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Tumor factors predicting for prognosis in metastatic breast cancer. The presence of P24 predicts for response to treatment and duration of survival.

Fifty-one patients with metastatic breast cancer were investigated to determine tumor parameters with prognostic significance. Investigations included determinations of P24 content by immunocytochemical means using a monoclonal antibody to P24 protein; immunocytochemical analysis of estrogen and progesterone receptors; ploidy analysis by flow cytometry, and histologic grading. There were significant correlations between the presence of P24 and estrogen receptor, between histologic grade and P24 expression, and between estrogen and progesterone receptors. Of the tumor factors investigated only P24 protein was, however, of prognostic significance. Patients with P24-positive tumors had a significantly higher rate of response to treatment as well as more prolonged duration of response and duration of survival from diagnosis of metastatic disease. None of the other variables investigated were significantly predictive of outcome. P24 protein may be a useful predictor of prognosis in metastatic breast cancer.

Antibodies, Monoclonal↗

Prediction of the three-dimensional structures of the biotinylated domain from yeast pyruvate carboxylase and of the lipoylated H-protein from the pea leaf glycine cleavage system: a new automated method for the prediction of protein tertiary structure.

A new, automated, knowledge-based method for the construction of three-dimensional models of proteins is described. Geometric restraints on target structures are calculated from a consideration of homologous template structures and the wider knowledge base of unrelated protein structures. Three-dimensional structures are calculated from initial partly folded states by high-temperature molecular dynamics simulations followed slow cooling of the system (simulated annealing) using nonphysical potentials. Three-dimensional models for the biotinylated domain from the pyruvate carboxylase of yeast and the lipoylated H-protein from the glycine cleavage system of pea leaf were constructed, based on the known structures of two lipoylated domains of 2-oxo acid dehydrogenase multienzyme complexes. Despite their weak sequence similarity, the three proteins are predicted to have similar three-dimensional structures, representative of a new protein module. Implications for the mechanisms of posttranslational modification of these proteins and their catalytic function are discussed.

Amino Acid Oxidoreductases↗

A prospective randomised trial comparing individualised pharmacokinetic dosage prediction for aminoglycosides with prediction based on estimated creatinine clearance in critically ill patients.

A prospective randomised trial was conducted in critically ill patients to evaluate a computer aided pharmacokinetic method of aminoglycoside dose prediction based on 3 measured plasma concentrations following the loading dose. The ability of this method to achieve therapeutic plasma aminoglycoside concentrations early in the course of treatment was compared with that of a nomogram approach based on creatinine clearance estimated using the formula of Cockroft and Gault. Ninety-two percent of patients in the computer group achieved peak plasma concentrations within the optimum range of 6-10 mg/l at 48-72 h compared with 21% of control group patients (p = 0.0009). The mean peak plasma concentration of 7.45 mg/l at 48-72 h in the computer group was closer to the target concentration of 8 mg/l than was the 5.14 mg/l in the control group (p = 0.0004). There was no significant difference between the groups in measured indices of renal function, both groups showing an improvement in mean estimated creatinine clearance from the beginning to the end of the course of treatment. Dosing based on individualised pharmacokinetic data is therefore a more reliable method of achieving therapeutic blood concentrations early in the course of treatment than is nomogram based dosing. Other studies suggest that this should be associated with a reduction in mortality in severe infections.

Adult↗

Prediction of cerebral vasospasm value of fibrinogen degradation products (FDP) in the cerebro-spinal fluid (CSF) for prediction of vasospasm following subarachnoid haemorrhage due to a ruptured aneurysm.

In a new treatment regimen with antifibrinolytic drugs in patients with aneurysmal subarachnoid haemorrhages, we have systematically controlled the level of fibrinogen degradation products (FDP) in the cerebrospinal fluid (CSF). The frequency of severe vasospasm with clinical ischaemia has been compared with the patient's initial level of FDP. Fifty patients have been included in this study. (All in Hunt and Hess's grades I or II on their arrival.) Patients with a secondary deterioration unrelated to vasospasm were excluded. The FDP levels were measured in the first three days following the bleeding and we were informed of them at the end of the study. The diagnosis of severe vasospasm was confirmed by arteriography and computed tomography (CT) and it was named "severe" when accompanied with signs of clinical ischaemia. Twenty patients developed a severe vasospasm with clinical ischaemia. In these patients, the mean value of the initial FDP level was between 80 and 320 mcg/ml compared with 20 to 80 mcg/ml for those who had not developed clinical ischaemia (p = 0.0009). Furthermore, two different groups may be discriminated by their initial FDP level: FDP greater than 80 mcg/ml; n = 23, 65% severe vasospasm; FDP less than 80 mcg/ml; n = 27.8% no severe vasospasm (p less than 0.001). These results do not imply a direct role of FDP in pathophysiological mechanisms of vasospasm, but they suggest a relationship between the clot lysis and the appearance of vasospasm with clinical ischaemia. To our knowledge this is the first time that such a predictive role can be attributed to the initial FDP level in the prognosis of vasospasm.

Female↗

Use of 123I-IMP brain SPET to predict outcome following STA-MCA bypass surgery: cerebral blood flow but not vasoreactivity is a predictive parameter.

Superficial temporal artery - middle cerebral artery (STA-MCA) bypass surgery might improve the cerebral blood flow (CBF) but fail to reduce the risk of post-surgical events such as ischaemic stroke. In this study, we studied retrospectively whether the risk of post-surgical events corresponded to the change in resting CBF and/or the change in vasoreactivity observed before and after STA-MCA surgery using N-isopropyl-I-123-p-iodoamphetamine (123I-IMP) brain single-photon emission tomography (SPET). 123I-IMP brain SPET images obtained at rest and following acetazolamide challenge both before and after STA-MCA surgery were studied in 30 patients. Resting CBF was estimated semiquantitatively using the resting count ratios of the middle cerebral artery (MCA) area to the cerebellum. Acetazolamide c hallenge was assumed to result in an average increase in flow of 40% in the cerebellum. The vasoreactive response was then estimated as the ratio of the change in counts (acetazolamide - rest) to the resting cerebellar counts multiplied by 1.4. We classified 14 patients (50.5 +/- 19.3 years) into group I, who h a change in their resting CBF from before to after surgery of >10%, and 16 patients (54.0 +/- 18.8 years) into group II, who had a change in their resting CBF from before to after surgery of ¿leq10%. Oxygen-15 positron emission tomography (PET) studies were performed in five patients from group I and five patients from group II. One post-surgical event occurred in group I while there were eight post-surgical events in group II (P<0.05). Resting CBF improved by 20.4% +/- 7.5% in group I and by 0.9% +/- 6.9% in group II patients after surgery (P<0.001). No significant difference in the improvement in vasoreactivity was observed between group I patients (32.6% +/- 17.7%) and group II patients (24.6% +/- 15.6%) following surgery. Patients in the group I PET subset showed normalization of oxygen extraction fraction (OEF) from 0.59 +/- 0.09 before surgery to 0.46 +/- 0.06 after surgery (P<0.05), while patients in the group II PET subset showed no statistical difference in OEF before surgery (0.58 +/- 0.14) and after surgery (0.54 +/- 0.05). We conclude that the outcome of STA-MCA bypass surgery can be predicted by the improvement in resting CBF but not by the improvement in vasoreactivity.

Acetazolamide↗

The preterm prediction study: failure of midtrimester cervical sialidase level elevation to predict subsequent spontaneous preterm birth.

OBJECTIVE: Our objective was to determine any associations among midtrimester cervical fluid sialidase activity, bacterial vaginosis, and subsequent spontaneous preterm birth. STUDY DESIGN: In this nested case-control study all patients (n = 126) with spontaneous preterm birth at <35 weeks' gestation and selected control subjects delivered at >/=37 weeks' gestation (n = 126, matched for race, parity, and center) were derived from women enrolled in the multicenter National Institute of Child Health and Human Development Preterm Prediction Study. Sialidase activity and presence of bacterial vaginosis according to Gram stain were determined in cervical swabs and vaginal smears, respectively, obtained at 22 weeks' to 24 weeks 6 days' gestation. RESULTS: The mean +/- SD sialidase activities were similar in case patients and control subjects (0.64 +/- 1.60 vs 0.41 +/- 0.94 nmol. mL-1. min-1, P =.21). Neither sialidase activity above the 90th percentile (10.3% vs 9.5%, P =.8) nor sialidase activity above the 95th percentile (7.9% vs 4. 8%, P =.3) of control specimens (>1.43 and >2.23 nmol. mL-1. min-1, respectively) was associated with spontaneous preterm birth. The frequency of combinations of bacterial vaginosis and elevated sialidase activity was similar (P >/=.63 with either cutoff) in case patients and control subjects. Sialidase activity was significantly higher among women with bacterial vaginosis than among those without bacterial vaginosis (1.35 +/- 1.87 vs 0.03 +/- 0.14 nmol. mL-1. min-1, P <.0001). CONCLUSIONS: Elevated cervical fluid sialidase activity at 22 to 24 weeks' gestation did not distinguish women at increased risk for spontaneous preterm birth, nor did it discriminate a subgroup of patients who had bacterial vaginosis associated with spontaneous preterm birth.

Case-Control Studies↗

Prediction of internal standards in reversed-phase liquid chromatography. III. Evaluation of an alternative solvation parameter model to correlate and predict the retention of ionizable compounds.

This paper describes the results of the evaluation of an alternative solvation parameter model for ionizable compounds. The new model is described as Log(k) = Int + rR2 + spi2(H) + asigmaalpha2(H) + bsigmabeta2(H) + mVx + U/(1 + V10 (+/-(pH-Pk))). The first six terms are the usual solvation parameter equation for neutral solutes, and the last term represents the contribution to retention from the ionization of solutes. Retention data obtained for 30 solutes in acetonitrile/aqueous buffer mobile phases are used to evaluate the capability of the function using different pH/pK scales. Because the function is not linear, nonlinear least-squares analysis is used to perform the data processing. It is concluded that the model function describes similarly the retention of ionizable compounds to the literature model without the need to accurately measure the mobile phase pH and solute's pK. Accordingly, the function simplifies the application of linear solvation energy relationships (LSERs) to ionizable compounds, and allows us to easily predict their retention for chromatographic optimization.

Chromatography, Liquid↗

Enhanced dopamine efflux in the amygdala by a predictive, but not a non-predictive, stimulus: facilitation by prior repeated D-amphetamine.

Extracellular levels of dopamine within the amygdala were monitored using in vivo microdialysis during performance of an appetitive Pavlovian conditioning task in sensitized rats and unsensitized controls. Animals received exposure either to D-amphetamine or to vehicle for seven consecutive days (2 mg/kg/day, i.p.) in the home cage. Training began following a further seven injection-free days. Animals were exposed to two session types: during conditioning sessions, a stimulus (tone or light) immediately preceded sucrose pellet delivery. During control sessions, the alternative stimulus was also presented, but not in temporal proximity to an otherwise identical schedule of pellet delivery. There was a total of three alternating presentations of each session type during training. Sensitization enhanced Pavlovian conditioned approach behaviour to the stimulus predictive of imminent pellet delivery, and was without effect upon approach behaviours either to the food pellets themselves or to the control stimulus. Extracellular levels of dopamine within the amygdala were assessed during the fourth conditioning and control sessions. Mesoamygdaloid dopamine efflux increased significantly during the conditioning test session, but not during the control session, and this dopaminergic response was more marked in rats with prior repeated D-amphetamine experience. Hence, these results add to evidence suggesting a role for amygdaloid dopamine in appetitive Pavlovian conditioning, and in the facilitation of associative learning following prior experience of D-amphetamine.

Acoustic Stimulation↗

Predictive value of dose-volume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer.

PURPOSE: To clarify whether the percentage of pulmonary volume irradiated to >20 Gy (V20) is related to the incidence and grade of radiation pneumonitis (RP) in cases of lung cancer treated with concurrent chemoradiation. METHODS AND MATERIALS: The subjects comprised 71 patients with lung cancer who were treated with conventionally fractionated definitive concurrent chemoradiation. The chemotherapy agents were carboplatin or cisplatin combined with taxane for most patients. Radiotherapy was delivered at 1.8-2.0 Gy fractions once daily to a total of 48-66 Gy (median 60). We analyzed the relation between RP grade and V20. Univariate and multivariate analyses were performed to assess patient- and treatment-related factors, including age, gender, smoking history, pulmonary function (forced expiratory volume in 1 s), tumor location (upper lobe vs. middle/lower lobe), chemotherapy regimen (platinum + taxane vs. other), total dose, overall radiation periods in addition to V20. RESULTS: With a median follow-up of 7.5 months, an RP grade of 0, 1, 2, 3, and 5 was observed in 16, 35, 17, 1, and 2 patients, respectively; the corresponding mean V20 values were 20.1%, 22.0%, 26.3%, 27.0%, and 34.5%. The 6-month cumulative incidence of RP greater than Grade 2 was 8.7%, 18.3%, 51%, and 85% in patients with a V20 of or=31%, respectively (p <0.0001). According to both univariate and multivariate analyses, V20 was the only factor associated with RP of Grade 2 or greater. CONCLUSION: The incidence and grade of RP are significantly related to the V20 value. Thus, V20 appears to be a factor that can be used to predict RP after concurrent chemoradiation for lung cancer.

Adult↗

Are silent coronary stenoses predictable in diabetic patients and predictive of cardiovascular events?

OBJECTIVES: We have previously shown that silent coronary stenoses (CS) were predictors of subsequent major cardiac events in diabetic patients with silent myocardial ischemia (SMI). The aim of this study was to determine their correlates and their prognostic value for other cardiovascular events. METHODS: 362 asymptomatic diabetic patients, without prior myocardial infarction, with > or =1 additional risk factor and a normal resting electrocardiogram underwent a myocardial scintigraphy to detect SMI. The patients with SMI subsequently underwent a coronary angiography to detect CS. A total of 345 (95.3%) patients were followed up for 41 +/- 24 months with regard to the occurrence of stroke, gangrene or a peripheral revascularization procedure, exercise occurrence of angina, and nonfatal arrhythmia. RESULTS: 121 patients had SMI and 44 had CS. The univariate correlates of CS were age > 65 years (Odds Ratio 2.1 [CI 95%: 1.1-4.0]; p=0.021), male gender (OR 3.1 [1.5-6.3]; p=0.001), smoking (OR 2.8 [1.4-5.6]; p=0.004), > or =2 risk factors (OR 2.1 [1.09-4.09]; p=0.024) and peripheral arterial disease (OR 3.2 [1.2-8.7]; p=0.018). Logistic regression showed that age > 65 years (p=0.034), male gender (p=0.001) and > or =2 risk factors (p=0.013) were independently associated with the presence of CS. The univariate predictors of the 16 minor events were peripheral arterial disease (OR 8.8 [2.7-28.5]; p<0.001), CS (OR 4.9 [1.7-14.2]; p=0.002), SMI (OR 3.7, [1.3-10.5]; p=0.009) and smoking (OR 3.2 [1.1-9.2]; p=0.024). In the multivariate analysis, arterial occlusive disease (p<0.001), smoking (p<0.036) and CS (p=0.044) were independent predictors of events. CONCLUSION: Silent CS predict major cardiac events but also other cardiovascular events and are more common in diabetic patients > 65 years-old, of male gender and with > or =2 risk factors.

Aged↗

Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption.

A method for the rapid computation of polar molecular surface area (PSA) is described. It is shown that consideration of only a single conformer when computing PSA gives an excellent correlation with intestinal absorption data-as good as previously reported methods employing multiple conformers. Circumventing a time-consuming conformational analysis opens the possibility of computationally screening large numbers of compounds for problems relating to absorption prior to synthesis. The robustness of the criterion for identifying poorly absorbed compounds (PSA >/= 140 A(2)) is illustrated through its application to a diverse test set of 74 drugs. The PSA-based method is also compared to an experimental method for absorption prediction recently described in the literature.

Chemical Phenomena↗

The Preterm Prediction Study: prediction of preterm premature rupture of membranes through clinical findings and ancillary testing. The National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.

OBJECTIVE: Our objective was to determine the relative importance of demographic characteristics, clinical risk factors, and ancillary screening tests in the prediction of preterm birth as a result of premature rupture of membranes. STUDY DESIGN: A total of 2929 women were evaluated in 10 centers at 23 to 24 weeks' gestation. Demographic and clinical characteristics were ascertained. Cervicovaginal fetal fibronectin and bacterial vaginosis were evaluated. Cervical length was measured by vaginal ultrasonography. Patients were evaluated for spontaneous preterm birth caused by preterm premature rupture of membranes at <37 and <35 weeks' gestation. Multivariate analyses were performed separately for nulliparous women and multiparous women. RESULTS: Premature rupture of membranes at <37 weeks' gestation complicated 4.5% of pregnancies, accounting for 32.6% of preterm births. Univariate analysis revealed low body mass index, pulmonary disease, contractions within 2 weeks, short cervix (</=25 mm), positive results of fetal fibronectin screening, bacterial vaginosis, and a previous preterm birth caused by premature rupture of membranes (in multiparous women) to be significantly associated with preterm birth caused by premature rupture of membranes in the current gestation. Short cervix, previous preterm birth caused by premature rupture of membranes in multiparous women, and presence of fetal fibronectin were the strongest predictors for both preterm birth caused by premature rupture of membranes at <37 and <35 weeks' gestation. Women with positive fetal fibronectin screening results and a short cervix had greater risks both of preterm birth caused by premature rupture of membranes at <37 weeks' gestation (relative risk, 4.9) and of preterm birth caused by premature rupture of membranes at <35 weeks' gestation (relative risk, 13.5) than did those without these risk factors. Multiparous women with all three risk factors had a 31. 3-fold increased risk of preterm birth caused by premature rupture of membranes at <35 weeks' gestation. CONCLUSION: The combination of short cervical length, previous preterm birth caused by preterm premature rupture of membranes, and positive fetal fibronectin screening results was highly associated with preterm delivery caused by preterm premature rupture of membranes in the current gestation.

Cervix Uteri↗

The role of the airline transportation network in the prediction and predictability of global epidemics.

The systematic study of large-scale networks has unveiled the ubiquitous presence of connectivity patterns characterized by large-scale heterogeneities and unbounded statistical fluctuations. These features affect dramatically the behavior of the diffusion processes occurring on networks, determining the ensuing statistical properties of their evolution pattern and dynamics. In this article, we present a stochastic computational framework for the forecast of global epidemics that considers the complete worldwide air travel infrastructure complemented with census population data. We address two basic issues in global epidemic modeling: (i) we study the role of the large scale properties of the airline transportation network in determining the global diffusion pattern of emerging diseases; and (ii) we evaluate the reliability of forecasts and outbreak scenarios with respect to the intrinsic stochasticity of disease transmission and traffic flows. To address these issues we define a set of quantitative measures able to characterize the level of heterogeneity and predictability of the epidemic pattern. These measures may be used for the analysis of containment policies and epidemic risk assessment.

Aviation↗

Fatness at birth predicts adult susceptibility to ovarian suppression: an empirical test of the Predictive Adaptive Response hypothesis.

Poor fetal environments are thought to produce adaptive changes in human developmental trajectories according to the Predictive Adaptive Response hypothesis. Although many studies have demonstrated correlations between indicators of fetal environment and negative adult health outcomes, the adaptive significance of these outcomes is unclear. Our study explicitly tests the adaptive nature of fetal programming in humans. We show that differences in nutritional status at birth are associated with adaptive differences in the sensitivity of adult ovarian function to energetic stress. Women who were born as relatively fat babies do not exhibit ovarian suppression in response to moderate levels of physical activity at adulthood, in contrast to women who were born as skinnier babies. The levels of estradiol in women born in the highest tertile of ponderal index (an indicator of neonatal nutritional status) were 37% and 46% higher, respectively, than levels of estradiol in women born in the low and middle ponderal index tertiles. These findings suggest that fetal programming of reproductive function results in developmentally plastic, but essentially adaptive, shifts in set points of ovarian response to energetic stress, such that women who were gestated under conditions of energetic constraint show greater sensitivity to energetic stress in adulthood. Our results have practical implications in terms of behavioral strategies for reducing the risk of breast cancer. We suggest that the amount of activity necessary to reduce levels of estrogen, which may in turn reduce cancer risk, can depend on a woman's nutritional status at birth.

Adaptation, Physiological↗

Inhibition of oxidative cross-linking between engineered cysteine residues at positions 332 in predicted transmembrane segments (TM) 6 and 975 in predicted TM12 of human P-glycoprotein by drug substrates.

Each homologous half of P-glycoprotein consists of a transmembrane domain with six potential transmembrane segments and an ATP-binding domain. Labeling studies with photoactive drug analogs show that labeling occurs within or close to predicted transmembrane segments (TM) 6 (residues 331-351) and TM12 (residues 974-994). To test if these segments are in near-proximity we generated 42 different P-glycoprotein mutants in which we re-introduced a pair of cysteine residues into a Cys-less P-glycoprotein, one within TM6 (residues 332-338) and one within TM12 (residues 975-980) and assayed for cross-linking between the cysteines. All the mutants retained verapamil-stimulated ATPase activity. We found that only the mutant containing Cys-332 and Cys-975 was cross-linked in the presence of oxidant as judged by its decreased mobility on SDS gels. Similar results were obtained when the same mutations were introduced into Cys-less NH2-terminal and COOH-terminal half-molecules of P-glycoprotein followed by coexpression and treatment with oxidant. Cross-linking between Cys-332 and Cys-975, however, was inhibited by verapamil or vinblastine but not by colchicine. These results suggest that residues Cys-332 and Cys-975, which occupy equivalent positions when TM6 and TM12 are aligned, are close to each other in the tertiary structure of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Total body iron in HIV-positive and HIV-negative Zimbabwean newborns strongly predicts anemia throughout infancy and is predicted by maternal hemoglobin concentration.

One method of preventing postnatal iron deficiency is to ensure that the infant is born with a full endowment of iron. We calculated total body iron at birth (TBI) as the sum of hemoglobin iron (HbI) and body storage iron (BSI) in 2021 Zimbabwean newborns, and related TBI to subsequent anemia from 3 to 12 mo of age and to maternal and fetal characteristics. We estimated the mean +/- SD TBI to be 210 +/- 41 mg. There was an inverse dose-response association between TBI quartile and risk of anemia at all postnatal ages. The odds of anemia were >3 times higher in the lowest vs. highest TBI quartile (P < 0.001) at 6, 9 and 12 mo. Preterm birth and parity were not independently associated with TBI after controlling for birthweight. The predicted change in TBI per kilogram increase in birthweight was 68 mg (P < 0.001). After adjusting for birthweight, TBI increased by 25 mg with each 10-y decrement in maternal age (P = 0.033). Maternal hemoglobin was a strong linear predictor of TBI (P < 0.001). Maternal and infant HIV infection, especially among girls, was associated with apparently greater estimated TBI. We speculate that this is actually an artifact, explained by an inflammatory response, and that there was a sex difference in the response. We conclude that we can make satisfactory estimates of TBI and that the assumptions required for this approach are sufficiently robust to lead to an acceptable estimate of the prenatally acquired iron endowment. Babies born with low birthweight or to mothers with low hemoglobin are born with less TBI, which confers a substantially greater risk of anemia from 3 to 12 mo of age.

Anemia↗

A proposed international scoring system for predicting fetal status derived from fetal heart rate patterns: compatible with current tests. (The fetal heart rate response as an aid in predicting perinatal status).

Fetal response is measured from the reaction shown in the FHR pattern. This response can be predictive of fetal health. Testing the response can be started usefully after 30 weeks of amenorrhea. Repeat testing every 3 weeks may be helpful. In high risk cases and those with medical complications testing once or twice a week may be required. There is a need for adoption of an international scoring system of the fetal response, based on percentages. Such a system is presented consisting of 10 parameters.

Animals↗

A simple method for the prediction of ABO incompatibility using Sephadex A-50. Prediction of ABO incompatibility.

A rapid and simple method of demonstrating the presence of high titre IgG anti-A or anti-B (anti A/B) is described. The method requires the separation of IgG anti-A/B from IgM anti-A/B using DEAE Sephadex A-50 by a simple spin technique, and the subsequent titration of the IgG fraction to detect the presence of high titre IgG anti-A/B. Since high titre IgG anti-A/B is usually associated with ABO incompatibility the test is a useful guide to the prediction of ABO incompatibility in routine antenatal samples.

ABO Blood-Group System↗