The Rat Genome Database (RGD) facilitates genomic and phenotypic data integration across multiple species for biomedical research.

Model organism research is essential for discovering the mechanisms of human diseases by defining biologically meaningful gene to disease relationships. The Rat Genome Database (RGD, ( https://rgd.mcw.edu )) is a cross-species knowledgebase and the premier online resource for rat genetic and physiologic data. This rich resource is enhanced by the inclusion and integration of comparative data for human and mouse, as well as other human disease models including chinchilla, dog, bonobo, pig, 13-lined ground squirrel, green monkey, and naked mole-rat. Functional information has been added to records via the assignment of annotations based on sequence similarity to human, rat, and mouse genes. RGD has also imported well-supported cross-species data from external resources. To enable use of these data, RGD has developed a robust infrastructure of standardized ontologies, data formats, and disease- and species-centric portals, complemented with a suite of innovative tools for discovery and analysis. Using examples of single-gene and polygenic human diseases, we illustrate how data from multiple species can help to identify or confirm a gene as involved in a disease and to identify model organisms that can be studied to understand the pathophysiology of a gene or pathway. The ultimate aim of this report is to demonstrate the utility of RGD not only as the core resource for the rat research community but also as a source of bioinformatic tools to support a wider audience, empowering the search for appropriate models for human afflictions.

Sphagnum bleaching: Bicarbonate 'toxicity' and tolerance for seven Sphagnum species.

Growth and functioning of Sphagnum mosses are closely linked to water level and chemistry. Sphagnum mosses occur in wet, generally acidic conditions, and when buffered, alkaline water is known to negatively impact Sphagnum. The effects of time, dose and species-specific responses of buffered, alkaline water on Sphagnum are largely unknown. We investigated the effects of bicarbonate and calcium on the survival, growth and physiological functioning of seven Sphagnum species occurring in contrasting environments, from raised bogs to (rich) fens. Mosses were submerged in different concentrations of bicarbonate and calcium solutions for 10 weeks under climate-controlled circumstances. After 2 weeks, all species exposed to the high bicarbonate treatment (2.0 mM) showed severe potassium leakage and swift discoloration. In contrast, species showed differential responses to the intermediate bicarbonate treatment (0.8 mM), some with a later onset of potassium leakage. S. squarrosum, S. teres & S. contortum generally persisted the longest, with all species dying after 6 to 10 weeks. Calcium alone, in contrast, negatively affected S. squarrosum, S. teres & S. contortum, causing discoloration and potassium leakage. Our study shows enrichment with bicarbonate, but not calcium, is detrimental for most Sphagnum species tested. A mechanistic model was developed that is consistent with dose and duration dependence and the species specificity. Future conservation and restoration measures for Sphagnum-dominated habitats and Sphagnum farming (cultivation, production and harvest of Sphagnum moss biomass) should limit flooding with bicarbonate-rich waters while investigating new management options, like acidifying surface waters to lower bicarbonate levels.

The effect of induced hindlimb lameness on thoracolumbar kinematics during treadmill locomotion.

REASON FOR PERFORMING STUDY: There are no detailed studies describing a relationship between hindlimb lameness and altered motion of the back. OBJECTIVES: To quantify the effect of induced subtle hindlimb lameness on thoracolumbar kinematics in the horse. METHODS: Kinematics of 6 riding horses were measured during walk and trot on a treadmill before and during application of pressure on the sole of the left hindlimb using a well-established sole pressure model. Reflective markers were located at anatomical landmarks on the limbs, back, head and neck for kinematic recordings. Ground reaction forces (GRF) in individual limbs were calculated from kinematics to detect changes in loading of the limbs. RESULTS: When pressure on the sole of the hindlimb was present, horses were judged as lame (grade 2 on the AAEP scale 1-5) by an experienced clinician. No significant unloading of this limb was found in the group of horses (unloading was observed in 4 animals, but was not detectable in the other 2), but statistically significant effects on back kinematics were detected. The overall flexion-extension (FE) range of motion (ROM) of the vertebral column was increased at walk, especially in the thoracic segments. Axial rotation (AR) ROM of the pelvis was also increased. At trot, the FE ROM was decreased only in the segment L3-L5-S3. During the stance phase of the lame limb, the segment T6-T10-T13 was more flexed and the neck was lowered at both gaits; the thoracolumbar segments were more extended at walk and trot. There were no significant changes in the stride length or protraction-retraction angles in any of the limbs. CONCLUSIONS: Subtle hindlimb lameness provoked slight but detectable changes in thoracolumbar kinematics. The subtle lameness induced in this study resulted in hyperextension and increased ROM of the thoracolumbar back, but also in decreased ROM of the lumbosacral segment and rotational motion changes of the pelvis. POTENTIAL RELEVANCE: Even subtle lameness can result in changes in back kinematics, which emphasises the intricate link between limb function and thoracolumbar motion. It may be surmised that, when chronically present, subtle lameness induces back dysfunction.

The effect of induced forelimb lameness on thoracolumbar kinematics during treadmill locomotion.

REASONS FOR PERFORMING STUDY: Lameness has often been suggested to result in altered movement of the back, but there are no detailed studies describing such a relationship in quantitative terms. OBJECTIVES: To quantify the effect of induced subtle forelimb lameness on thoracolumbar kinematics in the horse. METHODS: Kinematics of 6 riding horses was measured at walk and at trot on a treadmill before and after the induction of reversible forelimb lameness grade 2 (AAEP scale 1-5). Ground reaction forces (GRF) for individual limbs were calculated from kinematics. RESULTS: The horses significantly unloaded the painful limb by 11.5% at trot, while unloading at walk was not significant. The overall flexion-extension range of back motion decreased on average by 0.2 degrees at walk and increased by 3.3 degrees at trot (P<0.05). Changes in angular motion patterns of vertebral joints were noted only at trot, with an increase in flexion of 0.9 degrees at T10 (i.e. angle between T6, T10 and T13) during the stance phase of the sound diagonal and an increase in extension of the thoracolumbar area during stance of the lame diagonal (0.7degrees at T13, 0.8 degres at T17, 0.5 degres at L1, 0.4 degrees at L3 and 0.3 degrees at L5) (P<0.05). Lameness further caused a lateral bending of the cranial thoracic vertebral column towards the lame side (1.3 degrees at T10 and 0.9 degrees at T13) (P<0.05) during stance of the lame diagonal. CONCLUSIONS: Both range of motion and vertebral angular motion patterns are affected by subtle forelimb lameness. At walk, the effect is minimal, at trot the horses increased the vertebral range of motion and changed the pattern of thoracolumbar motion in the sagittal and horizontal planes, presumably in an attempt to move the centre of gravity away from the lame side and reduce the force on the affected limb. POTENTIAL RELEVANCE: Subtle forelimb lameness affects thoracolumbar kinematics. Future studies should aim at elucidating whether the altered movement patterns lead to back and/or neck dysfunction in the case of chronic lameness.

Radial oxygen loss by the cushion plant Eriocaulon schimperi prevents methane emissions from an East-African mountain mire.

Groundwater-fed fens are known sources of methane (CH4 ) emissions to the atmosphere, and these are known to be mediated by the vegetation. In a fen located in the Bale Mountains, Ethiopia, we assessed the effects of a cushion plant (Eriocaulon schimperi) and a sedge (Carex monostachya) on rhizosphere biogeochemistry. Methane and CO2 concentrations and pH were measured in pore-water at different depths in the profile. Redox potentials and NaCl-extractable element concentrations were analysed in soil samples from sites dominated by either E. schimperii or C. monostachya. Nutrient and element concentration were analysed in plant tissues. At Carex-dominated sites, CH4 concentrations increased from 70 µmol·l-1 at a depth of 10 cm to 130 µmol·l-1 at a depth of 100 cm. CH4 concentrations at Eriocaulon-dominated sites were almost zero (<1 µmol·l-1 ) to a depth of 100 cm. Simultaneously, soil redox potentials and CO2 concentrations were higher at Eriocaulon-dominated sites, indicating a low potential for CH4 production and a high potential for CH4 oxidation. Eriocaulon schimperi displayed a root investment strategy to cope with the harsh environment, similar to the cushion plant Astelia pumila in Patagonian bogs. This strategy is characterised by high root/shoot ratios, high root porosity and density under high redox conditions. Both cushion plant species create an aerobic rhizosphere through radial oxygen loss from deep roots, which strongly reduce CH4 fluxes to the atmosphere.

Differential responses of two wetland graminoids to high ammonium at different pH values.

Enhanced soil ammonium (NH4+) concentrations in wetlands often lead to graminoid dominance, but species composition is highly variable. Although NH4+ is readily taken up as a nutrient, several wetland species are known to be sensitive to high NH4+ concentrations or even suffer toxicity, particularly at low soil pH. More knowledge about differential graminoid responses to high NH4+ availability in relation to soil pH can help to better understand vegetation changes. The responses of two wetland graminoids, Juncus acutiflorus and Carex disticha, to high (2 mmol·l(-1) ) versus control (20 µmol·l(-1) ) NH4+ concentrations were tested in a controlled hydroponic set up, at two pH values (4 and 6). A high NH4+ concentration did not change total biomass for these species at either pH, but increased C allocation to shoots and increased P uptake, leading to K and Ca limitation, depending on pH treatment. More than 50% of N taken up by C. disticha was invested in N-rich amino acids with decreasing C:N ratio, but only 10% for J. acutiflorus. Although both species appeared to be well adapted to high NH4+ loadings in the short term, C. disticha showed higher classic detoxifying responses that are early warning indicators for decreased tolerance in the long term. In general, the efficient aboveground biomass allocation, P uptake and N detoxification explain the competitive strength of wetland graminoids at the expense of overall biodiversity at high NH4+ loading. In addition, differential responses to enhanced NH4+ affect interspecific competition among graminoids and lead to a shift in vegetation composition.

[Measuring the quality of life in economic evaluations: the Dutch EQ-5D tariff]. / Kwaliteit van leven meten in economische evaluaties: het Nederlands EQ-5D-tarief.

OBJECTIVE: To value EQ-5D health states by a general Dutch public. EQ-5D is a standardised questionnaire that is used to calculate quality-adjusted life-years for cost-utility analysis. DESIGN: Descriptive. METHOD: A sample of 309 Dutch adults from Rotterdam and surroundings was asked to value 17 EQ-5D health states using the time trade-off method. Regression analysis was applied to the valuations of these 17 health states. By means of the estimated regression coefficients, which together constitute the so-called Dutch tariff, valuations can be determined for all possible EQ-5D health states. These values reflect the relative desirability of health states on a scale where 1 refers to full health and 0 refers to death. Societal valuations are necessary in order to correct life-years for the quality of life. RESULTS: Complete data were obtained from 298 persons. Theywere representative for the Dutch population as far as age, gender and subjective health were concerned, but had a somewhat higher educational level. The estimated Dutch EQ-5D tariff revealed that the respondents assigned the most weight to (preventing) pain and anxiety or depression, followed by mobility, self-care and the activities of daily living. The Dutch tariff differed from the UK ('Measurement and Valuation of Health') tariff, which is currently used in Dutch cost-utility analyses. Compared to UK respondents, Dutch respondents assigned more weight to anxiety and depression and less weight to the other dimensions. Conclusion. The valuation of health states by this representative Dutch study group differed from the valuation that is currently used in Dutch cost-utility analyses.

Pulmonary homograft repair of a mycotic aortic aneurysm in an infant.

Thoracic aortic aneurysms are rare in children and even more unusual in infants. The vast majority are mycotic. Frequently, those with mycotic thoracic aortic aneurysm do not survive and the diagnosis is made at autopsy. We present the case of an asymptomatic infant found to have a mycotic thoracic aortic aneurysm. The clinical course, diagnosis, and surgical repair of the aneurysm with pulmonary homograft are discussed.

Risk-adjusted capitation: recent experiences in The Netherlands.

The market-oriented health care reforms taking place in the Netherlands show a clear resemblance to the proposals for managed competition in U.S. health care. In both countries good risk adjustment mechanisms that prevent cream skimming--that is, that prevent plans from selecting the best health risks--are critical to the success of the reforms. In this paper we present an overview of the Dutch reforms and of our research concerning risk-adjusted capitation payments. Although we are optimistic about the technical possibilities for solving the problem of cream skimming, the implementation of good risk-adjusted capitation is a long-term challenge.

Risk sharing as a supplement to imperfect capitation: a tradeoff between selection and efficiency.

This paper describes forms of risk sharing between insurers and the regulator in a competitive individual health insurance market with imperfectly risk-adjusted capitation payments. Risk sharing implies a reduction of an insurer's incentives for selection as well as for efficiency. In a theoretical analysis, we show how the optimal extent of risk sharing may depend on the weights the regulator assigns to these effects. Some countries employ outlier or proportional risk sharing as a supplement to demographic capitation payments. Our empirical results strongly suggest that other forms of risk sharing yield better tradeoffs between selection and efficiency.

Risk-adjusted capitation based on the Diagnostic Cost Group Model: an empirical evaluation with health survey information.

OBJECTIVE: To evaluate the predictive accuracy of the Diagnostic Cost Group (DCG) model using health survey information. DATA SOURCES/STUDY SETTING: Longitudinal data collected for a sample of members of a Dutch sickness fund. In the Netherlands the sickness funds provide compulsory health insurance coverage for the 60 percent of the population in the lowest income brackets. STUDY DESIGN: A demographic model and DCG capitation models are estimated by means of ordinary least squares, with an individual's annual healthcare expenditures in 1994 as the dependent variable. For subgroups based on health survey information, costs predicted by the models are compared with actual costs. Using stepwise regression procedures a subset of relevant survey variables that could improve the predictive accuracy of the three-year DCG model was identified. Capitation models were extended with these variables. DATA COLLECTION/EXTRACTION METHODS: For the empirical analysis, panel data of sickness fund members were used that contained demographic information, annual healthcare expenditures, and diagnostic information from hospitalizations for each member. In 1993, a mailed health survey was conducted among a random sample of 15,000 persons in the panel data set, with a 70 percent response rate. PRINCIPAL FINDINGS: The predictive accuracy of the demographic model improves when it is extended with diagnostic information from prior hospitalizations (DCGs). A subset of survey variables further improves the predictive accuracy of the DCG capitation models. The predictable profits and losses based on survey information for the DCG models are smaller than for the demographic model. Most persons with predictable losses based on health survey information were not hospitalized in the preceding year. CONCLUSIONS: The use of diagnostic information from prior hospitalizations is a promising option for improving the demographic capitation payment formula. This study suggests that diagnostic information from outpatient utilization is complementary to DCGs in predicting future costs.

Mandatory pooling as a supplement to risk-adjusted capitation payments in a competitive health insurance market.

Risk-adjusted capitation payments (RACPs) to competing health insurers are an essential element of market-oriented health care reforms in many countries. RACPs based on demographic variables only are insufficient, because they leave ample room for cream skimming. However, the implementation of improved RACPs does not appear to be straightforward. A solution might be to supplement imperfect RACPs with a form of mandatory pooling that reduces the incentives for cream skimming. In a previous paper it was concluded that high-risk pooling (HRP), is a promising supplement to RACPs. The purpose of this paper is to compare HRP with two other main variants of mandatory pooling. These variants are called excess-of-loss (EOL) and proportional pooling (PP). Each variant includes ex post compensations to insurers for some members which depend to various degrees on actually incurred costs. Therefore, these pooling variants reduce the incentives for cream skimming which are inherent in imperfect RACPs, but they also reduce the incentives for efficiency and cost containment. As a rough measure of the latter incentives we use the percentage of total costs for which an insurer is at risk. This paper analyzes which of the three main pooling variants yields the greatest reduction of incentives for cream skimming given such a percentage. The results show that HRP is the most effective of the three pooling variants.

Chronic conditions, psychological distress and the use of psychoactive medications.

OBJECTIVE: The purpose of this study was to examine whether number and type of chronic conditions are related to psychological distress, fatigue, and the use of psychoactive medications. METHODS: Data were taken from a community-based sample of adults who had responded to a health survey mailing (N = 9428). Chronic conditions were assessed by self-report. Information on the use of psychoactive medications was extracted from a claims database of prescribed drugs. Chronic conditions were compared controlling for confounding factors. RESULTS: Strong associations were found between the number of chronic conditions, on the one hand, and psychological distress and fatigue, on the other. There was a less strong association between these factors and the use of medication for anxiety and stress, the use of sleeping pills or tranquilizers, and the use of antidepressants. There was only a partial association between type of condition, psychological distress, and fatigue. Migraine had the broadest impact, having an effect on psychological distress and fatigue and on the use of anxiolytics, as well as the use of antidepressants. CONCLUSION: The association of chronic conditions with psychological distress, fatigue, and the use of psychoactive medications appeared to be related more to the number of conditions than to the type of condition.

Patient and doctor delay in acute myocardial infarction: a study in Rotterdam, The Netherlands.

BACKGROUND: Early thrombolytic therapy for patients having a myocardial infarct size and improves survival. AIM: A study was undertaken to examine the components of pre-hospital delay in patients with retrospectively proven myocardial infarction. METHOD: Data were gathered from 300 patients with a documented myocardial infarction admitted to three hospitals in Rotterdam, the Netherlands. Interviews were carried out with patients, questionnaires were given to their spouses or significant others, medical information was provided by cardiologists, and logbook information was gathered from the ambulance service. RESULTS: Half of all patients (51%) called for medical help within 30 minutes of symptom onset. General practitioners arrived within 11 minutes in half of the 257 cases to which they were called. However, in half of the 257 cases, decision making by the general practitioner before the patient was sent to a hospital took more than 82 minutes. The ambulance arrived within 15 minutes in 90% of all 242 cases, while the time required for stabilization of the patient by the ambulance staff and transport to the hospital took a median of 15 minutes. CONCLUSION: Compared with earlier studies, patients with a myocardial infarction called for help sooner. However, it may take a considerable time before the general practitioner refers the patient to hospital. Further research is needed to design measures which will improve the diagnostic power of the general practitioner in order to further reduce pre-hospital delay.

Risk-adjusted capitation payments: developing a diagnostic cost groups classification for the Dutch situation.

In many countries market-oriented health care reforms are high on the political agenda. A common element of these reforms is that the consumers may choose among competing health insurers or health plans, which are largely financed through premium-replacing capitation payments. Since 1993, Dutch sickness funds receive risk-adjusted capitation payments based on demographic factors. It has been shown that the predictive accuracy of a demographic capitation model improves when it is extended with diagnostic information from prior hospitalizations, in the form of Diagnostic Costs Groups (DCGs). In this study a DCG classification is developed using Dutch cost data of sickness fund members of all ages. The study also dealt with the question of how to handle high discretion diagnoses. For the Dutch situation high discretion diagnoses may be defined as those diagnoses for which day case treatment is a possible alternative for a hospital admission. Grouping persons with a hospital admission for high discretion diagnoses together with people without an admission resulted in a slight reduction of the predictive accuracy of the DCG model. Adequate risk-adjustment is critical to the success of market-oriented health care reforms. The use of diagnostic information from prior hospitalizations seems a promising option for improving the capitation formula.

Interactions between copper and cadmium modify metal organ distribution in mature tilapia, Oreochromis mossambicus.

Sexually mature female tilapia were exposed to sublethal concentrations of waterborne Cu and/or Cd over 6 days, and subsequent body concentrations of these metals were determined in several organs. The results show that the distribution of Cu and Cd was metal and organ specific. This is demonstrated, for example, by the observation that in tilapia, Cu exposure did not result in Cu accumulation in the liver, whereas in the intestinal wall, notably high concentrations of Cu and Cd were measured in metal exposed fish. In addition to single metal exposed fish, we also determined Cu and Cd body distribution in Cu?Cd co-exposed fish. The observed interactions in metal accumulation were most pronounced in the organs of fish exposed to low, environmentally realistic, metal concentrations.

Health-based risk adjustment: is inpatient and outpatient diagnostic information sufficient?

Adequate risk adjustment is critical to the success of market-oriented health care reforms in many countries. Currently used risk adjusters based on demographic and diagnostic cost groups (DCGs) do not reflect expected costs accurately. This study examines the simultaneous predictive accuracy of inpatient and outpatient morbidity measures and prior costs. DCGs, pharmacy cost groups (PCGs), and prior year's costs improve the predictive accuracy of the demographic model substantially. DCGs and PCGs seem complementary in their ability to predict future costs. However, this study shows that the combination of DCGs and PCGs still leaves room for cream skimming.

Health-based risk adjustment Improving the pharmacy-based cost group model to reduce gaming possibilities.

The pharmacy-based cost group (PCG) model uses medication prescribed to individuals in a base-year as marker for chronic conditions which are employed to adjust capitation payments to their health plans in the subsequent year. Although the PCG model enhances predictive performance, possibilities for gaming may arise as it is based on prior utilization. This study investigates several strategies to mitigate this problem. The best strategies appear to be: use a (high) number of prescribed daily doses to assign persons to PCGs, do not allow for comorbidity, and remove PCGs with low future costs. This PCG model accounts for almost twice as much variance as do demographic models. In 2002 the Dutch government implemented this model in the sickness fund sector (two-thirds of the population).

[Delay in hospitalization of patients with myocardial infarct]. / Vertraging bij de opname van hartinfarctpatiënten.

Timely treatment of patients with an evolving myocardial infarction improves the short and long term prognoses. Because of a wrong judgement of the situation by the patient, a significant other or by a general practitioner (GP), treatment may be delayed. To examine this delay 300 patients with myocardial infarction took part in a study between March 1990 and October 1991. After written consent was given, they were interviewed about the pre-hospital period. The significant others received a questionnaire about this period. Medical information was collected from the cardiologists. Fifty percent of all patients called for medical help within 30 minutes. The GP arrived within 11 minutes at the patient's place in 50% of all cases. However, in 50% of all cases the decision making of the GPs before the patient was sent to a hospital required more than 82 minutes. The ambulance arrived within 15 minutes at the patient's place in 90% of all cases. Stabilisation of the patient by the ambulance staff and transport to the hospital took slightly more time. Compared with earlier studies, the patient with a possible myocardial infarction calls for help sooner. Subsequently, in many cases it takes considerable time before the GP refers the patient to a hospital. Further research is needed to improve the diagnostic power of the GP.

Limited toxicity of NH(x) pulses on an early and late successional tropical seagrass species: interactions with pH and light level.

Seagrasses have declined at a global scale due to light reduction and toxicity events, caused by eutrophication and increased sediment loading. Although several studies have tested effects of light reduction and toxicants on seagrasses, there is at present no information available on their interacting effects. In a full-factorial 5-day laboratory experiment, we studied short-term interactive effects of light conditions, pH and reduced nitrogen (NH(x)) in the water layer, mimicking pulses of river discharge, on the tropical early successional species Halodule uninervis and the late successional species Thalassia hemprichii. In contrast to recent results reported for the temperate species Zostera marina, increased NH(x) supply did not affect leaf mortality or photochemical efficiency in H. uninervis and in 7 out of 8 treatments for T. hemprichii. However, both tropical species demonstrated striking differences in nitrogen accumulation, free amino acid composition and free NH3 accumulation. The increase in tissue nitrogen content was two times higher for H. uninervis than for T. hemprichii. Nitrogen stored as free amino acids (especially asparagine) only increased in H. uninervis. High pH only affected T. hemprichii, but only when not shaded, by doubling its free NH3 concentrations, concomitantly decreasing its photosynthetic efficiency. Our results indicate that the early successional H. uninervis has higher tolerance to high NH(x) loads as compared to the late successional T. hemprichii. H. uninervis was better able to avoid toxic internal NH(x) levels by further assimilating glutamine into asparagine in contrast to T. hemprichii. Moreover, both tropical species seem to cope much better with high NH(x) than the temperate Z. marina. The implications for the distribution and succession of seagrass species under high nutrient loads are discussed.