians), Finnic (Finns and Saamis) and Germanic (Swedes). The Ala frequency in an Asiatic population (Chinese) was significantly lower than in most European populations. This polymorphism may affect the mitochondrial targeting rate of MnSOD which may result in mitochondrial damage with implication in various late-onset neurological diseases.
Positional Cloning of Disease Genes: Advantages of Genetic Isolates
Authors: Peltonen Leena
Published: April 2003

Genetic isolates with a history of a small founder population, long-lasting isolation and population bottlenecks represent exceptional resources in the identification of disease genes. Specific rare, monogenic diseases become enriched, and families with multiple affected individuals occur frequently enough to be used in linkage analyses for locus identification. Further, the vast majority of cases are caused by the same mutation, and disease alleles reveal linkage disequilibrium (LD) with markers over significant genetic intervals; this facilitates disease locus identification by similarity search for a shared genotype or haplotype in small study samples consisting of few affected individuals. LD observed in disease alleles adds power to linkage analyses and helps to define the exact location of disease loci on the genetic map. Typically, based on the linkage disequilibrium and the ancient haplotype, the critical DNA region can be defined from the original 1- to 2-cM resolution obtained in linkage analysis to 50–200 kb, greatly facilitating the targeting of physical cloning and sequencing efforts. These advantages have been well demonstrated in the positional cloning of several rare monogenic diseases enriched in population isolates like the example of Finland used here. How useful genetic isolates will prove to be in the identification of complex disease genes is dependent on the genealogical history of the isolate, including the size of the founding population and the expansion rate during the history of the population.
Complex Inheritance and Localizing Disease Genes
Authors: Hoh Josephine J. , Ott Jürg
Published: April 2003

Most methods for localizing genes underlying complex traits work under the implicit or explicit assumption of a single disease gene with the possible exception of heterogeneity, that is, different disease genes in different families. We discuss current single-locus and multi-locus methods. Novel approaches are proposed that take into account all marker loci over the genome. A simple example is given for an unconventional statistic, i.e. the mean of allele sharing over all markers on a chromosome.
Fine Mapping of the Human Biotinidase Gene and Haplotype Analysis of Five Common Mutations
Authors: Blanton Susan Halloran , Pandya Arti , Landa Barbara L. , Javaheri Razieh , Xia Xia-Juan , Nance Walter E. , Pomponio Robert J. , Norrgard Karen J. , Swango Katie L. , Demirkol Mübeccel , Gülden Hüner , Coskun Turgay , Tokatli Aysegül , Ozalp Imran , Wolf Barry
Published: April 2003

Biotinidase deficiency is an autosomal recessive defect in the recycling of biotin that can lead to a variety of neurologic and cutaneous symptoms. The disease can be prevented or effectively treated with exogenous biotin. The biotinidase locus (BTD) has been maped to 3p25 by in situ hybridization. The gene has been cloned, the coding region sequenced, the genomic organization determined, and a spectrum of mutations has been characterized in more than 90 individuals with profound or partial biotinidase deficiency. We have conducted haplotype analysis of 10 consanguineous and 39 nonconsanguineous probands from the United States and 8 consanguineous probands from Turkey to localize BTD with respect to polymorphic markers on 3p and to investigate the origins of five common mutations. The inbred probands were homozygous for overlapping regions of 3p ranging in size from 1.1 to 80 cM which were flanked most narrowly by D3S1259 and D3S1293. Radiation hybrids and haplotype analysis of markers within this region suggest that BTD is located within a 0.1-cM region flanked by D3S3510 and D3S1286. The radiation hybrid data suggest that the BTD gene is oriented 5′ to 3′ between the centromere and the 3p telomere. Association studies indicate that the gene is closer to a third locus D3S3613 than D3S3510, two markers which cannot be resolved by existing linkage data. The BTD locus and D3S3613 must therefore lie between D3S3510 and D3S1286. Comparison of haplotypes reveals evidence for possible founder effects for four of the five common mutations.
α-Thalassemia in Bantu Population from Congo-Brazzaville: Its Interaction with Sickle Cell Anemia
Authors: Mouélé R. , Pambou O. , Feingold J. , Galactéros F.
Published: April 2003

Deletional α+-thalassemia (–α3.7) was investigated in four groups of unrelated individuals from the Bantu population (newborns, normal adults, sickle cells trait carriers, sickle cell anemia patients) of Brazzaville, Congo. The frequency of the (–α3.7) chromosome was similar between newborns (f = 0.40) and adult subjects (f = 0.36), and between sicklers and nonsickler subjects. The frequency of the (–α3.7) chromosome in sickle cell anemia patients (SS patients) did not change when age was stratified. The hematological characteristics of SS patients with (–α/αα, –α/–α) and without (αα/αα) α+-thalassemia were similar to those reported in Jamaican and US sickle cell anemia patients. α+-Thalassemia had an effect on the percentage of hemoglobin S in sickle cell trait carriers. Thus, the high frequency of α+-thalassemia in the Congolese population presumably results from this disorder having a selective advantage favoring survival. However, the frequency of α+-thalassemia was not affected by age. Although in this selective tropical environment, α+-thalassemia as elsewhere markedly affects the hematological characteristics of sickle cell anemia patients, however our data provide no evidence that α+-thalassemia increases survival of SS patients.
Model-Free Analysis and Permutation Tests for Allelic Associations
Authors: Zhao Jing Hua , Curtis David , Sham Pak Chung
Published: April 2003

In this short report, we address some practical problems in performing likelihood-based allelic association analysis of case-control data. Model-free statistics are proposed and their properties assessed by simulation, and procedures based on permutation tests are described for marker-marker as well as marker-disease associations. A memory-efficient algorithm is developed which enables several highly polymorphic markers to be analysed.
A New Inherited Interstitial Deletion of the Distal Long Arm of Chromosome 4,
Authors: Aladhami Saad M.S. , Gould C.P. , Muhammad Fatima A.
Published: April 2003

A 12-year-old boy showed mild dysmorphic features, late presentation of learning difficulties and behaviour problems, obesity, breast hypertrophy and bilateral slipped capital femoral epiphysis. His mother also has mild dysmorphic features, obesity, and a similar history of late presentation of learning difficulties and behaviour problems. Cytogenetic analysis demonstrated an inherited distal long arm deletion of one chromosome 4. The boy’s karyotype was interpreted as 46,XY,del(4)(q32 q33)mat and the mother’s karyotype as 46,XX,del(4)(q32 q33). This is the second report of an inherited distal 4q deletion and the first report of interstitial chromosome 4 deletion involving q32 q33 segments.
Apolipoprotein B 3′-VNTR Polymorphism in the Udmurt Population
Authors: Spitsyn V.A. , Khorte M.V. , Pogoda T.V. , Slominsky P.A. , Nurbaev S.D. , Agapova R.K. , Limborska S.A.
Published: April 2003

An analysis of a highly polymorphic region of the apolipoprotein B gene 3′-end DNA (Apo B 3′-VNTR), represented by 10 alleles, was carried out using the polymerase chain reaction. Data inferred from the principal component analysis indicate that the Udmurts occupy an isolated position among the populations constituting the northern branch of Caucasoid peoples.
K5 D328E: A Novel Missense Mutation in the Linker 12 Domain of Keratin 5 Associated with Epidermolysis bullosa simplex (Weber-Cockayne)
Authors: Liovic Mirjana , Podrumac Bozana , Dragos Vlasta , Vouk Katja , Komel Radovan
Published: April 2003

A novel missense mutation was detected in the L12 region of keratin 5 (K5) in a Slovene family diagnosed with a Weber-Cockayne variant of epidermolysis bullosa simplex (EBS). Direct sequencing identified a heterozygous GAC to GAA substitution altering codon 328 of K5 from Asp to Glu in all affected family members, while no mutation was observed either in the healthy individual or the 50 unrelated control samples. Asp328 of K5 (position 12 in the L12 domain) is remarkably conserved among all type II keratins. K5 L12:D12E is the third mutation found to affect this residue in K5-related EBS, indicating the importance of Asp328 for K5 structure and the dramatic effect that fine changes can have on keratin intermediate filament integrity.
Evidence for a Founder Effect in Sicilian Patients with Glycogen Storage Disease Type II
Authors: Dagnino Fabio , Stroppiano Marina , Regis Stefano , Bonuccelli Gloria , Filocamo Mirella
Published: April 2003

Glycogen storage disease type II (GSD II) is an autosomal recessive inherited disorder due to the deficiency of the enzyme acid α-glucosidase, which causes an accumulation of glycogen in lysosomes. The deletion of exon 18 (Δ18) is a frequent mutation associated with a severe phenotype. We analyzed 25 Italian patients, 5 of whom were found to be Δ18 carriers. All these 5 patients came from Catania, a town in Sicily. We report on the analysis of 5 intragenic single-point polymorphic markers in the Δ18 patients and on the subsequent characterization of a Δ18-associated haplotype. The frequency of this haplotype in GSD II patients and normal individuals was 1 and 0.196, respectively (χ2 = 20.9; p < 0.001). The high frequency of the Δ18 allele in this Italian subpopulation is likely to be due to a founder effect.
TPH Gene May Be Associated with Suicidal Behavior, but Not with Schizophrenia in the Korean Population
Authors: Paik In-ho , Toh Kyu-young , Kim Jung-jin , Lee Chul , Lee Chang-uk
Published: April 2003

Tryptophan hydroxylase (TPH) is a rate-limiting enzyme in the biosynthesis of serotonin. This study was designed to examine whether A218C polymorphism, which has been identified in intron 7 of the TPH gene, may be associated with schizophrenia or the suicidal behavior of schizophrenics in the Korean population. TPH genotypes were determined in DNA samples from 217 schizophrenics and 236 healthy volunteers. Among the schizophrenic group, 27 patients had a history of suicidal behavior. Genomic DNA was amplified by a polymerase-chain-reaction-based method and restricted by NheI. A218C polymorphism was associated with a history of suicidal behavior in schizophrenics. This finding suggests that the TPH gene or a gene in its vicinity may influence suicidal behavior in schizophrenics. However, genotypic and allelic distrubutions of this polymorphism did not significantly differ between schizophrenics and controls.
Haptoglobin Phenotypes in HIV-1-Seropositive Patients in Ghana: Decreased Risk for Hp0 Individuals
Authors: Quaye I.K.E. , Ekuban F.A. , Brandful J.A.M. , Gyan B.A. , Akanmori B.D. , Ankrah N.-A.
Published: April 2003

Plasma haptoglobin phenotypes were determined by polyacrylamide gel electrophoresis, followed by benzidine staining for 58 HIV-1 seropositive Ghanaians and 79 randomly selected age-matched controls. Hp0 was present in only 14% of HIV-1 seropositive individuals compared with more than 40% of the controls. The Hp0 individuals showed a highly significant reduced risk for HIV-1 infection (OR = 0.21, 95% CI = 0.09–0.51, p = 0.0002). Hp0 may have a protective effect in HIV-1 infection.
Association between Minihaplotypes and Mutations at the PAH Locus in Polish Hyperphenylalaninemic Patients
Authors: Żekanowski Cezary , Jurkowska Monika , Bal Jerzy
Published: April 2003

Hereditary hyperphenylalaninemia (HPA) is a disorder of amino acid metabolism and results from an insufficiency of hepatic phenylalanine hydroxylase (PAH). HPA phenotypes form a spectrum ranging from classical phenylketonuria (PKU) to mild hyperphenylalaninemia (MHP). The phenotypic diversity reflects heterogeneity at the molecular level, and more than 320 different mutations in the PAH gene are known to date. The association of 3 mutations (R408W, IVS10 and A403V) common in different European populations with a variable number tandem repeat (VNTR) and short tandem repeat sites (minihaplotype) in the PAH gene was examined in a group of Polish PKU and MHP patients. Additionally, minihaplotypes were established for another 16 mutations. The presented data support the hypothesis that the R408W/VNTR3/STR238 allele originated among pre-Indo-Europeans on the territory in present-day Lithuania and Belarus. Mutation IVS10nt–11g→a (IVS10) is strongly associated with VNTR7/STR250 minihaplotype and is possibly of Mediterranean origin.
C677T Methylenetetrahydrofolate Reductase Polymorphism Is Not a Risk Factor for Pre-Eclampsia/Eclampsia among Australian Women
Authors: Kaiser Thomas , Brennecke Shaun P. , Moses Eric K.
Published: April 2003

The C677T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism results in reduced MTHFR enzymatic activity. This in turn results in increased levels of homocysteine. It has been suggested that increased levels of homocysteine cause vascular disease, which is known to increase the risk of developing pre-eclampsia (PE) during pregnancy. However, recent studies on Japanese, Italian and American populations have failed to reach agreement on an association between the C677T polymorphism and PE. In this study, 156 cases of eclampsia (E)/PE and 79 normal pregnant control cases from an Australian population were genotyped for this mutation. No significant difference could be found in the incidence of the homozygote mutation or in the allele frequency. We conclude from this study that the C677T mutation in our population is not associated with the development of PE/E.
β-Globin Gene Haplotype Characteristics of Colombian Amerinds in South America
Authors: Shimizu Koji , Hashimoto Toyoko , Harihara Shinji , Tajima Kazuo , Sonoda Shunro , Zaninovic Vladimir
Published: April 2003

Haplotypes and subhaplotypes in the β-globin gene cluster were identified in 146 and 156 chromosomes, respectively, of three tribes of Colombian Amerinds. Subhaplotype [+––––] was a major one in Colombian Amerinds as in most human ethnic groups except Africans. A major subhaplotype [––––+] in Africans was observed in only one chromosome. The framework 2 frequencies were very low (0.018–0.067). Haplotype [+––––++], which is a major one in Europeans, but not in Asians, and [+–––––+], which is a major one in Asians, but not in Europeans, were two major haplotypes. Subhaplotype data showed the closest genetic affinities between Colombian Amerinds and Polynesians, Micronesians, and Asians, but the haplotype data did not necessarily support this.
A Robust Identity-by-Descent Procedure Using Affected Sib Pairs: Multipoint Mapping for Complex Diseases
Authors: Liang Kung-Yee , Chiu Yen-Feng , Beaty Terri H.
Published: April 2003

Multipoint linkage analysis is a powerful tool to localize susceptibility genes for complex diseases. However, the conventional lod score method relies critically on the correct specification of mode of inheritance for accurate estimation of gene position. On the other hand, allele-sharing methods, as currently practiced, are designed to test the null hypothesis of no linkage rather than estimate the location of the susceptibility gene(s). In this paper, we propose an identity-by-descent (IBD)-based procedure to estimate the location of an unobserved susceptibility gene within a chromosomal region framed by multiple markers. Here we deal with the practical situation where some of the markers might not be fully informative. Rather the IBD statistic at an arbitrary within the region is imputed using the multipoint marker information. The method is robust in that no assumption about the genetic mechanism is required other than that the region contains no more than one susceptibility gene. In particular, this approach builds upon a simple representation for the expected IBD at any arbitrary locus within the region using data from affected sib pairs. With this representation, one can carry out a parametric inference procedure to locate an unobserved susceptibility gene. In addition, here we derive a sample size formula for the number of affected sib pairs needed to detect linkage with multiple markers. Throughout, the proposed method is illustrated through simulated data. We have implemented this method including exploratory and formal model-fitting procedures to locate susceptibility genes, plus sample size and power calculations in a program, GENEFINDER, which will be made available shortly.
The Split of the Arara Population: Comparison of Genetic Drift and Founder Effect
Authors: Ribeiro-dos-Santos Ândrea K.C. , Guerreiro João Farias , Santos Sidney E.B. , Zago Marco Antonio
Published: April 2003

The total genetic diversity of the Amerindian population is as high as that observed for other continental human populations because a large contribution from variation among tribes makes up for the low variation within tribes. This is attributed mainly to genetic drift acting on small isolated populations. However, a small founder population with a low genetic diversity is another factor that may contribute to the low intratribal diversity. Small founder populations seem to be a frequent event in the formation of new tribes among the Amerindians, but this event is usually not well recorded. In this paper, we analyze the genetic diversity of the Arara of Laranjal village and the Arara of Iriri village, with respect to seven tandem repeat autosomic segments (D1S80, ApoB, D4S43, vW1, vW2, F13A1 and D12S67), two Y-chromosome-specific polymorphisms (DYS19 and DYS199), and mitochondrial DNA (mtDNA) markers (restriction fragment length polymorphisms and sequencing of a segment of the D loop region). The occurrence of a single Y chromosome and mtDNA haplotype, and only 1–4 alleles of the autosomic loci investigated, corroborates historic and demographic records that the Arara of Iriri were founded by a single couple of siblings who came from the Arara of Laranjal, the largest group. Notwithstanding this fact, the genetic distance and the molecular variance between the two Arara villages were greater than those observed between them and other Amazonian tribes, suggesting that the microevolutionary process among Brazilian Amerindians may be misinterpreted if historic demographic data are not considered.
Genetic Diversity in an Andean Population from Peru and Regional Migration Patterns of Amerindians in South America: Data from Y Chromosome and Mitochondrial DNA
Authors: Rodriguez-Delfin Luis A. , Rubin-de-Celis Verónica E. , Zago Marco A.
Published: April 2003

The genetic variability of a Quechua-speaking Andean population from Peru was examined on the basis of four Y chromosome markers and restriction sites that define the Amerindian mitochondrial DNA (mtDNA) haplogroups. Forty-nine out of 52 (90.4%) individuals had mtDNA which belonged to one of the four common Amerindian haplogroups, with 54% of the samples belonging to haplogroup B. Among 25 males, 12 had an Amerindian Y chromosome, which exists as four haplotypes defined on the basis of the DYS287, DYS199, DYS392 and DYS19 markers, three of which are shared by Amazonian Amerindians. Thus, there is a clear directionality of marriages, with an estimated genetic admixture with non-Amerindians that is 9 times lower for mtDNA than for Y chromosome DNA. The comparison of mtDNA of Andean Amerindians with that of people from other regions of South America in a total of 1,086 individuals demonstrates a geographical pattern, with a decreasing frequency of A and C haplotypes and increasing frequency of the D haplotype from the north of the Amazon River to the south of the Amazon River, reaching the lowest and the highest frequencies, respectively, in the more southern populations of Chile and Argentina. Conversely, the highest and lowest frequencies of the haplogroup B are found, respectively, in the Andean and the North Amazon regions, and it is absent from some southern populations, suggesting that haplotypes A, C and D, and haplotype B may have been dispersed by two different migratory routes within the continent.
Serotoninergic Involvement in Gonadotropin and TSH Secretion in Normal Cycling and Postmenopausal Women
Authors: Krause B.Th. , Möller S. , Schmeisser J.-O.
Published: April 2003

We investigated the influence of a specific serotonin receptor blockade on pituitary hormone secretion in normal cycling women and postmenopausal women not receiving hormone replacement therapy. Serotonin receptor blockade was performed by using the HT-3 receptor subtype antagonist ondansetron as an i.v. bolus injection of 8 mg. Blood samples were taken before as well as 20, 30 and 40 min after ondansetron administration for the estimation of LH, FSH, and TSH. We could not find any hormonal changes in the normal cycling women. The postmenopausal women showed a significant decline in LH secretion, whereas FSH and TSH levels remained unchanged. Our results suggest serotoninergic involvement in LH secretion in postmenopausal hypoestrogenic hypergonadism.
Effect of Seasonal Changes in Daylength on Human Neuroendocrine Function
Authors: Wehr Thomas A.
Published: April 2003

The circadian pacemaker imposes stereotypic patterns of daily variation on the activity of human neuroendocrine systems. In a number of cases, these patterns exhibit waveforms that are characterized by distinct diurnal and nocturnal periods with relatively discrete transitions between them (corresponding to a biological day, a biological dusk, a biological night, and a biological dawn). In humans, for example, diurnal periods of absence of melatonin secretion, low prolactin secretion, and falling levels of cortisol alternate with nocturnal periods of active melatonin secretion, high prolactin secretion and rising levels of cortisol. In response to light, the circadian pacemaker synchronizes the timing of the biological day and night so that their timing and duration are appropriately matched with the timing and duration of the solar day and night. As the pacemaker carries out this function, it is able to adjust the duration of the biological day and night to match seasonal variation in the duration of the solar day and night. Thus, after humans have been chronically exposed to long nights (scotoperiods), the duration of nocturnal periods of active melatonin secretion, high prolactin secretion and rising levels of cortisol is longer than it is after they have been chronically exposed to short nights. Furthermore, the sleep-related peak of growth hormone secretion is half as high after exposure to long nights as it is after exposure to short nights. These responses to seasonal changes in duration of the natural scotoperiod are suppressed in most individuals – especially men – who live in modern urban environments in which they are exposed to artificial light after dark and artificial darkness during the daytime.
Ultradian Rhythms in Hydromineral Hormones
Authors: Brandenberger G. , Charloux A. , Gronfier C. , Otzenberger H.
Published: April 2003

The maintenance of hydromineral homeostasis depends on the coordinated action of arginine vasopressin (AVP), atrial natriuretic peptide (ANP), the renin-angiotensin-aldosterone system and other recently identified endocrine or paracrine hormones. Several reports have pointed out the changes in urinary excretion and osmolality during the sleep-wake cycle and the rapid eye movement (REM)-non(N)REM sleep cycles. No such changes occur for ANP levels which have a flat profile over 24 h. The pulsatile fluctuations of AVP are described as random. The ultradian rhythm of plasma renin activity (PRA) depends on the regularity of the REM-NREM sleep cycles and the nocturnal curves reflect all disturbances in the internal sleep structure. A study with a shift in the normal sleep time clearly demonstrated that both PRA and aldosterone oscillations are sleep-stage dependent. These hormones could account for the ultradian variations in renal function. The nocturnal oscillations in sympathovagal balance may play an additional role. It is suggested that a central generator synchronizes endocrine, renal, autonomic and sleep processes.
The Physiology and Pharmacology of Melatonin in Humans
Authors: Geoffriau Martine , Brun Jocelyne , Chazot Guy , Claustrat Bruno
Published: April 2003

Melatonin (MLT) is a methoxyindole secreted principally by the pineal gland. It is synthesized at night under normal environmental conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained by the light/dark cycle. Light is able to both suppress or entrain MLT production on light schedule. The nyctohemeral rhythm of this hormone can be determined by repeated measurement of plasma or saliva MLT or urine sulfatoxy-MLT, the main hepatic metabolite. MLT can be considered as the output (the hand) of the endogenous clock. Since the regulating system follows a central and sympathetic nervous pathway, an abnormality at any level could unspecifically modify the MLT secretion, especially in patients with sympathalgia or dysautonomia. MLT plays the role of an endogenous zeitgeber on core temperature or sleep-wake cycle. Exogenous MLT is able to influence the endogenous secretion of the hormone according to a phase-response curve. There are practical implications for this property in situations when biological rhythms are disturbed (jet-lag syndrome, delayed sleep phase syndrome, insomnia in blind people, shift-work, insomnia in elderly people). Improvement of pharmaceutical forms (controlled release preparations) or development of MLT analogs could lead to decisive progress.
Alterations of Circadian Rhythmicity and Sleep in Aging: Endocrine Consequences
Authors: van Cauter Eve , Plat Laurence , Leproult Rachel , Copinschi Georges
Published: April 2003

All 24-hour endocrine rhythms partially reflect the interaction of circadian rhythmicity with sleep-wake homeostasis but their relative contributions vary from one system to another. In older adults, many 24-hour rhythms are dampened and/or advanced, including those of cortisol and GH. Amplitude reduction and phase advance of 24-hour rhythms may represent age-related changes in the central nervous systems underlying circadian rhythmicity and sleep-wake homeostasis. Age-related alterations in circadian function could also reflect decreased exposure and/or responsivity to the synchronizing effects of both photic (e.g. light exposure) and nonphotic (e.g. social cues) inputs. There are pronounced age-related alterations in sleep quality in aging which consist primarily of a marked reduction of slow-wave sleep, a reduction in REM stages and a marked increase in the number and duration of awakenings interrupting sleep. Alterations in slow-wave sleep occur abruptly in young adulthood (30–40 years of age) whereas disturbances in amounts of REM and wake appear more gradually. This article reviews evidence indicating that deficits in characteristics of sleep-wake homeostasis and circadian function may mediate age-related alterations in somatotropic and corticotropic function. Because sleep loss in young subjects results in endocrine disturbances which mimic those observed in aging, it is conceivable that the decrease in sleep quality which characterizes aging may contribute to age-related alterations in hormonal function and their metabolic consequences.
Sleep and Circadian Disturbances in Shift Work: Strategies for Their Management
Authors: van Reeth Olivier
Published: April 2003

More and more businesses are providing their full range of services 24 h a day, 7 days a week, thus forcing their employees to work either rotating shifts or fixed night shifts. Dictates of our endogenous circadian clock prevent our brains and bodies to be indefinitely adaptable to those work schedules. Shift work operations are thus associated with serious healthy and social problems for the workers. Various interventions can counteract circadian desynchronization, sleep disturbances, and social disruption associated with shift work: changes in work schedules, sleeping and napping strategies, use of appropriately timed exposure to bright light, experimental drug treatments, or exercise.
Interaction between Menstrual Cyclicity and Gonadotropin Pulsatility
Authors: Filicori M. , Tabarelli C. , Casadio P. , Ferlini F. , Gessa G. , Pocognoli P. , Cognigni G. , Pecorari R.
Published: April 2003

Pulsatile gonadotropin secretion is a critical endocrine component of the regulation of the normal menstrual cycle. Pulsatile luteinizing hormone (LH) secretion changes dynamically across the menstrual cycle. Derangements of pulsatile LH secretion are found in virtually every menstrual disorder. This article summarizes the key features of pulsatile LH secretion in the normal menstrual cycle and in ovulatory disorders.
Ultradian Pulsatility of Plasma Glucose and Insulin Secretion Rate: Circadian and Sleep Modulation
Authors: Simon C.
Published: April 2003

Insulin release is a complex oscillatory process with rapid pulses (10 min) superimposed on slower circhoral oscillations (50–100 min). The exact mechanism of the circhoral oscillations, which are probably in part the consequence of a negative feedback loop linking glucose and insulin secretion rate, remains unclear. Stimulatory effects of sleep on insulin secretion are achieved by an enhancement of the oscillation amplitude which could be partly mediated by GH. The different patterns observed after acute or chronic shift of sleep suggest however an interaction between sleep influence and circadian rhythmicity, as described for numerous pituitary hormones. The intra-sleep awakenings have a modulatory effect on glucose levels but no systematic relationship exists between glucose or insulin secretion rate oscillations and the REM-NREM sleep cycles. Irrespective of the mechanisms involved, sleep or GH stimulatory effects result from a modulation of the oscillation amplitude rather than of their frequency which is probably an important feature of insulin efficacy.
Three Cases of Malignant Pheochromocytoma Treated withCyc lophosphamide, Vincristine, and Dacarbazine Combination Chemotherapy and Alpha-Methyl- p-Tyrosine to Control Hypercatecholaminemia
Authors: Tada Kaoruko , Okuda Yukichi , Yamashita Kamejiro
Published: April 2003

We describe 3 cases of malignant pheochromocytoma with multiple metastases which were treated with cyclophosphamide, vincristine and dacarbazine (CVD) combination chemotherapy and α-methyl-p-tyrosine. Case 1 was operated on first but hypercatecholaminemia could not be completely controlled. Cases 2 and 3 received chemotherapy, CVD combination chemotherapy and/or α-methyltyrosine and good control of hypercatecholaminemia was attained. In all cases it was possible to control hypercatecholaminemia during most of the time they were administered α-methyltyrosine despite the presence of tumors. None of the patients suffered hypertension crises. In our patients treatment with CVD plus α-methyl-p-tyrosine proved to be safe and ameliorated the clinical course.
Three-Month Sustained-Release Form of Triptorelin in Patients with Advanced Prostatic Adenocarcinoma: Results of an Open Pharmacodynamic and Pharmacokinetic Multicenter Study
Authors: Bouchot Olivier , Soret Jean Yves , Jacqmin Didier , Lahlou N. , Roger M. , Blumberg Joëlle
Published: April 2003

The pharmacodynamics and the pharmacokinetic characteristics of a new longer-acting formulation containing 11.25 mg of triptorelin (Decapeptyl) to be administered every 3 months were evaluated in 14 patients with advanced prostate carcinoma. After one single injection, the mean time to reach the surgical castration testosterone range is 22 days, and this effective testosterone suppression is maintained for the 3-month therapy. After a first plasma surge (35.70 ng/ml) occurring 2.5 h after injection and a rise between day 17 and day 31 (maximum on day 24: 0.32 ng/ml), the mean triptorelin plasma level is stable (0.06 ± 0.05 ng/ml) and maintained until day 91. This new formulation was well tolerated both locally and systemically.
Effect of Glucagon on Glucose Production, Lipolysis, and Gluconeogenesis in Familial Hyperinsulinism
Authors: Cederblad Fredrik , Ewald Uwe , Gustafsson Jan
Published: April 2003

We present an infant with severe familial hyperinsulinism in whom glucose production rate, lipolysis, and gluconeogenesis from glycerol were measured by use of glucose and glycerol labelled with stable isotopes. Administration of a single dose of glucagon (0.1 mg/kg) caused an increase in glucose production rate by near 140% from 4.2 to 10.1 mg·kg–1·min–1. The rate of appearance of glycerol, reflecting the rate of lipolysis, decreased from 15.1 to 12.6 µmol· kg–1·min–1. The amount of glycerol converted to glucose by gluconeogenesis was 9.1 µmol·kg–1·min–1 before and 10.5 µmol·kg–1·min–1 after glucagon administration. We conclude that the marked rise in glucose production rate was mainly the result of increased glycogenolysis. Following the trial, the child was started on long-acting (zinc-protamine) glucagon which made it possible to discontinue intravenous treatment with glucose.
Regulation of PTP-1 and Insulin Receptor Kinase by Fractions from Cinnamon: Implications for Cinnamon Regulation of Insulin Signalling
Authors: Imparl-Radosevich Jennifer , Deas Shenequa , Polansky Marilyn M. , Baedke Deborah A. , Ingebritsen Thomas S. , Anderson Richard A. , Graves Donald J.
Published: April 2003

Bioactive compound(s) extracted from cinnamon potentiate insulin activity, as measured by glucose oxidation in the rat epididymal fat cell assay. Wortmannin, a potent PI 3′-kinase inhibitor, decreases the biological response to insulin and bioactive compound(s) from cinnamon similarly, indicating that cinnamon is affecting an element(s) upstream of PI 3′-kinase. Enzyme studies done in vitro show that the bioactive compound(s) can stimulate autophosphorylation of a truncated form of the insulin receptor and can inhibit PTP-1, a rat homolog of a tyrosine phosphatase (PTP-1B) that inactivates the insulin receptor. No inhibition was found with alkaline phosphate or calcineurin suggesting that the active material is not a general phosphatase inhibitor. It is suggested, then, that a cinnamon compound(s), like insulin, affects protein phosphorylation-dephosphorylation reactions in the intact adipocyte. Bioactive cinnamon compounds may find further use in studies of insulin resistance in adult-onset diabetes.
Circadian Plasma Leptin Levels in Patients with Anorexia nervosa: Relation to Insulin and Cortisol
Authors: Herpertz Stephan , Wagner Richard , Albers Norbert , Blum Werner F. , Pelz Barbara , Langkafel Mathias , Köpp Werner , Henning Andreas , Oberste-Berghaus Corinna , Mann Klaus , Senf Wolfgang , Hebebrand Johannes
Published: April 2003

In anorexia nervosa, underweight results from a loss of body mass due to a restricted energy intake. Circulating leptin levels have been shown to be low in the acute stage of the disorder. We studied diurnal secretion characteristics of leptin, insulin and cortisol in a study group of anorectic patients prior to refeeding, a second study group of anorectic patients after initiation of refeeding and study groups of healthy underweight and normal-weight controls. Spontaneous secretion of leptin, insulin and cortisol was measured by drawing blood samples every 2 h for 24 h. The temporal relationships between the diurnal secretion patterns of the three hormones were assessed by cross-correlation analysis in every study group. Plasma levels of leptin and cortisol were secreted with a specific circadian rhythmicity and displayed an intricate temporal relationship in anorectic patients. Semistarvation in the non-refed patients was associated with (1) exceedingly low plasma leptin levels, (2) a qualitative alteration in the circadian rhythm of leptin and cortisol levels and (3) an alteration in the temporal coupling between cortisol and leptin. In contrast, in the patients who had gained weight, leptin levels were higher; furthermore, the diurnal pattern of leptin and the temporal relationship between leptin and cortisol were similar to controls. Increments in insulin secretion preceded those of leptin by 4–6 h in both anorectic patients and in controls. Leptin levels increased 4 h prior to those of cortisol in controls and in refed patients, whereas in the non-refed patients cortisol increased prior to leptin. Thus, anorexia nervosa leads to pronounced, albeit reversible changes in the secretion dynamics of leptin and cortisol.
Developmental Gene Expression and Immunohistochemical Study of the Human Endocrine Pancreas during Fetal Life
Authors: Sanchez Didier , Moriscot Christine , Marchand Stéphanie , Fredouille Catherine , Figarella Catherine , Guy-Crotte Odette
Published: April 2003

The development of human endocrine pancreas has been the subject of many immunohistochemical studies but very little is known at the molecular level. We have determined the patterns of gene expression of glucagon, somatostatin and pancreatic polypeptide during fetal life (16–41 weeks of gestation) using the dot-blot hybridization method. In spite of some dispersion in the mRNA levels, no progressive increase or decrease during this period of fetal life could be found, as previously observed for insulin. In keeping with these molecular data, no increase in immunostaining of the four hormones was observed, but a dispersion of endocrine cells within the exocrine tissue was noticed at 20 weeks of gestation followed by a clear differentiation of the Langerhans islets at 31 weeks. Interestingly, the mRNA levels of the four hormones were always higher in the fetal pancreas than in the adult pancreas.
Longitudinal Evaluation of Salivary Cortisol Levels in Full-Term and Preterm Neonates
Authors: Bettendorf Markus , Albers Norbert , Bauer Jacqueline , Heinrich UdoE. , Linderkamp Otwin , Maser-Gluth Christiane
Published: April 2003

The aim of the present study was to test the practicability of sequential cortisol determinations in saliva of low birth weight neonates and to evaluate the impact of systemic and inhaled glucocorticoid therapy on saliva concentrations of cortisol in preterm neonates with bronchopulmonary dysplasia (BPD). Salivary cortisol levels were measured by RIA in saliva samples from 10 full-term and 10 preterm healthy neonates and from 20 preterm neonates with BPD during systemic [dexamethasone (DEX); n = 10] or topical steroid therapy [budesonide (BUD); n = 10]. Saliva samples of each individual were collected on 3 consecutive days at 06.00, 12.00, 18.00 and 24.00 h. Cortisol levels in saliva ranged from 0.8 to 60.6 nmol/l (median 6.5 nmol/l) in full-term neonates, from 0.6 to 52.1 nmol/l (median 5.5 nmol/l) in preterm neonates, from 0.4 to 14.0 nmol/l (median 1.0 nmol/l) in preterm neonates treated with DEX and from 0.4 to 15.2 nmol/l (median 2.5 nmol/l) in preterm neonates treated with BUD. Autocorrelation analysis revealed a distinct endogenous cortisol rhythm in 2 of the 10 healthy full-term neonates and in 3 of the 10 healthy preterm neonates with a wavelength of 12–30 h. Salivary cortisol levels in preterm neonates treated with DEX or BUD were significantly lower than those measured in healthy preterm neonates. These results demonstrate that the measurement of salivary cortisol levels is a reliable and practicable way of assessing adrenal function in full-term and preterm neonates. This study also shows for the first time that some neonates display an endogenous cortisol rhythm which is not coupled to the exogenous day/night cycle. Furthermore, systemic and nebulized glucocorticoids suppress adrenal function in low-birth-weight neonates. After treatment these children should be closely monitored for potential adrenal insufficiency.
Absence of Catch-Down Growth in Russell-Silver Syndrome after Short-Term Growth Hormone Treatment
Authors: Azcona C. , Stanhope R.
Published: April 2003

We describe 3 children with Russell-Silver syndrome without growth hormone insufficiency who were treated with growth hormone for 2, 3.7 and 6 years, showing a rapid growth acceleration. After cessation of growth hormone treatment, they grew at a normal rate without ‘catch-down’ growth. It may be possible that short intra-uterine growth retardation (IUGR) children with dysmorphic features respond to growth hormone therapy differently from non-dysmorphic IUGR short children. Short-term growth hormone treatment for children with Russell-Silver syndrome may avoid side effects and diminish costs.