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PubMed2006

Repeated measurement of pregnancy-associated plasma protein-A (PAPP-A) in Down syndrome screening: a validation study.

OBJECTIVES: To confirm that measuring pregnancy-associated plasma protein-A (PAPP-A) in both first- and second-trimester serum samples improves Down syndrome screening. METHODS: We selected paired first- and second-trimester stored serum samples from 34 Down syndrome pregnancies (cases) and 514 unaffected pregnancies (controls) and tested the second-trimester samples for PAPP-A and dimeric inhibin-A (DIA). First-trimester PAPP-A measurements were already available, as were second-trimester measurements of alpha-fetoprotein, unconjugated estriol (uE3), and human chorionic gonadotrophin (hCG). RESULTS: PAPP-A was lower among cases than controls (0.47 MoM) in the first trimester (at an average of 12.5 weeks); in the second trimester, it was not different (0.91 MoM). Using repeated measures of PAPP-A alone, 21 of 34 cases were detected (62%, 95%CI 44% to 78%) with 5% false positives. At an observed 2% false-positive rate, the detection rates (DR) for the quadruple (69%) and serum integrated (69%) tests were lower than for the repeated measures test (75%). Modelled performance at 12 weeks was similar to these observed findings (70, 75, and 82%, respectively). If the first-trimester samples were collected at 10 weeks, however, DR would be higher (70, 81, and 91%, respectively). CONCLUSIONS: Adding a repeated measure of PAPP-A to existing serum markers improves Down syndrome screening to levels that are currently obtainable only by including ultrasound measurement of nuchal translucency (NT). Serum-based screening has the advantages of higher availability and reliability at a lower cost, resulting in a more effective screening strategy. A serum-based repeated measures test has a place in routine Down syndrome screening.

Adult↗

PubMed2026

GenProb-PCSM: A Simplified Weighted Germline Score for Prostate Cancer-Specific Mortality.

BACKGROUND: We previously developed a tier-based germline classification using the National Comprehensive Cancer Network (NCCN)-recommended DNA damage repair (DDR) genes and KLK3 I179T to predict prostate cancer (PCa)-specific mortality (PCSM). To provide an easier-to-use single inherited risk score while preserving gene-specific effects, we developed GenProb-PCSM. METHODS: We analyzed 14,644 men with incident PCa from the UK Biobank. The cohort was randomly divided into training (60%) and independent testing (40%) datasets. GenProb-PCSM was developed in the training cohort by integrating pathogenic variants in ten NCCN-recommended DDR genes and the KLK3 I179T variant using gene-specific weights derived from Fine-Gray competing-risk models. Performance was evaluated in the independent testing cohort by discrimination, calibration, and risk stratification. Secondary analyzes evaluated metastatic progression and the composite endpoint of metastatic progression and/or PCSM. RESULTS: Among 14,644 men with incident PCa, 1,581 died from PCa. GenProb-PCSM remained significantly associated with PCSM in the independent testing cohort (HR per SD, 1.18; 95% CI, 1.12-1.24; p < 0.001). Using predefined risk thresholds derived from the training cohort, patients in the intermediate- and high-risk groups had significantly increased risks of PCSM compared with the low-risk group (HR 1.49, 95% CI 1.22-1.84; and HR 4.04, 95% CI 2.58-6.33, respectively). GenProb-PCSM also predicted independent metastatic progression and the composite endpoint of metastatic progression and/or PCSM. CONCLUSIONS: GenProb-PCSM transforms complex germline findings into a single inherited risk score for PCSM and metastatic progression. Its simplicity and preservation of gene-specific effects may facilitate clinical implementation of germline prognostic assessment in PCa.

DNA damage repair genes↗

PubMed2003

Detecting distant homologs using phylogenetic tree-based HMMs.

It is often desired to identify further homologs of a family of biological sequences from the ever-growing sequence databases. Profile hidden Markov models excel at capturing the common statistical features of a group of biological sequences. With these common features, we can search the biological database and find new homologous sequences. Most general profile hidden Markov model methods, however, treat the evolutionary relationships between the sequences in a homologous group in an ad-hoc manner. We hereby introduce a method to incorporate phylogenetic information directly into hidden Markov models, and demonstrate that the resulting model performs better than most of the current multiple sequence-based methods for finding distant homologs.

Algorithms↗

PubMed2006

Confidence intervals for an effect size measure based on the Mann-Whitney statistic. Part 2: asymptotic methods and evaluation.

Several asymptotic confidence interval methods for U/mn, the Mann-Whitney U statistic divided by the product of the two sample sizes, are developed and evaluated alongside published methods. Novel methods derived from Gaussian and beta models perform well, though overall a modification of the Hanley-McNeil approach (method 5 in this evaluation) performed better and is recommended for calculating confidence intervals for U/mn for continuously distributed data.

Confidence Intervals↗

PubMed1999

CombiTool--a new computer program for analyzing combination experiments with biologically active agents.

CombiTool is a new computer program for the analysis of combination effects of biologically active agents. It performs model calculations and an analysis of experimental combination effects for two or three agents according to both the Bliss independence and the Loewe additivity criteria. Zero interaction response surfaces are calculated from single-agent dose-response relations and compared to experimental combination data. The calculation of response surfaces for Loewe additivity is based on a new approach which combines the implicit definition equation in terms of doses alone with single-agent dose-response relations. The simultaneous analysis of experimental data according to both Loewe additivity and Bliss independence within one program can hopefully contribute to a better understanding of the meaning and limits of the two criteria. CombiTool has a built-in graphics facility which allows the direct visualization of the response surfaces or the corresponding contour plots and the experimental data.

Algorithms↗

PubMed1998

Irsogladine maleate inhibits angiogenesis in wild-type and plasminogen activator-deficient mice.

BACKGROUND: The activation of the zymogen plasminogen to the serine protease plasmin by urokinase-type (uPA) and tissue-type (tPA) plasminogen activators (PA) is an important event in a variety of physiologic and pathophysiologic processes in mammals. Enhanced PA activity occurs during angiogenesis and has been correlated in vitro and in vivo with increased tumor aggressiveness and is an indicator of poor prognosis in a variety of tumors in humans. Preliminary studies suggest that the antiulcer drug irsogladine maleate (IM) diminishes PA activity in vitro and may inhibit angiogenesis in vivo. To define the precise mechanism of angiogenesis inhibition by IM in vivo, we tested the ability of IM to blunt angiogenesis in a mouse cornea neovascularization model performed in wild-type and PA-knockout mice. METHODS: Three days prior to pellet implantation, groups of C57Bl/6 wild-type, uPA-deficient (upA-/-), and tPA-deficient (tPA-/-) mice received IM (300 mg/kg), IM (500 mg/kg), or vehicle (0.5% carboxymethylcellulose) via oral gavage. After 3 days of treatment, hydron polymer-coated pellets of sucrose aluminum sulfate containing 100 ng of basic fibroblast growth factor (bFGF) were inserted into surgically created pockets in the cornea of each mouse. On postoperative day 6, the neovascularization of each cornea was evaluated by a blinded observer using slit lamp microscopy and photographed. Angiogenesis was quantified by calculating vascular area (mm2) +/- SEM using a modified formula for a half ellipse that incorporates calibrated vessel measurements [Vessel length (mm) x Clock hours x pi x 0.2]. RESULTS: IM treatment (300 and 500 mg/kg/day) resulted in a dose-dependent reduction of angiogenesis in wild-type mice by 21 and 45.3% (P < 0.02, P < 0.001), in tPA-deficient mice by 42.6 and 46% (P < 0.001, P < 0.001), and in uPA-deficient mice by 27.2 and 46% (P < 0.05, p < 0.001), respectively. No quantitative differences in neovascularization were observed in either treatment group between transgenic mouse strains. No toxicity was noted in any group. CONCLUSION: IM inhibits bFGF-induced angiogenesis in wild-type, tPA-knockout, and uPA-knockout mice. The observation that IM significantly diminishes angiogenesis in both PA-deficient mice and wild-type mice suggests that the mechanism of action of IM may be independent of plasminogen activation.

Animals↗

PubMed1992

Bone mass and bone cellular variations after five months of physical training in rhesus monkeys: histomorphometric study.

Five Rhesus Monkeys (Macaca mulatta), a suitable nonhuman model, performed 5 months of rope-climbing exercise. Duration of the training sessions was progressively increased to reach 1 hour/day after 1 month of training and was maintained until the end of the experiment. Bone mass parameters, bone resorption, and bone formation activity were measured by histomorphometric analysis on iliac crest bone biopsies before and after the experiment. Mineral apposition rate was measured in cortices and trabecular bone after double calcein labeling. Five months of rope-climbing exercise had determined a significant decrease of bone volume with a slight decrease of the number and thickness of trabeculae. This might induce an alteration of biomechanical properties of bone. These architectural modifications were associated with a nonsignificant decrease of bone resorption activity. But the main effect of training was an important decrease of bone formation activity without change of the mineral apposition rate. Endurance exercise at low intensity has determined a decreased bone turnover with osteoblastic depression. This animal experiment points out that exercise modalities might be important in the bone response to training and should be carefully defined for preventive use in humans.

Animals↗

PubMed1993

The effects of sleep deprivation and incentives on human performance.

This study explores whether KR (knowledge of results) and reward compensate for the negative joint effects of sleep deprivation and signal degradation in a choice-reaction task. The negative effect of signal degradation on performance was aggravated by sleep loss and time-on-task, whereas KR improved performance, especially when signals were degraded. Reward changed the effects of time-on-task owing to lack of sleep. Performance was also improved by a brief task interruption after 30 minutes' work, with 5 more minutes to go. These results can be interpreted in terms of the performance model of Sanders (1983), which links energetic mechanisms to stages of information processing. A lack of energetic supply from the arousal mechanism to perceptual processing, induced by signal degradation, sleep deprivation, and time-on-task, was effectively counteracted by KR:KR enables the mobilization of effort to compensate for this lack of arousal. The relation between reward and KR is not yet clear. The interruption effect suggests that the influence of time-on-task is not due to loss of arousal, but causes a reallocation of resources by effort.

Adult↗

PubMed1980

The sloping alveolar plateau at synchronous ventilation.

We performed model calculations on the slope of the alveolar plateau at single breath washout of helium (He) and sulphurhexafluoride (SF6). Calculations wre carried out on an extensible axis-symmetric lung model, which was synchronously ventilated either equally or unequally. The calculated slopes of the alveolar plateau were small (<0.3%), which is in agreement with the results of other investigators. However, calculations carried out on a synchronously equally ventilated axis-asymmetric lung model related to the terminal lung unit (acinus), yielded slopes for the alveolar plateau ranging from 0 up to 14% per liter between 1.2 and 1.8 1 expired volume. Even with a post inspiratory apnea of 1 s, we still found slopes ranging from 0--4%. Our findings are in contrast to the conclusions of Engel et al. (1979), who ascribe the slope of the alveolar plateau to asynchronous unequal ventilation.

Computers↗

PubMed2004

Morphodynamics and surgical correction of the body's creases, folds, and wrinkles.

The aesthetics of the human body are a balance of furrows and orifices, and artists of every period have studied the distance between ear and eye, eye and nostrils, nostrils and mouth, nipple and submammary crease, subgluteus folds and iliac crest and so on, to create a code for all body proportions. Currently, the ideal of female beauty prefers more elongated shapes than in the past, and surgical body modeling, performed in accordance with anthropometric rules, uses a combination of techniques to alter the orientation and depth of aesthetic reference points, such as body folds and curves. These must be integrated into the body's biodynamics to both prevent and correct defects and irregularities of the body, which has an inherent disposition to change shape, both because of the physical forces acting on it and because of constant tissue replacement.

Clinical Competence↗

PubMed1998

Processes in Pollution Management: An Australian Model

/ This paper describes a model of the social and institutional processes involved in the solution of major pollution problems from the time they are first identified until they are resolved. The model is empirically demonstrated using four case studies of water and air pollution problems from Sydney, New South Wales, Australia. Each process of the model is quantified by the use of an indicator, e.g., number of articles in newspapers to measure the process "publicconcern," number of pages of text devoted to parliamentary debates to measure the process "political action." The case study data are presented on a time-line graph that shows the duration and magnitude of each process. The paper illustrates three aspects of the solution of major pollution problems: the long time frames involved, the importance of public opinion in initiating the solution process, and the partial nature of solutions-problems may be politically resolved but often a complete solution is not achieved. An understanding of social and institutional processes and time frames will enable planners and policy makers to communicate to the public and politicians the consequences of delay in acting to solve pollution and to direct attention to critical areas to expedite solutions.KEY WORDS: Pollution problems; Management process model; Performance indicators; Air pollution; Water pollution

Journal Article↗

PubMed2006

The distribution and ecological preferences of Boophilus microplus (Acari: Ixodidae) in Mexico.

This paper focuses on the distribution of the cattle tick, Boophilus microplus, in Mexico. The study is aimed to understand the climate factors responsible of the recorded distribution that can statistically define the suitable habitat for the tick. Sites where the tick is recorded display significantly higher values of some climate variables in comparison with those where the tick is absent, namely mean monthly temperature (T) and atmospheric water vapour (W), yearly accumulated T, W and rainfall (R) (p < 0.001 for every variable), with smaller significance for the yearly sum of T/R and T/W ratios (p < 0.05). Interestingly, variables involving the Normalized Derived Vegetation Index (NDVI) do not shown statistical differences between the sites where the tick is present or absent. The best set of habitat-defining variables was integrated into a framework to assess the habitat suitability for the tick in Mexico. We used a point-to-point similarity metric to assign a classification value to a candidate site based on the proximity in environmental space of the most similar record site. A combination of 7 yearly and monthly values for temperature, rainfall and water vapour variables captured the tick distribution. Model performance, as tested with a separate set of distribution tests and defined by the AUC value, was 0.89. Causes of errors as detected with a visual comparison of both known and predicted distribution of the tick may be attributed to the use of a medium resolution, unable to capture locally important features of tick distribution, and to incomplete collections in some parts of the country.

Animals↗

PubMed2005

Molecular biology of ureteral bud and trigonal development.

Advances in molecular biology have provided valuable insight into the development of the urinary tract, particularly ureteral bud formation. Reciprocal inductive signals between the ureteral bud and growing kidney are crucial for normal development. The Wolffian duct serves as the site of origin of the ureteral bud and forms distal excretory ducts that are incorporated into the developing bladder to become the trigone. Vesicoureteral reflux and renal dysplasia can result from abnormal position of the ureteral orifice on the trigone. The presumed origin of trigone formation is based largely on evaluation of human and animal models performed nearly a century ago. The trigone is thought to develop from the mesodermal germ cell layer; however, several recent studies have shown that endoderm may be the tissue of origin. This review highlights important discoveries in the field of molecular biology as it relates to the development of normal and abnormal ureteral bud formation. It also describes the anatomic relationship between the developing bud and trigone as it pertains to clinically relevant urinary tract anomalies, including recent discoveries that attempt to prove the origin of the trigone.

Female↗

PubMed1994

Quantitative gas transfer of an intravascular oxygenator.

The intravascular oxygenator is a newly developed device for intracaval gas exchange in critically ill patients with respiratory failure. In an experimental ex vivo model, performance characteristics of the intravascular oxygenator/carbon dioxide removal device were studied. With a mean hemoglobin concentration of 6.2 +/- 1.9 g/dL (mean +/- standard deviation), total O2 transfer was 21.8 +/- 4.8 mL/min at a blood flow of 1 L/min, 37.0 +/- 12.6 mL/min at 2 L/min, at 2 L/min, and 47.5 +/- 16.7 mL/min at 3 L/min. Total CO2 transfer was 27.3 +/- 6.6 mL/min at a blood flow of 1 L/min, 38.6 +/- 8.9 mL/min at 2 L/min, and 40.4 +/- 9.3 mL/min at 3 L/min. In contrast to total gas transfer, O2/CO2 transfer rates (mL/L) diminished significantly with increasing blood flow. In addition, there was a negative correlation between O2 transfer rate and venous O2 partial pressure (r = -0.73; p < 0.0001), a positive correlation between CO2 transfer rate and venous CO2 partial pressure (r = 0.65; p < 0.0001), and a positive correlation between O2 and CO2 transfer rates and blood hemoglobin level (r = 0.57 [p < 0.01] and r = 0.70 [p < 0.01], respectively). These results demonstrate that the behavior of the intravascular hollow-fiber oxygenator is similar to that of the classic membrane oxygenator used for cardiopulmonary bypass: total gas transfer correlates directly with blood flow and venous CO2 partial pressure and indirectly with venous O2 partial pressure. The O2 and CO2 transfer rates increase significantly with increasing hemoglobin content of the blood.

Animals↗

PubMed1992

Advanced computer programs for drug dosing that combine pharmacokinetic and symbolic modeling of patients.

In this paper, we describe our design for advanced drug dosing programs that "reason" using a combination of Bayesian pharmacokinetic modeling and symbolic modeling of patient status and drug response. Our design is similar to the design of the Digitalis Therapy Advisor program, but extends this previous work by incorporating a Bayesian pharmacokinetic model, performing a "meta-level" analysis of drug concentrations to identify sampling errors and changes in pharmacokinetics, and including the results of this analysis in reasoning for dosing and therapeutic monitoring recommendations. The design has been implemented in a program for aminoglycoside antibiotics called Aminoglycoside Therapy Manager. The program is user-friendly and runs on low-cost general-purpose hardware. The initial validation study showed that the program was as accurate in predicting future drug concentrations as an expert using commercial Bayesian forecasting software and that its dosing recommendations were similar to those of an expert.

Aminoglycosides↗

PubMed2006

Symptoms of internalizing and externalizing problems: modeling recovery curves after the death of a parent.

BACKGROUND: The death of a parent is a major family disruption that can place children at risk for later depression and other mental health problems. DESIGN: Theoretically based randomized controlled trial for parentally bereaved children. SETTING/PARTICIPANTS: Two-hundred and forty-four children and adolescents and their caregivers from 156 families were randomly assigned to the Family Bereavement Program (FBP) intervention condition (90 families; 135 children) or to a control condition (66 families; 109 children). Data collection occurred from 1996 to 1998. INTERVENTION: Children and caregivers in the intervention condition met separately for 12 two-hour weekly sessions. Skills targeted by the program for children included positive coping, stress appraisals, control beliefs, and self-esteem. The caregiver program targeted caregiver mental health, life stressors, and improved discipline in the home. Both child and caregiver programs focused on improved quality of the caregiver-child relationship. MAIN OUTCOME MEASURES: Child and caregiver reports of internalizing and externalizing symptoms. RESULTS: Longitudinal growth curve modeling was performed to model symptoms over time from the point of parental death. The rate of recovery for girls in the program condition was significantly different from that of girls in the control condition across all outcomes. Boys in both conditions showed reduced symptoms over time. CONCLUSIONS: The methodology offers a conceptually unique way of assessing recovery in terms of reduced mental health problems over time after an event and has contributed to further understanding of FBP intervention effects. The intervention program facilitated recovery among girls, who did not show reduction in behavior problems without the program, while boys demonstrated decreased symptoms even without intervention.

Adolescent↗

PubMed2005

Development of a large titanium bone chamber to study in vivo bone ingrowth.

In the bone conduction chamber (BCC) various materials and factors have been tested for their effect on bone graft incorporation and bone healing. However, biomaterials often have to be crushed to fit in this small chamber. Since cellular responses to biomaterials are influenced by the size and shape of particles, research concerning the evaluation of biomaterials is limited by the dimensions of this bone chamber. We enlarged and modified the BCC in order to be able to investigate the in vivo influences of biomaterials, growth factors and bone graft processing on tissue and bone ingrowth. Seven goats received four bone chambers each, three modified models and a BCC. The first model (BCC+) had two ingrowth openings, similar to that of the BCC. The second model had two round ingrowth openings (ROU). The third model had a open bottom for bone ingrowth (BOT). After 12 weeks, bone ingrowth distances were measured on histological sections and using muCT. Bone ingrowth was significantly higher (p=0.009 and 0.008) in the ROU compared to the BCC+ and the BOT, respectively. Similar results were found using muCT. The ROU model performed most similar to the BCC (gold standard) and is considered to be a promising new tool in biomaterials research.

Animals↗

PubMed2005

Trunk anthropometry of Hong Kong Chinese infants.

BACKGROUND: Disturbed growth of the trunk may result in abnormal sternocostal relationship and a variety of pectus deformities. AIMS: The purposes of this study were to establish norms of trunk anthropometry for dysmorphology identification in the newborns and to evaluate chest circumference as a predictor for low birth weight for outborn infants where weighing scales were unavailable. STUDY DESIGN AND SUBJECTS: A total of 10,339 Chinese infants (5478 males, 4861 females) with gestation 24-42 weeks from 12 hospitals were included. The anthropometric measurements analyzed included chest circumference, inter-nipple distance, sternal length and abdominal circumference. OUTCOME MEASURES: The LMS method using maximum penalized likelihood was used to perform model fitting of the anthropometric centiles for these physical parameters. RESULTS: References tables of the four physical parameters for newborns were constructed. Chest circumference showed the highest correlation with birth weight (male: r = 0.866, female: r = 0.883). The cut-off points for chest circumference of 295 (male) and 299 mm (female) were the best predictor for low birth weight. There were also racial differences in these parameters. When compared with French infants, Chinese newborns had smaller chest circumference. CONCLUSION: These physical parameters provide useful references and aid dysmorphology diagnosis in newborns of ethnic Chinese origin.

Anthropometry↗