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PubMed1998

BMS-181885, a 5-HT1B/1D receptor ligand, in experimental models predictive of antimigraine activity and coronary side-effect potential.

Many acutely acting antimigraine drugs have the ability to constrict porcine arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have investigated the effects of BMS-181885 (3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5-(1,2-dioxo-4-me thyl-3-cyclobuten-3-yl)amino-1H-indole), a 5-HT1B/1D receptor ligand. In anaesthetised pigs, BMS-181885 (10, 30, 100 and 300 microg kg(-1)) decreased the total carotid blood flow and conduction, exclusively at the expense of the arteriovenous anastomotic fraction as the capillary fraction did in fact increase. The highest dose (300 microg kg(-1)) produced a reduction of 52+/-6% from the baseline arteriovenous anastomotic flow. When carotid haemodynamic changes after a single 100 microg kg(-1)dose of BMS-181885 or sumatriptan were studied at different time-points, BMS-188185 had a longer duration of action. Both BMS-181885 (pD2:7.9+/-0.1; Emax:9+/-3% of the contraction to 100 mM K+) and sumatriptan (pD2:6.3+/-0.1; Emax:28+/-8% of the contraction to 100 mM K+) contracted the human isolated coronary artery. The above results suggest that (i) the longer-lasting vasoconstrictor action of BMS-181885 on porcine carotid arteriovenous anastomoses may be related to its reported slow dissociation from 5-HT1B/1D receptor, and (ii) BMS-181885 should be able to abort migraine headaches in patients. It will be interesting to find out whether these properties are clinically important so that the drug exhibits less headache recurrence and coronary side-effects than sumatriptan.

Animals↗
PubMed1990

To assess the efficacy of prophylaxis in digestive tract surgery using a predictive model of complication risk.

One hundred and ninety-one patients, all candidates for major clean-contaminated surgery, were classified according to the risk of developing postoperative wound infection, using clinical and nutritional factors. A widely validated nutritional assessment model, the Prognostic Nutritional Index (PNI), was used preoperatively to evaluate the risk and probability of post-operative septic complications. Based on the predicted outcome, patients were assigned to either a poor or a good risk group for statistical comparison. A prospective, double-blind, randomized trial was performed to compare the effectiveness of the monocyclic beta-lactam, aztreonam, with gentamicin for short-term perioperative prophylaxis. In the poor risk group (PNI greater than 40), aztreonam prophylaxis significantly reduced postoperative septic complications (p less than 0.05). The use of an objective scoring system to assess the risk of postoperative sepsis is recommended for future studies on antibiotic prophylaxis as it offers a realistic assessment basis.

Aztreonam↗
PubMed2024

Predictive modeling of gene mutations for the survival outcomes of epithelial ovarian cancer patients.

Epithelial ovarian cancer (EOC) has a low overall survival rate, largely due to frequent recurrence and acquiring resistance to platinum-based chemotherapy. EOC with homologous recombination (HR) deficiency has increased sensitivity to platinum-based chemotherapy because platinum-induced DNA damage cannot be repaired. Mutations in genes involved in the HR pathway are thought to be strongly correlated with favorable response to treatment. Patients with these mutations have better prognosis and an improved survival rate. On the other hand, mutations in non-HR genes in EOC are associated with increased chemoresistance and poorer prognosis. For this reason, accurate predictions in response to treatment and overall survival remain challenging. Thus, analyses of 360 EOC cases on NCI's The Cancer Genome Atlas (TCGA) program were conducted to identify novel gene mutation signatures that were strongly correlated with overall survival. We found that a considerable portion of EOC cases exhibited multiple and overlapping mutations in a panel of 31 genes. Using logistical regression modeling on mutational profiles and patient survival data from TCGA, we determined whether specific sets of deleterious gene mutations in EOC patients had impacts on patient survival. Our results showed that six genes that were strongly correlated with an increased survival time are BRCA1, NBN, BRIP1, RAD50, PTEN, and PMS2. In addition, our analysis shows that six genes that were strongly correlated with a decreased survival time are FANCE, FOXM1, KRAS, FANCD2, TTN, and CSMD3. Furthermore, Kaplan-Meier survival analysis of 360 patients stratified by these positive and negative gene mutation signatures corroborated that our regression model outperformed the conventional HR genes-based classification and prediction of survival outcomes. Collectively, our findings suggest that EOC exhibits unique mutation signatures beyond HR gene mutations. Our approach can identify a novel panel of gene mutations that helps improve the prediction of treatment outcomes and overall survival for EOC patients.

Humans↗
PubMed2006

A simple physical model predicts small exon length variations.

One of the most common splice variations are small exon length variations caused by the use of alternative donor or acceptor splice sites that are in very close proximity on the pre-mRNA. Among these, three-nucleotide variations at so-called NAGNAG tandem acceptor sites have recently attracted considerable attention, and it has been suggested that these variations are regulated and serve to fine-tune protein forms by the addition or removal of a single amino acid. In this paper we first show that in-frame exon length variations are generally overrepresented and that this overrepresentation can be quantitatively explained by the effect of nonsense-mediated decay. Our analysis allows us to estimate that about 50% of frame-shifted coding transcripts are targeted by nonsense-mediated decay. Second, we show that a simple physical model that assumes that the splicing machinery stochastically binds to nearby splice sites in proportion to the affinities of the sites correctly predicts the relative abundances of different small length variations at both boundaries. Finally, using the same simple physical model, we show that for NAGNAG sites, the difference in affinities of the neighboring sites for the splicing machinery accurately predicts whether splicing will occur only at the first site, splicing will occur only at the second site, or three-nucleotide splice variants are likely to occur. Our analysis thus suggests that small exon length variations are the result of stochastic binding of the spliceosome at neighboring splice sites. Small exon length variations occur when there are nearby alternative splice sites that have similar affinity for the splicing machinery.

Animals↗
PubMed1996

Prognosis in lung cancer: physicians' opinions compared with outcome and a predictive model.

BACKGROUND: Although the study of prognostic factors in small cell lung cancer has reached the stage where they are used to guide treatment, fewer data are available for non-small cell lung cancer. Although correct management decisions in non-small cell lung cancer depend upon a prognostic assessment by the supervising doctor, there has never been any measurement of the accuracy of physicians' assessments. METHODS: A group of consecutive patients with non-small cell lung cancer was studied and the predictions of their physicians as to how long they would survive (in months) was compared with their actual survival. A prognostic index was also developed using features recorded at the patients' initial presentation. RESULTS: Two hundred and seven consecutive patients diagnosed and managed as non-small cell lung cancer, who did not receive curative treatment for their condition, were studied. Of the 196 patients whose date of death was known, physicians correctly predicted, to within one month, the survival of only 19 patients (10%). However, almost 59% of patients (115/196) had their survival predicted to within three months and 71% (139/196) to within four months of their actual survival. Using Cox's regression model, the sex of the patient, the activity score, the presence of malaise, hoarseness and distant metastases at presentation, and lymphocyte count, serum albumin, sodium and alkaline phosphatase levels were all identified as useful prognostic factors. Three groups of patients, distinct in terms of their survival, were identified by the use of these items. When the prediction of survival made by the physician was included as a prognostic factor in the original model, it was shown to differentiate further between the group with a poor prognosis and the other two groups in terms of survival. CONCLUSIONS: Physicians were highly specific in identifying patients who would live less than three months. However, they had a tendency to overestimate survival in these patients, failing to identify almost half the patients who actually died within this time. Both the physicians and the prognostic factor model gave similar performances in that they were more successful in identifying patients who had a short time to survive than those who had a moderate or good prognosis. Physicians appear to use information not identified in the prognostic factor analysis to reach their conclusions.

Adult↗
PubMed1994

Effects of strychnine on fictive swimming in the lamprey: evidence for glycinergic inhibition, discrepancies with model predictions, and novel modulatory rhythms.

1. Inhibitory postsynaptic potentials (ipsps) produced by two classes of interneurons, CC (Contralateral and caudal projecting) and lateral interneurons, were tested for strychnine sensitivity using paired intracellular recordings in the lamprey spinal cord. The ipsps were partially blocked by 0.2-0.5 microM strychnine and were completely blocked by 5 microM strychnine. Thus, the ipsps may be glycinergic. 2. These interneurons are key participants in a proposed circuit model for fictive swimming. A connectionist-type computer simulation of the model demonstrated that the cycle period of the network increased with decreasing ipsp strength. 3. Application of strychnine (0.1-0.5 microM) to the spinal cord during fictive swimming induced by an excitatory amino acid increased cycle period, consistent with previous reports, but at odds with stimulation predictions. 4. Strychnine also produced slow rhythmic modulation of fictive swimming (period = 12 s) which maintained left-right alternation and rostral-caudal coordination. Auto- and cross-correlation analyses revealed that the slow modulation was present in a weaker form in most control preparations during fictive swimming. 5. Since the proposed model for the swimming pattern generator in the lamprey spinal cord does not predict the observed speeding with strychnine, nor the slow modulatory rhythm, it appears to be deficient in its present formulation.

Animals↗
PubMedDate not supplied

Comparison of R-R interval prediction models.

Changes in the sequence or pattern of R-R intervals is an integral part of electrocardiogram detection of most clinically important arrhythmias. Moreover, there is inherent interest in these patterns and their method of study as basic physiological phenomena. Prediction of R-R interval changes based on past history and detection of departure from an established pattern have been utilized in automated monitoring strategies and algorithms. The studies described her further clarify the usefulness of Markov processes for this purpose, compare the accuracy of linear and nonlinear regression models, and indicate some advantages of both.

Arrhythmias, Cardiac↗
PubMed2004

A predictive model for survival after in-hospital cardiopulmonary arrest.

BACKGROUND: In-hospital cardiopulmonary resuscitation (CPR) has seen a steady increase in the application of technology and techniques since the introduction of closed cardiac massage in 1960. Despite this progress, there has not been a demonstrated improvement in survival rates after in-hospital cardiac arrest over the last 40 years. Identification of prognostic factors associated with survival after a resuscitation attempt can help physician decisions and patients' end-of-life choices in a pre-arrest situation. METHODS: Using an Utstein-based template we analyzed 219 consecutive adult attempted resuscitations in a large urban teaching hospital over a 3-year period. The main outcome measures were survival to discharge, 1 and 3 months. Backwards stepwise logistic regression was used to select baseline variables that predict survival at discharge, 1 and 3 months. RESULTS: Survival rates at discharge, 1 and 3 months were 15.1, 13.3, and 11.5%. Meaningful neurological status (cerebral performance score of 1) at discharge was achieved in 61% of survivors. Independent predictors of survival were: higher body-mass index (BMI), presence of chronic renal insufficiency (CRI), respiratory arrest, ventricular tachycardia/fibrillation (VT/VF) as initial rhythm and arrest early during the hospital stay. A risk model based on these variables demonstrated a significant fit between predicted and observed survival at discharge with goodness of fit test P-value of 0.87. CONCLUSIONS: Survival after in-hospital cardiopulmonary arrest is poor and can be estimated by using clinical variables. If validated in a large prospective trial, this score could help physicians in attempting resuscitation, patients and families in making end-of-life decisions and hospitals in resource allocation.

Aged↗
PubMed2002

Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model.

Liver biopsy is required for staging hepatic fibrosis in patients with chronic hepatitis C, but it is an expensive procedure with occasional complications and poor patient acceptance. This cohort study was designed to assess the accuracy of a noninvasive method aimed to discriminate between patients with and without significant liver fibrosis (stages 2-4 versus 0-1). Clinically relevant variables were analyzed in a cohort of 476 consecutive untreated patients (estimation group, 351 patients; validation group, 125 patients) with chronic hepatitis C who underwent a liver biopsy. Multivariate analysis identified age, gamma glutamyl transpeptidase (GGT), cholesterol, platelet count, and prothrombin time as independent predictors of fibrosis. We constructed a model and a score system combining age, GGT, cholesterol, and platelet count that proved useful to identify patients without significant hepatic fibrosis. The area under the ROC curve was 0.86 for the estimation group and 0.81 for the validation group. Using the best cutoff score (less than 4.2), presence of significant fibrosis (F2 to F4) could be excluded with high accuracy (negative predictive value of 96%) in 125 (36%) of 351 patients. Similarly, it could be excluded with the same certainty in 49 (39%) of the 125 patients of the validation group. Only 2 patients with liver fibrosis stage 2 were incorrectly classified. In conclusion, a combination of easily accessible variables accurately predicts the absence of significant fibrosis and might render liver biopsy unnecessary in more than one third of patients with chronic hepatitis C.

Adult↗
PubMedDate not supplied

Neural correlates of learning in the prefrontal cortex of the monkey: a predictive model.

The principles underlying the organization and operation of the prefrontal cortex have been addressed by neural network modeling. The involvement of the prefrontal cortex in the temporal organization of behavior can be defined by processing units that switch between two stable states of activity (bistable behavior) in response to synaptic inputs. Long-term representation of programs requiring short-term memory can result from activity-dependent modifications of the synaptic transmission controlling the bistable behavior. After learning, the sustained activity of a given neuron represents the selective memorization of a past event, the selective anticipation of a future event, and the predictability of reinforcement. A simulated neural network illustrates the abilities of the model (1) to learn, via a natural step-by-step training protocol, the paradigmatic task (delayed response) used for testing prefrontal neurons in primates, (2) to display the same categories of neuronal activities, and (3) to predict how they change during learning. In agreement with experimental data, two main types of activity contribute to the adaptive properties of the network. The first is transient activity time-locked to events of the task and its profile remains constant during successive training stages. The second is sustained activity that undergoes nonmonotonic changes with changes in reward contingency that occur during the transition between stages.

Animals↗
PubMed1987

Haemopoietic spleen colony growth: a versatile, parsimonious, predictive model.

Substantial support has been obtained for the stochastic model for stem cell differentiation first proposed by Till, McCulloch & Siminovitch (1964), over 20 years ago. By adding a cell maturation pathway, it is possible to predict (by computer simulation) the total number of cells and consequently the time at which individual colonies appear and disappear. Only a few uncontroversial assumptions are required to predict that cells, uniform with respect to self-renewal, are capable of producing the high proportions of late disappearing and late appearing colonies observed experimentally in the spleens of irradiated mice that have been injected with normal haemopoietic cells. It is shown that differences in stem cell self-renewal only slightly influence the time of appearance of colonies; whereas changes in the kinetics of the maturing cells, by changing the size of colonies, has a marked effect on the time of appearance and disappearance of colonies and on the average doubling-time of colony-forming cells per colony (but not the doubling-time of individual colonies). These results (1) seriously question the prevailing view that spleen colonies scored at 8 days measure a separate population (without the capacity for self-renewal), from those scored at 12 days; (2) argue against the existence of multiple sub-populations of stem cells with differing self-renewal and toxicity to cytotoxic agents; (3) help to identify those experiments for which it is obligatory to postulate heterogeneity, and (4) are consistent with self-renewal being regulated by a feedback control of stem cell differentiation, to which only proliferating stem cells can respond and where the stimulus for differentiation decreases at a time when the bone marrow is known to be depleted.

Animals↗
PubMed2005

Oscillations in plant membrane transport: model predictions, experimental validation, and physiological implications.

Although oscillations in membrane-transport activity are ubiquitous in plants, the ionic mechanisms of ultradian oscillations in plant cells remain largely unknown, despite much phenomenological data. The physiological role of such oscillations is also the subject of much speculation. Over the last decade, much experimental evidence showing oscillations in net ion fluxes across the plasma membrane of plant cells has been accumulated using the non-invasive MIFE technique. In this study, a recently proposed feedback-controlled oscillatory model was used. The model adequately describes the observed ion flux oscillations within the minute range of periods and predicts: (i) strong dependence of the period of oscillations on the rate constants for the H+ pump; (ii) a substantial phase shift between oscillations in net H+ and K+ fluxes; (iii) cessation of oscillations when H+ pump activity is suppressed; (iv) the existence of some 'window' of external temperatures and ionic concentrations, where non-damped oscillations are observed: outside this range, even small changes in external parameters lead to progressive damping and aperiodic behaviour; (v) frequency encoding of environmental information by oscillatory patterns; and (vi) strong dependence of oscillatory characteristics on cell size. All these predictions were successfully confirmed by direct experimental observations, when net ion fluxes were measured from root and leaf tissues of various plant species, or from single cells. Because oscillatory behaviour is inherent in feedback control systems having phase shifts, it is argued from this model that suitable conditions will allow oscillations in any cell or tissue. The possible physiological role of such oscillations is discussed in the context of plant adaptive responses to salinity, temperature, osmotic, hypoxia, and pH stresses.

Adaptation, Physiological↗
PubMed2001

The pharmacodynamics of gatifloxacin and ciprofloxacin for pneumococci in an in vitro dynamic model: prediction of equiefficient doses.

Enhanced activity against Streptococcus pneumoniae is one of the putative advantages of gatifloxacin over older fluoroquinolones such as ciprofloxacin. This study examined ciprofloxacin and gatifloxacin pharmacodynamics against two differentially susceptible clinical isolates of S. pneumoniae (gatifloxacin MIC, 0.125 and 2 mg/L; ciprofloxacin MIC, 1 and 32 mg/L). The pharmacokinetics of gatifloxacin (single dose) and ciprofloxacin (two 12 hourly doses) with half-lives of 6 and 5 h, respectively, were simulated using a two-compartment dynamic model. The AUC/MIC ratios in the peripheral compartments that contain bacterial cultures varied over a four- to five-fold range, from 11 to 48 h with ciprofloxacin and from 15 to 78 h with gatifloxacin. The intensity of the antimicrobial effect (IE) increased with increasing AUC/MIC ratios in a strain-independent fashion, although different relationships of IE to log AUC/MIC were inherent for each drug (r2 0.73 for gatifloxacin and r2 0.94 for ciprofloxacin). Subsequently, the respective dose-response relationships of gatifloxacin and ciprofloxacin for a hypothetical strain of S. pneumoniae with MIC equal to the MIC50 were modelled. Based on these relationships, the equiefficient doses of gatifloxacin and ciprofloxacin were predicted for MIC50S of 0.4 and 1 mg/L, respectively. Gatifloxacin 400 mg was predicted to be equiefficient to ciprofloxacin 1400 mg. To provide the same anti-pneumococcal effect as the usual 1000 mg daily dose of ciprofloxacin, the respective daily dose of gatifloxacin could be as low as 180 mg. This in vitro study demonstrates advantages of gatifloxacin relative to ciprofloxacin in terms of the dose-dependent total antimicrobial effect.

Anti-Infective Agents↗
PubMedDate not supplied

Predictive modelling of fluorescent AFLP: a new approach to the molecular epidemiology of E. coli.

Amplified fragment length polymorphism (AFLP) permits simultaneous sampling of multiple loci distributed throughout a genome, using restriction site/adaptor-specific primers under stringent conditions. Fluorescent detection instrumentation further refines this methodology, permitting internal size standards and accurate, reproducible sizing of amplified fragments. We have evaluated the potential of fluorescent AFLP (FAFLP) as a potentially definitive genotyping method for bacteria, by comparing MseI/EcoRI fragments derived experimentally from the Escherichia coli K12 MG1655 genome with those predicted by analysis of its published sequence. In silico, MseI/EcoRI digestion of this sequence produced 1200 fragments from 36 and 2151 base pairs (bp) in size. Fragment subsets which would be amplified by seven different selective (1-2 bases added to the 3' end of the core primer sequence) primer combinations were modelled. Depending on the primer pair, three to 54 fragments (range 70-400 bp) were predicted, while all seven primer pair combinations together generated 121 predicted fragments. When genomic DNA of strain MG1655 was subjected to experimental FAFLP with these seven primers, 111 correctly sized fragments were observed (+/- 1 bp) out of the 121 predicted (92% accuracy). Twenty-five unpredicted fragments were obtained; an average of four per primer pair. The size and number of fragments in FAFLP, and their gel distribution, were dictated by the choice of restriction endonucleases and the degree of primer selectivity. Our data show that FAFLP is accurate, discriminatory, reproducible and capable of standardisation. Under agreed conditions, this method shows considerable promise as a generally applicable standardised bacterial genotyping method. The fragments predicted in silico to result from amplification of MseI/EcoRI-digested DNA with the seven primer pairs described are here used to define a prototypic FAFLP analysis of E. coli.

Escherichia coli↗
PubMed2002

Pharmacokinetic modeling to predict morphine and morphine-6-glucuronide plasma concentrations in healthy young volunteers.

OBJECTIVE: This investigation focused on the development of a predictive model of morphine, including morphine-6-glucuronide (M6G) for healthy young volunteers after morphine administration. METHODS: Population compartmental pharmacokinetic modeling with NONMEM was applied to the plasma concentration-time data of morphine and M6G obtained from 8 healthy volunteers (4 men and 4 women; age range, 23 to 30 years) after intravenous bolus injection of 5.64 mg morphine base (7.5 mg morphine sulfate) and of 1 mg deuterium-labeled M6G. RESULTS: Two models were identified that described the plasma concentration versus time courses of morphine and M6G after administration of morphine. The model consisted of a standard 3-compartment model for morphine and a standard 2-compartment model for M6G, with input into and output from the central compartments. The formation of M6G from morphine was modeled as a fraction of morphine clearance of about 14%, which accounted for the formation of M6G, and a delay of the appearance of M6G in plasma modeled as a first-order process, with a mean metabolic transit time of 17.2 minutes. An alternative model assigned the formation of M6G among the first peripheral compartment of morphine and the central compartment of M6G. Therefore the alternative 3-compartment model of morphine had the input into the central compartment and renal excretory elimination from the central compartment, but the metabolic clearance of morphine started from the first peripheral compartment. M6G was again modeled with a standard 2-compartment model. Both models predicted morphine and M6G plasma concentrations available from an independent study with acceptable accuracy and without bias. CONCLUSIONS: Two models are provided that can predict plasma concentrations of morphine and M6G with acceptable accuracy in healthy young volunteers.

Adult↗