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Liver X receptors (LXRs) alpha and beta are ligand-induced transcription factors that regulate transcription of genes encoding key regulators of cholesterol metabolism and transport, and of lipogenesis. Despite their high similarity, LXRalpha is the functionally dominant LXR isotype in the liver. The function of nuclear proteins can be affected by their sequestration in the nucleoli. Whereas most nuclear receptors are excluded from the nucleolus, some are not. To explore nucleolar exclusion of LXRalpha and LXRbeta, we used cells expressing cyan fluorescent protein (CFP) chimeras with LXRalpha (CFP-LXRalpha) and wild-type and mutant CFP-LXRbeta and marked the nucleolus with anti-fibrillarin antibody. Significantly more CFP-LXRbeta than CFP-LXRalpha in the nucleoli. Mutations in basic-rich sequences in the DNA binding domain caused some exclusion of CFP-LXRbeta from the nucleolus. Moreover, mutations in the activation function-2, an important protein-protein interaction site in all nuclear receptors, resulted in exclusion of CFP-LXRbeta from the nucleolus. These data suggest protein-protein interactions that may regulate nucleolar sequestration of LXRbeta.

Background: DNA vaccines offer unique potential for generating protective and therapeutic immunity against infectious and malignant diseases. Unfortunately, rapid degradation and poor cellular uptake has significantly limited the efficacy of 'naked' plasmid DNA vaccines. We have previously described stabilized plasmid lipid particles (SPLP) as effective nonviral gene delivery vehicles for the transfection of tumours at distal sites following intravenous administration. Based on their low toxicity and favourable transfection profile following systemic administration, we investigate SPLP as gene delivery vehicles for the generation of a systemically administered genetic vaccine., Methods: The uptake of SPLP and their ability to transfect splenic antigen presenting cells (APC) following systemic administration is assessed through fluorescently-labelled SPLP in combination with phenotype markers and a very sensitive flow cytometry-based assay for the detection of the transgene, beta-galactosidase. The priming of antigen-specific adaptive and humoural immune responses following vaccination with SPLP alone or in combination with liposomal nanoparticle encapsulated CpG-ODN containing oligodeoxynucleotides (LN CpG-ODN) is characterized through the use of antigen-specific cytotoxicity assays, interferon-gamma secretion assays and enzyme-linked immunosorbant assay., Results: We demonstrate that SPLP are taken up by and transfect APC in the spleen following intravenous administration and that, in the presence of a strong immunostimulatory signal provided by LN CpG-ODN, are able to prime transgene-specific humoural and cellular immune responses., Conclusions: SPLP represent an effective candidate for the nonviral delivery of a systemic genetic vaccine when combined with additional immune stimulation provided by LN CpG-ODN., ((c) 2008 John Wiley & Sons, Ltd.)

Objective: To compare and contrast the duration and content of physician-patient interaction for patients presenting to an emergency department with problems of low acuity in 1990 and 2005 treated by different grades of physician., Methods: Observational study with data collection in May-July 1990 and May-July 2005. Patients identified at nurse triage as presenting with 'primary care' problems were allocated by time of arrival to senior house officers (1990, n=7; 2005, n=10), specialist registrars/staff grades (1990, n=4; 2005, n=7) or sessionally employed general practitioners (1990, n=8; 2005, n=12) randomly rostered to work in a consulting room that had a wall-mounted video camera. A stratified sample of 430 video-taped consultations (180 (42%) from 1990 and 250 (58%) from 2005) was analysed using the Roter Interaction Analysis System. Main outcome measures -- length of consultation; numbers of utterances of physician and patient talk related to building a relationship, data gathering, activating/partnering (i.e. actively encouraging the patient's involvement in decision-making), and patient education/counselling., Results: On average consultation length was 251s (95% CI for difference: 185-316) longer in 2005 than in 1990. The difference was especially marked for senior house officers (mean duration 385s in 1990 and 778s in 2005; 95% CI of difference: 286-518). All groups of physician showed increased communication related to activating and partnering and building a therapeutic relationship with the patient. While senior house officers demonstrated a greatly increased focus on data gathering, only general practitioners substantially increased the amount of talk centred on patient education and counselling; compared to senior house officers, the odds ratio for the number of such utterances included in consultations was 2.8 (95% CI: 1.4, 5.3)., Conclusion: Although patient-centredness together with consultation length increased for all three physician groups over the duration of this study, senior house officers and specialist registrars/staff grades continued to place less emphasis on advice-giving and counselling than did general practitioners. The extent to which these observed changes in practice were determined by policy, management and training initiatives, and their impact on patient outcome, needs further study., Practice Implications: Video-recording consultations is feasible in an acute hospital setting, and could be used to support training and workforce development. General practitioners can make a distinctive contribution to the workforce of emergency departments. Their consulting style differs from that of hospital physicians and may benefit patient care through a greater focus on patient education and counselling.

Intraparenchymal pericatheter cyst is a rare complication of shunt surgery. It occurs as a consequence of increased CSF outflow resistance distal to a patent ventricular catheter. Treatment has traditionally consisted of shunt revision. We report on two such cases managed conservatively. The role of shunt revisions in cases with asymptomatic intraparenchymal pericatheter cyst is debatable.

Silicone elastomers have proven to be useful implantable release matrices for hydrophobic drugs. However, their utility for the release of hydrophilic materials is less well developed and, even with the addition of polar excipients such as poly(ethylene oxide) (PEO), burst release profiles are often observed-achieving longer term release is more challenging. We report that linoleic acid, initially used to solubilize polar, cationic nicotine in silicone precursors, additionally acted to change the internal morphology of resulting silicone+PEO elastomers. The unexpected consequence of this change was a change in the distribution of hydrophilic domains of PEO/drug within the silicone and the ability to control the rate of release of the drug in vitro. The relationship between excipients, silicone morphology, and release profile is examined.

Objectives: To evaluate the effectiveness of a multifactorial fall prevention program in prespecified subgroups of nursing home residents., Design: Secondary analysis of a cluster-randomized, controlled trial., Setting: Six nursing homes in Germany., Participants: Seven hundred twenty-five long-stay residents; median age 86; 80% female., Intervention: Staff and resident education on fall prevention, advice on environmental adaptations, recommendation to wear hip protectors, and progressive balance and resistance training., Measurements: Time to first fall and the number of falls. Falls were assessed during the 12-month intervention period. Univariate regression analyses were performed, including a confirmatory test of interaction., Results: The intervention was more effective in people with cognitive impairment (hazard ratio (HR)=0.49, 95% confidence interval (CI)=0.35-0.69) than in those who were cognitively intact (HR=0.91, 95% CI=0.68-1.22), in people with a prior history of falls (HR=0.47, 95% CI=0.33-0.67) than in those with no prior fall history (HR=0.77, 95% CI=0.58-1.01), in people with urinary incontinence (HR=0.59, 95% CI=0.45-0.77) than in those with no urinary incontinence (HR=0.98, 95% CI=0.68-1.42), and in people with no mood problems (incidence rate ratio (IRR)=0.41, 95% CI=0.27-0.61) than in those with mood problems (IRR=0.74, 95% CI=0.51-1.09)., Conclusion: The effectiveness of a multifactorial fall prevention program differed between subgroups of nursing home residents. Cognitive impairment, a history of falls, urinary incontinence, and depressed mood were important in determining response.

Conjugated linoleic acid (CLA) is found naturally in dairy and beef products at levels of 0.2% to 2% of the total fat. A more concentrated source of dietary CLA, low in saturated fat, would be highly desirable to obtain optimum CLA levels of about 3 g/d. We recently reported photoisomerization of soy oil with iodine catalysis to be a simple way of producing CLA in laboratory without high-energy input or expensive enzymes and microorganisms. However, a long irradiation time of 144 h has been a limitation for this technique to be of practical value. The objectives of this study were to build a pilot plant unit to rapidly produce high-CLA soy oil by photoirradiation and optimize the processing parameters to obtain high-CLA soy oil. Degassed oil with dissolved-iodine catalyst was irradiated by UV lamps in an illuminated laminar flow unit (ILFU). The ILFU consists of 2 borosilicate glass plates in a silicone lined stainless steel frame. The static mode of operation yielded 5.7% of total CLA isomers and performed twice as well than the continuous mode with 2.5% of total CLA. Irradiating oil in a static mode with reflective surfaces increased the CLA yields 3-fold to 16.4%. About 22% of total CLA isomers can be rapidly produced from soy oil linoleic acid with 0.35% iodine catalyst in a 0.5-cm-thick oil layer maintained at 48 degrees C for 12 h. The peroxide value and GC-MS analysis did not identify any volatile compounds characteristic of lipid oxidation. This study is a definitive step toward the commercialization of large-scale production of CLA-rich soy oil.

Objectives: To evaluate the measurement properties of the EuroQoL EQ-5D and two condition-specific patient-reported outcome measures--the Symptom Severity Index (SSI) and the Urinary Incontinence-Specific Quality of Life instrument (I-QoL)--in women with urinary incontinence., Methods: A questionnaire comprising all instruments was completed by women taking part in a clinical trial of physiotherapy for urinary incontinence. Follow-up questionnaires were at 6 weeks and 5 months. Data quality, internal consistency reliability, validity and responsiveness were assessed., Results: One hundred and seventy-four patients taking part in the clinical trial completed the questionnaire. Instruments had low levels of missing data. The EQ-5D had a large ceiling effect and poor responsiveness. The SSI had poor validity and responsiveness. The I-QoL had levels of reliability that supported application in group assessment, and in some cases, individual assessment, and good evidence of validity. The I-QoL was the most responsive instrument at both 6 weeks and 5 months., Conclusion: The I-QoL was the best performing instrument and is recommended as a continence-specific measure of quality of life in a clinical trial setting. The SSI and EQ-5D are not recommended. Alternative generic instruments, which support economic evaluation, require further evaluation in trials of female urinary incontinence.

Motivation: Metal reduction kinetics have been studied in cultures of dissimilatory metal reducing bacteria which include the Shewanella oneidensis strain MR-1. Estimation of system parameters from time-series data faces obstructions in the implementation depending on the choice of the mathematical model that captures the observed dynamics. The modeling of metal reduction is often based on Michaelis-Menten equations. These models are often developed using initial in vitro reaction rates and seldom match with in vivo reduction profiles., Results: For metal reduction studies, we propose a model that is based on the power law representation that is effectively applied to the kinetics of metal reduction. The method yields reasonable parameter estimates and is illustrated with the analysis of time-series data that describes the dynamics of metal reduction in S.oneidensis strain MR-1. In addition, mixed metal studies involving the reduction of Uranyl (U(VI)) to the relatively insoluble tetravalent form (U(IV)) by S. alga strain (BR-Y) were studied in the presence of environmentally relevant iron hydrous oxides. For mixed metals, parameter estimation and curve fitting are accomplished with a generalized least squares formulation that handles systems of ordinary differential equations and is implemented in Matlab. It consists of an optimization algorithm (Levenberg-Marquardt, LSQCURVEFIT) and a numerical ODE solver. Simulation with the estimated parameters indicates that the model captures the experimental data quite well. The model uses the estimated parameters to predict the reduction rates of metals and mixed metals at varying concentrations., Supplementary Information: Supplementary data are available at Bioinformatics online.

Background: Low back pain (LBP) is a major public health problem. Risk factors for the development and persistence of LBP include physical and psychological factors. However, most research activity has focused on physical solutions including manipulation, exercise training and activity promotion., Methods/design: This randomised controlled trial will establish the clinical and cost-effectiveness of a group programme, based on cognitive behavioural principles, for the management of sub-acute and chronic LBP in primary care. Our primary outcomes are disease specific measures of pain and function. Secondary outcomes include back beliefs, generic health related quality of life and resource use. All outcomes are measured over 12 months. Participants randomised to the intervention arm are invited to attend up to six weekly sessions each of 90 minutes; each group has 6-8 participants. A parallel qualitative study will aid the evaluation of the intervention., Discussion: In this paper we describe the rationale and design of a randomised evaluation of a group based cognitive behavioural intervention for low back pain.

Background: Blood transfusion is a risk factor for many inflammatory processes. Its supernatant fraction has been proven to activate neutrophils. We hypothesized that pentoxifylline (PTX) would attenuate stored blood-induced neutrophil activation and pro-inflammatory mediator production., Methods: Whole blood was incubated with HBSS, LPS (100 microg/mL), leukoreduced PRBC supernatant + LPS, or supernatant + LPS + PTX (2 mmol/L). TNF-alpha levels were measured by ELISA. MMP-9 was evaluated with zymography. Neutrophil CD66b expression was determined by flow cytometry in blood treated with HBSS, fMLP (1 micromol/L), supernatant + fMLP, or supernatant + fMLP + PTX., Results: TNF-alpha levels were elevated in both the LPS and supernatant + LPS groups (100%; P < 0.01 and 120%; P < 0.01, respectively). PTX administration resulted in a 106% decrease in TNF-alpha (P < 0.0001). MMP-9 levels were increased in all groups. Administration of PTX to the supernatant + LPS group generated a 33% decrease in MMP-9 levels, which was not statistically significant (P < 0.4). Upregulation of CD66b expression was seen in LPS and supernatant + LPS groups. Significant attenuation was seen with PTX (47%; P < 0.01)., Conclusions: PTX downregulates CD66b and TNF-alpha expression in supernatant-induced whole blood. Because blood transfusion can contribute to inflammatory injury, the adjunctive use of PTX may have therapeutic potential.

Source apportionment may be useful in epidemiological investigation of PM health effects, but variations and options in these methods leave uncertainties. An EPA-sponsored workshop investigated source apportionment and health effects analyses by examining the associations between daily mortality and the investigators' estimated source-apportioned PM(2.5) for Washington, DC for 1988-1997. A Poisson Generalized Linear Model (GLM) was used to estimate source-specific relative risks at lags 0-4 days for total non-accidental, cardiovascular, and cardiorespiratory mortality adjusting for weather, seasonal/temporal trends, and day-of-week. Source-related effect estimates and their lagged association patterns were similar across investigators/methods. The varying lag structure of associations across source types, combined with the Wednesday/Saturday sampling frequency made it difficult to compare the source-specific effect sizes in a simple manner. The largest (and most significant) percent excess deaths per 5-95(th) percentile increment of apportioned PM(2.5) for total mortality was for secondary sulfate (variance-weighted mean percent excess mortality=6.7% (95% CI: 1.7, 11.7)), but with a peculiar lag structure (lag 3 day). Primary coal-related PM(2.5) (only three teams) was similarly significantly associated with total mortality with the same 3-day lag as sulfate. Risk estimates for traffic-related PM(2.5), while significant in some cases, were more variable. Soil-related PM showed smaller effect size estimates, but they were more consistently positive at multiple lags. The cardiovascular and cardiorespiratory mortality associations were generally similar to those for total mortality. Alternative weather models generally gave similar patterns, but sometimes affected the lag structure (e.g., for sulfate). Overall, the variations in relative risks across investigators/methods were found to be much smaller than those across estimated source types or across lag days for these data. This consistency suggests the robustness of the source apportionment in health effects analyses, but remaining issues, including accuracy of source apportionment and source-specific sensitivity to weather models, need to be investigated.

As part of an EPA-sponsored workshop to investigate the use of source apportionment in health effects analyses, the associations between the participant's estimated source contributions of PM(2.5) for Phoenix, AZ for the period from 1995-1997 and cardiovascular and total nonaccidental mortality were analyzed using Poisson generalized linear models (GLM). The base model controlled for extreme temperatures, relative humidity, day of week, and time trends using natural spline smoothers. The same mortality model was applied to all of the apportionment results to provide a consistent comparison across source components and investigators/methods. Of the apportioned anthropogenic PM(2.5) source categories, secondary sulfate, traffic, and copper smelter-derived particles were most consistently associated with cardiovascular mortality. The sources with the largest cardiovascular mortality effect size were secondary sulfate (median estimate=16.0% per 5th-to-95th percentile increment at lag 0 day among eight investigators/methods) and traffic (median estimate=13.2% per 5th-to-95th percentile increment at lag 1 day among nine investigators/methods). For total mortality, the associations were weaker. Sea salt was also found to be associated with both total and cardiovascular mortality, but at 5 days lag. Fine particle soil and biomass burning factors were not associated with increased risks. Variations in the maximum effect lag varied by source category suggesting that past analyses considering only single lags of PM(2.5) may have underestimated health impact contributions at different lags. Further research is needed on the possibility that different PM(2.5) source components may have different effect lag structure. There was considerable consistency in the health effects results across source apportionments in their effect estimates and their lag structures. Variations in results across investigators/methods were small compared to the variations across source categories. These results indicate reproducibility of source apportionment results across investigative groups and support applicability of these methods to effects studies. However, future research will also need to investigate a number of other important issues including accuracy of results.

The unexpectedly long, and still unfinished, path towards a reliable mathematical model of glycolysis and its regulation in Lactococcus lactis is described. The model of this comparatively simple pathway was to be deduced from in vivo nuclear magnetic resonance time-series measurements of the key glycolytic metabolites. As to be expected from any nonlinear inverse problem, computational challenges were encountered in the numerical determination of parameter values of the model. Some of these were successfully solved, whereas others are still awaiting improved techniques of analysis. In addition, rethinking of the model formulation became necessary, because some generally accepted assumptions during model design are not necessarily valid for in vivo models. Examples include precursor-product relationships and the homogeneity of cells and their responses. Finally, it turned out to be useful to model only some of the metabolites, while using time courses of ubiquitous compounds such as adenosine triphosphate, inorganic phosphate, nicotinamide adenine dinucleotide (oxidised) and nicotinamide adenine dinucleotide (reduced) as unmodelled input functions. With respect to our specific application, the modelling process has come a long way, but it is not yet completed. Nonetheless, the model analysis has led to interesting insights into the design of the pathway and into the principles that govern its operation. Specifically, the widely observed feedforward activation of pyruvate kinase by fructose 1,6-bisphosphate is shown to provide a crucial mechanism for positioning the starving organism in a holding pattern that allows immediate uptake of glucose, as soon as it becomes available.

Background: Neutrophils play a major role as the first line in host defense after exposure to bacterial products. However, an exaggerated inflammatory response characterized by overwhelming neutrophil activation can be injurious to the host. Pentoxifylline (PTX), a nonspecific phosphodiesterase inhibitor, has been shown to attenuate neutrophil oxidative burst and decrease proinflammatory mediator synthesis. We hypothesized that PTX down-regulates neutrophil activation by decreasing the surface expression of both CD35 and CD66b, two markers of neutrophil degranulation., Materials and Methods: Venous blood was obtained from three healthy volunteers. Whole blood was incubated with HBSS (control), f-methionyl-leucyl-phenylalanine (fMLP, 1 microM/L), PTX (2 mM/L), or fMLP + PTX. CD35 and CD66b expression were measured by flow cytometry., Results: fMLP treatment caused a significant increase in CD35 and CD66b expression of when compared to controls (P < 0.01). PTX treatment revealed expression of both markers comparable to the control group. A 38% decrease in CD35 (64 +/- 12 versus 100; P < 0.01) and a 52% decrease in CD66b (48 +/- 7 versus 100; P < 0.01) expression were demonstrated in the fMLP + PTX group when compared to fMLP alone., Conclusion: In addition to the known effects of PTX on neutrophil oxidative burst, PTX also affects neutrophil degranulation, an essential step in enzyme release and subsequent tissue injury. These findings may have clinical relevance in the treatment of disease processes due to inflammation in which primed neutrophils play a role.

During the past three decades, receptor models have been used to identify and apportion ambient concentrations to sources. A number of groups are employing these methods to provide input into air quality management planning. A workshop has explored the use of resolved source contributions in health effects models. Multiple groups have analyzed particulate composition data sets from Washington, DC and Phoenix, AZ. Similar source profiles were extracted from these data sets by the investigators using different factor analysis methods. There was good agreement among the major resolved source types. Crustal (soil), sulfate, oil, and salt were the sources that were most unambiguously identified (generally highest correlation across the sites). Traffic and vegetative burning showed considerable variability among the results with variability in the ability of the methods to partition the motor vehicle contributions between gasoline and diesel vehicles. However, if the total motor vehicle contributions are estimated, good correspondence was obtained among the results. The source impacts were especially similar across various analyses for the larger mass contributors (e.g., in Washington, secondary sulfate SE=7% and 11% for traffic; in Phoenix, secondary sulfate SE=17% and 7% for traffic). Especially important for time-series health effects assessment, the source-specific impacts were found to be highly correlated across analysis methods/researchers for the major components (e.g., mean analysis to analysis correlation, r>0.9 for traffic and secondary sulfates in Phoenix and for traffic and secondary nitrates in Washington. The sulfate mean r value is >0.75 in Washington.). Overall, although these intercomparisons suggest areas where further research is needed (e.g., better division of traffic emissions between diesel and gasoline vehicles), they provide support the contention that PM(2.5) mass source apportionment results are consistent across users and methods, and that today's source apportionment methods are robust enough for application to PM(2.5) health effects assessments.

Background: Conventional fluid resuscitation with Ringer's lactated (RL) activates neutrophils and causes end-organ damage. We have previously shown that HSPTX, a combination of small volume hypertonic saline (HS) and pentoxifylline (PTX), a phosphodiesterase-inhibitor, downregulates in vitro neutrophil activation and proinflammatory mediator synthesis. Herein, we hypothesized that HSPTX decreases end-organ injury when compared with RL in an animal model of hemorrhagic shock., Methods: Sprague-Dawley rats were bled to a mean arterial pressure of 35 mm Hg for 1 hour. Animals were divided into 3 groups: sham (no shock, no resuscitation, n = 7), RL (32 mL/kg, n = 7), and HSPTX (7.5% NaCl 4 mL/kg + PTX 25 mg/kg; n = 7). Shed blood was infused after fluid resuscitation. Blood pressure was monitored until the end of resuscitation. Animals were sacrificed at 24 hour after resuscitation. Bronchoalveolar lavage fluid (BALF) was obtained for white cell count (total and differential) and TNF-alpha and IL-1beta levels were measured by ELISA. Lung and intestinal injury at 24 hour were evaluated by histopathology. Organ damage was graded by a pathologist and a score was created (0 = no injury; 3 = severe). Lung neutrophil infiltration was evaluated by MPO immune staining., Results: There were no differences in mean arterial pressure between groups. At 24 hours, BALF leukocyte count was decreased by 30% in HSPTX animals (p < 0.01). TNF-alpha and IL-1beta levels were markedly decreased in HSPTX-resuscitated animals compared with their RL counterparts (p < 0.01). HSPTX-resuscitated animals (lung injury score = 1.0 +/- 0.4) had markedly decreased acute lung injury compared with RL-treated animals (2.5 +/- 0.3) (p < 0.01). RL resuscitation led to a two-fold increase in lung neutrophil infiltration whereas in HSPTX-treated animals, the number of MPO + cells was similar to sham animals (p < 0.001). Intestinal injury was markedly attenuated by HSPTX (1.1 +/- 0.3) compared with RL animals (2.6 +/- 0.4) (p < 0.001)., Conclusions: HSPTX, a small volume resuscitation strategy with marked immunomodulatory potential led to a marked decrease in end-organ damage. HSPTX is an attractive alternative to RL in hemorrhagic shock resuscitation.

Although the association between exposure to ambient fine particulate matter with aerodynamic diameter < 2.5 microm (PM2.5) and human mortality is well established, the most responsible particle types/sources are not yet certain. In May 2003, the U.S. Environmental Protection Agency's Particulate Matter Centers Program sponsored the Workshop on the Source Apportionment of PM Health Effects. The goal was to evaluate the consistency of the various source apportionment methods in assessing source contributions to daily PM2.5 mass-mortality associations. Seven research institutions, using varying methods, participated in the estimation of source apportionments of PM2.5 mass samples collected in Washington, DC, and Phoenix, Arizona, USA. Apportionments were evaluated for their respective associations with mortality using Poisson regressions, allowing a comparative assessment of the extent to which variations in the apportionments contributed to variability in the source-specific mortality results. The various research groups generally identified the same major source types, each with similar elemental makeups. Intergroup correlation analyses indicated that soil-, sulfate-, residual oil-, and salt-associated mass were most unambiguously identified by various methods, whereas vegetative burning and traffic were less consistent. Aggregate source-specific mortality relative risk (RR) estimate confidence intervals overlapped each other, but the sulfate-related PM2.5 component was most consistently significant across analyses in these cities. Analyses indicated that source types were a significant predictor of RR, whereas apportionment group differences were not. Variations in the source apportionments added only some 15% to the mortality regression uncertainties. These results provide supportive evidence that existing PM2.5 source apportionment methods can be used to derive reliable insights into the source components that contribute to PM2.5 health effects.

Modern biology is increasingly developing techniques for measuring time series of global gene expression and of many simultaneous proteins or metabolites. These data contain valuable information on the dynamics of cells, which has to be extracted with computational means. Given a suitable mathematical model, this extraction is in principle a straightforward regression task, but the complexity and nonlinearity of the differential equations that describe biological systems cause severe difficulties when the systems are of realistic size. We propose a method of stepwise regression that can be applied effectively to linear portions of pathways. The method may be combined with other estimation methods and either directly yields reasonable parameter estimates or at least provides appropriate start values for subsequent nonlinear search algorithms. We illustrate the method with the analysis of in vivo NMR data describing the dynamics of glycolytic metabolites in Lactococcus lactis.

Background: Among older people, somatization has been reported to be common and to be predictive of high attendance in primary care. Its relationship with quality of life among older people has not been investigated., Objectives: The objective was to establish whether, among older primary care attenders, somatized symptoms are independently associated with relevant measures of quality of life., Method: Older primary care attenders (n = 127) completed measures of somatized symptoms, psychiatric status, physical health and health-related quality of life. Logistic regression analyses established independent relationships of health and sociodemographic variables with reports of overall quality of life, overall health, restriction of physical activities by health and restriction of social activities by health., Results: For all four outcomes, somatized symptoms independently predicted poorer quality of life ratings., Conclusions: Somatized symptoms independently influence quality of life in older primary care patients and are worthy of clinical attention., (Copyright (c) 2005 John Wiley & Sons, Ltd.)

Background: Hypertonic saline (HS) and pentoxifylline (PTX) have been shown to modulate polymorphonuclear neutrophil (PMN) functions after shock and sepsis. We hypothesized that a combination of HS and PTX (HSPTX) would down-regulate PMN functions and inflammatory mediator synthesis more effectively than each alone, possibly by acting at different steps of the signaling pathways, ultimately leading to an enhanced effect., Methods: Whole blood from healthy volunteers was stimulated with lipopolysaccharide (LPS) (100 microg/mL), f-methionyl-leucyl-phenylalanine (1 micromol/L), and phorbol 12-myristate 13-acetate (1 microg/mL). Baseline oxidative burst was measured by flow cytometry. Two different concentrations of NaCl to achieve increases of 10 mmol/L (HS10) and 40 mmol/L (HS40) above isotonicity, simulating increases in sodium levels seen after infusion of 3% HS and 7.5% HS, were used. PTX (2 mmol/L), HS10, HS40, HSPTX10, and HSPTX40 were added to whole blood concomitantly to the activators. PMN CD14 and CD11b expression were measured by flow cytometry and tumor necrosis factor-alpha levels by enzyme-linked immunosorbent assay in LPS-stimulated whole blood., Results: The combination of PTX with HS10 and with HS40 markedly decreased LPS- (27 +/- 7 and 23 +/- 6 vs. 100; p < 0.01), f-methionyl-leucyl-phenylalanine- (54 +/- 11 and 55 +/- 8 vs. 100; p < 0.05), and phorbol 12-myristate 13-acetate- (30 +/- 4 and 54 +/- 9 vs. 100; p < 0.01 and p < 0.05, respectively) induced PMN oxidative burst. Furthermore, a significant decrease in LPS-induced neutrophil CD11b expression after PTX treatment (79 +/- 5 vs. 100; p < 0.05) and HSPTX40 (68 +/- 7 vs. 100; p < 0.05) was observed. HSPTX10 (7 +/- 0.6; p < 0.001) or HSPTX40 (6 +/- 1.4; p < 0.001) markedly decreased tumor necrosis factor-alpha production to levels similar to those observed with PTX alone (6.5 +/- 0.5; p < 0.001) and significantly lower than HS10 (110 +/- 4.9; p < 0.001) and HS40 alone (83 +/- 1.5; p < 0.001), Conclusion: HSPTX down-regulates neutrophil activation and proinflammatory mediator synthesis more effectively that HS alone. HSPTX may have significant applications as a novel fluid resuscitation strategy in hemorrhagic shock.

The mineral concentration of meconia of small for gestational age (SGA) newborns were compared with those of appropriate for gestational age (AGA) newborns of similar gestational ages (GA) to determine whether differences may provide clues of possible nutritional deficits of SGA infants, given that levels of meconium minerals could indicate the use of minerals by the fetus and the sufficiency of the maternal supply of minerals. Twenty-one SGA and 24 AGA newborns were included. Eleven SGA and 15 AGA were < or = 35 weeks GA. Ten SGA and nine AGA infants were > or = 36 weeks GA. All meconia from each neonate was processed and assayed for iron, zinc, copper, manganese, calcium, magnesium, and phosphorus. In the < or = 35-week subgroups, the SGA infants had lower meconium iron and manganese concentrations than that of the AGA. Among > or = 36-week newborns, SGA infants had a higher birthweight-adjusted copper concentration than AGA infants, but no differences were observed for the remaining elements. Lower iron and manganese meconium in < or = 35-week SGA infants may reflect either a greater use or a decreased maternal supply. The higher birthweight-adjusted meconium copper in the > or = 36-week SGA infants may be due to a comparatively reduced fetal use or increased maternal supply. These data may assist in clarifying potential mechanisms affecting intrauterine growth and/or potential nutrient deficits in the neonatal period.

Modern methods of high-throughput molecular biology render it possible to generate time series of metabolite concentrations and the expression of genes and proteins in vivo. These time profiles contain valuable information about the structure and dynamics of the underlying biological system. This information is implicit and its extraction is a challenging but ultimately very rewarding task for the mathematical modeler. Using a well-suited modeling framework, such as Biochemical Systems Theory (BST), it is possible to formulate the extraction of information as an inverse problem that in principle may be solved with a genetic algorithm or nonlinear regression. However, two types of issues associated with this inverse problem make the extraction task difficult. One type pertains to the algorithmic difficulties encountered in nonlinear regressions with moderate and large systems. The other type is of an entirely different nature. It is a consequence of assumptions that are often taken for granted in the design and analysis of mathematical models of biological systems and that need to be revisited in the context of inverse analyses. The article describes the extraction process and some of its challenges and proposes partial solutions.

Background: The osmotic fragility of red blood cells reflects their membrane ability to maintain structural integrity. The osmolality at which the cells lyse is related to their shape, deformability, surface area/volume ratio and intrinsic membrane properties. In cord blood, there may be differences between premature and term infants, and be influenced by maternal medication and other factors. There have been no definitive findings on possible differences between preterm and full-term infant osmotic fragility., Aims: To determine if cord blood erythrocyte osmotic fragility differs between premature and full-term newborn infants, using two parallel techniques., Patients and Methods: Cord blood samples were obtained from preterm singletons (N=11), preterm multiple births (N=10), full-term infants (N=24), as well as adults (N=22), for comparison. An osmotic fragility test was used to determine the NaCl concentration at which 20%, 50% and 80% of hemolysis occurred using individual logistic curves. A glycerol lysis test determined the time needed to lyse 50% of red blood cells., Results: Cord blood red cells of multiple birth premature infants were more hemolysis-resistant than erythrocytes from full-term infants or adults. Another index of osmotic fragility, the difference in NaCl concentration for 80% and 20% red cell hemolysis showed that premature infants had greater differences than full-term infants or adults. Glycerol lysis time revealed that both preterm and full-term infants had an erythrocyte subpopulation that took longer than adult blood to attain 50% hemolysis. Correlation between both tests was very significant (r=-0.603, P<0.0001, N=67)., Conclusions: This study shows that erythrocytes of premature infants, although, in average, less osmotically fragile than those of healthy full-term infants, contain a more hemolysis-susceptible cell subpopulation.

Reactive dyes constitute a significant portion of colorants used in industries ranging from the textile industry to the paper industry. In most cases, the effluent streams from textile plants are highly colored, and treatment methods for dye decolorization such as chemical oxidation need to be explored. The oxidation processes investigated in this study are those of ozonation, ultrasound, and ultrasound-enhanced ozonation. The oxidation of an anthraquinone dye was studied under conditions of varying ultrasonic power, dye concentration, ozone concentration, pH, and temperature. Laboratory experiments were performed using a semibatch reactor by ozonating dye samples with and without ultrasound. Under conditions of constant ultrasonic radiation and continuous gas application, decolorization rates have been enhanced by ultrasound. The apparent first-order rate constants increased between 35 and 204% for the ultrasonic power inputs between 40 W/L and 120 W/L compared with ozonation alone. The effects of ultrasonic power input on the gas-liquid mass-transfer coefficient were also investigated and the results indicate that an increase in ultrasonic power input increases the mass-transfer coefficient. The mass-transfer coefficient increased between 89 and 93% for ozone inlet concentrations between 5.4 and 9.4 mg/L at an ultrasonic power of 120 W/L compared with ozonation alone. The reactions of the dye with ultrasound-enhanced ozone occurred through the hydroxyl radical pathway.

The Metabolic Reaction Analysis Database (MRAD) is a relational database based on the Entity-Relationship (ER) model which combines information about organisms, biochemical pathways, reactions, enzymes, substrates, products and genes. It describes 244,596 genes in 79 organisms, 6,552 enzymes, and 3,552 reactions, 3,100 substrates, 2,866 products and 118 metabolic pathways. The MRAD graphical user interface allows for the identification of metabolic reactions which are similar and dissimilar in multiple organisms, reactions in a pathway which are missing in an organism and using any combination between one to six of the biological entities of organisms, genes, pathways, enzymes, substrates and products to determine metabolic reactions. MRAD provides a powerful and efficient tool for the construction of flux balance models for metabolic engineering applications., (Copyright 2003 S. Karger AG, Basel)

There has been increasing emphasis in medical research on the design and analysis of quality of life scales. Many quality of life scales are ordinal and statistical methods such as ordinal regression models have been reviewed on a number of occasions. However, when such models are applied, the way the data have been generated is often overlooked. In this paper we illustrate the use of ordinal regression models, in particular the proportional odds model, the partial proportional odds model and the stereotype model in the MRC Cognitive Function and Ageing Study (MRC CFAS). The partial proportional odds and the stereotype models are often under-utilized, perhaps due to the lack of available software. However, in this paper, analysis based on these models has been carried out using the popular statistical software package SAS and macros devised in SAS. Furthermore, bootstrapping techniques have been applied to obtain valid estimates of the standard errors of the parameters in the stereotype model. Strikingly different results were obtained using the different ordinal regression models. We conclude that the way the data have been generated is particularly important for the analysis of quality of life assessments. Different methods of generating scores yield data with different properties. It is now possible to fit a variety of ordinal regression models and so select the appropriate one that correctly models the data.

Previous research suggests that mentor relationships are facilitative of career success, career satisfaction, and retention in organizations. Yet, little research has been done to explore the prevalence or function of mentor relationships in military populations. In this study, preliminary data were collected regarding the prevalence of mentor relationship experiences among 576 third year midshipmen at the U.S. Naval Academy. Only 40% of respondents had ever experienced a mentor relationship. Most mentors were senior military personnel, and 87% were male. Most relationships were mutually initiated, and they tended to last for several years. Although both career and psychosocial mentor functions were present in these relationships, psychosocial functions were most notable and most highly correlated with positive appraisals of mentor relationships. Midshipmen viewed mentoring as extremely important and rated their own mentor relationships as extremely positive. Implications for further research on mentoring are discussed.

Health Related Quality of Life (HRQoL) measures are becoming more frequently used in clinical trials, as both primary and secondary endpoints. Investigators are now asking statisticians for advice on how to plan (e.g., sample size) and analyze studies using HRQoL measures. HRQoL measures such as the SF-36 are usually measured on an ordered categorical (ordinal) scale. In the designing stages and when analyzing, the scales are often scored and the scores treated as if they were continuous and normally distributed. However the ordinal scaling of HRQoL measures leads to problems in determining sample size, and conventional parametric methods of estimation and hypothesis testing may not be appropriate for such outcomes. We present practical guidelines for the design and analysis of trials with HRQoL measures as outcomes. We used conventional statistical methods (i.e., t-tests and multiple regression), various ordinal regression models (proportional odds, continuation ratio, polytomous and stereotype) and bootstrap methods to analyze an HRQoL dataset. To illustrate the various methods we used HRQoL data on the SF-36 Role Limitations Emotional dimension for two groups of patients with leg ulcers. The bootstrap, t-test, and multiple regression methods gave similar results. The various ordinal regression models also gave similar results. If the HRQoL measure has a large number of ordered categories, most of which are occupied, and the underlying scale really is continuous but measured imperfectly by an instrument with a limited number of discrete values, then an informal rule of thumb is that this discrete scale should be treated as continuous if it has seven or more categories and as ordinal otherwise.

Relatively little is known about the personality characteristics of military personnel, particularly those who are most successful in military careers. This study evaluated the personality characteristics of 530 third-year midshipmen at the U.S. Naval Academy. Participants completed the Hogan Personality Inventory and a demographic questionnaire. Class ranking data were also obtained as an indicator of success at the Naval Academy. The results indicated that compared with national norms, midshipmen scored somewhat higher on scales of ambition, sociability, intellectance, and school success and lower on scales of adjustment, likability, and prudence. Ambition, prudence, intellectance, and school success were each significantly positively correlated with class standing. The implications of these findings for understanding personality correlates of success in military leadership are discussed.

Objective personality assessment instruments offer a comparatively underutilized source of clinical data in attempts to evaluate and predict risk for suicide. In contrast to focal suicide risk measures, global personality inventories may be useful in identification of long-standing styles that predispose persons to eventual suicidal behavior. This article reviews the empirical literature regarding the efficacy of established personality inventories in predicting suicidality. The authors offer several recommendations for future research with these measures and conclude that such objective personality instruments offer only marginal utility as sources of clinical information in comprehensive suicide risk evaluations. Personality inventories may offer greatest utility in long-term assessment of suicide risk.

Risk factors for suicide among active-duty members of the United States Marine Corps were investigated. Three groups were suicide attempters (n = 172), completers (n = 22), and a nonpsychiatric comparison group (n = 384). A series of multiple regression and discriminant analyses were conducted to assess whether any of 137 selected risk-factors differentiated the suicidal group from the comparison group. The following factors differentiated suicide attempters and completers from the comparison group and were associated with increased suicide risk: History of Abuse, Neglect, or Rejection, Lower Performance Evaluation, Symptoms of Depression, No History of Gambling Behavior, Younger Age, History of Alcohol Abuse, and Hopelessness. A discriminant analysis using these seven variables resulted in a 77% accuracy rate. When evaluating variables that could be obtained by a review of military records alone, three variables differentiated the attempters and completers from the comparison group, Lower Performance Evaluation, Younger Age, and a History of Military or Legal Problems. These variables correctly classified 73% of the sample. Implications for suicide-risk assessment for individuals in the Marine Corps are provided.

Objective: To (a) review existing literature and current concepts on Hematuria-Loin Pain Syndrome (HLPS) and (b) to describe seven cases of this syndrome., Patients and Setting: Seven HLPS patients seen over a period of 8 years by the pain and nephrology services of the Toronto Hospital, Toronto, Ontario, Canada., Methods and Results: Retrospective analysis was performed. All patients were remarkable for the variability of clinical presentation, pain characteristics, and dissociation of pain and hematuria occurrence. Routine renal investigations revealed different benign kidney pathologies in 5 of 7 patients. All patients, however, displayed variable combinations of personality factors, drug seeking behaviour, psychopathology, and presence of significant psychosocial stressors. Four cases were managed conservatively with antidepressants, anxiolytics, and supportive counseling and did very well despite persistent hematuria in two., Conclusions: HLPS does not constitute a distinct clinicopathological entity. In a minority of cases only underlying kidney pathology is related to pain, and in many cases psychosocial stressors and underlying psychopathology may play a significant role in the reported disabling pain. A concerted medical/psychological approach is advocated.

Aim: To evaluate the role of recombinant human erythropoietin (R-HuEpo) in reducing iron infusion, which may exacerbate free radical damage, leading to chronic lung disease., Methods: A multicentre, randomised, placebo controlled, double blind study was carried out in four neonatal intensive care units in Yorkshire. Infants were randomly allocated and received either R-HuEpo (480 U/kg/wk) or placebo by twice weekly subcutaneous injection. The primary outcome measure was the number of days on respiratory support and a secondary outcome the number of blood transfusions required., Results: Forty two very low birthweight (VLBW) infants were randomly allocated. There was little difference in the need for respiratory support one month after randomisation, but subsequently there was a trend towards a reduction in the proportion requiring respiratory support in the R-HuEpo group (difference at three months -0.50, 95% confidence interval -1.00, 0.17). During stay in hospital, the median number of blood transfusions was lower for infants in the R-HuEpo group (difference in medians -2, 95% CI -4, 0). The study was stopped early because of failure to recruit babies at the expected rate., Conclusions: R-HuEpo seems to reduce the number of days in oxygen for ill VLBW infants. These data could be used to construct a larger multicentre study to evaluate this effect further.

This study evaluated the sexual knowledge (including contraceptive and reproductive knowledge), contraceptive use, and self-esteem among a sample of 158 male and female United States Navy sailors assigned to Navy ships. In spite of the fact that men and women viewed themselves as relatively knowledgeable with respect to contraception, results showed substantial knowledge deficits. Women demonstrated significantly greater sexual knowledge than men, and contraceptive/ reproductive knowledge was highly correlated with self-reported use of contraceptives. Finally, self-esteem was highly correlated with sexual knowledge and certain contraceptive use behaviors.

This study evaluated the personality characteristics of U.S. Navy divers. Seventy-two active duty Navy divers completed the Million Index of Personality Styles. The sample strongly showed the traits of Enhancing. Modifying, Individuating, Thinking, and Controlling. The results are discussed in terms of adaptation to the environmental demands of military diving. Suggestions for further research are offered.

This study evaluated the effects of locus of control, occupational stress, and psychological symptom distress on reported job satisfaction in a sample of 34 practicing nurses. As predicted, greater work-related stress and higher psychological symptom distress were significantly negatively correlated with job satisfaction. External locus of control was also negatively associated with job satisfaction.

This study evaluated the personality characteristics of senior enlisted and occupationally successful Navy submarine personnel. One hundred subjects completed the Schedule for Nonadaptive and Adaptive Personality (SNAP). Results indicated that the traits of detachment, propriety, and workaholism were most descriptive of the sample. Thirty-seven percent met SNAP criteria for a personality disorder, typically antisocial, obsessive-compulsive, or avoidant. The results are discussed in terms of adaptation to environmental demands aboard submarines. Suggestions for further research are offered.

The clinical spectrum of dengue fever ranges from asymptomatic infection through severe haemorrhage and sudden fatal shock. Increased capillary permeability is the diagnostic feature of dengue haemorrhagic fever (DHF). The pathophysiology of DHF/dengue shock syndrome (DSS) is related to sequential infection with different serotypes of the virus, variations in virus virulence, interaction of the virus with environmental or host factors and a combination of various risk factors. Infection due to low virulence strains is assumed to be the reason for the infrequent incidence of serious dengue disease in India. Since all four serotypes of the dengue virus have been implicated in various outbreaks in this country and several outbreaks of DHF/DSS have been recorded since the first report in 1963, further epidemics of the disease are likely. The situation is aggravated by the recent emergence of DHF/DSS in Sri Lanka. In view of the potential of this disease to spread, effective preventive and control measures should be a priority.

Undergraduate student volunteers either were given a choice of coping strategies or were assigned to a coping strategy which was used to help them tolerate the cold pressor. Subjects who were given a choice of coping strategies reported their strategy to be more credible and perceived a greater sense of control than subjects who were not given a choice. Improved pain tolerance, however, did not result directly from being given a choice. Increases in pain tolerance depended on locus of control. Subjects who had a high internal health locus of control reported a greater strength of self-efficacy and demonstrated increased pain tolerance following a choice of strategies. In comparison, subjects who reported a more external health locus of control did not benefit from receiving a choice. This study has implications for our understanding of the role of choice in therapy and for improving the effectiveness of our interventions with individuals.