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An endothelin-1 induced model of optic nerve ischemia in the rabbit.

PURPOSE: To evaluate blood flow reduction and topographic optic nerve changes after the local administration of endothelin-1 in vivo, delivered to the perineural region of the anterior optic nerve in the rabbit. METHODS: Endothelin-1 (five rabbits) in a dosage of 0.1 microgram/day or balanced salt solution (two rabbits) was delivered to the perineural region of the anterior optic nerve with osmotically driven minipumps. Optic nerve blood flow was determined by the colored microspheres technique after 14 days of local endothelin-1 or balanced salt solution administration to the microvasculature of the optic nerve. In addition, optic nerve blood flow was determined in two rabbits that had no minipump implants. The morphologic changes induced by reduction of blood flow were assessed in five additional rabbits implanted with osmotically driven minipumps containing endothelin-1 (0.1 microgram/day). These rabbits were observed for 8 weeks, and the morphologic optic nerve changes were monitored with a confocal scanning laser ophthalmoscope. RESULTS: Independent of intraocular pressure, endothelin-1 induced a decrease in blood flow of approximately 38% in the experimental eye, compared to the decrease induced by balanced salt solution or to the decrease in rabbits without minipumps (analysis of covariance, P = 0.0092). Multivariate statistical analysis showed a significant change in topometric parameters (cup area, cup depth, rim volume) obtained with a confocal scanning laser ophthalmoscope, indicating an increase in optic nerve cupping and a decrease of the perineural rim volume in the experimental eyes (P = 0.017). CONCLUSIONS: The current results suggest that morphologic optic nerve alterations can be induced experimentally in the rabbit model after ischemia produced by the local administration of endothelin-1 to the perineural region of the anterior optic nerve.

Animals↗

Poorly differentiated carcinomas of the thyroid with trabecular, insular, and solid patterns: a clinicopathologic study of 183 patients.

BACKGROUND: The term poorly differentiated (PD) carcinoma was proposed 20 years ago to define aggressive, follicular-derived thyroid carcinomas with behavior intermediate between follicular/papillary and anaplastic carcinomas. Among the variable histologic patterns recognized in such tumors, trabecular-insular-solid (TIS) areas usually are predominant. Conversely, some authors pointed out that PD carcinomas are characterized by unequivocal, high-grade histology with atypias, high mitotic counts, and necrosis rather than by a specific growth pattern. METHODS: The clinicopathologic features of a series of 183 thyroid carcinomas with predominant (n = 165 tumors) or focal (n = 18 tumors) TIS growth patterns were studied by univariate and multivariate overall survival analyses and were compared with clinical outcomes. Subgroups included tumors with predominant oxyphilic features (n = 66 tumors) and (residual) papillary carcinoma features (n = 24 tumors). Control groups of papillary (n = 68 tumors), follicular (n = 71 tumors), and anaplastic (n = 35 tumors) carcinomas also were included for overall survival analysis. RESULTS: TIS carcinomas had an intermediate behavior between papillary/follicular and anaplastic carcinomas (P < 0.0001). Univariate and multivariate statistical analyses demonstrated that age > 45 years (P = 0.007), the presence of necrosis (P < 0.0001), and a mitotic count > 3 per 10 high-power fields (P = 0.01) were associated with poor outcome. A simplified scoring system based on statistically significant parameters allowed the identification of three prognostic subgroups (P < 0.0001). CONCLUSIONS: PD TIS carcinomas overall followed a more aggressive course compared with differentiated thyroid carcinomas, irrespective of the extent of the TIS component. However, a numeric scoring system applied to specific clinicopathologic parameters further may identify three prognostic categories of patients who have significantly different survival rates at 5 years and 10 years.

Adenocarcinoma↗

Ultrasonic concentration measurement of aqueous solutions using PLS regression.

This work demonstrates the use of a multivariate statistical technique called partial least squares (PLS) to extract material related data by analyzing spectra of ultrasonic pulses. We show how PLS can be used to estimate the concentration of sodium chloride in an aqueous solution. The paper describes the use of PLS and discusses pre-processing of ultrasonic data, the PLS algorithm as well as model validation. The measured concentrations are compared to reference values. The influence of disturbances and parameter changes is highlighted. The proposed method is easily adaptable to similar applications and permits a cost-saving implementation using existing and approved hardware.

Algorithms↗

Setting objectives for community and systems change: an application of concept mapping for planning a statewide health improvement initiative.

The Hawaii Department of Health (HDOH) used concept mapping techniques to engage local stakeholders and national subject area experts in defining the community and system factors that affect individuals' behaviors related to tobacco, nutrition, and physical activity. Over eight working days, project participants brainstormed 496 statements (edited to a final set of 90), which were then sorted and rated for their importance and feasibility. A sequence of multivariate statistical analyses, including multidimensional scaling and hierarchical cluster analysis, generated maps and figures that were then interpreted by project stakeholders. The results were immediately incorporated into an official plan, approved by the governor and state legislature, recommending how Hawaii's tobacco settlement resources could be used to create sustainable changes in population health. The results also provide empirical support for the premise that both community and systems factors ought to be considered when planning comprehensive health improvement initiatives.

Cluster Analysis↗

[Early seizures after acute ischemic stroke].

In order to determine predictive factors of early seizures (ES) after acute stroke and to estimate prognosis, we retrospectively examined clinical data of 1,743 consecutive patients with acute ischemic stroke. The subjects were divided into two groups; an ES group (19 patients) and a non-ES group (1,724 patients). Multivariate statistical analysis revealed that the NIH-Stroke Scale score on admission (/10, OR, 1.1: 95% CI 1.04 to 1.13) and positive past history of cerebrovascular disease or brain injury (OR, 3.85: 95% CI 1.49 to 9.95) are significant factors to predict ES. There was no significant difference in the outcome between the two groups. A recurrence of seizures, after follow up for 4 to 40 months, was observed only in one patient with a history of ES.

Acute Disease↗

The determinants of elevated total plasma cholesterol levels in cardiac transplant recipients administered low dose cyclosporine for immunosuppression.

Elevated total plasma cholesterol level is a frequent finding after cardiac transplantation. To identify risk factors for the development of hypercholesterolemic states, we applied multivariate statistics in a logistic and linear manner. Six-month posttransplantation levels of total plasma cholesterol in 57 adult heart recipients were available for analysis. Maintenance immunosuppression was carried out with either cyclosporine and azathioprine or both agents plus low-dose steroids. Total plasma cholesterol levels were dichotomized for the logistic analysis (1) by the age- and sex-matched 75th and 90th percentiles of a reference population according to National Institutes of Health treatment guidelines and (2) by the cut point 250 mg/dl. Twelve potential risk factors were evaluated as covariates: recipient age, body weight after 6 months, body weight gain over 6 months, body mass index after 6 months, body mass index gain over 6 months, current cyclosporine dosage, trough level of cyclosporine in whole blood according to high-performance liquid chromatography after 6 months, cumulative cyclosporine dosage over 6 months, serum bilirubin, type of original cardiac disease, maintenance steroids, and steroid bolus treatment. Multivariate logistic regression yielded the type of original cardiac disease as a significant predictor of posttransplantation hypercholesterolemia exceeding the 90th percentile (p = 0.019) and of hypercholesterolemia exceeding 250 mg/dl (p = 0.032). Maintenance steroids were identified as a second significant cofactor (p = 0.069) for total plasma cholesterol levels exceeding 250 mg/dl. Multiple linear regression again revealed the type of original cardiac disease and maintenance steroids as significant predictors by p values of 0.005 and 0.013, respectively. Patients with coronary artery disease as the original cardiac pathology and low-dose maintenance steroids had the greatest risk for the development of elevated total plasma cholesterol levels after cardiac transplantation. However, the overall predictive quality of the linear model was limited (multiple r value 0.43), which indicates that other variables besides the tested ones attributed to elevated total plasma cholesterol levels. These results confirm the adverse role of maintenance steroids on posttransplantation hypercholesterolemia and demonstrate the type of original cardiac disease as the most important risk factor. They suggest that abnormalities of lipoprotein metabolism and dietary factors continue to affect total plasma cholesterol levels after cardiac transplantation.

Adult↗

A new generation of the IMAGIC image processing system.

One of the aims of modern microscopy is to quantify two-, three-, or even four-dimensional phenomena in biology, medicine, and material sciences. The requirements imposed on software by such data processing are exemplified by the design considerations of the IMAGIC-5 software system. This system includes facilities for multivariate statistical analysis of large data sets, for correlation averaging of two-dimensional crystals, and for three-dimensional reconstruction of macromolecular structures. The molecules may be arranged as two-dimensional crystals, as helices, or as single particles with arbitrary pointgroup symmetry. IMAGIC's novel angular reconstitution approach allows for the rapid determination of three-dimensional structures of uncrystallized molecules to high resolution. The general organization, user interaction strategy, file structure, and extendibility of IMAGIC are discussed and illustrated with some practical examples.

Animals↗

[Morphology versus prognosis in renal cell carcinoma a statistical approach].

In a group of 102 selected cases of renal cell carcinoma which at various periods after nephrectomy terminated fatally, age, sex, and 23 gross and/or histologic tumor characteristics were examined, subclassified, and evaluated. An attempt was made to correlate these parameters statistically to postoperative survival time. A newly developed and programmed statistical method, i.c. "dichotomic variance analysis", proved to be superior to both multiple regression and cluster analysis. Using infiltrative-destructive tumor growth, polymorphy, and chromatin density of tumor cell nuclei, extension of renal vein invasion, age and sex, as the only 6 required out of 25 distinguished tumor parameters, this statistical multivariate method comprised 7 distinctive groups of different mean geometrical postoperative survival time, obviously corresponding to 7 tumor types of increasing degree of malignancy. By step-wise dichotomic splitting of tumor groups it therefore was possible to delinate schematically some of the complex connections between the criteria or variables of prognostic significance. Conceivable sources of errors possibly influencing reproducibility and practical applicability of the presented dichotomic variance analysis in evaluating prognostic criteria in renal cell carcinoma are discussed.

Adult↗

Biological and chemical factors influencing shallow lake eutrophication: a long-term study.

The focus of eutrophication research has tended to be upon short-term and experimental studies. However, given the range of factors that can influence eutrophication dynamics, and that these matter over a range of time scales, some discrete, some continuous, eutrophication dynamics may only be fully investigated when long-term, time-series data are available. The present study aims to evaluate the interacting effects of abiotic processes and biotic dynamics in explaining variations of phytoplankton biomass in a eutrophic shallow lake, Barton Broad (Norfolk, UK) using a long-term data set. Multivariate statistical analysis shows that the inter-relationships between phytoplankton variability, nutrient and grazing factors were highly sensitive to seasonal periodicity. In spring phytoplankton biomass was related to phosphorus, nitrogen and silicon. In summer phytoplankton biomass was associated with phosphorus, nitrogen and zooplankton. In autumn phytoplankton was related to phosphorus, nitrogen, silicon and zooplankton. In winter, no significant relationship could be established between phytoplankton and environmental variables. This paper improves our understanding of the governing role of nitrogen, phosphorus, silicon and zooplankton upon phytoplankton variability, and hence, improves management methods for eutrophic lakes.

Animals↗

Anti-HIV-1 seroreactivity and HIV transmission route[R1]. The HEC/FIOCRUZ AIDS Clinical Research Group.

BACKGROUND: Antibody binding assays carried out by our group have consistently indicated a higher reactivity of sera from male HIV-1 infected individuals. This study was carried out in order to analyze the importance of gender, route of transmission, disease progression and HIV-1 genotype in seroreactivity assays. STUDY DESIGN: Specificity of antibody binding was studied in plasma of 247 HIV-1 seropositive individuals belonging to patient groups of pregnant women, injecting drug users (IDUs) and recent seroconvertors, resident in Rio de Janeiro, RJ. Recognition of synthetic peptides corresponding to antigenically important epitopes in the envelope of HIV-1 (gp41 immunodominant epitope, V3 loop, V2 loop and gp41 735-752 epitope) was determined. RESULTS: The immunodominant gp41 peptide (amino acids 594-613, HIV-1 MN sequence) was recognized by 85% of all plasma tested. Reactivity with the gp41 735-752 peptide and gp120 V2 loop peptides was low but quite variable, being generally more often specific to a Brazilian V2 peptide used than to the HIV-1 MN derived V2 peptide. The overall recognition of the different V3 peptides tested varied from 41 to 76%. Patients with more advanced disease showed a more frequent reactivity with the peptides studied than did asymptomatic patients. Statistically significant differences in peptide recognition were observed by multiple logistic analyses comparing plasma derived from individuals infected by blood or sexual HIV transmission, adjusting for disease progression and gender. Plasma from individuals infected by sexual transmission showed lower peptide recognition than did plasma from individuals infected through HIV positive blood. Association attempts between seroreactivity and genotype indicated that plasma derived from patients infected with HIV-1 of the F subtype showed highest recognition of heterologous V3 peptides, as well as a slightly more frequent recognition of the non-V3 peptides tested. Recognition of homologous peptides was generally higher than recognition of heterologous peptides. Differences were most pronounced between the prototypical HIV-1 B subtype and the Brazilian B" variant of this subtype but almost non-existent between the HIV-1 B and F subtypes. CONCLUSIONS: Individual gender was shown to be a confounder when investigating the relationships of peptide reaction to HIV-1 route of transmission through multivariate statistical methods: patients infected by blood transmission (IDU) present higher frequency of peptide recognition than individuals infected by sexual HIV-1 transmission. Plasma from individuals infected with the B" variant (GWG) of B subtype HIV-1 showed lower heterologous peptide recognition than that from HIV-1 B (GPG) or F infected individuals.

Amino Acid Sequence↗

Ultrastructure of the eukaryotic aminoacyl-tRNA synthetase complex derived from two dimensional averaging and classification of negatively stained electron microscopic images.

Several aminoacyl-tRNA synthetases in higher eukaryotes are consistently isolated as a multi-enzyme complex for which little structural information is yet known. This study uses computational methods for analysis of electron microscopic images of the particle. A data set of almost 2000 negatively stained images was processed through reference-free alignment and multivariate statistical analysis. Interpretable structural information was evident in five eigenvectors. Hierarchical ascendant classification extracted clusters corresponding to distinct image orientations. The class averages are consistent with rotations around and orthogonal to a central particle axis and provide particle measurements: approximately 25 nm in height, 30 nm at the widest point and 23 nm thick. The results also provide objective evidence in support of the working structural model and demonstrate the feasibility of obtaining the three dimensional structure of the multisynthetase complex by single particle reconstruction methods.

Algorithms↗

Assessment of 1H NMR spectroscopy and multivariate analysis as a technique for metabolite fingerprinting of Arabidopsis thaliana.

An approach to metabolite fingerprinting of crude plant extracts that utilizes 1H nuclear magnetic resonance (NMR) spectroscopy and multivariate statistics has been tested. Using ecotypes of Arabidopsis thaliana as experimental material, a method has been developed for the rapid analysis of unfractionated polar plant extracts, enabling the creation of reproducible metabolite fingerprints. These fingerprints could be readily stored and compared by a variety of chemometric methods. Comparison by principal component analysis using SIMCA-P allowed the generation of residual NMR spectra of the compounds that contributed significantly to the differences between samples. From these plots, conclusions were drawn with respect to the identity and relative levels of metabolites differing between samples.

Arabidopsis↗

Association between prevalent care process measures and facility-specific mortality rates.

BACKGROUND: Medical communities often develop practice guidelines recommending certain care processes intended to promote better clinical outcome among patients. Conformance with those guidelines by facilities is then monitored to evaluate care quality, presuming that the process is associated with and can be used reliably to predict clinical outcome. Outcome is often monitored as a facility-specific mortality rate (SMR) standardized to the mix of patients treated, also presuming that inferior outcome implies a suboptimal process. The U.S. Health Care Financing Administration monitors three practice guidelines, called Core Indicators, in dialysis facilities to assist management of its end-stage renal disease program: (1) patients' hematocrit values should exceed 30 vol%, (2) the urea reduction ratio (URR) during dialysis should equal or exceed 65%, and (3) patients' serum albumin concentrations should equal or exceed 3.5 g/dL. METHODS: The associations of a facility-specific SMR were evaluated with the fractions of hemodialysis patients not conforming to (that is, at variance with) the Core Indicators during three successive years (1993 to 1995) in large numbers of facilities (394, 450, and 498) using one-variable and multivariable statistical models. Three related strategies were used. First, the association of the SMR with the fraction of patients not meeting the guideline was evaluated. Second, each facility was classified by whether its SMR exceeded the 80% confidence interval above 1.0 (worse than 1.0, Group 3), was less than the interval below 1.0 (better than 1.0, Group 1), or was within the interval (Group 2). The fraction of those patients who did not meet the Indicator guidelines was then evaluated in each group. Third, the ability of variance from Indicator guidelines to predict into which of the three SMR groups a facility would be categorized was evaluated. RESULTS: SMR was directly correlated with variance from the Indicator guidelines, but the strengths of the associations were weak particularly for the hematocrit (R(2) = 2.2%, 5.6, and 2.2 for each of the 3 years) and URR Indicators (R(2) = 2.6, 0.6, 3.3). It was stronger for the albumin Indicator (R(2) = 11.6, 20.4, 21.8). The fractions of patients falling outside of the Indicator guidelines tended to be higher in the highest SMR group. The groups were not well separated, however, particularly for the hematocrit and URR Indicators, and there was substantial overlap between them. Finally, although the likelihood that a facility would be a member of the high or low SMR group was associated with fractional variance from Core Indicator guidelines, the strengths of association were weak, and the probability that a facility would be a member of the high or low group could not be easily distinguished from the probability that it would be a member of the middle group. CONCLUSIONS: While there were statistical associations between SMR and the fraction of patients in facilities who were at variance with these guidelines, they were weak and variances from the guidelines could not be used reliably to predict high or low SMR. Such findings do not imply that measures reflecting anemia, dialysis dose, or medical processes that influence serum albumin concentration are irrelevant to the quality of care. They do suggest, however, that more attention needs be paid to these and other associates and causes of mortality among dialysis patients when developing care process indicator guidelines.

Humans↗

Laryngeal aerodynamic aspects of women with adductor spasmodic dysphonia.

OBJECTIVE: To determine if laryngeal aerodynamic parameters distinguish the voice of patients diagnosed as having adductor spasmodic dysphonia (SD) from individuals with normal voice production. DESIGN: A group comparison between 10 women diagnosed as having adductor SD and 10 women with no evidence of vocal abnormalities or vocal dysfunction. SETTING: University and university-affiliated health center. PATIENTS: Ten women (age range, 38 through 82 years) diagnosed as having adductor SD and 10 age-matched women (+/- 2 years) with no evidence of pathologic vocal features or vocal dysfunction. RESULTS: Multivariate statistical analysis revealed significantly higher values for amplitude-based glottal airflow measures of maximum flow declination rate, peak glottal airflow, and minimum glottal airflow. CONCLUSIONS: Spasmodic dysphonia affects the ability of the laryngeal mechanism to function effectively. To date, few empirical studies have examined glottal airflow characteristics associated with adductor SD. Results from our study demonstrate that certain amplitude-based glottal airflow parameters distinguish adductor SD from normal voice. Therefore, aerodynamic measures may offer additional objectivity for the study.

Adult↗

Secondary patellar resurfacing in total knee arthroplasty: results of multivariate analysis in two case-matched groups.

Although patellofemoral symptoms after patellar-retaining knee arthroplasty are common, no evidence has been published in the literature on the potential benefit from patellar resurfacing at a later stage. This study evaluates the effect of secondary (delayed) patellar resurfacing using comparisons between 2 case-matched groups of patients with primary and secondary patellar resurfacing. Furthermore, multivariate statistical methods were applied to study factors that may influence the final outcome. Our results suggest that although significant clinical improvement was seen after delayed patella resurfacing, the outcome of secondary patellar resurfacing is inferior to that expected for a similar group of patients with primary resurfacing. Furthermore, the timing (delay period) of the secondary resurfacing procedure appears to negatively affect the final outcome. This suggests that secondary patellar resurfacing, when indicated, should be considered at an early stage.

Aged↗

Chiral chromatography and multivariate quantitative structure-property relationships of benzimidazole sulphoxides.

Various benzimidazole sulphoxides were chirally resolved employing an amylase-based chiral stationary phase. The structure-property relationships of these compounds were investigated using calculated physicochemical properties, molecular modelling and multivariate statistical techniques. A data set of 254 molecular descriptors was used to represent the series of compounds. Analysis of the data set using principal components analysis and non-linear mapping suggested that the separation factor of each enantiomeric pair was associated with nine molecular properties and, in particular, molar refractivity of the Z substituent and the partial charge of atom 6. The separation factor of a sulphoxide not used in the analysis was well predicted thus suggesting that these models may be used to generalize.

Anti-Ulcer Agents↗

Shortcuts in genome-scale cancer pharmacology research from multivariate analysis of the National Cancer Institute gene expression database.

Application of a soft multivariate statistical procedure, called PLS, partial least squares modelling in latent variables or projections to latent structures, allows extensive exploitation of the enormous amount of information embedded in the National Cancer Institute gene expression and antitumour screen databases. Interpretation of the statistical results provides new significant biological insights such as classification of human tumour cell lines based on their gene expression patterns, evaluation of the influence of gene transcripts on drug efficacy and assessment of their selectivity for classes of compounds which act by the same mechanism, and identification of uncharacterized gene expression targets involved in cancer chemotherapy. Among them, the transcripts GC11121, GC17689, and GC18564 (unknown gene products extremely selective for RNA/DNA antimetabolites) are indicated by the present work as deserving high priority in future molecular studies.

Databases, Factual↗

Single 8-oxo-guanine and 8-oxo-adenine lesions induce marked changes in the backbone structure of a 25-base DNA strand.

Structural changes in a 25-base DNA strand, induced by single 8-oxo-guanine or 8-oxo-adenine substitutions, were shown by using Fourier transform-infrared spectroscopy with multivariate statistics. Pronounced differences were demonstrated between the parent and derivatives with respect to base interactions and changes in the phospho-deoxyribose backbone. The greatest degree of change in the backbone likely occurred immediately adjacent to the 8-oxo group, potentially altering the stereochemistry at a distance. The 8-oxo lesions, formed from reactive oxygen species (e.g., hydroxyl radicals), may appreciably alter the conformational properties of strands at the replication fork, thus affecting the selectivity of polymerases, the proofreading capability of repair enzymes, and the fidelity of the transcriptional machinery.

Adenine↗