High performance computation of landscape genomic models including local indicators of spatial association.

With the increasing availability of both molecular and topo-climatic data, the main challenges facing landscape genomics - that is the combination of landscape ecology with population genomics - include processing large numbers of models and distinguishing between selection and demographic processes (e.g. population structure). Several methods address the latter, either by estimating a null model of population history or by simultaneously inferring environmental and demographic effects. Here we present samßada, an approach designed to study signatures of local adaptation, with special emphasis on high performance computing of large-scale genetic and environmental data sets. samßada identifies candidate loci using genotype-environment associations while also incorporating multivariate analyses to assess the effect of many environmental predictor variables. This enables the inclusion of explanatory variables representing population structure into the models to lower the occurrences of spurious genotype-environment associations. In addition, samßada calculates local indicators of spatial association for candidate loci to provide information on whether similar genotypes tend to cluster in space, which constitutes a useful indication of the possible kinship between individuals. To test the usefulness of this approach, we carried out a simulation study and analysed a data set from Ugandan cattle to detect signatures of local adaptation with samßada, bayenv, lfmm and an FST outlier method (FDIST approach in arlequin) and compare their results. samßada - an open source software for Windows, Linux and Mac OS X available at http://lasig.epfl.ch/sambada - outperforms other approaches and better suits whole-genome sequence data processing.

Calmodulin regulation of adenylate cyclase activity in human platelet membranes.

The mechanism of calmodulin dependent regulation of adenylate cyclase has been studied in human platelet membranes. Calmodulin activated adenylate cyclase exhibited a biphasic response to both Mg2+ and Ca2+. A stimulatory effect of Mg2 on adenylate cyclase was observed at all Mg2+ concentrations employed, although the degree of activation by calmodulin was progressively decreased with increasing concentrations of Mg2+. These results demonstrate that the Vmax of calmodulin dependent platelet adenylate cyclase can be manipulated by varying the relative concentrations of Mg2+ and Ca2+. The activity of calmodulin stimulated adenylate cyclase was always increased 2-fold above respective levels of activity induced by GTP, Gpp(NH)p and/or PGE. The stimulatory influence of calmodulin was not additive but synergistic to the effects of PGE1, GTP and Gpp(NH)p. GDP beta S inhibited GTP-and Gpp(NH)p stimulation of adenylate cyclase but was without effect on calmodulin stimulation. Since the inhibitory effects of GDP beta S have been ascribed to apparent reduction of active N-protein-catalytic unit (C) complex formation, these results suggest that the magnitude of calmodulin dependent adenylate cyclase activity is proportional to the number of N-protein-C complexes, and that calmodulin interacts with preformed N-protein-C complex to increase its catalytic turnover. Our data do not support existence of two isoenzymes of adenylate cyclase (calmodulin sensitive and calmodulin insensitive) in human platelets.

Application of statistical graphics to facilitate selection of health status measures for clinical practice and evaluative research.

Relatively little attention has been directed towards the study of the ability of health status measures to demonstrate clinically meaningful change. We examined the use of Tukey's stem and leaf plots and time-path diagrams to assess the sensitivity of a health status measure in showing change. We compared the evaluative characteristics of the physical ability scales of the Sickness Impact Profile (PSIP), and the SF-36 (PSF-36), in 54 consecutive patients undergoing elective primary or revision total hip replacement. To validate time-path diagrams, we used patients' perception of change in physical function (transition question) as an external standard. At baseline there was no clustering at the end of the scales. At 3 months, the distribution of the PSIP showed a clustering at the upper end of the scale and a strong skewness towards lower scores, whereas the PSF-36 showed a wide distribution of the scores. Seven out of 54 patients had perfectly normal scores on the PSIP at 3 months, whereas one patient had a perfect score on the PSF-36 at 3 months. In time-path diagrams the response pattern of the PSIP was similar to that of the PSF-36, with the exception of the patient-fifth with the best initial health status. The overall impression of the time-path diagram for these patients was that of no change. A closer examination revealed that half of these patients had horizontal or downwards sloping lines, indicating a worsening in physical function. However, all these patients perceived themselves as improved. The PSIP has a ceiling effect for patients with relatively good physical health. It was concluded that stem and leaf plots are useful in the assessment of health status measures, for discriminative purposes, to differentiate patients' health cross-sectionally. Time-path diagrams stratified by baseline health status with information on patients' perception or valuation of change provide useful information about the ability of an instrument to detect change over time.

Impact of moisture on volatility of heavy metals in municipal solid waste incinerated in a laboratory scale simulated incinerator.

In this work, the impact of moisture on the volatility of heavy metals present in municipal solid wastes (MSW) in a laboratory scale simulated incinerator was studied, using synthetic waste consisting of 5.4 g of wood powder, 2.6 g lava, 1.9 polythene, 0.19 g polyvinyl chloride, and a given quantity of water and heavy metals represented by lead, zinc and copper in forms of metallic, chlorides and oxides. It is found that the presence of high moisture in MSW will greatly reduce the volatilization of heavy metals in MSW in the incineration process. The volatilization behavior of chlorides, oxides and the metallic species with respect to the effect of moistures is quite different. For copper, the presence of moisture in MSW depresses the volatilization of oxides, and increases that of chloride and the metallic species, while in contrast, the volatilization of both lead and zinc is always depressed by the presence of moisture in MSW, regardless of the chemical forms used. The chemical mechanisms, which govern the volatilization behaviors of different chemical forms in the incineration process, are proposed. Hydrolysis, dewatering of hydrolyzed species, sublimation, chemical transformation of less volatiles to more volatiles or reverse, may participate in and affect the volatilization of heavy metals in MSW.

A study of the NASS-CDS system for injury/fatality rates of occupants in various restraints and a discussion of alternative presentation methods.

An analysis was performed using the National Automotive Sampling System Crashworthiness Data System (NASS-CDS) database to compare the injury/fatality rates of variously restrained driver occupants as compared to unrestrained driver occupants in the total database of drivers/frontals, and also by Delta-V. A structured search of the NASS-CDS was done using the SAS statistical analysis software to extract the data for this analysis and the SUDAAN software package was used to arrive at statistical significance indicators. In addition, this paper goes on to investigate different methods for presenting results of accident database searches including significance results; a risk versus Delta-V format for specific exposures; and, a percent cumulative injury versus Delta-V format to characterize injury trends. These alternative analysis presentation methods are then discussed by example using the present study results.

[Patient-centered evaluation of illness outcome in musculoskeletal diseases: model of illness sequelae and definition of the concept]. / Patienten-zentrierte Evaluation der Krankheitsauswirkungen bei muskuloskelettalen Erkrankungen: Modell der Krankheitsauswirkungen und Begriffsdefinitionen.

Musculoskeletal conditions usually cause pain, physical, psychological and social disability, and consequently reduce a patient's quality of life. Nowadays, it is generally accepted that patients are truly capable to assess disease consequences, if they are questioned with appropriate instruments. Models of disease and the disabling process provide the conceptual background for the measurement of disease consequences. To date, standardized assessment of outcomes with psychometrically sound instruments is commonplace in clinical trials, clinical epidemiology, economic studies, and health services research. However, standardized assessment tools are not yet widely used in clinical practice.

[Patient-centered evaluation of illness outcome in musculoskeletal diseases: selection and testing of outcome instruments]. / Patienten-zentrierte Evaluation der Krankheitsauswirkungen bei muskuloskelettalen Erkrankungen: Auswahl und Testung von Outcome-Instrumenten.

Effectiveness research, economic evaluation, epidemiologic studies of disease consequences and clinical quality management all rely on standardized assessment of disease consequences with psychometrically sound questionnaires. For scientific, ethical and economical reasons, careful selection and evaluation of instruments is critical. Selection of instruments includes searches of medical databases (e.g. MEDLINE), testing of face-validity (does the instrument measure what we intend to measure?), and compatibility (is the instrument used internationally?). Evaluation of instruments includes the assessment of reliability, internal consistency and sensitivity. Most important is careful consideration of the practical usefulness (Interpretation of scores and scales, acceptance in the study population). Contact with instrument developers is advisable (Copyright issues, scoring, current version).

[Patient-centered evaluation of illness outcome in musculoskeletal diseases: adaptation and revision of outcome instruments]. / Patienten-zentrierte Evaluation der Krankheitsauswirkungen bei muskuloskelettalen Erkrankungen: Adaptation und Neuentwicklung von Outcome-Instrumenten.

Assessment of disease consequences (outcome) requires reliable, valid, and sensitive instruments. Psychometrically sound generic health-status instruments such as the SF-36 have been validated for many languages and are available in German. Instead, most disease specific instruments have been developed in English and need to be adapted for the German language. To allow for cross-cultural comparisons and use of results across cultures, for instance, in international multicenter studies, instruments need to have both content and metric equivalence. Thus, adaptation of health-status instruments requires a standarized process including translation, backtranslation, review and assessment of metric properties (reliability, internal consistency, factors), and validity. Developments of new instruments from scratch are time and cost intensive and should only be considered if no current instrument is available. Ideally, newly developed instruments have interval-scale properties.

Studying the evaporation behavior of heavy metals by thermo-desorption spectrometry.

"Thermal desorption experiments" were carried out during which heavy metal evaporation was studied by on-line monitoring. This could be achieved by the use of a tubular furnace connected to a heavy metal detector, i.e. an ICP-OES (inductively coupled plasma optical emission spectrometer), by a specially designed and patented interface. The spectrograms typically had a time resolution of four different elements per minute using a conventional (sequentially operating) ICP-OES. This study shows how thermo-desorption spectrometry (TDS) can be applied to study the evaporation of high boiling substances, such as heavy metal and alkali metal compounds. The future scope of the method is discussed.

Ceiling effects of the Health Assessment Questionnaire and its modified version in some ambulatory rheumatoid arthritis patients.

OBJECTIVE: To examine if the reduced number of items in the modified version of the Health Assessment Questionnaire (MHAQ) concerning difficulty of performing activities of daily living may lead to a reduced ability to detect clinical changes compared with the original HAQ. METHODS: In 56 consecutive ambulatory patients with rheumatoid arthritis, we examined the mean change in clinical and laboratory parameters for those who recorded improved, unchanged, or worse MHAQ scores one year after a baseline assessment. RESULTS: At baseline, about 50% of the patients had an MHAQ score < 0.3 and clustered at the normal end of the scale. Because of a ceiling effect, the MHAQ failed to detect clinical improvement in 18% of the patients. Changes in clinical and laboratory parameters were associated with improved, unchanged, or worse scores with the HAQ but not the MHAQ. CONCLUSION: Although the format of the MHAQ has the advantage of eliciting a 'satisfaction' score, limitations in its sensitivity to detect clinical improvement in patients with relatively little difficulty in activities of daily living may not justify the use of this particular version of shorter questionnaire in certain clinical settings.

Isometric muscle strength is an indicator of self-reported physical functional disability in patients with rheumatoid arthritis.

The objective of our study was to examine (1) whether isometric muscle strength contributes to the explanation of the physical functional disability of a rheumatoid arthritis (RA) patient population after accounting for other disease parameters and demographic variables and (2) whether change in isometric muscle strength is an indicator of change in physical functional disability. Sixty-five consecutive patients fulfilling the American Rheumatism Association 1987 revised criteria for RA were included in the study. Isometric muscle strength was measured with a validated Muscle Strength Index (MSI) calculated as the mean score of standardized isometric extension and flexion strength of the knee and elbow joints. Physical functional disability was measured with the physical dimension of the Health Assessment Questionnaire (HAQ). For 56 patients, we could obtain 1 yr follow-up data. Cross-sectionally, there was a significant correlation (r = -0.51, P < 0.01) between the MSI and the HAQ. Muscle strength remained a significant determinant of the HAQ in multivariate analysis accounting for disease and demographic variables. Longitudinally, change in MSI explained additional variance of change in HAQ after accounting for change in pain, the most important correlate of change in HAQ.

The influence of activating hormones on human platelet membrane Ca2+-ATPase activity.

Intact platelets were pretreated with hormones and thereafter membranes were prepared and Ca2+-ATPase activity determined. Thrombin decreased the Vmax of Ca2+-ATPase after pretreatment of intact platelets. Platelet activating factor, vasopressin and ADP also decreased Ca2+-ATPase activity. 12-O-tetradecanoylphorbol-13-acetate (TPA) or A23187 or ionomycin alone had no effect, whilst the simultaneous pretreatment with TPA and Ca2+-ionophore decreased Ca2+-ATPase activity. cAMP elevating agents prostaglandin E1 (PGE1) and forskolin had no influence per se on Ca2+-ATPase, but antagonized the inhibitory effect of thrombin. The data suggest a close connection between phosphoinositide metabolism and the Ca2+-ATPase system.

Biphasic Ca2+ response of adenylate cyclase. The role of calmodulin in its activation by Ca2+ ions.

The Ca2+-dependent regulation of human platelet membrane adenylate cyclase has been studied. This enzyme exhibited a biphasic response to Ca2+ within a narrow range of Ca2+ concentrations (0.1-1.0 microM). At low Ca2+ (0.08-0.3 microM) adenylate cyclase was stimulated (Ka = 0.10 microM), whereas at higher Ca2+ (greater than 0.3 microM) the enzyme was inhibited to 70-80% control (Ki = 0.8 microM). Membrane fractions, prepared by washing in the presence of LaCl3 to remove endogenous calmodulin (approximately equal to 70-80% depletion), exhibited no stimulation of adenylate cyclase by Ca2+ but did show the inhibitory phase (Ki = 0.4 microM). The activation phase could be restored to La3+-washed membranes by addition of calmodulin (Ka = 3.0 nM). Under these conditions it was apparent that calmodulin reduced the sensitivity of adenylate cyclase to Ca2+ (Ki = 0.8 microM). Prostaglandin E1 (PGE1) did not alter Ki or Ka values for Ca2+. Calmodulin did not alter the EC50 for PGE1 stimulation of adenylate cyclase but increased the Vmax (1.5-fold). The calmodulin antagonist trifluoperazine potently inhibited adenylate cyclase in native membranes (80%) and to a much lesser extent in La3+-washed membranes (15%). This inhibition was due to interaction of trifluoperazine with endogenous calmodulin since trifluoperazine competitively antagonized the stimulatory effect of calmodulin on adenylate cyclase in La3+-washed membranes. We propose that biphasic Ca2+ regulation of platelet adenylate cyclase functions to both dampen (low Ca2+) and facilitate (high Ca2+) the haemostatic function of platelets.

Low serum creatine kinase activity is associated with muscle weakness in patients with rheumatoid arthritis.

OBJECTIVE: In rheumatoid arthritis (RA) serum creatine kinase (CK) is reduced in association with inflammatory response variables. Our objective was to examine whether low CK is associated with muscle weakness and to what extent the hypothesized relationship between CK and muscle weakness can be explained by anthropometric and sociodemographic variables and/or disease variables. METHODS: Cross sectional and longitudinal retrospective analyses of clinical, radiological, and biochemical data of a prospective cohort of consecutive patients with RA. Isometric muscle strength was measured with a validated muscle strength index (MSI); CK was measured with an enzymatic assay (N-acetyl-cysteine, 37 degrees C). RESULTS: 65 patients were enrolled in the study and we obtained complete one year followup data from 47. In cross sectional analysis, CK was a significant, moderate correlate of the MSI (r = 0.43, p < 0.01). CK remained a significant explanatory variable of the MSI in multivariate models that controlled for demographic variables and lean body mass, corticosteroid use, and biochemical, clinical, and radiological disease variables. In longitudinal dichotomous analyses, worsening in CK was weakly but significantly associated with decreased muscle strength, whereas in linear analyses the association did not reach significance. CONCLUSION: In patients with RA, low CK activity is associated with muscle weakness. Demographic, anthropometric, and disease variables related to muscle mass or muscle atrophy explain only part of this association. Our findings support the hypothesis that muscle weakness may be partly caused by a disease related reduction of CK activity independent of muscle atrophy.

Comparison of the validity and reliability of self-reported articular indices.

Our objective was to compare the validity and reliability of three formats for self-administered articular indices assessing pain (PAI) or swelling (SAI). Fifty-five patients with rheumatoid arthritis were asked to mark the degree of pain on a list of 16 joints (PAI list), to mark 'painful joints' on a mannequin presenting 42 joints (PAI diagram), and to mark 'swollen or tender joints' on a mannequin presenting 38 joints (SAI diagram). The test--retest reliability (intraclass correlation coefficient) ranged from 0.63 (SAI diagram) to 0.67 (PAI diagram) and 0.85 (PAI list). The correlation with clinical parameters was strongest for the PAI list and the SAI diagram. The association of the SAI diagram with clinical parameters increased with omission of the less reliable toe joints and/or weighting for joint size according to Lansbury. As expected, the short and weighted SAI diagram correlated more strongly with the physician-derived swollen joint count (r = 0.49), C-reactive protein (r = 0.49) and erythrocyte sedimentation rate (r = 0.41) than did the PAI list whereas the PAI list correlated more strongly with physician-derived tender joint count (r = 0.43), global pain measured on a numerical rating scale (r = 0.57) and the Health Assessment Questionnaire (r = 0.49) than did the SAI diagram. We concluded that patients' rating of tender and swollen joints on a mannequin diagram and calculation of a 26-joint and weighted articular index produces an excellent estimate of total joint inflammation, which may be useful in clinical, health services and epidemiological research. An articular index calculated from ratings of pain degree of 16 joints or joint groups may provide complementary information.

A self-administered rheumatoid arthritis disease activity index (RADAI) for epidemiologic research. Psychometric properties and correlation with parameters of disease activity.

OBJECTIVE: To examine the psychometric properties and construct validity of a self-administered Rheumatoid Arthritis Disease Activity Index (RADAI). METHODS: Five items of the Rapid Assessment of Disease Activity in Rheumatology (RADAR) questionnaire were aggregated into the RADAI and assessed for their factor loading, internal consistency, and construct validity. RESULTS: In 55 patients with RA, the RADAI had a high internal consistency (Cronbach's alpha = 0.91) and correlated with physician's assessment of disease activity (r = 0.54, P < 0.01), the swollen joint count (r = 0.54, P < 0.01), and the C-reactive protein value (r = 0.43, P < 0.01). CONCLUSION: The RADAI is a highly reliable and valid self-administered measure of disease activity for clinical, health services, and epidemiologic research. Its sensitivity to change in longitudinal studies needs further study.

Weighting for joint surface area improves the information provided by a reduced 28-joint articular index of swollen joints.

The objective of our study was to examine whether weighting for joint surface area or recording of simultaneously tender and swollen joints increases the association of a reduced 28-joint articular index with clinical and outcome parameters. In a cross-sectional study we examined 61 consecutive outpatients with RA fulfilling the American Rheumatism Association 1987 revised criteria. Tender, swollen, and simultaneously tender and swollen joints were recorded. The association of 28- and 68-joint articular indices with clinical and outcome parameters were estimated with nonparametric correlation analyses. Weighting for joint surface yielded consistently increased correlation of clinical and outcome parameters with swollen and tender and swollen but not with tender joint counts. The correlation of the 28-joint articular and 68-articular indices with these parameters were similar. In conclusion, weighting for joint surface notably improves the information provided by swollen joint counts, whereas it does not appear to improve the information provided by tender joint counts.

[Evaluation of a German version of WOMAC (Western Ontario and McMaster Universities) Arthrosis Index]. / Evaluation einer deutschen Version des WOMAC (Western Ontario und McMaster Universities) Arthroseindex.

The WOMAC (Western Ontario and McMaster Universities) Osteoarthritis Index is a tested questionnaire to assess symptoms and physical functional disability. We adapted the WOMAC for the German language and tested its metric properties, test-retest reliability and validity in 51 patients with knee and hip OA. All WOMAC scales (pain, stiffness, function) were internally consistent with Cronbach's coefficient alpha ranging from 0.80 to 0.96. Test-retest reliability was satisfactory with intraclass correlation coefficients ranging from 0.55 to 0.74. All scales and the global index calculated as the mean of scale scores had a bimodal distribution and a slight ceiling effect. As hypothesized the WOMAC scales were associated with radiological OA-severity and limitations of range-of-motion. Patients with more severe symptoms and functional disability perceived more limitations in their roles at home and at work. The presented German version of the WOMAC is a reliable and valid instrument for the assessment of symptoms and physical functional disability in patients with knee and hip OA.

[Evaluation of a German questionnaire version of the Lequesne cox- and gonarthrosis indices]. / Evaluation einer deutschen Fragebogenversion der Lequesne Cox- und Gonarthrose-Indizes.

The Lequesne algofunctional indices for the knee and the hip require a physician interview. We adapted the Lequesne indices for the German language and tested the metric properties, test-retest reliability and validity of a self-report questionnaire-format in 51 patients with hip or knee OA. The symptom and function components as well as the global indices had a high test-retest reliability (intraclass correlation coefficient knee: 0.87/0.92 and 0.86, hip: 0.96/0.85 and 0.94). The symptom component showed an insufficient internal consistency (Cronbach's coefficient alpha knee: 0.55; hip: 0.63). Also, the symptom component was not or only weakly associated with radiological OA-severity and the limitations of range-of-motion. The most likely explanation is the grading of the Lequesne symptom questions which addresses such different concepts as pain presence, pain on movement, duration of pain and appearance of pain after a certain period of time. Because of the insufficient internal consistency and questionable validity the tested self-report German-version of the Lequesne algofunctional indices may not be recommended for use in clinical research and practice.

Comparison of the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index and a self-report format of the self-administered Lequesne-Algofunctional index in patients with knee and hip osteoarthritis.

OBJECTIVE: To compare the metric properties and validity of German versions of the WOMAC (Western Ontario and McMaster Universities) and a self-administered questionnaire-format of the Lequesne-Algofunctional-Index in patients with osteoarthritis (OA) of the lower extremities. DESIGN: Cross-sectional analysis of the instruments' internal consistency (Cronbach's coefficient alpha) and construct validity (correlation with radiological OA-severity and limitation in range-of-motion) in ambulatory patients and patients before hip arthroplasty. Test-retest reliability was assessed on a subsample after 10 days. RESULTS: Data from 51 patients out of 91 contacted could be analyzed. Twenty-nine patients had knee and 22 patients had hip OA. Both the WOMAC and Lequesne OA-indices and their scales or sections had a satisfactory test-retest reliability (Intraclass correlation coefficient 0.43-0.96). All scales of the WOMAC were internally consistent (Cronbach's coefficient alpha 0.81-0.96) and associated with radiological OA-severity and joint range of motion. However, only the function but not the symptom sections (Cronbach's coefficient alpha knee: 0.55; hip: 0.63) of the self-administered Lequesne OA index were internally consistent for both, patients with knee and hip OA. Also, the symptom components were not or only weakly associated with radiological OA-severity and joint range of motion. CONCLUSIONS: Although our results are based on a German version using a self-report format we may caution using the self-administered Lequesne OA index without prior testing of its metric properties and validity.