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The combined evaluation of p53 accumulation and of Ki-67 (MIB1) labelling index provides independent information on overall survival of ovarian carcinoma patients.

BACKGROUND: The prognostic implications of p53 accumulation, bcl-2 immunoreactivity and tumour proliferative fraction in ovarian carcinomas are still debated. PATIENTS AND METHODS: One hundred twelve ovarian carcinomas were immunostained for p53 protein, for bcl-2 and for the cell cycle-associated Ki-67 antigen. The immunostaining results were correlated with conventional clinico-pathological variables, response to induction chemotherapy, and patient survival. RESULTS: p53 accumulation and bcl-2 immunoreactivity in more than 10% of neoplastic cells were detected in 61 (54.5%) and 42 (37.5%) cases, respectively. A positive correlation between p53 accumulation and high (more than 30% neoplastic cells) MIB1 labelling index (r = 0.235; P = 0.015) was ascertained, whereas no significant association was found between bcl-2 immunoreactivity and p53 accumulation or MIB1 labeling index. Both p53 accumulation and MIB1 immunoreactivity correlated significantly with a reduced overall survival, but the association was lost in multivariate analysis. However, patients with tumours simultaneously showing p53 accumulation and MIB1 labelling index higher than 30% had significantly reduced overall survivals, in both univariate and multivariate analyses. CONCLUSION: The simultaneous evaluation of p53 accumulation and MIB1 labelling index has independent prognostic implications in common epithelial malignancies of the ovary, irrespective of the disease stage.

Cell Division↗

Oxidative folding of bovine pancreatic ribonuclease A: insight into the overall catalysis of the refolding pathway by phosphate.

The effects of the strong stabilizing anion, phosphate, on the oxidative folding of bovine pancreatic ribonuclease A were examined. Phosphate was found to catalyze several steps involved in the oxidative folding process at pH 8.0 and 25 degrees C, resulting in an increase in the rate of pre-equilibration of unstructured species on the folding pathway. In the presence of 400 mM phosphate, the overall increase in the rate of regeneration of native protein was caused primarily by the increased formation and stabilization of tertiary structure in the nativelike intermediates, des-[40-95] and des-[65-72], involved in the rate-determining step. Based on the regeneration of native protein and the stability of Cys--> Ala substituted mutant analogs of the des-species, (C40A, C95A) and (C65A, C72A), it is suggested that the primary role of phosphate is to catalyze the overall regeneration of native protein through nonspecific electrostatic and hydrogen-bonding effects on the protein and solvent.

Animals↗

Development of an overall index of pollution for surface water based on a general classification scheme in Indian context.

Various National and International Agencies involved in water quality assessment and pollution control have defined water quality criteria for different uses of water considering different indicator parameters. Classification schemes for water quality criteria/standards developed by these agencies differ in addition to terminologies used such as Action level, Guide level etc. in defining the concentration values in these classes. In the present article a general classification scheme viz. Excellent, Acceptable, Slightly Polluted, Polluted and Heavily Polluted water is proposed for surface water quality assessment. The concentration ranges in these classes are defined in Indian scenario considering Indian Standards and CPCB criteria. Standards by the European Community (EC), WHO etc. and the reported facts about the pollution effects of important water quality indicator parameters on the surrounding were also taken into account. The mathematical equations to transform the actual concentration values into pollution indices are formulated and corresponding value function curves are plotted. Based on the individual index values, an 'Overall Index of Pollution' (OIP) is estimated. The application of OIP is demonstrated at a few sampling stations on river Yamuna based on observed water quality data. The general classification scheme along with concentration ranges defined in these classes will be of immense use for determining the surface water quality status with reference to specific individual parameter, and the OIP for assessing the overall water quality status in Indian context.

India↗

Reducing the overall treatment time for radiotherapy of metastatic spinal cord compression (MSCC): 3-year results of a prospective observational multi-center study.

BACKGROUND: This prospective multi-center study investigates a reduction of the overall treatment time for radiotherapy of MSCC, which is important for these mostly disabled patients. PATIENTS AND METHODS: Two standard fractionation schedules, 30 Gy/10 fractions/2 weeks (n = 71) and 40 Gy/20 fractions/4 weeks (n = 65) were compared for functional outcome and ambulatory status. Motor function was graded using an 8-point-scale before RT, at the end and at 6, 12 and 24 weeks after RT. A multi-variate analysis was performed for functional outcome. Included variables were the fractionation schedule and the three relevant prognostic factors. These factors are the type of primary tumor, the time of developing motor deficits before RT and the pre-treatment ambulatory status. RESULTS: The ambulatory rates were 49% in the 30 Gy group and 52% in the 40 Gy group before RT (P = 0.888), and 56% and 60% after RT (P = 0.888). Improvement of motor function occurred in 45% of the 30 Gy group and 40% of the 40 Gy group (P = 0.752). The relevant prognostic factors were comparably distributed in both groups. According to the multivariate analysis, a slower development of motor deficits (P < 0.001), a favorable histology (P = 0.040) and being ambulatory (P = 0.045) were associated with better functional outcome, whereas the fractionation schedule had no significant impact (P = 0.311). CONCLUSIONS: The data suggest both schedules to be comparably effective for functional outcome. Thus, 30 Gy/10 fractions/2 weeks should be applied instead of 40 Gy/20 fractions/4 weeks. The reduction of the overall treatment time from 4 to 2 weeks means less discomfort for the paraparetic or paraplegic patient.

Adult↗

Importance of the overall similarity of objects of adults' and children's classifications.

Previous work has shown that adults and older children tend to classify multi-dimensional objects by identity on one dimension, whereas children under 8 years of age tend to classify these same objects by a relation of overall similarity. The present study investigated the hypothesis that this developmental trend is restricted to the classification of simple objects that differ only by limited amounts on a few dimensions. The specific hypothesis was that overall-similarity relations structure both adults' and children's classifications of heterogenous objects (objects that differ in a variety of ways). This hypothesis was suggested by the correspondence between the structure of young children's classifications and the structure of natural categories. The result of two experiments supported the hypothesis. When the to-be-classified objects varied simultaneously on relatively many dimensions, adults as well as children constructed classifications that maximized within-category similarity on all varying dimensions. The implications of these results for accounts of the perception of multidimensional relations and classificatory behavior are discussed.

Adult↗

Predictors of overall and on-the-job substance use among young workers.

Predictors of overall and on-the-job substance (alcohol and marijuana) use were studied in a sample of young workers. The 18 predictors represent 6 general domains of risk factors: demographic, personality, substance use outcome expectancies, workplace substance availability, workplace social control, and work stressors. Data were obtained from a sample of 319 individuals ages 16 to 19. Hierarchical tobit regression analyses revealed that 5 of the 6 domains of risk factors were related to employee substance use. Similarities and differences were found in the predictors of overall and on-the-job substance use and in the predictors of alcohol and marijuana use.

Adolescent↗

Sexual versus nonsexual workplace aggression and victims' overall job satisfaction: a meta-analysis.

A meta-analytic approach was used to examine whether sexual and nonsexual forms of nonviolent workplace aggression (both verbal and nonverbal) share equivalent or differential relationships with victims' overall job satisfaction. When the meta-analytic comparison was restricted to all-female samples to hold victims' gender constant, nonsexual aggression was found to share a significantly stronger negative relationship with victims' overall job satisfaction than was sexual aggression. In addition, nonsexual aggression was found to share a stronger negative link with women's level of job satisfaction than with men's.

Aggression↗

The time course of delivery of furosemide into urine: an independent determinant of overall response.

After an oral or intravenous dose of furosemide, there is considerable interindividual variability in the amount of unchanged drug delivered into the urine. On average, approximately half as much reaches the intraluminal site of action with an oral compared to an intravenous dose. However, the natriuretic response to the same dose administered by either route is virtually the same. Similarly, after pretreatment with probenecid, the same total amount of furosemide in urine causes a greater overall response. It has been presumed that this paradox is accounted for by differences in rate of delivery of furosemide to the active site such that after an oral dose, or after pretreatment with probenecid, amounts of drug are for longer periods of time at the "steep" portion of the dose-response curve. Our analysis shows this not to be the case. For furosemide, the "slope factor" of the dose-response curve is such that the amount of diuretic delivered into the urine which is maximally efficient (21.5 micrograms/min) is considerably less than the amount causing half-maximal response (69.8 micrograms/min). Oral administration or pretreatment with probenecid maintains drug close to this maximally efficient amount more persistently than does intravenous administration. By so doing, total response to an oral dose approaches that of intravenous dosing despite delivering half the amount of drug to the active site, and after probenecid an intravenous dose causes a greater response than intravenous dosing alone despite delivering the same amount of drug to the active site. These data emphasize the importance of the time course of delivery of drug to the active site as an independent determinant of overall response.

Administration, Oral↗

Proline scanning mutagenesis of a molten globule reveals non-cooperative formation of a protein's overall topology.

Small proteins generally fold cooperatively: disruption of significant parts of the folded structure leads to unfolding of the rest of the protein. We show here, using proline scanning mutagenesis, that the native-like tertiary fold of the alpha-lactalbumin (alpha-LA) molten globule is formed by the non-cooperative assembly of its constituent helices. In contrast to the drastic destabilizing effects of proline substitutions in cooperatively folded proteins, proline mutations in the molten globule appear to cause only individual helices to unfold, without significantly influencing the other helices or the overall topology. Thus, the key determinants of a protein's overall fold may not be of the all-or-none type.

Circular Dichroism↗

Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer.

Squamous cell carcinoma of the oesophagus (SCCO) is still a pathology of bad prognosis. Specific therapies are now developed against epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, c-kit receptor (CD117), vascular endothelial growth factor (VEGF) and p53 protein. This study was aimed at assessing their expression in a large series of SCCO, as well as their potential therapeutic interest in this pathology. Immunohistochemical expression of these factors was assessed retrospectively in 107 cases of SCCO with primary surgery, as well as their relationships to recurrence, metastasis and overall survival on a long-term follow-up. Human epidermal growth factor receptor 2 and CD117 were expressed in less than 3% of the cases. Epidermal growth factor receptor and p53 were overexpressed in 68.2 and 66.4% of the cases, and VEGF in 38.3%. Epidermal growth factor receptor overexpression was significantly related to vascular invasion (P=0.023). Its diffuse positivity was significantly related in multivariate analysis to higher local recurrence (P=0.006) and lower overall survival (P=0.003), in a subgroup of patients of poor outcome who had received postoperative adjuvant treatment. These results highlight the great potential prognostic and therapeutic interest of evaluating EGFR diffuse positivity in locally advanced SCCO.

Aged↗

Improved efficiency of remission induction facilitates autologous BMT harvesting and improves overall survival in adults with AML: 108 patients treated at a single institution.

A hundred and eight patients less than 60 years old with de novo acute myeloid leukemia were treated between 1982 and 1994 by protocols including final intensification with a transplant using autologous bone marrow purged by mafosfamide in first remission in the absence of an HLA-matched sibling donor available for allograft. From 1989, we attempted to improve tumor control by using high-dose anthracyclines in induction, by increasing from one to two the number of consolidation courses pre-transplant and by introducing intermediate doses of cytarabine in the first consolidation course. The CR rate was 77% (33/43) before 1989 and 90% (59/65) after 1989 (P = 0.06). Forty-five out of the 59 patients (76%) who achieved CR after 1989 could undergo bone marrow grafting in CR1 vs 16/33 (48%) before 1989 (P = 0.01). In spite of the higher proportion of patients above 50 years after 1989 (32%) toxicity was mild and an adequate graft was obtained more frequently after one collection. The principal factor relating to improvement in graft feasibility was the post-1989 modification of induction and consolidation regimens. This improvement in graft feasibility was associated with a better disease-free survival (DFS) (48 +/- 7% vs 32 +/- 8%, P = 0.04) and overall survival (OS) (53 +/- 6% vs 30 +/- 7%, P = 0.007) at 5 years. By multivariate analysis four factors were associated with overall survival (OS): karyotype, white blood cell count at diagnosis, treatment regimen and bone marrow grafting in CR1. This global approach should be prospectively compared with intensive chemotherapy.

Acute Disease↗

Leptin concentrations in relation to overall adiposity, fat distribution, and blood pressure in a rural Chinese population.

OBJECTIVE: To examine the associations between leptin levels and body mass index (BMI), fat distribution (reflected by waist to hip ratio and skinfold measurements), and blood pressure in a rural Chinese population. DESIGN AND SUBJECTS: A cross-sectional study of 294 participants who provided blood samples. MEASUREMENTS: Plasma concentrations of leptin, BMI, waist to hip ratio, skinfold thickness, and blood pressure. RESULTS: The average leptin concentration was 5.2 microg/l (3.1 for men and 7.3 for women). In univariate analyses, leptin levels were significantly correlated with BMI (r=0.47), abdominal skinfold thickness (r=0.53), triceps skinfold thickness (r=0.56), waist circumference (r=0.41), hip circumference (r=0.51), waist to hip ratio (r=0.17), and diastolic blood pressure (r=0.13). In multivariate analyses controlling for age, sex, education, current smoking, and alcohol use, independent associations between leptin levels and BMI, waist to hip ratio, waist circumference, and abdominal skinfold thickness remained. However, the significant association between leptin and blood pressure disappeared after adjusting for BMI, whereas the association between BMI and blood pressure persisted after adjusting for leptin level. CONCLUSIONS: We observed a strong positive relationship between overall adiposity and leptin levels in both men and women in a rural Chinese population. In addition, leptin concentrations were significantly associated with central obesity measured by waist to hip ratio and abdominal skinfold, independent of overall obesity. The observed positive association between leptin and blood pressure was largely explained by BMI. International Journal of Obesity (2001) 25, 121-125

Adipose Tissue↗

Overall deregulation in gene expression as a novel indicator of tumor aggressiveness in colorectal cancer.

Malignant transformation of the cell is accompanied and characterized by disruption of genetic material and aberrant expression of multiple genes. Systematic analysis of differential gene expression in human tumor samples may provide an estimate of the degree of genetic and epigenetic deregulation in neoplastic cells. We have assessed, by means of a RNA differential display technique, the overall gene expression deregulation in a prospectively collected series of 68 human colorectal carcinomas. An index of differential expression has been calculated for each case. A similar proportion of the displayed sequences (23%) was under- and over-represented in the tumor in respect of the normal tissue. An increased variation in the expression profile was observed in advanced Dukes' stages (P < 0.02) and correlated with lymph node invasion (P < 0.05). Furthermore, a diminished overall survival was associated to increased rates of deregulation (Log-rank, P < 0.02) and especially down-regulation (P < 0.001). When Cox multivariate analysis was performed in front of Dukes' stage, both indexes of differential expression were independent indicators of a worse outcome (P = 0.05 and P < 0.01 respectively). We conclude that estimation of the fraction of differentially displayed tags by RNA fingerprinting may have relevant applications in the prognostic assessment of colorectal cancer.

Blotting, Northern↗

Specific conformational changes of plasminogen induced by chloride ions, 6-aminohexanoic acid and benzamidine, but not the overall openness of plasminogen regulate, production of biologically active angiostatins.

The overall conformation of plasminogen depends upon the presence of anions and molecules such as AHA (6-aminohexanoic acid) and BZ (benzamidine). The purpose of the present study was to determine the effect of conformation on the initial and secondary cleavages of plasminogen to generate active angiostatins. Plasminogen was digested with the physiologically relevant neutrophil elastase in one of the four Tris/acetate buffers: buffer alone or buffer plus NaCl, AHA or BZ. The initial cleavage of Glu1-plasminogen was much slower in the tight NaCl-induced alpha-conformation, fastest in the intermediate BZ-induced beta-conformation and intermediate both in the control and in the AHA-induced open gamma-conformation. Although the buffer system determined the relative amounts of the initial cleavage products, the same four cleavage sites were utilized under all conditions. A fifth major initial cleavage within the protease domain was observed in the presence of BZ. N-terminal peptide cleavage required for angiostatin formation occurred as either the initial or the secondary cleavage. Angiostatins were generated fastest in the presence of BZ and slowest in the presence of NaCl. Both the initial and secondary cleavages were affected by the modifying agents, indicating that they influence the conformation of both Glu-plasminogen and the initial cleavage products. The angiostatins produced under the different conditions inhibited proliferation of human umbilical-vein endothelial cells. These results suggest that plasminogen conversion into active angiostatins is dependent more on the specific conformation changes induced by the various modifying reagents rather than on the overall openness of the molecule.

Aminocaproic Acid↗

Prediction of PICA overall score by short versions of the test.

Two short versions (SPICAs) of the Porch Index of Communicative Ability (PICA) were developed and investigated, with specific attention to their ability to predict standard PICA overall scores of patients with aphasia. Ninety-three patients were administered three versions of the test in randomized order. Results indicate that SPICAs predict overall scores by standard administration at acceptable confidence levels in approximately one-third of the time required for the administration of the standard PICA.

Evaluation Studies as Topic↗

Overall haemostatic potential can be used for estimation of thrombin-activatable fibrinolysis inhibitor-dependent fibrinolysis in vivo and for possible follow-up of recombinant factor VIIa treatment in patients with inhibitors to factor VIII.

Thrombin generation induced by recombinant factor VIIa (rFVIIa) in patients with haemophilia and/or inhibitors to factor VIII/IX could enhance generation of thrombin-activatable fibrinolysis inhibitor (TAFI), a recently described link between coagulation and fibrinolysis. TAFI is unstable and it is not easy to measure its active form in vivo. Overall haemostatic potential (OHP) is a novel method for haemostasis estimation, based on determination of the fibrin aggregation curve in which tiny amounts of thrombin are used for activation of clotting. We measured OHP in six patients with inhibitors to factor VIII before injection of rFVIIa and 10 and 120 min thereafter. Overall fibrinolytic potential (OFP) and clot lysis time (CLT) analysed by this method could be used for indirect estimation of TAFI generation. We found no change in pro-TAFI and total TAFI antigen before and after treatment with rFVIIa. OHP was almost undetectable before treatment but increased into the range of normal pooled plasma 10 and 120 min after rFVIIa treatment, as did CLT. However, after addition of potato tuber carboxypeptidase inhibitor, a specific inhibitor of TAFI, the shortening of CLT was lower than that in NPP. OFP was increased in patient plasma both 10 and 120 min after treatment compared with NPP. There was a strong positive correlation between pro-TAFI concentration and shortening of CLT after PTCI addition and a negative correlation between pro-TAFI concentration and OFP 10 min after rFVIIa injection. Thus, rFVIIa normalizes OHP and CLT 10 min after injection. While this improvement slightly decreases, but still exists after 2 hours, it suggests efficacy in bleeding prevention using a protocol based on rFVIIa administration every 2 hours.

Carboxypeptidase B2↗

The overall effectiveness of prophylaxis in severe haemophilia.

The aim of this retrospective review was to assess the overall effectiveness of prophylaxis when compared with on-demand treatment of haemophilic patients. Twenty-five children (22 with severe haemophilia A and three with severe haemophilia B) were evaluated. Five haemophilia A patients received primary prophylaxis (instituted before the onset of any joint bleed) while the other 17 haemophilia A and all three haemophilia B patients were on secondary prophylaxis. We compared factor usage, number of bleeding episodes, emergency room (ER) visits and hospitalizations while on prophylaxis to those while on demand therapy. All subjects were male, the median age at time of review was 11.4 years and at start of prophylaxis was 4.5 years. Thirteen of the 25 patients (52%) required indwelling venous catheters for access, seven of these had one or more (one-six) episodes of line sepsis. Haemophilia A patients received an average of 23.8 U kg(-1) (20-30 U kg(-1)) of recombinant factor VIII three times a week while haemophilia B patients received 50 U kg(-1) recombinant FIX twice weekly. There was a significant reduction in the mean number of major bleeds on prophylaxis from 15.5 to 1.9 per year and a significant decrease in target joints, ER visits and hospitalizations. Although factor usage per year was higher on prophylaxis, there was an overall reduction in number of bleeds and resultant decrease in hospitalizations and ER visits. By preventing new target joints, prophylaxis can lead to reduction in long-term morbidity and a better quality of life despite increased central lines and higher factor usage.

Adolescent↗

The effects of age on the overall population and on sub-populations of myenteric neurons in the rat small intestine.

Previous studies on ageing animal and human subjects have demonstrated a significant overall decline in neuronal numbers in the myenteric plexus of the enteric nervous system (ENS). Our study aimed to confirm this observation by counting myenteric neurons stained with the panneuronal markers PGP 9.5 and NADH-diaphorase. We also wished to examine the possibility that particular subpopulations of neurons are vulnerable. Therefore, we have immunostained and counted a number of nerve cell groups within the myenteric plexus of old and young Sprague Dawley rats using markers which reflect some of the neuronal phenotypes present, including ChAT and VIP. The number of neurons demonstrating NADH-diaphorase activity was significantly reduced (P < 0.05) by approximately 15 % in old rats. However, the number of neurons stained for PGP 9.5 immunohistochemistry was not reduced and demonstrated larger numbers of neurons than the NADH-diaphorase method. None of the other neuronal markers studied showed any significant reductions with age. In contrast to previous work, this study has gathered little evidence for extensive cell loss in the myenteric plexus of the aged rat, either in overall populations, or in any of the principal functional groups of neurons.

Aging↗