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PubMed1998

Strategies for the capillary electrophoretic separation of indole alkaloids in Psilocybe semilanceata.

While the hallucinogenic mushrooms Psilocybe semilanceata have previously been analyzed for the indole alkaloids psilocybin and baeocystin by capillary zone electrophoresis (CZE) at pH 11.5, the present work focused on the development of an alternative and complementary capillary electrophoretic method for their identification. Owing to their structural similarity and zwitterionic nature, the compounds were difficult to resolve based on different interactions with cationic or anionic micelles. However, while the attempts with micellar electrokinetic chromatography (MEKC) were unsuccessful, rapid derivatization with propyl chloroformate and reanalysis by CZE at pH 11.5 was effective to support identification of the two indole alkaloids. Psilocin was difficult to analyze by CZE at pH 11.5 owing to comigration with the electroosmotic flow. For this compound, the pH of the running buffer was reduced to 7.2 to effectively enhance the electrophoretic mobility.

Alkaloids↗
PubMed1998

Rapid identification of comigrating gel-isolated proteins by ion trap-mass spectrometry.

In the search for novel nuclear binding proteins, two bands from a sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gel were analyzed and each was found to contain a number of proteins that subsequently were identified by tandem mass spectrometry (MS/MS) on a quadrupole ion trap instrument. The bands were digested with trypsin in situ on a polyvinylidene difluoride (PVDF) membrane following electroblot transfer. Analysis of a 2.5% aliquot of each peptide mixture by matrix assisted laser desorption/ionization-mass spectrometry (MALDI-MS) followed by an initial database search with the peptide masses failed to identify the proteins. The peptides were separated by reversed-phase capillary high performance liquid chromatography (HPLC) in anticipation of subsequent Edman degradation, but mass analysis of the chromatographic fractions by MALDI-MS revealed multiple, coeluting peptides that precluded this approach. Selected fractions were analyzed by capillary HPLC-electrospray ionization-ion trap mass spectrometry. Tandem mass spectrometry provided significant fragmentation from which full or partial sequence was deduced for a number of peptides. Two stages of fragmentation (MS3) were used in one case to determine additional sequence. Database searches, each using a single peptide mass plus partial sequence, identified four proteins from a single electrophoretic band at 45 kDa, and four proteins from a second band at 60 kDa. Many of these proteins were derived from human keratin. The protein identifications were corroborated by the presence of multiple matching peptide masses in the MALDI-MS spectra. In addition, a novel sequence, not found in protein or DNA databases, was determined by interpretation of the MS/MS data. These results demonstrate the power of the quadrupole ion trap for the identification of multiple proteins in a mixture, and for de novo determination of peptide sequence. Reanalysis of the fragmentation data with a modified database searching algorithm showed that the same sets of proteins were identified from a limited number of fragment ion masses, in the absence of mass spectral interpretation or amino acid sequence. The implications for protein identification solely from fragment ion masses are discussed, including advantages for low signal levels, for a reduction of the necessary interpretation expertise, and for increased speed.

Amino Acid Sequence↗
PubMed2004

Refining the results of a whole-genome screen based on 4666 microsatellite markers for defining predisposition factors for multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with a complex genetic background. In order to identify loci associated with the disease, we had performed a genome screen initially using 6000 microsatellite markers in pooled DNA samples of 198 MS patients and 198 controls. Here, we report on the detailed reanalysis of this set of data. Distinctive features of microsatellites genotyped in pooled DNA causing false-positive association or masking existing association were met by improved evaluation and refined correction factors in the statistical analyses. In order to assess potential errors introduced by DNA pooling and genotyping, we resurveyed the experiment in a subset of microsatellite markers using de novo-composed DNA pools. True MS associations of markers were verified via genotyping all individual DNA samples comprised in the pools. Microsatellites share characteristically superb information content but they do not lend themselves to automation in very large scale formats. Especially after DNA pooling many artifacts of individual marker systems require special attention and treatment. Therefore, in the near future comprehensive whole-genome screens may rather be performed by typing single nucleotide polymorphisms on chip-based platforms.

DNA Primers↗
PubMed2005

The molecular end effect and its critical impact on the behavior of charged-uncharged polymer conjugates during free-solution electrophoresis.

Recently two novel techniques using free-solution electrophoresis to separate charged-uncharged polymer conjugates have proven successful: end-labeled free-solution electrophoresis (ELFSE) for DNA sequencing, and free-solution conjugate electrophoresis (FSCE) for molar mass profiling of uncharged polymers. The approach taken to analyze the experimental data was an extension of the theory of Long and co-workers (Long, D., Dobrynin, A. V., Rubinstein, M., Ajdari, A., J. Chem. Phys. 1998, 108, 1234-1244) for the electrophoresis of molecules with varying charge distributions. This theory also predicts that the ends of the polymers play a large role in determining the polymer's overall mobility; however, this aspect of the theory was neglected in previous work. Until now this "end effect" has, to the knowledge of the authors, not been recognized in experimental data. Through a careful investigation of the predicted end effect and a reanalysis of the experimental data, we demonstrate that indeed this effect critically impacts on the behavior of charged-uncharged polymer conjugates during electrophoresis. This work indicates that not only does the end effect need to be taken into account to avoid significant errors in data analysis, but also it provides novel system optimization approaches.

Electrophoresis↗
PubMed1984

A genetic study of hypoalphalipoproteinemia.

Complex segregation analysis under the unified mixed model of inheritance (major gene and multifactorial) is performed on families ascertained through 23 probands with hypoalphalipoproteinemia (depressed HDL-cholesterol, denoted HDL-c). Evidence for segregation of a recessive major gene for depressed HDL-c with frequency q = 0.116, in addition to multifactorial transmission (H = 0.572), is found in these families. Reanalysis of a subset of families with severely depressed HDL-c confirms the conclusions based on the original analysis, except that different definitions of "affection" give rise to different estimates of gene frequency. Our finding of a recessive mode of inheritance differs from previous claims for a dominant gene because previous analyses did not use a mixed model for segregation analysis of hypoalphalipoproteinemia. When the significant multifactorial background is neglected, we also find evidence for the invalid claim of a dominant gene. This demonstrates the necessity of using mixed models for determining the mode of inheritance of a given phenotype.

Cholesterol, HDL↗
PubMed1986

Etiological heterogeneity in Hodgkin's disease: HLA linked and unlinked determinants of susceptibility independent of histological concordance.

Forty-one multiplex families, from published sources and new data from the National Cancer Institute, segregating for Hodgkin's disease and HLA, have been studied. A reanalysis of these data strongly suggests a recessive mode of inheritance for susceptibility to Hodgkin's disease. The HLA haplotype sharing data between affected relatives demonstrate that approximately 60% of cases in multiplex families are due to an HLA-linked susceptibility gene, the remaining 40% being due to other familial factors. The data clearly support the hypothesis of etiological heterogeneity for Hodgkin's disease, with both HLA-linked and HLA-unlinked factors being responsible. Finally, there is an increased concordance of histological types between affected relatives, but this concordance seems independent of HLA sharing.

Female↗
PubMed1988

Genetic analysis of human breast cancer: implications for family study designs.

Genetic analysis of human breast cancer, as with many common diseases, raises several problems including sampling strategies, genetic heterogeneity, and gene-environment interactions. A reanalysis of 200 Danish breast cancer pedigrees, under the unified mixed model, was conducted to investigate more specifically these three points. We found that use of different sampling schemes leads to similar conclusions: familial transmission of breast cancer in this whole Danish sample cannot be accounted for by the Mendelian segregation of a dominant gene. Homogeneity tests, based on an a priori subdivision of the sample, were all nonsignificant under a given genetic model. However, it was possible to isolate a particular subgroup of pedigrees displaying only breast cancer, which was compatible with the segregation of a dominant gene. We have also shown that correct specification of a liability indicator according to epidemiological factors is of major importance to detect a major effect under the mixed model. Our results emphasize the need to design family studies including various types of information in the probands and family members to permit some progress in the understanding of complex diseases.

Breast Neoplasms↗
PubMed1999

Hunting genetic diseases: exploring a multistage approach to identifying disease loci.

Genomic screen data for a hypothetical disease was used in a two-stage analysis to search for disease loci. We performed both trait-model-dependent and trait-model-free analyses to test their relative power. Results of our first-stage screen in 200 families suggested 13 regions for further analysis. Second-stage follow-up in another 200 families confirmed a single region on chromosome 3 near marker D3G045 with a combined lod score across all 400 families of 6.24 and a sib-pair maximum lod score (MLS) of 4.79. The MLS were highly correlated with both the autosomal dominant and autosomal recessive lod scores in all data sets, suggesting that both trait-model-dependent and trait-model-free methods can be useful for identifying candidate regions for complex disease loci. Reanalysis of the data using alternative sampling schemes suggested that sampling variation has a significant effect on locus detection.

Genetic Markers↗
PubMed2005

Somatic symptoms of depression in elderly patients with medical comorbidities.

OBJECTIVE: Somatic symptoms of depression such as fatigue create a diagnostic dilemma when assessing an older patient with medical comorbidities, since chronic medical illnesses may produce similar symptoms. Alternatively, somatic symptoms attributed to medical illness may actually be caused by depression. These analyses were designed to determine if somatic symptoms in older patients are more strongly associated with chronic physical problems or with depression. DESIGN: Reanalysis of data from an observational study of depression in primary care and a randomized trial of paroxetine and nortriptyline for the treatment of major depression. Patients were evaluated with a structured diagnostic interview and a battery of psychiatric, physical, and psychosocial measures. PARTICIPANTS: Two hundred and forty eight primary care and psychiatric patients aged >or= 60 years. METHODS: Associations among depression, somatization, and chronic physical problems were examined using correlations and regression modeling. RESULTS: Two somatization measures, the Asberg Side Effects Rating Scale and the Utvalg for Kliniske Undersogelser (UKU), were significantly associated with psychological symptoms of depression (r = 0.73 and r = 0.76, p < 0.0001) but not with medical comorbidities (r = 0.02, p = 0.16 and r = 0.10, p = 0.78). In multiple regression models, psychological symptoms of depression remained significant predictors of somatization (p < 0.0001) after controlling for age, gender, and medical comorbidities. CONCLUSIONS: In older patients with medical disorders and multiple somatic complaints, clinicians should consider the possibility of depression. Rating scales emphasizing somatic symptoms associated with depression may provide a more accurate measure of depression severity than those excluding such symptoms.

Aged↗
PubMed1996

Severity of liver disease in liver transplantation recipients with hepatitis C virus infection: relationship to genotype and level of viremia.

Infection with hepatitis C virus (HCV) genotype 1b has been reported to be associated with more severe posttransplantation liver disease than infection with non-1b genotypes. To address this issue, we evaluated the outcome in 124 patients who underwent liver transplantation for chronic HCV infection. The HCV genotype and/or serotype responsible for infection was determined by four different methods. HCV RNA was detected in serum samples by polymerase chain reaction (PCR) amplification, and quantified by branched DNA assay. Disease severity was expressed as a histological score (which included grading of portal inflammation, lobular activity, fibrosis, and cytopathic changes). Median duration of histological follow-up was 25 months (range 1-75 months). Genotype was assignable in 112 (92.5%) patients. Genotypes responsible for infection were as follows: 1a = 32.2%, 1b = 27.3%, 2a = 7.4%, 2b = 8.3%, 3a = 14%, and mixed infection (more than one subtype) = 3.3%. Level of viremia, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and total histological score were not significantly different in patients infected with type 1b compared with patients infected with other genotypes. While duration of histological follow-up was greater in patients infected with type lb versus other types (P = .02), by univariate and multivariate analysis neither HCV genotype (lb versus others), level of viremia nor duration of histological follow-up were associated with disease severity. Moreover, there was no significant difference in the actuarial graft survival in patients infected with type lb compared with that of patients infected with non-lb types (82% and 87% at 3 years, respectively). Reanalysis using HCV genotype 1 showed no association with disease severity, graft survival, and patient survival. We conclude that HCV genotype 1 and subtype 1b are not associated with disease severity or graft survival in liver transplantation recipients.

Adult↗
PubMed2001

Relationship between magnitude of damage to the hippocampus and impaired recognition memory in monkeys.

Two recent meta-analyses, drawing on data from many of the same studies with monkeys, reached different conclusions about the relationship between hippocampal damage and recognition memory performance. Both studies found evidence of recognition memory impairment following hippocampal damage. However, Zola et al. (J Neurosci 2000;20:451-463) found no significant correlation between extent of hippocampal damage and recognition memory performance, whereas Baxter and Murray (Hippocampus 2001;11:61-71) concluded that the extent of hippocampal damage in monkeys was inversely correlated with impaired performance. Here, we first consider the requirements for carrying out a valid meta-analysis, and point out that the analysis carried out by Baxter and Murray (Hippocampus 2001;11:61-71) is invalid on simple statistical grounds. We then adopt the appropriate statistical procedures (multiple regression analyses rather than simple correlational analysis) to assess the relationship between extent of hippocampal damage and recognition performance across different studies. None of these analyses, including a reanalysis of the data of Baxter and Murray (Hippocampus 2001;11:61-71), revealed a significant inverse relationship between lesion size and behavioral impairment. Most of the variance was explained by differences between the studies that contributed to the meta-analysis, not by lesion size itself. Indeed, analysis of covariance indicated that there were differences among the studies beyond lesion size that significantly affected performance. Finally, we consider what relationship might hold between lesion size and memory performance in the monkey.

Animals↗
PubMed2002

Long-term effects of oral contraceptives on ovarian cancer risk.

Several epidemiologic studies have reported a protective effect of oral contraceptives (OCs) on ovarian cancer. However, there remain open issues, including better quantification of time-related factors such as time since last use, age at first use and time since first use. We performed a collaborative reanalysis of 6 case-control studies conducted between 1978 and 1999 in the United Kingdom, Greece and Italy, including a total of 2,768 incident, histologically confirmed cases of epithelial ovarian cancer and 6,274 hospital controls under age 70 years. A reduced risk of ovarian cancer was found for ever- compared to never-users [odds ratio (OR) = 0.66, 95% confidence interval (CI) 0.56-0.79], and a stronger reduction was observed for women who had used OCs for > or =5 years (OR = 0.50, 95% CI 0.33-0.76) compared to those who had used them for <5 years. The protective effect of OCs on ovarian cancer was consistent across strata of age, parity, menopausal status and family history of breast or ovarian cancer. After allowance for duration of use, no other time factor was related to ovarian cancer risk: the reduced risk was similar for women who stopped OC use > or =20 years before compared to <10 years; likewise, no significant modification of risk reduction was observed for age at first OC use and time since first OC use. The present analysis indicates that, after taking into account duration of OC use, the OC protection from ovarian cancer persists for a long time after stopping use.

Adult↗
PubMed2006

Frequent EGFR mutations in noninvasive bronchioloalveolar carcinoma.

Mutations of the epidermal growth factor receptor gene (EGFR) have been reported to be present in a considerable fraction of lung adenocarcinomas showing dramatic response to EGFR tyrosine kinase inhibitors. To clarify pathogenic significance of the mutations for the development of lung adenocarcinoma, we investigated stage I lung adenocarcinomas for the mutations. First, 107 cases of macrodissected stage I adenocarcinomas were examined for mutations in exons 18-21 of the EGFR gene. EGFR mutations were detected in 36 of the 107 cases (34%). In particular, among the stage I cases, the mutations were detected in 17 of 42 small-sized adenocarcinomas (<or=2 cm in diameter) (40%), including 7 of 11 noninvasive bronchioloalveolar carcinomas (BACs) (64%) and 7 of 25 invasive adenocarcinomas with BAC components (28%). Second, 26 cases of laser capture microdissected small-sized adenocarcinomas, including 9 cases in the first analysis, were examined for the mutations. Reanalysis of microdissected materials in the 9 cases identified the mutations in 2 more adenocarcinomas with BAC components. Moreover, in the analysis of the other 17 microdissected materials, EGFR mutations were detected in 7 of 12 BACs (58%) and in 3 of 5 adenocarcinomas with BAC components (60%). EGFR mutations are present frequently in BACs, and are thus likely to be a critical genetic alteration for the formation of noninvasive lung adenocarcinoma.

Adenocarcinoma↗
PubMed1987

Another look at the pentoxifylline efficacy data for intermittent claudication.

Porter et al have reported that pentoxifylline shows statistically significant superiority over placebo in a seven-center, double-blind, parallel group, randomized trial of outpatients with intermittent claudication secondary to chronic occlusive arterial disease. The objective of this report is convey results of the intention-to-treat population, paying careful attention to relevant methodologic issues relating to the analysis of clinical trials. At the same time, a new measure of clinical efficacy, minimum distance walked, is proposed. The rationale for this measure is discussed and results are compared with those for walking distances at each visit. The reanalysis of the Porter et al data by "intention to treat" and by use of the minimum-distance-walked measure confirms the published findings of efficacy of pentoxifylline for treatment of intermittent claudication.

Aged↗
PubMed2005

Comparison of implantation and cytotoxicity testing for initially toxic biomaterials.

To evaluate the predictive value of cytotoxicity testing, the present study compares the in vivo tissue responses to in vitro cytotoxicity before and after implantation. Material toxicity was caused by addition of the toxic substance Zincdiethyldithiocarbamate (ZDEC) that is used as a standard for in vitro cytotoxicity testing. Polyurethane discs with the addition of 0.5% or 1% ZDEC as well as nontoxic discs were inserted in the abdominal wall of rats for 1 day up to 6 weeks. After explantation the foreign body response was analyzed immunohistochemically. An in vitro reanalysis of the explanted reference materials (RMs) revealed remaining high concentrations of toxic compounds after 1-week implantation, whereas no toxicity was seen after 6 weeks implantation. This was reflected in the foreign body response where a significantly thicker capsule and more inflammatory cells were seen at 1 week for the toxic implants. Over time, with decreasing toxicity, these differences disappeared. Test samples that only were subjected to in vitro extraction with water did not elute toxic compounds to the same extent as the in vivo conditions. It is concluded that many clinically useful implant materials may be unnecessarily rejected due to the results of in vitro tests.

Absorbable Implants↗
PubMed1994

Precision of measurement by dual-energy X-ray absorptiometry of bone mineral density and content in rat hindlimb in vitro.

Dual-energy x-ray absorptiometry (DXA) is a precise and effective method for measuring bone mineral density (BMD) and content (BMC) at various skeletal sites in the human, but its precision for measuring low BMD and BMC in tiny rat bones has scarcely been evaluated. The short-term precision of DXA (Norland XR-26) for eight regions of interest (ROI) was determined by measuring dissected, not totally defleshed hindlimbs from four rats of differently weights 10 times consecutively. The accuracy of the BMD (area) measurement was also evaluated. The following average precision values (coefficients of variation) with negligible reanalysis error were obtained for BMD and BMC measurements: 0.7 and 1.2% (total); 0.9 and 1.2% (femur); 1.3 and 2.8% (tibia); 1.3 and 2.1% (foot); 2.1 and 4.7% (proximal femur); 1.4 and 2.9% (femoral shaft); 1.8 and 5.6% (distal femur); and 2.7 and 7.6% (proximal tibia). As for the accuracy, BMD measured in tiny bones is likely to be markedly underestimated. We conclude that the standard DXA technique without additional modification for small animal measurements is a precise method for BMD and BMC measurements at multiple sites in rat hindlimb in vitro.

Absorptiometry, Photon↗
PubMed1994

Quality control of bone densitometry in a national health survey (NHANES III) using three mobile examination centers.

A quality control (QC) program for bone mineral measurements at the proximal femur by dual-energy x-ray absorptiometry (DXA) was designed for the osteoporosis component of the Third National Health and Nutrition Examination Survey (NHANES III). Major elements of the QC program are (1) a QC center for review of all scans, (2) setup procedures for and continuous monitoring of daily QC procedures, (3) reference standards for cross-calibration, (4) longitudinal studies for assessment of instrument stability, (5) monitoring of technologist performance, and (6) training. This report describes the results of the QC program of the first half of this 6 year study, which began in 1988. Measurements were performed on 7376 subjects in three mobile examination centers, which traveled to a new location about every 3 months, a total of 44 locations. A small percentage (3.5%) of all scans were rejected, mostly because of patient motion during scanning, but 33% of the remaining scans required reanalysis at the QC center to refine the location of the regions of interest. Precision in spine and hip phantoms was below 1% at all ROIs. In 535 subjects with duplicate scans, age 20-91 of both sexes, examined in a blinded review, precision for BMD at the femur neck ROI was 3.2% (CV) and 5.1% for Ward's triangle BMD. The central review improved scan quality, increased the number of usable scans, and reduced significantly the range of the mean percentage difference in the duplicate scans. Minor alterations in machine function were observed and corrected. QC results on phantoms were similar to those obtained with stationary instruments in dedicated laboratories. Retrospective analysis of the regression slopes from QC records did not show a need for correction of the data base, indicating that the instruments were stable during the course of the study.

Absorptiometry, Photon↗
PubMed2001

Theory of the growth and evolution of feather shape.

We present the first explicit theory of the growth of feather shape, defined as the outline of a pennaceous feather vane. Based on a reanalysis of data from the literature, we propose that the absolute growth rate of the barbs and rachis ridges, not the vertical growth rate, is uniform throughout the follicle. The growth of feathers is simulated with a mathematical model based on six growth parameters: (1) absolute barb and rachis ridge growth rate, (2) angle of helical growth of barb ridges, (3) initial barb ridge number, (4) new barb ridge addition rate, (5) barb ridge diameter, and (6) the angle of barb ramus expansion following emergence from the sheath. The model simulates growth by cell division in the follicle collar and, except for the sixth parameter, does not account for growth by differentiation in cell size and shape during later keratinization. The model can simulate a diversity of feather shapes that correspond closely in shape to real feathers, including various contour feathers, asymmetrical feathers, and even emarginate primaries. Simulations of feather growth under different parameter values demonstrate that each parameter can have substantial, independent effects on feather shape. Many parameters also have complex and redundant effects on feather shape through their influence on the diameter of the follicle, the barb ridge fusion rate, and the internodal distance. Simulated isochrones-the loci, or sets, of feather cells of the same age-have the same oblique chevron-shaped position in the mature feather as fault bars, which are isochronic defects in the barbules created by a disruptions during development. Accurate simulation of fault bar shape and position confirms the uniform absolute growth rate hypothesis and the general realism of the model. The theory defines a six-parameter feather morphospace, and provides many predictions about the developmental determination of feather shape that can be tested with detailed observations and experiments on developing feathers. This theory also provides testable predictions about the changes in developmental mechanisms required to evolve different feather shapes to accomplish various functions.

Animals↗