bluuebunny/crossref_metadata_2025_split huggingface dataset:
Undertreatment of patients with Alzheimer's disease in an elderly United States population
Authors: Sano Mary , Amatniek Joan , Feely Morgan , Sinyak Feliks , Holton Denise , Ascher Steve , Finkel Sanford I. 
Published: December 2005

BackgroundThe aim of this study was to assess the undertreatment of elderly mild to moderate Alzheimer's disease (AD) patients in the United States utilizing baseline data from a community‐based trial that has established comparability to national survey samples on demographic characteristics.MethodsBaseline data were used from an open‐label, 12‐week, postapproval study of compliance with galantamine, an AChEI and nicotinic receptor modulator, and vitamin E. A total of 2,114 patients from 406 community‐based US practices in which physicians had previously treated patients with acetylcholinesterase inhibitors (AChEIs) were included in the study. This population reflects a large, ethnically diverse patient pool consistent with the demographics of the elderly population in the United States, atypical of those enrolled in most AD trials.ResultsThe majority of patients (64.5%) were described by either themselves or their caregivers as not having received prior AChEI treatment. Positive associations were found between past AChEI treatment and longer time since diagnosis, white race, higher education, medical care by a neurologist, and older caregivers. The likelihood of having received previous AChEI treatment was higher among white patients (61.9%) than among those from other ethnic groups combined (25.8%).ConclusionsThe similarity of patient demographic characteristics to the 2000 US Census figures for the population aged ≥65 years makes this data set a potentially powerful tool for planning public health initiatives. Findings suggest that patients with mild to moderate AD are undertreated and that specialist and nonspecialist organizations should discuss and implement ways to optimize management of this disease.
Role of biomarkers in studies of presymptomatic Alzheimer's disease
Authors: Morris John C. , Kimberly A. , Quaid K. , Holtzman David M. , Kantarci Kejal , Kaye Jeffrey , Reiman Eric M. , Klunk William E. , Siemers Eric R. 
Published: December 2005

BackgroundBiomarkers that have been developed largely for the study of patients with clinically diagnosed Alzheimer's disease (AD) can also be used in the study of cognitively normal individuals who may harbor underlying AD pathology.MethodsA meeting of invited experts on AD biomarkers was held on November 11 and 12, 2004 to review currently available data and to discuss unmet needs for biomarker research in presymptomatic AD.ResultsNeuroimaging biomarkers have been studied to some extent in subjects at risk for AD. These imaging techniques include volumetric magnetic resonance imaging and positron emission tomography using either fluorodeoxyglucose or newer ligands that bind directly to amyloid plaque. Similarly, biochemical measures from cerebrospinal fluid or other physiologic fluids are emerging as potentially useful tools. Such biomarkers may be used either as diagnostic tools or as indicators of disease severity when followed longitudinally. A clinical diagnosis of asymptomatic individuals using biomarkers and studies involving asymptomatic subjects may raise logistical and ethical concerns.ConclusionsThe technical development of biomarkers that are used for presymptomatic AD diagnosis and for longitudinally measuring disease severity is evolving rapidly. Ethical and privacy considerations must be made before such biomarkers can be applied routinely to asymptomatic populations.
SMALL DEVIATIONS OF RIEMANN--LIOUVILLE PROCESSES IN ${L_{\lowercase{q}}}$ SPACES WITH RESPECT TO FRACTAL MEASURES
Authors: LIFSHITS MIKHAIL A. , LINDE WERNER , SHI ZHAN 
Published: December 2005

We investigate Riemann--Liouville processes $R_H$, with $H > 0$, and fractional Brownian motions $B_H$, for $0 < H < 1$, and study their small deviation properties in the spaces $L_q([0, 1], \mu)$. Of special interest here are thin (fractal) measures $\mu$, that is, those that are singular with respect to the Lebesgue measure. We describe the behavior of small deviation probabilities by numerical quantities of $\mu$, called mixed entropy numbers, characterizing size and regularity of the underlying measure. For the particularly interesting case of self-similar measures, the asymptotic behavior of the mixed entropy is evaluated explicitly. We also provide two-sided estimates for this quantity in the case of random measures generated by subordinators.While the upper asymptotic bound for the small deviation probability is proved by purely probabilistic methods, the lower bound is verified by analytic tools concerning entropy and Kolmogorov numbers of Riemann--Liouville operators.
Ethiopia: between Sub‐Saharan Africa and Western Eurasia
Authors: Lovell A. , Moreau C. , Yotova V. , Xiao F. , Bourgeois S. , Gehl D. , Bertranpetit J. , Schurr E. , Labuda D. 
Published: December 2005

SummaryEthiopia is central to population genetic studies investigating the out of Africa expansion of modern humans, as shown by Y chromosome and mtDNA studies. To address the level of genetic differentiation within Ethiopia, and its relationship to Sub‐Saharan Africa and Eurasia, we studied an 8kb segment of the X‐chromosome from 72 chromosomes from the Amhara, Oromo and Ethiopian Jews, and compared these results with 804 chromosomes from Middle Eastern, African, Asian and European populations, and 22 newly typed Saharawi. Within Ethiopia the two largest ethnic groups, the Amhara and Oromo, were not found to be statistically distinct, based on an exact test of haplotype frequencies. The Ethiopian Jews appear as an admixed population, possibly of Jewish origin, though the data remain equivocal. There is evidence of a close relationship between Ethiopian and Yemenite Jews, likely a result of indirect gene flow. Within an African and Eurasian context, the distribution of alleles of a variable Tn repeat, and the spread of haplotypes containing Africa‐specific alleles, provide evidence of a genetic continuity from Sub‐Saharan Africa to the Near East, and furthermore suggest that a bottleneck occurred in Ethiopia associated with an out of Africa expansion. Ethiopian genetic heterogeneity, as evidenced by principal component analysis of haplotype frequencies, most likely resulted from periods of subsequent admixture. While these results are from the analysis of one locus, we feel that in association with data from other marker systems they add a complementary perspective on the history of Ethiopia.
Simultaneous Selection of the Wild‐type Genotypes of the G894T and 4B/ 4A Polymorphisms of NOS3 Associate with High‐altitude Adaptation
Authors: Ahsan A. , Norboo T. , Baig M. A. , Qadar Pasha M. A. 
Published: December 2005

SummaryThe routine performance of high‐altitude (HA) natives in the hypoxic environment of HA exemplifies the process of adaptation mainly through natural selection. The recent therapeutic application of nitric oxide (NO) in HA disorders, for the improvement of oxygenation and vasodilation, ushered us to investigate the endothelial nitric oxide synthase gene (NOS3) with respect to HA adaptation. The study subjects, 131 HA monks (HAM), 136 HA controls (HAC), and 170 lowlanders (LLs) were screened for NOS3 G894T (Glu298Asp) and 4B/4A polymorphisms. The NO levels were estimated, for a correlation with the polymorphisms. The three groups were in Hardy‐Weinberg equilibrium for the polymorphisms. The overall genotype distributions for the G894T and 4B/4A polymorphisms were significant (P = 0.01 and 0.02, respectively) in the three groups. Wild‐type alleles G and 4B were significantly over‐represented in the HA groups as compared to the LLs (P = 0.006 and P = 0.02, respectively). The NO levels were in the order of HAM>HAC>LLs (P < 0.0001). Furthermore, combinations of the GG and BB genotypes were distributed significantly more frequently in the HAM (P < 0.0001) and HAC (P = 0.0005) than in LLs. The NO levels contributed by the wild‐type genotype combination GG, BB were significantly elevated when compared with the remaining eight genotype combinations together in the HAM, HAC and LLs (P = 0.003, P = 0.0006 and P < 0.0001, respectively). To conclude, the genotype combination of NOS3 wild‐type homozygotes (GG, BB) was found significantly more frequently in HA groups than in LLs, by contributing to higher NO levels associated with HA adaptation.
Analysis of Dystrophin Gene Deletions Indicates that the Hinge III Region of the Protein Correlates with Disease Severity
Authors: Carsana A. , Frisso G. , Tremolaterra M. R. , Lanzillo R. , Vitale D. F. , Santoro L. , Salvatore F. 
Published: December 2005

SummaryWe have investigated the frequency of deletions in the dystrophin gene in 108 unrelated Duchenne and Becker muscular dystrophy (DMD/BMD) patients from southern Italy (DMD, n. 47; BMD, n. 61) and identified 89 deletions. The de novo mutation rate (about 30%), and the preferentially maternal origin of deletional mutations, analysed in families in which the maternal grandparents were available or their haplotypes could be unequivocally reconstructed, are in agreement with data reported for other populations. The correlation between BMD phenotype and type of deletion suggests that, in the distal rod domain region, the deletion size may not be as crucial as the particular combination of missing exons. In fact, we provide immunohistochemical and clinical evidence that in‐frame deletion of the hinge III region in the distal rod domain results in a milder phenotype as compared with shorter deletions that do not include the hinge III region. Our data obtained in BMD patients, by confirming inferences arising from minigene transfection experiments in mdx mice, represent an important contribution to gene therapy approaches.
The Effect of Genetic Drift in a Young Genetically Isolated Population
Authors: Pardo Luba M. , MacKay Ian , Oostra Ben , van Duijn Cornelia M. , Aulchenko Yurii S. 
Published: December 2005

SummaryThe genetic make‐up of genetically isolated populations may differ from a general population as a result of genetic drift and founder effects. We assessed the extent of this deviation in a recently isolated population located in the southwest of the Netherlands and studied as part of the Genetic Research in Isolated Population (GRIP) program. A gene‐dropping experiment was performed in a large pedigree from this isolate, assuming different initial frequencies in the population founders came from. Allelic frequencies in the last generations of this pedigree were estimated. Simulation analysis showed large fluctuations, as measured by variation coefficient and sufficient loss probability, when initial frequencies were lower than or equal to 1%. For initial frequencies larger than 1% the fluctuations were small. We also analyzed mean heterozygosity and allele diversity of 592 markers in a random sample from the GRIP population. The results were compared with a general population (CEPH sample), old large isolate (Icelandic sample) and the small‐sized population of Talana (Sardinia). GRIP mean heterozygosity and mean number of alleles were significantly lower as compared with CEPH and Iceland, but much higher when compared with the Talana population. We also concluded that the findings from the GRIP population for common variants (>1%) are likely to be extendable to other young isolates in Europe as well as to outbred populations.
Nucleotide Sequence Analyses of Human Complement 6 (C6) Gene Suggest Balancing Selection
Authors: Soejima M. , Tachida H. , Tsuneoka M. , Takenaka O. , Kimura H. , Koda Y. 
Published: December 2005

SummaryThe sixth complement component (C6) has a common charge polymorphism, C6A and C6B, with similar gene frequencies in all major populations. In addition, C6B2 is also found in Japanese populations at a frequency of about 6%. Sequence analyses of the coding region of three human and ape C6 alleles indicated four nonsynonymous and three synonymous changes in C6*B2 relative to C6*A, suggesting that a recombination event occurred between C6*B2 and C6*A to give rise to C6*B. Sequence variation in a 3.86 kb region encompassing exon 3, where the causal base change of the common C6 polymorphism is found, indicated that several single nucleotide polymorphisms (SNPs) were in extensive linkage disequilibrium (LD), with little differentiation among populations. Sliding window estimates of two test statistics for neutrality revealed significant values in a subregion where the replacement coding polymorphism resides, in all three human populations. These results raise the possibility that the two common C6 alleles in human populationsw are maintained by balancing selection.
Power and Related Statistical Properties of Conditional Likelihood Score Tests for Association Studies in Nuclear Families with Parental Genotypes
Authors: Li Z. , Gastwirth J. L. , Gail M. H. 
Published: December 2005

SummaryBoth population based and family based case control studies are used to test whether particular genotypes are associated with disease. While population based studies have more power, cryptic population stratification can produce false‐positive results. Family‐based methods have been introduced to control for this problem. This paper presents the full likelihood function for family‐based association studies for nuclear families ascertained on the basis of their number of affected and unaffected children. The likelihood of a family factors into the probability of parental mating type, conditional on offspring phenotypes, times the probability of offspring genotypes given their phenotypes and the parental mating type. The first factor can be influenced by population stratification, whereas the latter factor, called the conditional likelihood, is not. The conditional likelihood is used to obtain score tests with proper size in the presence of population stratification (see also Clayton (1999) and Whittemore & Tu (2000)). Under either the additive or multiplicative model, the TDT is known to be the optimal score test when the family has only one affected child. Thus, the class of score tests explored can be considered as a general family of TDT‐like procedures. The relative informativeness of the various mating types is assessed using the Fisher information, which depends on the number of affected and unaffected offspring and the penetrances. When the additive model is true, families with parental mating type Aa×Aa are most informative. Under the dominant (recessive) model, however, a family with mating type Aa×aa(AA×Aa) is more informative than a family with doubly heterozygous (Aa×Aa) parents. Because we derive explicit formulae for all components of the likelihood, we are able to present tables giving required sample sizes for dominant, additive and recessive inheritance models.
Wilson Disease: High Prevalence in a Mountaineous Area of Crete
Authors: Dedoussis G. V. Z. , Genschel J. , Sialvera T‐E. , Bochow B. , Manolaki N. , Manios Y. , Tsafantakis E. , Schmidt H. 
Published: December 2005

SummaryWilson disease (WD) is an autosomal recessive disorder of copper metabolism. The disorder is caused by mutations in the ATP7B gene, encoding a copper transporting P‐type ATPase. The worldwide incidence is in the order of 30 cases per million, with a gene frequency of 0.56% and a carrier frequency of 1 in 90. The increased number of Wilson disease patients in the island of Crete led us to study the spectrum of mutations in a small village close to the city of Heraklion, from where many patients have been referred during the last 25 years. In order to estimate the frequency of the disease, we firstly investigated the number of births and the number of WD patients in the village since 1978. Six out of 90 births were diagnosed as WD patients, presenting the highest prevalence of WD reported so far. Analysis of the whole gene in three Wilson disease patients, and relatives of a boy who died from WD, led to the detection of 4 different point mutations. Two of them were missense (p.I1148T and p.G1176R) and cosegregated in cis in the same patient; the other allele of this patient carried a nonsense mutation (p.Q289X). This is the first report in the literature of three mutations co‐segregating in the same WD patient. The fourth mutation identified was a novel frameshift mutation (c.398delT) with documented cosegregation. When screening 200 inhabitants originating from the same area, 18 were found to be carriers of one of these mutations. These findings indicate the need for health education intervention, genetic counselling and newborn screening for the Wilson disease.
Hyperglycaemia acutely decreases circulating dehydroepiandrosterone levels in healthy men
Authors: Boudou P. , Sobngwi E. , Ibrahim F. , Porcher R. , Vexiau P. , Calvo F. , Gautier J.‐F. 
Published: December 2005

SummaryObjective  This study was conducted in order to evaluate the effect of glucose‐insulin homeostasis on adrenal steroids and was designed to separate the effects of hyperglycaemia from those of insulin.Design  Eight healthy men aged 22·6 ± 3·4 (SD) underwent an 80 mU/m2/min hyperinsulinaemic euglycaemic 100‐min clamp, a 200‐min graded glucose infusion at 2–16 mg/kg/min and a measurement of fat mass.Measurements  Circulating glucose, insulin and adrenal steroid levels including dehydroepiandrosterone (DHEA) were determined before and during both infusion tests. Steroid variations in relation to insulinaemia and glycaemia were analysed using univariate, multivariate tests and nonlinear mixed models.Results  Hyperinsulinaemia induced no significant modification of adrenal steroid levels. By contrast, hyperglycaemia decreased all adrenal steroids except DHEA‐sulphate by 47–66%. The drop occurred early, averaging 51% for 17OH pregnenolone and 57% for DHEA at the 80th minute of glucose infusion, whereas blood glucose was 7·1 ± 1·2 mmol/1. This effect was independent of insulinaemia, fat mass and waist circumference. Thus, we estimated models that could best predict steroid variations according to blood glucose. At thresholds defining impaired fasting glycaemia and diabetes, the estimated decrease in DHEA was 40% and 45%, respectively, culminating at 60% at 9·3 mmol/1 glycaemia, with no detectable further decrease.Conclusions  Our data suggest that hyperglycaemia dramatically decreases adrenal androgen levels in men, possibly by acting at early steps of synthesis, independently of insulinaemia and fat mass.
Serum ghrelin concentrations in patients with chronic renal failure undergoing dialysis
Authors: Iglesias Pedro , Díez Juan J. , Fernández‐Reyes María J. , Codoceo Rosa , Alvarez‐Fidalgo Pilar , Bajo María A. , Aguilera Abelardo , Selgas Rafael 
Published: December 2005

SummaryBackground   Ghrelin is a recently discovered protein hormone mainly synthesized in the gastric endocrine cells. This hormone not only is a potent growth hormone secretagogue but also is involved in the regulation of food ingestion and energy metabolism. Derangements in ghrelin secretion in patients with chronic renal failure (CRF) have not been fully evaluated.Objective   Our aim has been to quantify serum concentrations of total ghrelin in a group of patients with CRF on chronic therapy with both haemodialysis (HD) and peritoneal dialysis (PD) in comparison with a group of patients on conservative management (predialysis).Patients and measurements   We studied 68 CRF patients treated by HD (n = 30, 16 men, age 61·2 ± 1·8 years) and PD groups (n = 38, 21 men, age 54·4 ± 1·7 years). A group of 19 uraemic patients on conservative management served as the control. Serum concentrations of ghrelin, leptin, insulin, IGF I and GH were measured in all subjects.Results   Patients undergoing HD showed similar concentrations of ghrelin in comparison with the control group (9491 ± 787 vs 9280 ± 918 pg/ml, NS). However, PD patients exhibited baseline ghrelin concentrations significantly lower than those found in patients on conservative management (3230 ± 216 pg/ml, P < 0·0001). Men and women showed similar serum ghrelin levels in both HD (9845·9 ± 1071 vs 9085 ± 1194 pg/ml) and PD patients (3214 ± 297 vs 3250 ± 324 pg/ml). Hypertension and diabetes mellitus did not influence ghrelin levels. Serum GH levels were positively correlated with serum ghrelin concentrations in both HD (r = 0·46, P < 0·05) and PD (r = 0·53, P < 0·001) patients; however, no relationships between ghrelin, leptin, insulin and IGF I were found.Conclusions   These results suggest that PD is accompanied by a striking decrement in baseline ghrelin concentrations in comparison with values found both in HD and control patients. Further studies are necessary to determine mechanisms involved in ghrelin regulation in uraemic patients.
Assessing the HPA axis in patients with pituitary disease: a UK survey
Authors: Reynolds Rebecca M. , Stewart Paul M. , Seckl Jonathan R. , Padfield Paul L. 
Published: December 2005

SummaryObjective   Assessing the integrity of the hypothalamic–pituitary–adrenal (HPA) axis following pituitary surgery is necessary to determine the requirement for glucocorticoid replacement therapy, but there remains controversy about the optimum way to measure this.Design and measurements  Postal questionnaire survey among UK endocrinologists to evaluate the current methods used.Results   The response rate was low (81 out of 598 questionnaires mailed), although 85% were consultants. Fifty‐five percent measured 9:00 h plasma cortisol in the immediate postoperative phase. Most carried out definitive testing between 4 and 12 weeks: 36% routinely used the insulin tolerance test (ITT), 59% used the short synacthen test (SST). The 30‐min cortisol value was used by 67% as a ‘pass’ when interpreting the results. Others included cortisol measurement at 60 min (17%) or incremental value (7%). For long‐term follow‐up of patients not rendered ACTH‐deficient by surgery, 64% used the SST for patients who had received radiotherapy. If patients had not had radiotherapy, 42% used the SST, whereas 33% did no routine testing unless the patient was symptomatic or there was evidence of tumour recurrence on imaging. If patients were symptomless but ‘failed’ the chosen test, 28% still treated the patient with glucocorticoid replacement, 38% retested before treatment and 24% recommended glucocorticoid cover for when unwell or ‘stressed’. Fifty‐six percent used hydrocortisone at doses of 20 mg/day as replacement therapy.Conclusion   Thus, assessment of the HPA axis remains controversial. Although the SST is becoming more popular, there is still considerable variation in the interpretation of results and, in particular, the decision of whether or not to treat with lifelong glucocorticoid replacement therapy.