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PubMed1997

A consensus approach to diagnosing coronary artery disease based on clinical and exercise test data.

OBJECTIVE: To demonstrate that a consensus approach for combining prediction equations based on clinical and exercise test variables derived from different populations can stratify patients referred for possible coronary artery disease (CAD) into low-, intermediate-, and high-risk groups. DESIGN: Retrospective analysis of consecutive patients with complete data from exercise testing and coronary angiography referred for evaluation of possible CAD. After derivation of a logistic equation in our own training set of patients, this equation, along with two other equations developed independently by other investigators, was validated in a test set. The validation strategy for the consensus approach included the following: (1) calculation of probability scores for each patient using each logistic equation independently; (2) determination of probability thresholds in the training set to divide the patients into three groups-low risk (prevalence CAD <5%), intermediate risk (5 to 70%), and high risk (>70% prevalence of CAD); (3) using agreement among at least two of three of the prediction equations to generate "consensus" for each patient; and (4) application of the consensus approach thresholds to the test set of patients. SETTINGS: Two university-affiliated Veteran's Affairs medical centers. PATIENTS: We studied 718 consecutive men between 1985 and 1995 who had coronary angiography within 3 months of an exercise treadmill test for suspected CAD. The population was randomly divided into a training set of 429 patients and a test set of 289 patients. Patients with previous myocardial infarction or coronary artery bypass surgery, valvular heart disease, left bundle branch block, or any Q waves present on their resting ECG were excluded from the study. MEASUREMENTS: Recording of clinical and exercise test data along with visual interpretation of the ECG recordings on standardized forms and abstraction of visually interpreted angiographic data from clinical catheterization reports. RESULTS: We demonstrated that by using simple clinical and exercise test variables, we could improve on the standard use of ECG criteria during exercise testing for diagnosing CAD. Using the consensus approach divided the test set into populations with low, intermediate, and high risk for CAD. Since the patients in the intermediate group would be sent for further testing and would eventually be correctly classified, the sensitivity of the consensus approach is 94% and the specificity is 92%. The consensus approach controls for varying disease prevalence, missing data, inconsistency in variable definition, and varying angiographic criterion for stenosis severity. The percent of correct diagnoses increased from the 67% for standard exercise ECG analysis and from the 80% for multivariable predictive equations alone to >90% correct diagnoses for the consensus approach. CONCLUSIONS: The consensus approach has made population-specific logistic regression equations portable to other populations. Excellent diagnostic characteristics can be obtained using simple data and measurements. The consensus approach is best applied utilizing a programmable calculator or a computer program to simplify the process of calculating the probability of CAD using the three equations.

Coronary Angiography↗
PubMedDate not supplied

[New approaches to the measurement of clinical competence].

A new phase in the development of an instrument designed for the measurement of clinical competence is presented. The instrument (exam type) was previously validated; we report its use in three generations of students of a specialization course in internal medicine: those recently admitted to the course (group I); those finishing their first training year (group II) and those finishing the second year (group III). In the exam 304 out of the 600 questions included were classified as "experimental" (dealing with knowledge in internal medicine) and the remaining 296 questions corresponded to "control" questions (dealing with knowledge in other specialties). The variables considered in the exam were: 1) global result; 2) usage of diagnostic indicators; 3) omission of necessary procedures without a iatrogenic effect; 4) commission of unnecessary procedures without a iatrogenic effect; 5) omission of necessary procedures with resulting iatrogenic consequences; 6) commission of unnecessary procedures with resulting iatrogenic consequences; 7) global omission (variables 3 and 5); 8) global commission (variables 4 and 6); 9) global iatrogenesis (variables 5 and 6); 10) knowledge in nosology. Scores obtained by the three groups on the experimental questions differed in accordance with the respective time of clinical experience (group I obtained the lowest scores, group II showed intermediate scores, and group III showed the highest scores). Analysis of variance was significant (p less than 0.05) in variables 1, 2, 6, 8 and 9. The scores obtained by the three groups on the control questions were similar. In conclusion, we believe that this instrument is capable of detecting learning dependent on the time of clinical experience.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Competence↗
PubMed2001

Genetic variability and molecular identification of Brazilian Biomphalaria species (Mollusca: Planorbidae).

Freshwater snails belonging to the genus Biomphalaria are intermediate hosts of the trematode Schistosoma mansoni in the Neotropical region and Africa. In Brazil, one subspecies and ten species of Biomphalaria have been identified: B. glabrata, B. tenagophila, B. straminea, B. occidentalis, B. peregrina, B. kuhniana, B. schrammi, B. amazonica, B. oligoza, B. intermedia and B.t. guaibensis. However, only the first three species are found naturally infected with S. mansoni. The classical identification of these planorbids is based on comparison of morphological characteristics of the shell and male and female reproductive organs, which is greatly complicated by the extensive intra-specific variation. Several molecular techniques have been used in studies on the identification, genetic structure as well as phylogenetic relationships between these groups of organisms. Using the randomly amplified polymorphic DNAs (RAPD) analysis we demonstrated that B. glabrata exhibits a remarkable degree of intra-specific polymorphism. Thus, the genetics of the snail host may be more important to the epidemiology of schistosomiasis than those of the parasite itself. Using the simple sequence repeat anchored polymerase chain reaction (SSR-PCR) in intra-populational and intra-specific studies we have demonstrated that snails belonging to the B. straminea complex (B. straminea, B. kuhniana and B. intermedia) clearly presented higher heterogeneity. Using the low stringency polymerase chain reaction (LS-PCR) technique we were able to separate B. glabrata from B. tenagophila and B. tenagophila from B. occidentalis. To separate all Brazilian Biomphalaria species we used the restriction fragment length polymorphism (PCR-RFLP) of the internal transcribed spacer region (ITS) of the DNA gene. The method also proved to be efficient for the specific identification of DNA extracted from snail eggs. Recently we have sequenced the ITS2 region for phylogenetic studies of all Biomphalaria snails from Brazil.

Animals↗
PubMed1999

Attention deficit hyperactivity disorder: anxiety phenomena in children treated with psychostimulant medication for 6 months or more.

OBJECTIVE: The intermediate- to long-term use of psychostimulant medication has unclear benefits on the core symptoms of attention deficit hyperactivity disorder (ADHD) and delayed onset affective symptom side effects which can mimic these core ADHD symptoms. 'ADHD and anxiety' has also been associated with a poor response to short-term psychostimulant medication treatment. In addition, it is unclear whether 'ADHD and anxiety' should be defined from the child's and/or the parent's perspective. We propose that anxiety will be increased in children with ADHD who are treated with psychostimulant medication in the intermediate- to long-term who are identified by clinicians as poor responders. METHOD: Twenty children with ADHD who were medicated for 6 months or more and who had ongoing core symptoms of ADHD were compared to 20 age- and IQ-matched children with ADHD who were medication-naïve. Chi-squared tests were performed on the categorical dependent variables and independent t-tests on the dependent continuous variables. RESULTS: Anxiety is significantly increased in children with ADHD treated with psychostimulant medication in the intermediate- to long-term who are noted by clinicians to have ongoing core symptoms of ADHD. This statistically significant finding is evident with both categorical and dimensional measures of anxiety from the child's perspective. CONCLUSIONS: The recognition of anxiety and its management in children with ADHD is generally poorly understood. In this particular group of children with ADHD, anxiety may be a side effect of intermediate- to long-term psychostimulant medication and/or a potential marker for a poor response to intermediate- to long-term psychostimulant medication treatment.

Anxiety↗
PubMedDate not supplied

Metabolism of a nitrogen-containing steroid by rat hepatocytes and hepatic subcellular fractions.

Freshly isolated rat hepatocytes metabolized the nitrogen-containing steroid N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta- carboxamide (I) to six products analyzed by reverse phase HPLC. The major metabolite, which could account for greater than 50% of the total I-related material, exhibited chromatographic, NMR, and mass spectral properties identical to those of the authentic 4-carbinolamide of I. Thus, the major biotransformation pathway in hepatocytes was hydroxylation of the N-methyl group of I to form a stable carbinolamide intermediate of N-demethylation. Desmethyl-I was observed as a minor metabolite. Another metabolite which accounted for approximately 10% of the total I-related material had chromatographic and spectral properties identical to those of the authentic monoethyl analog of I. The other three metabolites were formed in variable quantities and were unstable when isolated. Mass spectral data suggested that one metabolite was the carbinolamide intermediate of N-deethylation. Treatment of rats with phenobarbital or dexamethasone increased the formation of the monoethyl metabolite of I in hepatocytes but had no effect upon the formation of the 4-carbinolamide metabolite. Rat hepatic microsomes catalyzed the NADPH-dependent metabolism of I to the same metabolites in the same relative amounts as observed with intact hepatocytes. Studies with alternative substrates and inhibitors demonstrated that microsomal cytochrome P-450 was responsible for the metabolism of I. Dog and human hepatic microsomes metabolized I to the same products as rat hepatic microsomes, but monoethyl I was the major metabolite.

Animals↗
PubMed2003

Vestibular, optokinetic, and cognitive contribution to the guidance of passive self-rotation toward instructed targets.

We ask how vestibular and optokinetic information is combined ("fused") when human subjects who are being passively rotated while viewing a stationary optokinetic pattern try to tell when they have reached a previously instructed angular displacement ("targeting task"). Inevitably such a task entices subjects to also draw on cognitive mechanisms such as past experience and contextual expectations. Specifically, because we used rotations of constant angular velocity, we suspected that they would resort, consciously or unconsciously, to extrapolation strategies even though they had no explicit knowledge of this fact. To study these issues, we presented the following six conditions to subjects standing on a rotatable platform inside an optokinetic drum: V, pure vestibular (passive rotation in darkness); O, pure optokinetic (observer motionless, drum rotating); VO, combined (passive rotation while viewing stationary drum); Oe, optokinetic extrapolation (similar to O, but drum visible only during first 90 degrees of rotation; thereafter subjects extrapolate the further course in their minds); VOe, combined extrapolation (similar to VO, but drum visible only during first 90 degrees ); AI, auditory imagination (rotation presented only metaphorically; observers imagine a drum rotation using the rising pitch of a tone as cue). In all conditions, angular velocities ( v(C)) of 15, 30, or 60 degrees /s were used (randomized presentation), and observers were to indicate when angular displacement (of the self in space or relative to the drum) had reached the instructed magnitude ("desired displacement", D(D); range 90-900 degrees ). Performance was analyzed in terms of the targeting gain ( G(T) = physical displacement at time of subjects' indication / D(D)) and variability (% E(R) = percentage absolute deviation from a subject's mean gain). In all six conditions, the global mean of G(T) (across v(C) and D(D)) was remarkably close to veracity, ranging from 0.95 (V) to 1.06 (O). A more detailed analysis of the gain revealed a trend of G(T) to be larger with fast than with slow rotations, reflecting an underestimation of fast and an overestimation of slow rotation. This effect varied significantly between conditions: it was smallest in VO, had intermediate values with the monomodal conditions V and O, and also with VOe, and was largest in Oe and AI. Variability was similar for all velocities, but depended significantly on the condition: it was smallest in VO, of intermediate magnitude in O, VOe, Oe, and largest in V and AI. Additional experiments with conditions V, O, and VO in which subjects repetitively indicated displacement increments of 90 degrees, up to a subjective displacement of 1080 degrees, yielded similar results and suggest, in addition, that the displacement perceptions measured at the beginning and during later phases of the rotation are correlated. With respect to the displacement perception during optokinetic stimulation, they also show that the gain and its variability are similar whether subjects feel stationary and see a rotating pattern, or feel rotated and see a stationary pattern (circular vection). We conclude that the vestibular and optokinetic information guiding the subjects' navigation toward an instructed target is not fused by straightforward averaging. Rather the subjects' internal velocity representation (which ultimately determines G(T)) appears to be a weighted average of (1) whatever sensory information is available and of (2) a cognitive default value reflecting the subjects' experiences and expectations. The less secure the sensory information (only one source as in V or O, additional degrading as in Oe or AI), the larger the weight of the default value. Vice versa, the better the information (e.g., two independent sources as in VO), the more the actual velocity and not the default value determines displacement perception. Moreover, we suggest that subjects intuitively proceeded from the notion of a constant velocity rotation, and therefore tended to carry on the perception built up during the beghe perception built up during the beginning of a rotation or, in the case of vestibular navigation, to compensate for the decaying vestibular cue by means of an internal recovery mechanism.

Adult↗
PubMed1980

Magnitude of the fetal hemoglobin response to acute hemolytic anemia in baboons is controlled by genetic factors.

When hemolytic anemia was induced in 26 baboons (Papio cynocephalus), aged 7-22 mo, they increased their production of fetal hemoglobin (HbF). Although the resulting reduction in hematocrits and increases of reticulocyte counts were similar in all stressed animals there was marked variability in the maximal rates of HbF synthesis. The maximal levels of HbF attained appeared to fall into three separate groups: low, intermediate, and high. These differences were not related to sex or several measures of erythrocyte metabolism. Animals exposed to repeated episodes of erythropoietic stress after full hematologic recovery demonstrated some variability in their maximal HbF levels attained from one episode to another, but these variations never extended to adjacent classes. The described biochemical and mating data suggest that the magnitude of the HbF response to hemolytic anemia is controlled by genetic factors.

Anemia, Hemolytic↗
PubMed1991

Predictors of length of stay of psychiatric adolescent inpatients.

This study reviewed 158 consecutive admissions to an inpatient adolescent psychiatric service for factors that determine length of hospitalization. Variables associated with length of stay included diagnostic category and the treatment variables of number and type of psychotropic medications prescribed. Patients with disruptive behavior disorders had the shortest hospitalizations, those with anxiety and affective disorders had stays of intermediate length, and patients with psychotic/organic disorders had the longest hospitalizations. Treatment with lithium, neuroleptics, or tricyclic antidepressants was associated with longer stays. Demographic variables and variables describing the social and family situation or level of dangerousness were not significantly associated with length of hospitalization.

Adolescent↗
PubMed1988

Pharmacy component of a hospital end-product cost-accounting system.

Determination of pharmacy department standard costs for providing drug products to patients at Thomas Jefferson University Hospital in Philadelphia is described. The hospital is implementing a cost-accounting system (CAS) that uses software developed at the New England Medical Center, Boston. The pharmacy identified nine categories of intermediate products on the basis of labor consumption. Standard labor times for each product category are based on measurement or estimation of time for each task in the preparation and distribution of a dose. Variable-labor standard time was determined by adjusting the cumulative time for the tasks to account for nonproductive time and nonroutine activities, and a variable-labor standard cost for each category was calculated. The standard cost per dose included the costs of labor and supplies (variable and fixed) and equipment; this standard cost plus the acquisition cost of a drug line item is the total intermediate product cost. Because the CAS is based on the hospital's patient charges, clinical pharmacy services are excluded. Intermediate products that substantially affect end-product costs (costs per patient case) will be identified for inclusion in CAS reports. The CAS will give a more accurate picture of resource consumption, enabling managers to focus their efforts to improve efficiency and productivity and reduce supply use; it could also improve the accuracy of the budgeting process. The CAS will support hospital administration decisions about marketing end products and department managers' decisions about controlling intermediate-product costs.

Accounting↗
PubMed1988

Marriage duration, marital adjustment and psychological symptoms: a cross-sectional study.

One hundred and nine couples completed questionnaire measures of psychological symptoms, personality, and marital adjustment. They were divided into groups of short, intermediate, and long marriage duration. Psychological symptoms and marital adjustment remained fairly stable over time, although wives scored significantly worse than husbands on most measures in the intermediate duration group. In the short marriages, half the variance in marital satisfaction was predicted by the partner's marital questionnaire score, but when this variable was eliminated from the regression equation, psychological symptoms (phobic anxiety in wives and depression in husbands) were the main predictors of marital satisfaction. In the intermediate group, hostility levels were the main predictors of marital satisfaction. In the long marriages, marital satisfaction was predicted mainly by personality factors (assertiveness in husbands and personal flexibility in wives) and by levels of generalized anxiety. The findings suggest that couples who constructively resolve difficulties in expressing hostility within marriage are more likely to remain married than those who fail to do so.

Adaptation, Psychological↗
PubMed1988

Prognostic factors for local recurrence and survival in patients with localized extremity soft-tissue sarcoma.

The charts of 423 patients with localized extremity soft-tissue sarcoma treated at our institution over a 10-year period (1968-1978) were reviewed. Data were subjected to both univariate and multivariate analysis, with independent variables in the multivariate analysis appearing in capital letters. Factors associated with an increased risk of local recurrence included the following: AGE greater than 53; PRESENTATION WITH RECURRENT DISEASE; HIGH TUMOR GRADE; positive regional nodes; TREATMENT BY LIMB-SPARING SURGERY (LSS); invasion of vital structures (LSS only); INADEQUATE MARGINS; and biopsy with delayed definitive resection. Survival was adversely affected by the following: AGE greater than 53; PAINFUL MASS; PROXIMAL SITE; SIZE greater than or equal to 10 cm; HIGH TUMOR GRADE; POSITIVE NODES; invasion of vital structures; TREATMENT BY AMPUTATION; INADEQUATE MARGINS; and local recurrence after treatment at our institution. Significant variations in both local recurrence and survival according to histopathology were also observed, with EMBRYONAL RHABDOMYOSARCOMA, ANGIOSARCOMA, and MALIGNANT PERIPHERAL NERVE TUMORS emerging as independent predictors of local recurrence. Using the Cox models for local recurrence and survival, patients were stratified into high-, intermediate-, and low-risk categories based on the presence or absence of each variable. Risk factor analysis should be part of the overall evaluation of each patient with extremity sarcoma.

Adolescent↗
PubMed2006

Alternative routes and mutational robustness in complex regulatory networks.

Alternative pathways through a gene regulation network connect a regulatory molecule to its (indirect) regulatory target via different intermediate regulators. We here show for two large transcriptional regulation networks, and for 15 different signal transduction networks, that multiple alternative pathways between regulator and target pairs are the rule rather than the exception. We find that in the yeast transcriptional regulation network intermediate regulators that are part of many alternative pathways between a regulator and target pair evolve at faster rates. This variation is not solely explicable by higher expression levels of such regulators, nor is it solely explicable by their variable usage in different physiological or environmental conditions, as indicated by their variable expression. This suggests that such pathways can continue to function despite amino acid changes that may impair one intermediate regulator. Our results underscore the importance of systems biology approaches to understand functional and evolutionary constraints on genes and proteins.

Evolution, Molecular↗
PubMed2003

Genetic determinants of the thiopurine methyltransferase intermediate activity phenotype in British Asians and Caucasians.

OBJECTIVE: Polymorphisms in the TPMT gene open reading frame (ORF) are associated with reduced TPMT activity. Variable number tandem repeats (VNTR*3 to VNTR*9) in the promoter region of the gene consisting of combinations of Type A, B and C repeat units, may modulate TPMT activity. Here we present the allele frequencies of genetic modifiers of TPMT activity in a British Asian population, as well as the concordance between intermediate TPMT activity and ORF and VNTR genotypes in a predominantly Caucasian population. METHODS: VNTR type and ORF mutations were determined in two selected TPMT activity ranges, intermediate activity (4-8 U, 108 patients), normal (12-15 U, 53 patients) and in 85 British Asians. RESULTS: In British Asians, TPMT*3C was the prevalent mutant allele (four heterozygotes). One patient was heterozygous for TPMT*3A. Overall VNTR frequencies did not differ from Caucasians. Three new VNTR alleles were designated VNTR*6c, VNTR*6d, and VNTR*7c. Forty-one percent of patients with intermediate activity were heterozygous for a TPMT ORF mutation (3A, 2B, 1C). Marked linkage disequilibrium was noted between VNTR*6b - TPMT*3A (D' = 1), VNTR*4b - TPMT*3C (D' = 0.67) and VNTR*6a - TPMT*1 (D' = 1) alleles. As a result, significant differences (P < 0.05) in the distribution of Type A, B or the total number of repeats summed for both alleles, were found between the ORF heterozygous intermediate activity group and the wild-type intermediate or normal activity groups. No significant difference was found between the two wild-type groups. CONCLUSION: Our results suggest that TPMT gene VNTRs do not significantly modulate enzyme activity.

Alleles↗
PubMed2006

Expression of MHC class I-related Chain B (MICB) molecules on renal transplant biopsies.

BACKGROUND: MICA and MICB (MHC class I-related chain A and B) are polymorphic genes that encode molecules related to MHC class I and are expressed on epithelial cells in response to stress. Incompatible donor MIC antigens can stimulate antibody production in transplant recipients. This study was designed to determine MICB expression in kidney pretransplant and any subsequent changes in expression following transplantation and to correlate changes with inflammatory markers and clinical events. METHODS: Paired renal biopsies obtained from living donor (n=10) and cadaveric allografts (n=50) before and 7 days posttransplant were stained for MICB, leukocytic infiltration, and HLA class II antigens. RESULTS: Variable tubular MICB expression was evident in donor biopsies [high 6/60 (10%), low/negative 13/60 (22%), intermediate 41/60 (68%)]. Following transplantation, MICB was up-regulated on renal tubules of 17/60 (28%) biopsies and was associated with MHC class II antigen induction (P=0.02) and leukocyte infiltration (P=0.01). Acute tubular necrosis leading to delayed graft function (DGF) and acute rejection (AR) cause cellular stress within the transplanted kidney. We found a strong association between up-regulation of MICB and cellular stress, 15/17 biopsies with up-regulated MICB expression had AR and/or DGF (P=0.003). CONCLUSIONS: This is the first study demonstrating variable levels of MICB expression in kidneys before transplantation and induction of MICB expression following renal transplantation. MICB expression is associated with HLA class II antigen induction, leukocytic infiltration of the graft and cellular stress in the transplanted kidney. Expression of MICB could contribute significantly to the alloimmune response in mismatched donors and recipients.

Adult↗
PubMed1996

Characterization of interactions between the neurofilament triplet proteins by the yeast two-hybrid system.

In the adult axon, the neurofilaments (NFs) are heteropolymers formed from the low (NFL), middle (NFM), and high (NFH) molecular weight neurofilament triplet proteins (NFTPs). All three proteins have the basic intermediate filament protein tripartite structure, which consists of a short amino-terminal head region, an alpha-helical rod region of approximately310 amino acids, and a carboxyl-terminal tail region of variable length. In vitro polymerization studies have shown that only NFL can assemble into homopolymeric 10-nm filaments. The assembly of intermediate filaments, including the NFs, begins with the formation of a coiled-coil dimer involving the alpha-helical rod domains of two molecules. In order to determine whether homodimers or heterodimers of NFTPs are the preferred intermediates in the assembly of NFs, we have used the yeast two-hybrid system to study the interactions between the different NFTPs. By monitoring the activity of the lacZ reporter gene product, we are able to show that the interactions of NFL with NFL, NFM, or NFH are stronger than the interactions of NFM with NFM or NFH and the interaction of NFH with NFH. These results imply that NFM and NFH are more likely to form heterodimers with NFL than homodimers and are consistent with the inability of NFM and NFH to self-polymerize in vitro and in vivo.

Animals↗
PubMed2002

The apomyoglobin folding pathway revisited: structural heterogeneity in the kinetic burst phase intermediate.

Extensive analysis of accurate quench-flow hydrogen exchange results indicates that the burst phase kinetic intermediate in the folding of apomyoglobin (apoMb) from urea is structurally heterogeneous. The structural variability is associated with the partial folding of the E helix during the burst phase (<6.4ms) of the folding process. Analysis of the effects of exchange-out of amide proton labels during the labeling pulse ( approximately pH 10) of the quench-flow process indicates that three of the amide protons in the E helix are in fact largely protected in the burst phase of folding, while the remainder of the E helix has a substantial complement of amide protons that show biphasic kinetics, i.e. are protected partly during the burst phase and partly during the slow phase of folding. The locations of these amide protons can be used to map the sites of structural heterogeneity in the kinetic molten globule. These sites include, besides the E helix, the ends of the A and B helices and part of the C helix. Our results give significant support to the hypothesis that the kinetic molten globule intermediate of apoMb is native-like.

Animals↗
PubMed1989

Extremity soft tissue sarcomas: analysis of prognostic variables in 300 cases and evaluation of tumor necrosis as a factor in stratifying higher-grade sarcomas.

From July 1975 to February 1985, 300 patients with extremity soft tissue sarcomas (STS) were entered into treatment protocols at the National Cancer Institute. Using the Cox proportional hazards model, the STS were analyzed for independent prognostic variables that had significant association with disease-free and overall survival. The effects of adjuvant treatment were also included in the analysis. Percent tumor necrosis was the basis for separating intermediate and high-grade STS (less than 15% necrosis = grade 2; greater than 15% necrosis = grade 3). The most important prognostic variable was histologic grade, which was highly associated with relative risk of metastasis and fatal outcome (P less than .0001). Histologic type of STS was not a significant prognostic variable in predicting metastases. Patients with tumors located on the proximal or middle part of the extremity had a fivefold increased risk of death (P = .02) compared with patients who had STS located more distally. Mitotic activity (P = .0005) and vascular invasion (P = .0034) were also associated with malignant behavior, but histologic grade was the most significant predictor of outcome. Histologic grade of malignancy was based upon a combination of tumor typing and visual estimation of extent of tumor necrosis; using these two features, one can reliably separate low-grade (i.e., grade 1) from high-grade STS and also stratify the more aggressive (i.e., grade 2 and 3) tumors. Over the 9.5-year period of study, the tumor-related mortality was as follows: grade 1 (1/38), 3%; grade 2 (19/142), 13%; and grade 3 (45/120), 38%.

Adult↗
PubMed2001

Differential metabolism of 1,1-dichloroethylene in livers of A/J, CD-1, and C57BL/6 mice.

1,1-Dichloroethylene (DCE) causes hepatocellular necrosis that preferentially affects centrilobular hepatocytes. The cytotoxic lesion has been attributed to DCE oxidation mediated mainly by CYP2E1, resulting in formation of reactive intermediates including the DCE epoxide. Here, we have tested the hypothesis that differing levels of hepatic CYP2E1 in A/J, CD-1, and C57BL/6 (B6) mice lead to differences in magnitudes of DCE metabolism and severities of hepatotoxicity. Our results showed that amounts of the CYP2E1 protein were higher in A/J mice than in B6 and CD-1 mice. Covalent binding of DCE to liver proteins was variable in the three strains of mice and was higher in A/J than in B6 mice; intermediate levels were found in CD-1 mice. Levels of a DCE epoxide-derived glutathione conjugate detected in liver cytosol correlated with those present in bile extracts and were significantly higher in A/J than in CD-1 and B6 mice. Immunohistochemical studies showed that formation of DCE epoxide-cysteine protein adducts was enhanced in the livers of A/J mice, compared with those produced in the livers of CD-1 and B6 mice. Similarly, centrilobular necrosis was more severe in the livers of A/J mice than in those in either CD-1 or B6 mice. Levels of glutathione were similar in the three strains of untreated mice and were diminished at comparable levels in all mice. These results indicated that high expression of hepatic CYP2E1 in A/J mice coincided with increased DCE metabolism and enhanced severity of hepatotoxicity, relative to those in CD-1 and B6 mice.

Animals↗