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PubMed2006

Variation in probability of first reproduction of Weddell seals.

1. For many species, when to begin reproduction is an important life-history decision that varies by individual and can have substantial implications for lifetime reproductive success and fitness. 2. We estimated age-specific probabilities of first-time breeding and modelled variation in these rates to determine age at first reproduction and understand why it varies in a population of Weddell seals in Erebus Bay, Antarctica. We used multistate mark-recapture modelling methods and encounter histories of 4965 known-age female seals to test predictions about age-related variation in probability of first reproduction and the effects of annual variation, cohort and population density. 3. Mean age at first reproduction in this southerly located study population (7.62 years of age, SD=1.71) was greater than age at first reproduction for a Weddell seal population at a more northerly and typical latitude for breeding Weddell seals (mean=4-5 years of age). This difference suggests that age at first reproduction may be influenced by whether a population inhabits the core or periphery of its range. 4. Age at first reproduction varied from 4 to 14 years, but there was no age by which all seals recruited to the breeding population, suggesting that individual heterogeneity exists among females in this population. 5. In the best model, the probability of breeding for the first time varied by age and year, and the amount of annual variation varied with age (average variance ratio for age-specific rates=4.3%). 6. Our results affirmed the predictions of life-history theory that age at first reproduction in long-lived mammals will be sensitive to environmental variation. In terms of life-history evolution, this variability suggests that Weddell seals display flexibility in age at first reproduction in order to maximize reproductive output under varying environmental conditions. Future analyses will attempt to test predictions regarding relationships between environmental covariates and annual variation in age at first reproduction and evaluate the relationship between age at first reproduction and lifetime reproductive success.

Age Factors↗
PubMed1995

Testing models predicting severity of respiratory syncytial virus infection on the PICNIC RSV database. Pediatric Investigators Collaborative Network on Infections in Canada.

OBJECTIVES: To determine the sensitivity and specificity of published prognostic models to predict morbidity resulting from lower respiratory tract disease caused by respiratory syncytial virus in an independent pediatric population and to assess the accuracy of single risk factors in predicting adverse outcome. DESIGN: All articles obtained from a MEDLINE search that used the terms prognosis or sequelae and respiratory syncytial virus, and from the references of these articles, were reviewed. Studies were included if risk factors and outcomes were defined and if information was available in a database of prospectively enrolled patients with respiratory syncytial virus infections. A probability of adverse outcome was assigned to each patient in the cohort using prognostic models described in the articles. A test was considered positive if the probability of the adverse outcome was 5% or more. PATIENTS: Six hundred eighty-nine patients hospitalized with respiratory syncytial virus in seven tertiary care centers across Canada were prospectively enrolled in the Pediatric Investigators Collaborative Network on Infections in Canada database. MAIN OUTCOME MEASURES: The sensitivity and specificity of single predictors and of models in predicting severe disease were determined. RESULTS: The sensitivity of single predictors varied from 17% to 46%. A model that used age and oxygen saturation at admission in previously well infants had a sensitivity of 98% and a specificity of 47% when predicting intensive care unit admission. Another model that included age at hospitalization, gestational age, presence of an underlying condition, and respiratory syncytial virus subtype used to predict the outcome of a high severity index had a sensitivity of 77% and a specificity of 76%. When the above model was modified by exclusion of viral subgroup, sensitivity increased to 94%, but specificity decreased to 46%. CONCLUSION: Previously described prognostic models were generalizable to an independent study population.

Canada↗
PubMed1987

Use of a five-day test to predict the long-term effects of gastric antisecretory agents on serum gastrin in rats.

It has been hypothesized that prolonged achlorhydria causes compensatory elevation of serum gastrin, and that there is an association in rats between sustained hypergastrinemia, hyperplasia of gastric enterochromaffin-like cells, and subsequent formation of gastric carcinoids in 2-year carcinogenicity studies. The present study examined whether daily administration of gastric antisecretory drugs in rats for 4 days could cause hypergastrinemia associated with inhibition of acid output. Rats were dosed orally for 4 days with the histamine H2-receptor antagonist ranitidine or the H+,K+-sensitive ATPase inhibitor omeprazole, and examined on day 5 for effects on gastric acid secretion and serum gastrin. Omeprazole (138 mg/kg/day significantly inhibited gastric acid secretion and increased serum gastrin levels. Large, single daily doses of ranitidine (1000-2000 mg/kg/day) had no effect on 24-hr acid or gastrin secretion; however, ranitidine did inhibit next-day acid secretion with associated increases in serum gastrin when administered in three divided doses. These results with ranitidine support the hypothesis that a sustained gastric antisecretory action will cause a compensatory hypergastrinemia, regardless of the antisecretory agent used. The ability to detect increased serum gastrin levels associated with inhibition of acid secretion, after administration of antisecretory agents for only 4 days, suggest that this short 5-day test may be useful for determining the potential of antisecretory agents to cause hypergastrinemia due to 24-hr inhibition of acid secretion and may be predictive of long-term hyperplastic changes.

Animals↗
PubMed1977

A simple test for predicting pregnancy-induced hypertension.

One hundred thirty-one nulliparous patients between 28 to 34 weeks' gestation with no known history of renal disease or hypertension were placed in the left lateral recumbent position and their blood pressures were taken once and recorded. They then turned to the supine position where another blood pressure was taken within 2 minutes and also recorded. All these patients were then followed routinely throught their pregnancy, labor, delivery, and postpartum period. Of those patients whose diastolic blood pressure during the modified "roll-over" test rose less than 15 mmHg, only 2 of 99 developed pregnancy-induced hypertension (PIH). Of those whose roll-over test showed an increase of more than 15 mmHg, 23 of 32 developed PIH (P less than .000000001). Of those whose blood pressure during the roll-over developed PIH(P less than .00000001). Also, 10 of 11 patients whose diastolic blood pressure increased more than 25 mmHg during the roll-over test developed PIH (P less than .000000001).

Angiotensin II↗
PubMed1998

Colonic epithelial cell proliferation in hereditary non-polyposis colorectal cancer.

BACKGROUND: Despite the recent discovery of four genes responsible for up to 90% of all cases of hereditary non-polyposis colorectal cancer (HNPCC), there will still be families in whom predictive testing is not possible. A phenotypic biomarker would therefore be useful. An upwards shift of the proliferative compartment in colonic crypts is reported to be one of the earliest changes in premalignant mucosa. AIMS: To assess the role of crypt cell proliferation as a phenotypic biomarker in HNPCC. PATIENTS: Thirty five patients at 50% risk of carrying the HNPCC gene (21 of whom subsequently underwent predictive testing and hence gene carrier status was known) and 18 controls. METHODS: Crypt cell proliferation was measured at five sites in the colon using two different techniques. Labelling index was determined using the monoclonal antibody MIB1 and whole crypt mitotic index was measured using the microdissection and crypt squash technique. The distribution of proliferating cells within the crypts was also assessed. RESULTS: There were no significant differences in the total labelling index or mean number of mitoses per crypt, nor in the distribution of proliferating cells within the crypt, between the study and control groups at any site. When the 21 patients in whom gene carrier status was known were analysed separately there were no significant differences in the measured indices of proliferation between the HNPCC gene carriers and non-gene carriers. CONCLUSION: Crypt cell proliferation is not a discriminative marker of gene carriage in HNPCC.

Adolescent↗
PubMed2002

In vitro tests for predicting drug-drug interactions: the need for validated procedures.

Over the past decade, the prediction of drug-drug interactions from in vitro studies has become a rapidly expanding field of research. Numerous papers and excellent review articles (Bertz & Granneman 1997; Ito et al. 1998a & b; Lin 2000; Bachmann & Ghosh 2001; Ekins & Wrighton 2001; Weaver 2001) have been published in this area. Yet like any new and fast-growing subject, this one has been developing with some confusion and without any real, efficient organisation. Depending on the drug tested, the models and extrapolation parameters used, etc., results and conclusions may vary widely from study to study (von Moltke et al. 1998; Weaver 2001). Several authors have called for validation of these procedures (Rodrigues et al. 2001; Kummar & Surapaneni 2001; Pelkonen et al. 2001a & b; Kremers 2002), and regulatory authorities intend to require better traceability and reliability (FDA & EMEA guidelines). A systematic and reliable approach is needed also to allow such protocols to be incorporated into early screening for potential drugs and new chemical entities. There is certainly a great need to standardise these studies and to verify their conclusions, but is true validation possible in this field? The main purpose of the present paper is to discuss this issue and to examine what is possible and what is needed to improve the quality of predictions made from in vitro experiments.

Clinical Laboratory Techniques↗
PubMed1995

The importance of abnormalities of liver function tests in predicting mortality in chronic heart failure.

A number of simple clinical and laboratory variables were analysed in a group of patients with chronic heart failure to evaluate their prognostic significance. Five hundred and fifty-two patients were followed for a maximum of 13 years with a total exposure time to death or censored survival of 1148 years. Of the clinical variables, diuretic dose and NYHA class were related to mortality (P < 0.01), and ischaemic heart disease was associated with a worse prognosis than other aetiologies (P < 0.05). Of the laboratory variables, abnormalities of liver function tests including bilirubin (P < 0.01), aspartate transaminase (P < 0.005), gamma glutamyl transpeptidase (P < 0.005) and alkaline phosphatase (P < 0.01) were all related to mortality as was plasma urate (P < 0.01). Multivariate survival analysis of all variables showed aspartate transaminase (chi 2 17.36, P < 0.001) accounted for the greatest variance followed by serum bilirubin (chi 2 14.35, P < 0.005). Thus, abnormalities in liver function tests have prognostic importance in chronic heart failure.

Aged↗
PubMed1988

Pulmonary function tests cannot predict exercise-induced hypoxemia in chronic obstructive pulmonary disease.

We studied 40 patients with chronic obstructive pulmonary disease (COPD) to determine whether measurements of pulmonary function could predict a fall in arterial oxygen pressure (PaO2) with exercise. The PaO2 fell more than 3 mm Hg in 21 patients (group 1), did not change (+/- 3 mm Hg) in nine patients (group 2), and increased more than 3 mm Hg in ten patients (group 3). Group 3 had significantly less severe expiratory obstruction than groups 1 and 2. The most significant variables in predicting a change in PaO2 with exercise were the ratio of the forced expiratory volume in one second over the forced vital capacity (FEV1/FVC) and the single-breath carbon monoxide diffusing capacity (Dsb). Measurements of FEV1/FVC of 0.50 or more and Dsb of 20 ml/min/mm Hg or more were 100 percent predictive in excluding a fall in PaO2 with exercise. Measurements below these thresholds could not be used reliably to predict which patients would develop worsening hypoxemia with exercise. Because of wide variability in reference values from eight different published studies for diffusing capacity, recommended criteria based on the percent predicted Dsb should be used with caution. We conclude that pulmonary function measurements cannot be used to predict exercise-induced hypoxemia in patients with COPD; however, the measurements may be useful in identifying patients whose condition is less severe who are unlikely to develop worsening hypoxemia with exercise.

Carbon Dioxide↗
PubMed1998

Can clinical colour vision tests be used to predict the results of the Farnsworth lantern test?

Clinicians usually do not have access to a lantern test when making an occupational assessment of the ability of a person with defective colour vision to recognise signal light colours: they must rely on the results of ordinary clinical tests. While all colour vision defectives fail the Holmes Wright Type B lantern test and most fail the Holmes Wright Type A lantern, 35% of colour vision defectives pass the Farnsworth lantern. Can clinical tests predict who will pass and fail the Farnsworth lantern? We find that a pass (less than two or more diametrical crossings) at the Farnsworth Panel D 15 Dichotomous test has a sensitivity of 0.67 and specificity of 0.94 in predicting a pass or fail at the Farnsworth lantern test: a Nagel range of > 10 has a sensitivity of 0.87 and a specificity of 0.57. We conclude that neither the D 15 nor the Nagel Anomaloscope matching range are satisfactory predictors of performance on the Farnsworth Lantern.

Color Perception Tests↗
PubMed1997

Absence of mutations in the ATM gene in breast cancer patients with severe responses to radiotherapy.

The effectiveness of cancer radiotherapy is compromised by the small proportion (approximately 5%) of patients who sustain severe normal tissue damage after standard radiotherapy treatments. Predictive tests are required to identify these highly radiosensitive cases. Patients with the rare, recessively inherited, cancer-prone syndrome ataxia-telangiectasia (A-T) sustain extremely severe normal tissue necrosis after radiotherapy and their cultured cells are also highly radiosensitive. Clinically normal carriers (heterozygotes) of the A-T gene have an increased risk of breast cancer, account for approximately 4% of all breast cancer cases and show a modest increase in cellular radiosensitivity in vitro. It has been suggested that a substantial proportion of highly radiosensitive (HR) breast cancer patients may be A-T heterozygotes, and that screening for mutations in the A-T gene could be used as a predictive test. We have tested this hypothesis in a group of cancer patients who showed adverse reactions to radiotherapy. Sixteen HR breast cancer patients showing mainly acute reactions (and seven HR patients with other cancers) were tested for ATM mutations using the restriction endonuclease fingerprinting assay. No mutations typical of those found in obligate A-T heterozygotes were detected. If the estimate that 4% of breast cancer cases are A-T gene carriers is correct, then ATM mutations do not confer clinical radiosensitivity. These early results suggest that screening for ATM mutations in cancer patients may not be of value in predicting adverse reactions.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2007

Heterozygote BRCA1 status and skewed chromosome X inactivation.

A high frequency of skewed X-chromosome inactivation has been reported in peripheral blood lymphocytes from early onset breast cancer or invasive ovarian cancer patients. Recent findings have shown that breast and ovarian carcinoma cells from BRCA1 mutation carrier women lack the hallmarks of inactive X chromatin structure. These observations suggested that loss of functional BRCA1 in female cells may perturb the process of X inactivation and have lead us to the hypothesis that analysis of skewing could be used as a predictive test for BRCA1 germline mutation in lymphocytes from breast cancer patients. In the present study, we have compared the X inactivation pattern in lymphoblastoid cell lines from 38 females carrying heterozygous BRCA1 mutation to 41 controls. X inactivation analysis was assessed on the polymorphic CAG repeat within the human androgen receptor gene. Our observations rule out an effect of a monoallelic BRCA1 germline mutation on the choice of inactivated chromosome X and therefore the possibility of using analysis of Xi skewing as a predictive test for BRCA1 germline mutation carrier status.

Adult↗
PubMed1997

Predicting end-of-test semen quality in bulls prior to performance testing.

The first objective of this study was to determine if serum concentrations of specific hormones (testosterone, progesterone and androstenedione) in bulls at the start of performance testing could predict semen quality at the end-of-test when used in a multivariate model. The second objective was to evaluate other clinical measurements (breed, age, body weight, hip height and scrotal circumference) for predicting end-of-test semen quality. End-of-test semen quality was related to steroid concentrations and several pre-testing measurements, including age, body weight, hip height and scrotal circumference (SC). Combining the 3 steroid concentrations into a predictive test had a sensitivity of 0.6 and specificity of 0.5 at its most accurate point. The repeatability of the test result was extremely low (r(2) = 0.16; P < 0.05). In multivariate analyses, breed and start-of-test SC remained significant predictors of end-of-test semen quality (P < 0.05) while the other variables were nonsignificant (P > 0.1), suggesting that start-of-test SC was the most accurate predictor of end-of-test semen quality. Removing bulls at the start-of-test that had scrotal measurements of less than 20 cm, 24 cm, 28 cm or 32 cm resulted in sensitivities and specificities of 0.19, 0.94; 0.41, 0.81; 0.64, 0.56; and 0.94, 0.12, respectively. No cut-point had both adequate sensitivity and specificity. Because clinical tests were correlated, combining the tests to improve accuracy was not justified.

Journal Article↗
PubMed2006

Roles of K149, G352, and H401 in the channel functions of ClC-0: testing the predictions from theoretical calculations.

The ClC family of Cl(-) channels and transporters comprises membrane proteins ubiquitously present in species ranging from prokaryotes to mammals. The recently solved structures of the bacterial ClC proteins have provided a good model to guide the functional experiments for the eukaryotic Cl(-) channels. Theoretical calculations based on the bacterial ClC structures have identified several residues critical for the Cl(-) binding energy in the Cl(-) transport pathway. It was speculated that the corresponding residues in eukaryotic Cl(-) channels might play similar roles for the channel functions. In this study, we made a series of mutations in three such residues in eukaryotic ClC Cl(-) channels (K149, G352, and H401 in ClC-0) and studied the functional consequences on the channel properties. A cysteine modification approach was also employed to evaluate the electrostatic effects of the charge placed at these three positions. The experimental results revealed that among the three residues tested, K149 plays the most important role in controlling both the gating and the permeation functions of ClC-0. On the other hand, mutations of H401 alter the channel conductance but not the gating properties, while mutations of G352 result in very little functional consequence. The mutation of K149 into a neutral residue leucine (K149L) shifts the activation curve and leads to flickery channel openings. The anion permeability ratios derived from bi-ionic experiments are also significantly altered in that the selectivity of Cl(-) over other anions is decreased. Furthermore, removing the positive charge at this position reduces and increases, respectively, the accessibility of the negatively and positively charged methane thiosulfonate reagents to the pore. The control of the accessibility to charged MTS reagents and the regulation of the anion permeation support the idea that K149 exerts an electrostatic effect on the channel function, confirming the prediction from computational studies.

Amino Acid Substitution↗
PubMed1983

Amniotic fluid lecithin, phosphatidylglycerol, L/S ratio, and foam stability test in predicting respiratory distress in the newborn.

Amniotic fluid phospholipids (lecithin, sphingomyelin, phosphatidylglycerol) were extracted and separated by the method of Gluck and associates. In addition, these lipids were quantified against standards that were concurrently developed in three adjacent thin layer chromatography (TLC) channels. A log-log transformation of the reflectance and concentration values provided rectilinear plots for quantification. A foam stability assay (FS) of 0.48 or greater was associated with high values of L/S ratio and lecithin concentration, and values of 0.44 or less almost always were associated with low values. Lecithin values of 12 micrograms/mL or more were associated with L/ S ratios of 2.0 or greater. Phosphatidylglycerol was detected consistently only when lecithin levels were 40 micrograms/mL or greater and L/S ratios 4.0 or greater. Case reviews indicated that: (1) FS test of 0.48 almost always was associated with pulmonary maturity in the newborn; (2) that a pulmonary maturity index combining the lecithin concentration and L/S ratio was a better predictor of pulmonary maturity in the newborn then either one alone; (3) that phosphatidylglycerol added little to this discrimination; and (4) that these assays showed no significant interpretative differences between diabetic and non-diabetic mothers.

Amniotic Fluid↗
PubMed2000

Potential utility of antineoplaston A-10 levels in breast cancer.

Antineoplastons, first described by Burzynski, are naturally occurring peptides and amino acid derivatives, which control neoplastic growth. Antineoplaston A-10 (3-phenylacetyl amino-2, 6-pepridinedione) is the first chemically identified antineoplaston. Here we describe the potential utility of antineoplaston A-10 as a predictive test for breast cancer. Antineoplaston A-10 level was measured in the urine of 31 breast cancer patients and 17 normal women using high performance thin layer chromatography (HPTLC). Significantly lower antineoplaston A-10 levels were detected among patients with breast cancer with a P value <0.001. These data suggest a strong inverse association of urinary antineoplaston A-10 level with breast cancer. Such finding was the stimulus for further investigations of antineoplaston A-10 levels in some benign as well as other malignant diseases to determine the utility of this approach as a predictive test for women who are at risk of developing breast cancer.

Adult↗
PubMed1982

Failure of delayed hypersensitivity skin testing to predict postoperative sepsis and mortality.

Delayed hypersensitivity skin reactions to a battery of recall antigens, haemoglobin and albumin concentrations, arm-muscle circumference, and percentage of ideal weight were determined before operation in 244 patients undergoing elective major surgery. Depressed skin reactions were found in 70 patients (28%), but this group did not have significantly higher sepsis or mortality rates when compared with patients with normal reactions. Significant associations were found between depressed skin reactions and increasing age, anaemia, hypoalbuminaemia, low arm-muscle circumference, and low weight. Patients with benign and malignant disease had similar distributions of skin reactions. Hypoalbuminaemia was associated with a higher rate of serious postoperative sepsis, and hypoalbuminaemia, low arm-muscle circumference, and low weight were all associated with a higher mortality. These results suggest that the routine use of delayed hypersensitivity skin testing in the preoperative assessment of surgical patients is not justified.

Abdomen↗
PubMed1994

Ability of laboratory methods to predict in-use efficacy of antimicrobial preservatives in an experimental cosmetic.

The abilities of nine antimicrobial systems to preserve an experimental water-based cosmetic formulation were evaluated by six microbiological challenge tests: the U.S. Pharmacopeia test; the British Pharmacopeia test; the Cosmetic, Toiletry, and Fragrance Association test; the rapid screen test; the sequential challenge test; and the post-use test. The antimicrobial systems contained various combinations and amounts of two parabens and a quaternary compound in order to provide a broad range of preservation. The results obtained were compared with the abilities of the formulations to support maintenance and growth of microorganisms in microfloras obtained from human axilla areas and finger skin during an 8-week simulated in-use test. Without statistical analysis all of the tests predicted the results obtained with well-preserved or poorly preserved formulations. The rapid screen test was the best test for predicting differences at intermediate levels of preservation. Statistically, all of the tests were equivalent predictors of preservation efficacy in the in-use test (P = 0.05). At the P = 0.10 level, only the U.S. Pharmacopeia, British Pharmacopeia, rapid screen, Cosmetic, Toiletry, and Fragrance Association tests were significantly predictive. The results of prediction by a test, based on the preservative levels used, agreed well with the in-use test results (P = 0.01). A total of 20% of the formulations that contained excessive microbial levels contained human axilla microorganisms. The levels of preservation in failed products were similar to the levels of preservation in unused controls.

Axilla↗