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PubMed1999

Estimating intraclass correlation for binary data.

This paper reviews many different estimators of intraclass correlation that have been proposed for binary data and compares them in an extensive simulation study. Some of the estimators are very specific, while others result from general methods such as pseudo-likelihood and extended quasi-likelihood estimation. The simulation study identifies several useful estimators, one of which does not seem to have been considered previously for binary data. Estimators based on extended quasi-likelihood are found to have a substantial bias in some circumstances.

Biometry↗

PubMed1999

Assessment of familial patterns of microbial infection in periodontitis.

The purpose of this article is to review approaches to the assessment of familial patterns of microbial infection and disease in periodontitis, and to identify statistical methods appropriate to such considerations of family data. Previous studies have provided evidence for the presence of familial aggregation of periodontal pathogens and periodontitis and have alluded to possible transmissibility of these organisms within families. Modern statistical techniques permit the appropriate analysis of the correlated data inherent in families, properly allowing for these statistical dependencies while including the possibility of adjustment for risk factors which may also aggregate in families. Such approaches as multiple linear regression, multivariate logistic regression, and regressive modeling provide the necessary tools to assess the familial aggregation of risk factors and disease in periodontitis. In particular, regressive models permit the analysis of familiality (membership to family) as a risk factor without reference to a specific underlying biologic mechanism, and also permit the possibility of adjustment for covariates, such as age and access to dental care. They also allow consideration of specific mechanisms, e.g., susceptibility genes of major effect. Using such techniques, it is possible to more completely explore and describe familial patterns of periodontal infection and other aspects of periodontal disease.

Disease Transmission, Infectious↗

PubMed1987

Inability to predict diagnosis in febrile intravenous drug abusers.

Although hospitalization is recommended for all febrile intravenous drug abusers, this practice has not been tested and validated. To determine the distribution of disease and the predictive value of clinical information available in the emergency room for diagnosis in these patients, we prospectively evaluated the clinical and laboratory data for 87 consecutive admissions involving 75 intravenous drug abusers with temperature of 38.1 degrees C or more, emergency room physicians' diagnostic predictions, and final diagnosis. Final diagnoses were pneumonia in 38% of the patients, trivial illness (viral syndrome, pharyngitis, or pyrogen reaction) in 26%, infective endocarditis in 13%, and other conditions in 23%. Neither emergency room physicians' diagnostic predictions nor clinical data correlated with a final diagnosis of endocarditis. Although physicians' prediction of trivial illness was associated with a final diagnosis of trivial illness (p less than 0.05), 29% of these patients had a more serious final diagnosis. These data confirm the need to hospitalize all intravenous drug abusers presenting with fever at an emergency room.

Adult↗

PubMed1993

Siblings' neonatal mortality risks and birth spacing in Bangladesh.

This paper studies the familial association of neonatal mortality in Matlab, Bangladesh and its relationship to birth-spacing effects on mortality. Findings show that familial association is strongest for siblings of adjacent birth orders. Moreover, birth-spacing effects on neonatal mortality are stronger when the preceding child has survived the neonatal period than when it has died. Transitional (Markov), random-effects, and marginal models for correlated data are introduced, and are contrasted in interpretation and technique. Familial association of neonatal mortality can be approximately well by a first-order Markov model using generalized estimating equations (GEE) to allow for higher-order correlation.

Adult↗

PubMed1989

Transvaginal sonography in the evaluation of normal early pregnancy: correlation with HCG level.

Transvaginal sonography (TVS) is the procedure of choice in evaluating the viability of embryos early in pregnancy. However, viability based on TVS can be assessed more accurately when the exact gestational age from the last menstrual period is known or when the findings are correlated with beta human chorionic gonadotropin (HCG) levels. No large series has been reported with correlative data between early pregnancy findings, HCG, and gestational age. We performed 75 transvaginal examinations in 53 patients with proved normal pregnancy in the fifth through seventh weeks of gestation. The presence and size of the gestational sac, presence of a yolk sac, and identification of embryonic heart activity were correlated with the level of HCG. Sac size was correlated with yolk sac and heart activity and the three parameters correlated with gestational age in days. When the level of HCG reached 1000 mIU/ml by using the first International Reference Preparation, a gestational sac was seen sonographically in each patient. When the HCG level reached 7200 mIU/ml, a yolk sac was seen in every patient. Ten of 22 patients with HCG between 1000 and 7200 mIU/ml had a visible yolk sac. Every patient with an HCG level greater than 10,800 mIU/ml had a visible embryo with a heartbeat. A discriminatory level of 32 days was found for the presence of a gestational sac. A yolk sac was first seen in every patient between 36 and 40 days. Every patient with accurate dates greater than 40 days had an embryo with a heartbeat identified. When correlating sac size with structures within the sac, a yolk sac was first seen in a gestational sac between 6 and 9 mm and a heartbeat seen in every patient with a 9-mm or greater gestational sac diameter. These data allow identification of normal intrauterine pregnancy and distinction of normal from ectopic gestation at least 1 week earlier than is possible with transabdominal techniques.

Chorionic Gonadotropin↗

PubMed1998

Correlation of mechanistic data and histopathology in the evaluation of selected toxic endpoints of the endocrine system.

The objective of this review is to correlate endocrinologic data from mechanistic studies with quantitative histopathology in selected examples of toxic endpoints of the endocrine system in laboratory animals. Mechanistic data can aid in the interpretation of animal toxicology findings and help clarify their significance in risk assessment. Endocrine organs of rodents frequently undergo proliferative changes with advancing age and following chronic exposure to large doses of xenobiotic chemicals, and the sensitivity of rodent endocrine tissues appears to be increasing. Many xenobiotic chemicals in large doses disrupt thyroid function in rodents either by a direct effect on the thyroid influencing synthesis of thyroid hormones or by adversely influencing their peripheral metabolism. A number of chemicals disrupt thyroid function by inhibiting the important enzyme, thyroperoxidase (TPO). A contemporary example of a chemical acting as TPO-inhibitor is sulfamethazine. In short-term mechanistic studies in rats there was a log-dose response relationship in circulating levels of thyroid and pituitary hormones plus a similar non-linear dose-response in morphologic changes in thyroid follicular cells. Endocrinologic data from mechanistic studies and histopathologic/ultrastructural findings will also be presented for the effects of the food color, FDC Red No. 3 (Erythrosine), on the thyroid gland in rats and parathyroid hormone-related protein (a major causative factor in cancer-associated hypercalcemia) on parathyroid chief cells in mice.

Animals↗

PubMed1999

Structure elucidation of three isomeric metabolites of SYN-2836, a novel antifungal agent, in dogs via liquid chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry methodologies.

This paper presents liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS) approaches for the rapid characterization of three urinary isomeric metabolites and their two precursor metabolites of SYN-2836, a novel antifungal agent, in dogs administered multiple oral doses of the agent (30 mg kg(-1) day(-1)). A collection of correlative data regarding the SYN-2836 metabolites was obtained by LC/MS and LC/MS/MS performed under complementary conditions such as the columns (C(18) vs cyano type), the mobile phase systems (acetonitrile-water-formic acid vs acetonitrile-water-ammonium acetate) and the electrospray ionization modes (positive vs negative). Metabolite identification was accomplished based on not only the LC/MS/MS data (product ion spectra) but also the LC/MS data indicating chromatographic behaviors of the metabolites. SYN-2836 and SYN-2869, an analog of the former, showed almost the same metabolic pathways following the same multiple-dose administration of the individual agents to the dogs. Therefore, correlation analysis in product ion spectra between corresponding metabolites of SYN-2836 and SYN-2869, and also in metabolic pathways between the two agents, was strategically used to facilitate the identification of the SYN-2836 (and SYN-2869 if necessary) metabolites. For the reason that various elucidation strategies were used complementarily, the chemical structures of the metabolites were unambiguously attained and the isomeric metabolites were explicitly differentiated without the use of other analytical methods. The methodologies used in this study may be applicable to metabolite screening of several structurally related agents simultaneously, promoting lead finding and optimization of drug candidates using a metabolism-based approach.

Animals↗

PubMed1994

Modulation of fundamental frequency by laryngeal muscles during vibrato.

The variations in voice fundamental frequency (F0) that occur during vibrato production may be produced, at least in part, by modulation of laryngeal muscle activity. We have quantified this relation by using a cross-correlation analysis of the changes in F0 during vibrato and the changes either in motor unit firing rate or in gross electromyographic activity from the cricothyroid (CT) and the thyroarytenoid (TA) muscles. Two trained amateur tenors provided the data. Correlations were generally quite strong (mean r for the CT was 0.72 for singer 1 and 0.50 for singer 2; mean r for the TA was 0.31 for singer 2), thus providing support for previous evidence that fundamental frequency modulation in vibrato involves active modulation of the laryngeal motoneuron pool, especially by the CT muscle. In addition, phase delays between muscle modulation and changes in fundamental frequency were substantial (averaging approximately 130 degrees for the CT and 140 degrees for the TA). This finding may help provide insight regarding the mechanisms responsible for the production of vibrato.

Electromyography↗

PubMed1985

Problem behavior theory and consumption and consequences of alcohol use.

Self-report measures of heavy consumption and adverse consequences of alcohol use have been used as interchangeable or equivalent indicators of problem drinking although the literature shows them to be relatively independent, with generally about 15% variance in common. The purposes of the present study are to provide further evidence of the independence of self-reported consumption and problems, and to explore nonalcohol-related correlates. Data from 370 employed adults showed modest intercorrelations and a factor structure representing alcohol consumption levels (quantity-frequency, frequency of intoxication) and alcohol-related problems (self-other definition as a problem drinker, adverse consequences). Partial correlational analyses showed that, when controlling for the effects of consumption, alcohol-related problems were related to the use of other psychoactive drugs and to a set of attributes of the person and the social environment as distinct dimensions. Modification of Jessor's problem behavior theory is proposed to generate psychosocial explanation for the differential vulnerability to alcohol-related problems.

Alcohol Drinking↗

PubMed2004

A modified PAS stain combined with immunofluorescence for quantitative analyses of glycogen in muscle sections.

Simultaneous analyses of glycogen in sections with other subcellular constituents within the same section will provide detailed information on glycogen deposition and the processes involved. To date, staining protocols for quantitative glycogen analyses together with immunofluorescence in the same section are lacking. We aimed to: (1) optimise PAS staining for combination with immunofluorescence, (2) perform quantitative glycogen analyses in tissue sections, (3) evaluate the effect of section thickness on PAS-derived data and (4) examine if semiquantitative glycogen data were convertible to genuine glycogen values. Conventional PAS was successfully modified for combined use with immunofluorescence. Transmitted light microscopic examination of glycogen was successfully followed by semiquantification of glycogen using microdensitometry. Semiquantitative data correlated perfectly with glycogen content measured biochemically in the same sample (r2=0.993, P<0.001). Using a calibration curve (r2=0.945, P<0.001) derived from a custom-made external standard with incremental glycogen content, we converted the semiquantitative data to genuine glycogen values. The converted semiquantitative data were comparable with the glycogen values assessed biochemically (P=0.786). In addition we showed that for valid comparison of glycogen content between sections, thickness should remain constant. In conclusion, the novel protocol permits the combined use of PAS with immunofluorescence and shows valid conversion of data obtained by microdensitometry to genuine glycogen data.

Adult↗

PubMed2004

Remodelling of gap junctions and connexin expression in heart disease.

Different combinations and relative quantities of three connexins-connexin43, connexin40 and connexin45-are expressed in different subsets of cardiomyocyte. In the healthy heart, gap junctions assembled from these different connexin combinations form the cell-to-cell pathways for the precisely orchestrated patterns of current flow that govern the normal heart rhythm. Remodelling of gap junction organization and connexin expression is a conspicuous feature of human heart disease in which there is an arrhythmic tendency. This remodelling may take the form of structural remodelling, involving disturbances in the distribution of gap junctions (i.e., disruption of the normal ordered pathways for cell-to-cell conduction), and remodelling of connexin expression, involving alteration in the amount or type of connexin(s) present. Most notable among quantitative alterations in connexin expression is a reduction in ventricular connexin43 levels in human congestive heart failure. By correlating data from studies in experimental animal models, gap junction and connexin remodelling emerges as a factor to be considered in understanding the pro-arrhythmic substrate characteristic of many forms of heart disease. However, our knowledge of the functional correlates of the specific patterns of multiple connexin expression found in different regions of the heart in health and disease remains rudimentary, and the development of new experimental cell models heralds advances in this area over the next few years.

Animals↗

PubMed1992

Use of a molecular genetic approach to diagnosing the fragile X genotype.

We report the direct molecular detection of the fragile X genotype in 111 individuals from 17 families with a total of 31 cases of fragile X syndrome. Comparison of our molecular data with our previous cytogenetic and linkage data from these same families indicates the effectiveness of the direct molecular analysis. We have been able to assign a genotype unambiguously in 100% of the persons tested, and in all cases the molecular data correlated with the cytogenetic or linkage findings or both. Two of the three families presented in this study represent inheritance of this gene through normal transmitting males, and the third is strongly suggestive of this mode of inheritance. Our data show that the direct molecular approach will be of great utility for confirmation of the diagnosis and for the detection of female carriers and normal transmitting males who are at high risk for having affected children or grandchildren.

Blotting, Southern↗

PubMed2003

Kinetic barriers and ordering of non-covalently bound states.

Binding of a dimer of a glycopeptide antibiotic to two molecules of a ligand that are bound to a membrane surface (by a hydrocarbon anchor) has been investigated. This binding on a surface is cooperatively enhanced (surface enhancement) relative to the binding in solution, because the former occurs intramolecularly on a template. Previously a correlation between surface enhancement and thermodynamic stability of the dimer in free solution (Kdimsol) was hypothesised. However, we found that two weakly dimerising antibiotics (vancomycin and ristocetin A) with similar Kdimsol give very different surface enhancements. We propose a model to explain the data correlating surface enhancement to the kinetic barrier to dissociation of the dimer. The surface enhancement of binding can be expected to increase with increasing tightness of the non-covalent interactions formed at the dimer interface. The effect should be found in general where cooperativity is exercised within an organised template (e.g., DNA duplexes and proteins).

Anti-Bacterial Agents↗

PubMed1978

Cochlear nerve in neurilemomas. Audiology and histopathology.

Correlative data between the histopathologic changes in the cochlear nerve and audiologic findings are reported in 16 cases of neurilemomas. Poor speech discrimination, positive or absent recruitment, excessive adaptation, or separation of forward vs reverse continuous tone Bekesy tracings did not correlate with the number of preserved nerve fibers. There were several cases with profound hearing loss in which the nerve fiber population approached normal. Histologically, pathologic changes included dilated fibers and increased interfibrillary collagen. In many specimens the fibers were further apart than normally, especially in the immediate vicinity of the tumor, and many lay between tumor cells. The tumor-nerve interface was usually gradual and no abrupt change appeared at the transition from the nerve to the tumor, the Schwann cells appearing to continue as tumor cells. Nonspecific changes apparently due to specimen handling were seen in some areas of most specimens.

Adult↗

PubMed2007

Co-expression of ghrelin and its receptor in pancreatic endocrine tumours.

OBJECTIVE: Expression of ghrelin has been reported in pancreatic endocrine tumours, but data on ghrelin receptor protein expression are lacking. The aim of this study was to examine the ghrelin receptor, as well as ghrelin, in a selected series of these tumours, including multiple endocrine neoplasia 1 (MEN1) associated tumours, and to correlate data with clinical features including body mass index. DESIGN: Immunohistochemical detection of ghrelin and its receptor was performed on frozen tissue from 31 tumours: 9 MEN1 and 22 sporadic. Twenty tumours were analysed by quantitative PCR. Plasma ghrelin was assessed in 26 patients. RESULTS: Twenty-one (68%) of 31 tumours showed immunoreactivity for ghrelin (8/9 MEN1) and 19/20 expressed ghrelin mRNA. Ghrelin receptor protein was detected in 21/30 (70%) tumours (4/8 MEN1), and mRNA was detected in all analysed tumours. Insulinomas had significantly higher levels of receptor mRNA than other tumours. Five patients had elevated plasma ghrelin (> 2 SD above the control group mean). No significant difference in mean plasma ghrelin levels was found between patients (908 +/- 569 ng/l) and controls (952 +/- 164 ng/l). Mean BMI was 24.3 kg/m(2). There was no association between ghrelin or receptor expression and survival. CONCLUSIONS: We report the first immunohistochemical data on expression of the ghrelin receptor in pancreatic endocrine tumours: 70% of tumours in our material. Concomitant ghrelin and receptor expression was seen in 50% of tumours, indicating an autocrine loop. Ghrelin was expressed in 68% of tumours (8/9 MEN1). Despite frequent ghrelin expression, elevated circulating ghrelin is rare in these patients.

Adenoma, Islet Cell↗

PubMed1993

Simultaneous analysis of cell cycle kinetics at two different DNA ploidy levels based on DNA content and cyclin B measurements.

The methods of cell cycle analysis that rely on DNA content measurements cannot discriminate between cells at different phases of the cycle if these cells have similar DNA content. This limitation can be circumvented by measurement of another cell cycle phase-specific cell constituent in addition to DNA content, followed by bivariate analysis of the correlated data. The aim of the present study was to explore the utility of a monoclonal antibody against the G2- and M phase-specific regulatory protein cyclin B for discrimination of cell populations with overlapping DNA content. This analysis, which was based on correlated DNA/cyclin B content measurements by flow cytometry, was applied to human lymphocytic leukemic MOLT-4 cells. The onset of cyclin B synthesis was observed in the last one third of S phase with its maximum accumulation in G2 and M phases; cells in G1 and early- and mid-S phases were negative. Cells arrested in metaphase by vinblastine expressed high levels of this protein, although not as high as in cells arrested in G2 by the DNA topoisomerase II inhibitor m-AMSA. Disruption of cytokinesis by the protein kinase inhibitor staurosporine led to DNA rereplication, cell progression through the chromatin cycle at higher DNA ploidy, and induction of polyploidy. It was possible, utilizing the cyclin B antibody, to discriminate between G2 + M cells with a 2C level of DNA and G1 cells with 4C DNA, as well as to distinguish doublets of G1 cells with a 2C DNA level. Thus, the rate of cell entrance to G1 at the 4C DNA level and the rates of progression through the cycle at both the 2C and 4C DNA levels could be simultaneously estimated. The data indicate that, in the presence of 0.1 microM staurosporine, cytokinesis of all MOLT-4 cells is impaired and the cells enter to and progress through the chromosome cycle at 4C DNA at the same rates as at 2C DNA. This approach can be helpful in the analysis of DNA ploidy and the cell cycle of human tumors when there is an overlap in DNA content values between normal stromal or infiltrating cells and aneuploid tumor cell population and may be the method of choice to investigate the activity of antitumor drugs which impair cytokinesis but do not interfere with progression of cells through the chromatin cycle.

Alkaloids↗

PubMed2001

Assessing homeostasis through circadian patterns.

An organism is thought to be in a dynamic state of homeostasis when each physiological and behavioral system reaches a delicate balance within the framework of other regulatory processes. Many biological systems target specific set-point variables and generate circadian patterns. In this article, we focus on specific measurements representative of two systems, namely deep-body temperature and activity counts. We examine data collected every 30 minutes in mice, assume there are underlying circadian patterns, and extend the approach presented in Brumback and Rice (1998, Journal of the American Statistical Association 93, 961-976) in order to obtain estimates in the presence of correlated data. We then assess homeostasis using these estimates and their statistical properties.

Animals↗

PubMed2005

MR imaging and MR spectroscopic imaging in the pre-treatment evaluation of prostate cancer.

Magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRSI) are emerging as the most sensitive tools for the non-invasive, anatomic and metabolic evaluation of prostate cancer. This article reviews the current applications of MRI and 1H MRSI in clinical practice and discusses the promise of these modalities for improving prostate cancer management. MRI demonstrates zonal anatomy with excellent contrast resolution and can reveal tumours in areas not routinely sampled on biopsy and not palpable on digital rectal examination. In addition, MR images allow assessment of local extent (including extracapsular extension and seminal vesicle invasion) and thus can assist in local staging while providing surgeons and radiation therapists with a visual road-map for treatment planning. The addition of 1H MRSI to MRI can improve prostate cancer detection and assessment of tumour volume; it also contributes indirectly to improved local staging. In addition, 1H MRSI metabolic and volumetric data correlate with pathological Gleason grade and thus may offer a non-invasive means to better predict prostate cancer aggressiveness. Combined MRI/1H MRSI is currently of greatest value for high-risk patients. With greater understanding of the relationship between spectroscopic data and tumour biology, it may become possible to use MRI/1H MRSI to achieve more precise stratification of patients in clinical trials, to monitor the progress of patients who select watchful waiting or minimally aggressive cancer therapies, and to guide and assess emerging local prostate cancer therapies.

Aged↗