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PubMed2005

frailtypack: a computer program for the analysis of correlated failure time data using penalized likelihood estimation.

Correlated survival outcomes occur quite frequently in the biomedical research. Available software is limited, particularly if we wish to obtain smoothed estimate of the baseline hazard function in the context of random effects model for correlated data. The main objective of this paper is to describe an R package called frailtypack that can be used for estimating the parameters in a shared gamma frailty model with possibly right-censored, left-truncated stratified survival data using penalized likelihood estimation. Time-dependent structure for the explanatory variables and/or extension of the Cox regression model to recurrent events are also allowed. This program can also be used simply to obtain directly a smooth estimate of the baseline hazard function. To illustrate the program we used two data sets, one with clustered survival times, the other one with recurrent events, i.e., the rehospitalizations of patients diagnosed with colorectal cancer. We show how to fit the model with recurrent events and time-dependent covariates using Andersen-Gill approach.

Cluster Analysis↗

PubMed2005

Contribution of the familial and genetic factors on monocyte chemoattractant protein-1 variation in healthy human pedigrees.

Monocyte chemoattractant protein-1 (MCP-1) is a chemokine whose circulating levels have been detected in the lesions of several diseases such as pulmonary fibrosis, rheumatoid arthritis and atherosclerosis. However, the factors involved in the regulation of its production remain largely unknown. The main aim of the present paper was to ascertain the contribution of the familial/genetic factors on the production of MCP-1 in apparently healthy individuals. We also tested the possible relationships between the plasma levels of MCP-1 and other cytokines involved in bone metabolism (receptor activator NF-kB ligand (RANKL), osteoprotegerin (OPG), interleukin-6, macrophage-colony stimulating factor, tumor necrosis factor-alpha). Using ELISA assays the cytokine levels were measured in 570 apparently healthy individuals belonging to ethnically homogeneous Caucasian families. We found that MCP-1 levels were significantly (P<0.01) correlated with RANKL (in both sexes) and with OPG only in women. The study showed that adjusted for potential covariates, 72% of the MCP-1 variance, was attributable to familial effects. About 49% was due to potential genetic factors and the rest was explained by common environmental sources shared by spouses within each family. In conclusion, our data provide reliable evidence for the substantial role of genetic factors in the determination of the phenotypic variability of MCP-1 plasma levels. The association between the osteoclastogenic cytokines and MCP-1 levels in healthy pedigrees is of special interest and might shed light on MCP-1 involvement in bone remodeling.

Adult↗

PubMedDate not supplied

Descriptors of dyspnea by patients with chronic obstructive pulmonary disease versus congestive heart failure.

OBJECTIVES: The purpose of this study was to determine whether differences existed between reports of dyspnea in stable chronic obstructive pulmonary disease (COPD) and congestive heart failure (CHF) subjects. METHODS: Sixty stable COPD (n=30) and CHF (n=30) male, outpatient subjects were studied. Subjects were asked to both endorse (from a pre-designed list of descriptors) and volunteer terms that best described their breathing discomfort. Subjects also reported the frequency and the intensity of breathlessness (0-10 scale) using the Pulmonary Functional Status and Dyspnea Questionnaire. RESULTS: From the endorsed list of descriptors, my breath does not go out all the way, was significantly different (COPD=11, CHF=4, P<.05) between groups. The most common terms volunteered by COPD subjects were scary (n=5, P<.02), hard to breathe (n=5), shortness of breath (n=4), and cannot get enough air (n=4), whereas CHF subjects volunteered the terms, shortness of breath (n=9), gasping (n=6), and cannot get enough air (n=4). There was no difference in the frequency with which both groups experienced dyspnea or times per month they reported severe to very severe dyspnea. Subjects with COPD experienced a higher intensity of breathlessness on different occasions P<.05. CONCLUSIONS: Stable COPD and CHF patients use and recognize a variety of terms that describe their breathing distress. There was, however, only 1 unique term among the endorsed and volunteered terms, and that was among the COPD subjects. COPD and CHF subjects shared many common terms and also experienced dyspnea with similar frequency. The uniqueness of terms among the COPD group was less clear. The study highlights the variability of the dyspnea experience among COPD and CHF patients and the potential difficulty identifying unique dyspnea terms in these subjects.

Aged↗

PubMed2001

Fear of pain in orofacial pain patients.

In the present study, we examined whether fear of pain, dental fear, general indices of psychological distress, and self-reported stress levels differed between 40 orofacial pain patients and 40 gender and age matched control general dental patients. We also explored how fear of pain, as measured by the Fear of Pain Questionnaire-III (J Behav Med 21 (1998) 389), relates to established measures of psychological problems in our sample of patients. Finally, we examined whether fear of pain uniquely and significantly predicts dental fear and psychological distress relative to other theoretically-relevant psychological factors. Our results indicate that fear of severe pain and anxiety-related distress, broadly defined, are particularly elevated in orofacial pain patients relative to matched controls. Additionally, fear of pain shares a significant relation with dental fear but not other general psychological symptomology, and uniquely and significantly predicts dental fear relative to other theoretically-relevant variables. Taken together, these data, in conjunction with other recent studies, suggest greater attention be placed on understanding the fear of pain in orofacial pain patients and its relation to dental fear and anxiety.

Adult↗

PubMed2001

Identification of a negative Cis-regulatory element and multiple DNA binding proteins that inhibit transcription of the transforming growth factor-beta type II receptor gene.

Expression of the transforming growth factor-beta type II receptor (TGF-beta RII) is highly regulated and is a critical determinant of the cellular response to TGF-beta. Previous analysis of the promoter region for the TGF-beta RII gene introduced the possible existence of a negative regulatory element (NRE) upstream adjacent to the core promoter region (Bae et al., 1995. J. Biol. Chem. 270, 29460-29468). We have confirmed the presence of a strong NRE located between base pairs -100 and -67 relative to the transcription start site. Utilizing DNA transfection techniques and a series of synthesized oligonucleotide promoter fragments, we have shown that this NRE is active in a variety of cell lines. Electrophoretic mobility shift assays have revealed the presence of multiple DNA binding proteins specifically interacting with the NRE. At least three distinct protein complexes are variably present depending on the specific cell line examined, and mutational analysis of the NRE has identified a ten-base pair recognition sequence which is shared by all three complexes. This palindromic sequence has not been previously reported and does not share homology with any known transcription factor consensus sequences. When inserted into an E4Delta heterologous promoter construct, the NRE binding sequence failed to inhibit either basal or activated transcription of the target gene, indicating that the NRE does not act as a general repressor but may specifically operate within the context of the TGF-beta RII core promoter.

Animals↗

PubMed1998

Polymorphic sites in human mitochondrial DNA control region sequences: population data and maternal inheritance.

Sequence analysis of the mitochondrial DNA (mtDNA) control region is of central importance for forensic identity testing as well as for studies of human evolution. Here we report the sequencing data of the hypervariable regions I and II from 50 unrelated individuals from a western German population (Rhine area). In regions I and II, 52 and 26 sites of sequence polymorphism, respectively, were noted. Nucleotide substitution rather than insertion/deletion was the majority of variation. The distribution showed a large bias towards transitional changes than transversional changes. Furthermore we investigated uniparental inheritance in seven CEPH families each family with 7-9 maternal descendants. Most maternal relatives shared identical mtDNA sequences. Additionally sequences were compared for father:child pairs and as expected no evidence for paternal transmission of mtDNA was observed. The high variability of mtDNA control region sequences permits utility in forensic identity investigations. The data also indicate that the neomutation rate seems to be very low from one generation to the other.

Base Sequence↗

PubMed2003

Type IV pilin structure and assembly: X-ray and EM analyses of Vibrio cholerae toxin-coregulated pilus and Pseudomonas aeruginosa PAK pilin.

Pilin assembly into type IV pili is required for virulence by bacterial pathogens that cause diseases such as cholera, pneumonia, gonorrhea, and meningitis. Crystal structures of soluble, N-terminally truncated pilin from Vibrio cholera toxin-coregulated pilus (TCP) and full-length PAK pilin from Pseudomonas aeruginosa reveal a novel TCP fold, yet a shared architecture for the type IV pilins. In each pilin subunit a conserved, extended, N-terminal alpha helix wrapped by beta strands anchors the structurally variable globular head. Inside the assembled pilus, characterized by cryo-electron microscopy and crystallography, the extended hydrophobic alpha helices make multisubunit contacts to provide mechanical strength and flexibility. Outside, distinct interactions of adaptable heads contribute surface variation for specificity of pilus function in antigenicity, motility, adhesion, and colony formation.

Amino Acid Sequence↗

PubMed2001

Definition of respiratory symptoms and disease in early childhood in large prospective birth cohort studies that predict the development of asthma.

We have reviewed the prospective value of early respiratory symptoms for determining the risk of development of asthma later in life by using data from studies based on the general population, hospital population, and general practices. Although "wheezing" in infancy generally has a good prognosis, it is an important risk factor for the development of asthma later in life. The prognostic value of "coughing" and "shortness of breath" in infancy for the later development of asthma is less clear. Despite the fact that no internationally accepted criteria for the definition of asthma in early childhood are available, many studies have been performed on this topic. We also investigated the outcome variables that were used to describe respiratory symptoms and disease in early childhood in the publications of nine large prospective birth cohort studies on the development of asthma. From seven of these studies, we reviewed the original questionnaires. We found that various studies used different outcome variables, but the data actually collected were similar. This is an important observation because it implies that comparisons between studies can be markedly improved by data sharing among investigators.

Asthma↗

PubMed2001

Transcription factor AP-4 is a ligand for immunoglobulin-kappa promoter E-box elements.

Immunoglobulin (Ig)-kappa promoters from humans and mice share conserved sequences. The octamer element is common to all Ig promoters and pivotal for their function. However, other conserved sequence motifs, that differ between Ig variable gene families, are required for normal promoter function. These conserved motifs do not stimulate transcription in the absence of an octamer. One example is an E-box of the E47/E12 type (5'-CAGCTG-3'), which is found in all promoters of the human and murine Ig-kappa gene subgroups/families, with the exception of subgroups II and VI and their related murine families. In the present study we show that the ubiquitously expressed transcription factor AP-4, and not E47, interacts specifically with the kappa promoter E-boxes when tested in electrophoretic mobility-shift assays using nuclear extracts derived from human and murine B-cell lines. Furthermore, AP-4, unlike E47, did not act as a transactivator, which is in agreement with previous studies on intact kappa promoters, showing that transcription is absent when the octamer element has been mutated. Based on these data, and the conservation of the 5'-CAGCTG-3' motif among human and murine kappa promoters, we propose that AP-4 is the major ligand for Ig-kappa promoter E-boxes.

Animals↗

PubMed1996

A founder mutation as a cause of cerebral cavernous malformation in Hispanic Americans.

BACKGROUND: Cerebral cavernous malformation is a vascular disease of the brain causing headaches, seizures, and cerebral hemorrhage. Familial and sporadic cases are recognized, and a gene causing familial disease has been mapped to chromosome 7. Hispanic Americans have a higher prevalence of cavernous malformation than do other ethnic groups, raising the possibility that affected persons in this population have inherited the same mutation from a common ancestor. METHODS: We compared the segregation of genetic markers and clinical cases of cavernous malformation in Hispanic-American kindreds with familial disease; we also compared the alleles for markers linked to cavernous malformation in patients with familial and sporadic cases. RESULTS: All kindreds with familial disease showed linkage of cavernous malformation to a short segment of chromosome 7 (odds supporting linkage, 4X10(10).1). Forty-seven affected members of 14 kindreds shared identical alleles for up to 15 markers linked to the cavernous-malformation gene, demonstrating that they had inherited the same mutation from a common ancestor. Ten patients with sporadic cases also shared these same alleles, indicating that they too had inherited the same mutation. Thirty-three asymptomatic carriers of the disease gene were identified, demonstrating the variability and age dependence of the development of symptoms and explaining the appearance of apparently sporadic cases. CONCLUSIONS: Virtually all cases of familial and sporadic cavernous malformation among Hispanic Americans of Mexican descent are due to the inheritance of the same mutation from a common ancestor.

Adolescent↗

PubMed2002

Calcium effects on phosphorus absorption: implications for the prevention and co-therapy of osteoporosis.

OBJECTIVE: To evaluate the effect of calcium intake on absorption of dietary phosphorus, with special reference to typical calcium intakes and to those likely to be encountered in prevention and treatment of osteoporosis. SETTING: Two academic health sciences centers; inpatient metabolic research unit. METHODS: Evaluation of calcium and phosphorus balance data obtained in two data sets, the first, 543 studies of healthy women aged 35-65, and the second, 93 men and women aged 19-78; development of multiple regression models predicting fecal phosphorus (the complement of net absorbed phosphorus); data from the two centers analyzed separately as a check on the consistency of the findings. RESULTS: Mean net absorption of phosphorus was 60.3% (+/- 18.1) for data set 1 and 53.0% (+/-9.4) for data set 2. Just two variables, fecal calcium and diet phosphorus, were positively and independently associated with fecal phosphorus. These variables explained 73% of the variance in fecal phosphorus in data set 1 and 33% in data set 2. Fecal calcium alone explained the lion's share of the relationship. The coefficients of the fecal calcium term in the models fitted to the data were 0.332+/-0.022 and 0.155+/-0.039, for data sets I and 2, respectively. Adjusting for the relationship between fecal calcium and calcium intake and using the parameters of the larger data set, it follows that each increase in calcium intake of 0.5 g (12.5 mmol) decreases phosphorus absorption by 0.166 g (5.4 mmol). CONCLUSIONS: As calcium intake increases without a corresponding increase in phosphorus intake, phosphorus absorption falls and the risk of phosphorus insufficiency rises. Intakes with high Ca:P ratios can occur with use of supplements or food fortificants consisting of non-phosphate calcium salts. Older patients with osteoporosis treated with current generation bone active agents should receive at least some of their calcium co-therapy in the form of a calcium phosphate preparation.

Adult↗

PubMed1978

Dietary fibers: their definition and nutritional properties.

Fiber is a variable material with respect to its nutritional qualities depending upon its composition and physical properties. Biological properties possessed by one type of fiber might not be shared by another type. Separate methods are required to describe quantity, composition, and quality of fiber in foods. Fibers can be generally classified into three groups: vegetable fibers, which are highly fermentable with low indigestible residue; brans, which are less fermentable; and chemically purified fibers such as wood cellulose, which are relatively unfermentable. A class of soluble substances including pectins and gums may not be true fibers, but are considered part of the dietary fiber complex because of the similar effects they can elicit in the diet. A major need is the replacement of the crude fiber method, the present official method, which is seriously defective. Since crude fiber values are erratic and poorly related to the true fiber value of food, a second major need is the reanalysis of all foodstuffs by appropriate methods and the replacement of standard tables of food composition. Accomplishment of these purposes will require more support and promotion than is presently being received.

Cellulose↗

PubMed2005

Potential uptake and correlates of willingness to use a supervised smoking facility for noninjection illicit drug use.

Many cities are experiencing infectious disease epidemics and substantial community harms as a result of illicit drug use. Although medically supervised smoking facilities (SSFs) remain untested in North America, local health officials in Vancouver are considering to prepare a submission to Health Canada for an exemption to open Canada's first SSF for evaluation. Reluctance of health policymakers to initiate a pilot study of SSFs may be due in part to outstanding questions regarding the potential uptake and community impacts of the intervention. This study was conducted to evaluate the prevalence and correlates of willingness to use an SSF among illicit drug smokers who are enrolled in the Vancouver Injection Drug Users Study. Participants who reported actively smoking cocaine, heroin, or methamphetamine who returned for follow-up between June 2002 and December 2002 were eligible for these analyses. Those who reported willingness to use an SSF were compared with those who were unwilling to use an SSF by using logistic regression analyses. Four hundred and forty-three participants were eligible for this study. Among respondents, 124 (27.99%) expressed willingness to attend an SSF. Variables that were independently associated with willingness to attend an SSF in multivariate analyses included sex-trade work (adjusted odds ratio [AOR]=1.85), crack pipe sharing (AOR=2.24), and residing in the city's HIV epicentre (AOR =1.64). We found that participants who demonstrated a willingness to attend an SSF were more likely to be involved in the sex trade and share crack pipes. Although the impact of SSFs in North America can only be quantified by scientific evaluation, these data indicate a potential for public health and community benefits if SSFs were to become available.

Adult↗

PubMed1997

Parameters controlling the rate of gene targeting frequency in the protozoan parasite Leishmania.

In this study we investigated the role of several parameters governing the efficiency of gene targeting mediated by homologous recombination in the protozoan parasite Leishmania. We evaluated the relative targeting frequencies of different replacement vectors designed to target several sequences within the parasite genome. We found that a decrease in the length of homologous sequences <1 kb on one arm of the vector linearly influences the targeting frequency. No homologous recombination was detected, however, when the flanking homologous regions were <180 bp. A requirement for a very high degree of homology between donor and target sequences was found necessary for efficient gene targeting in Leishmania , as targeted recombination was strongly affected by base pair mismatches. Targeting frequency increased proportionally with copy number of the target only when the target was part of a linear amplicon, but remained unchanged when it was present on circles. Different chromosomal locations were found to be targeted with significantly variable levels of efficiency. Finally, different strains of the same species showed differences in gene targeting frequency. Overall, gene targeting mediated by homologous recombination in Leishmania shares similarities to both the yeast and the mammalian recombination systems.

Animals↗

PubMed1998

A comparison of manual versus computer-assisted radiographic measurement. Intraobserver measurement variability for Cobb angles.

STUDY DESIGN: A comparison between computer-assisted measurement using digitized radiographs, which has the potential to reduce error, and manual measurement using standard radiographs. OBJECTIVE: To assess measurement variability for the Cobb method on digital radiographs and compare it with that of manual measurements on standard radiographs. BACKGROUND DATA: Studies of the Cobb method have demonstrated multiple sources of error leading to significant intraobserver measurement variability. Estimates for the 95% confidence interval for intraobserver variability range from 2.8 degrees to 10 degrees. METHODS: Twenty-four scoliosis radiographs were measured by six examiners. Two measurement sets were done manually ("manual set"), and two measurement sets were done on digitized images using a computer mouse ("computer set"). RESULTS: For the manual set, the 95% confidence interval for intraobserver variability was 3.3 degrees (range, 2.5-4.5 degrees). For the computer set, the value was 2.6 degrees (range, 2.3-3.3 degrees). This difference in 95% confidence intervals between the manual and computer sets was statistically significant (P < 0.001). CONCLUSIONS: The results of this study demonstrate that intraobserver variability for manual and computer Cobb angle measurements yield a 95% confidence interval of approximately 3 degrees, with the computer having a slightly lower variability. The computer technique removes sources of intrinsic error, e.g., the variability introduced by using different manual protractors, the inaccuracy of standard protractors, and the use of wide-diameter radiographic markers. Identical digital images can be shared electronically between centers, without having to duplicate and mail films. Multicenter studies in which different examiners will be measuring Cobb angles may consider using the computer as a measuring device to reduce intrinsic measurement errors.

Arthrography↗

PubMed1992

HIV risk of transmission behaviour amongst HIV-infected prisoners and its correlates.

Thirty-eight from a total of 42 known HIV-positive prisoners in the Irish prison system voluntarily cooperated in a survey of psychological attitudes, knowledge of risk behaviour, intentions with respect to future risk behaviour, and actual past risk behaviour. Of this group, 65% reported that they had put others at risk of HIV, since they became aware of their own HIV+ status. Only 16% stated that they would definitely not share their drug-taking equipment in the future and 32% that they would always use a condom in sexual intercourse. In general, psychological and biographical variables were not strongly related to whether or not the respondents had put others at risk of HIV. Nor were there any significant differences in knowledge of at risk behaviour between those who had and those who had not put others at risk. However, there was some evidence for considerable independence between risk-taking behaviour in the sexual and in the drug-taking domains, in that risk-taking in one area was not highly predictive of risk-taking in the other.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Parentage analysis within a semi-free-ranging group of Barbary macaques Macaca sylvanus.

This study of a group of semi-free-ranging Barbary macaques Macaca sylvanus aimed to determine paternity, to establish whether any individual male achieved prominent mating success and to assess genetic variability. Analyses involved electrophoresis of 15 blood protein systems and multilocus DNA fingerprinting (isotopic and nonisotopic). Genetic variability was low; only two blood protein systems were polymorphic. Although all DNA-fingerprints were individual-specific, they showed a high average band-sharing index value (0.67). Nevertheless, a combination of all methods permitted inference of paternity in 11 out of 15 (73%) cases tested. Several males from different age classes fathered infants.

Animals↗

PubMed2001

Taxonomic characterization of two rubber degrading bacteria belonging to the species Gordonia polyisoprenivorans and analysis of hyper variable regions of 16S rDNA sequences.

Two cis-1,4-polyisoprene (isoprene rubber) degrading bacteria, strains VH2 and Y2K, were identified as strains of the species Gordonia polyisoprenivorans belonging to the Corynebacterineae, a suborder of the order Actinomycetales. Both showed characteristic growth and degradation of isoprene rubber as described previously for the type strain of G. polyisoprenivorans Kd2 (DSM 44302(T)). For strain VH2 the chemotaxonomic properties were investigated, and DNA-DNA hybridization experiments with the type strain revealed the affiliation to the species G. polyisoprenivorans. The comparison of the 16S rDNA sequences, and especially hyper variable regions of these, led to the classification of strain Y2K to the same species. At present, the species G. polyisoprenivorans comprises three different isolates which share the ability to degrade isoprene rubber potently but which were obtained from different geographic regions.

Actinomycetales↗