Metabolite profiles evaluated, according to sex, do not predict resting energy expenditure and lean body mass in healthy non-obese subjects.

PURPOSE: Differences in resting energy expenditure (REE) between men and women mainly result from sex-related differences in lean body mass (LBM). So far, a little is known about whether REE and LBM are reflected by a distinct human metabolite profile. Therefore, we aimed to identify plasma and urine metabolite patterns that are associated with REE and LBM of healthy subjects. METHODS: We investigated 301 healthy male and female subjects (18-80 years) under standardized conditions in the cross-sectional KarMeN (Karlsruhe Metabolomics and Nutrition) study. REE was determined by indirect calorimetry and LBM by dual X-ray absorptiometry. Fasting blood and 24 h urine samples were analyzed by targeted and non-targeted metabolomics methods using GC × GC-MS, GC-MS, LC-MS, and NMR. Data were evaluated by predictive modeling of combined data using different machine learning algorithms, namely SVM, glmnet, and PLS. RESULTS: When evaluating data of men and women combined, we were able to predict REE and LBM with high accuracy (> 90%). This, however, was a clear effect of sex, which is supported by the high degree of overlap in identified important metabolites for LBM, REE, and sex, respectively. The applied machine learning algorithms did not reveal a metabolite pattern predictive of REE or LBM, when analyzing data for men and women, separately. CONCLUSIONS: We could not identify a sex independent predictive metabolite pattern for REE or LBM. REE and LBM have no impact on plasma and urine metabolite profiles in the KarMeN Study participants. Studies applying metabolomics in healthy humans need to consider sex specific data evaluation.

The Value of Empirical Data for Estimating the Parameters of a Sociohydrological Flood Risk Model.

In this paper, empirical data are used to estimate the parameters of a sociohydrological flood risk model. The proposed model, which describes the interactions between floods, settlement density, awareness, preparedness, and flood loss, is based on the literature. Data for the case study of Dresden, Germany, over a period of 200 years, are used to estimate the model parameters through Bayesian inference. The credibility bounds of their estimates are small, even though the data are rather uncertain. A sensitivity analysis is performed to examine the value of the different data sources in estimating the model parameters. In general, the estimated parameters are less biased when using data at the end of the modeled period. Data about flood awareness are the most important to correctly estimate the parameters of this model and to correctly model the system dynamics. Using more data for other variables cannot compensate for the absence of awareness data. More generally, the absence of data mostly affects the estimation of the parameters that are directly related to the variable for which data are missing. This paper demonstrates that combining sociohydrological modeling and empirical data gives additional insights into the sociohydrological system, such as quantifying the forgetfulness of the society, which would otherwise not be easily achieved by sociohydrological models without data or by standard statistical analysis of empirical data.

Flood risk assessments at different spatial scales.

Managing flood risk, i.e. both the hazard and the potential consequences, is an important aspect of adapting to global change and has gained much traction in recent decades. As a result, a priori flood risk assessments have become an important part of flood management practices. Many methodologies have been set up, ranging from global risk assessments for the world as a whole, to local assessments for a particular stretch of a river/coast or small town. Most assessment frameworks generally follow a similar approach, but there are also notable differences between assessments at different spatial scales. This review article examines these differences, for instance those related to the methodology, use of assessments and uncertainties. From this review, future research needs are identified in order to improve flood risk assessments at different scales. At global/continental scale, there is a clear need for harmonised information on flood defences to improve assessments. Furthermore, inclusions of indirect economic effects at the macro-/meso-scale would give a better indication of the total effects of catastrophic flooding. At the meso-/micro-scale, there is an urgent need to improve our understanding of the effects of flooding on critical infrastructures, given their importance to society, the economy, emergency management and reconstruction. An overarching theme at all scales is the validation of flood risk assessments, which is often limited. More detailed post-disaster information would allow for improved calibration, validation and thus performance of flood risk models. Lastly, the link between spatial scales also deserves attention, for instance up- or downscaling methodologies.

Changes in body weight and obesity status in German adults: results of seven population-based prospective studies.

BACKGROUND/OBJECTIVES: The objective of this study was to quantify body weight changes in German adult populations during the past decades. SUBJECTS/METHODS: Longitudinal analysis of seven cohort studies covering different age ranges between 18 and 83 years. Baseline examinations were between 1994 and 2007 and follow-up durations between 4.0 and 11.9 years. For each study, mean change in body weight per year and 10-year change in body mass index (BMI) classification were analyzed. For the middle age group of 45-64 years, meta-analysis was conducted to obtain an overall estimate for Germany. RESULTS: Among men weight gain was highest in the youngest participants and decreased with advancing age. Among women weight gain was on a stable high level among those younger than 45 years and decreased at older age. Within 10 years, 30-40% of middle-aged participants with normal baseline weight became pre-obese or obese and 20-25% of those with pre-obesity at baseline became obese, whereas >80% of persons who were obese at baseline remained obese over time. The estimated average weight change in adults aged 45-64 years was 0.25 (95% confidence interval (CI): 0.18-0.33) kg/year among men and 0.24 (0.17-0.30) kg/year among women. CONCLUSIONS: We could observe a moderate weight gain over the past years in German middle-aged populations of 0.25 kg/year. Obesity prevention needs to be targeted to specific subgroups in the population, especially to younger adults, who seem to be most vulnerable for gaining weight. Obesity intervention needs to be improved, as the majority of obese adults remained obese over time.

Soy isoflavones exert modest hormonal effects in premenopausal women.

Soy isoflavones are hypothesized to be responsible for changes in hormone action associated with reduced breast cancer risk. To test this hypothesis, we studied the effects of isoflavone consumption in 14 premenopausal women. Isoflavones were consumed in soy protein powders and provided relative to body weight (control diet, 10 +/- 1.1; low isoflavone diet, 64 +/- 9.2; high isoflavone diet, 128 +/- 16 mg/day) for three menstrual cycles plus 9 days in a randomized cross-over design. During the last 6 weeks of each diet period, plasma was collected every other day for analysis of estrogens, progesterone, LH, and FSH. Diet effects were assessed during each of four distinctly defined menstrual cycle phases. Plasma from the early follicular phase was analyzed for androgens, cortisol, thyroid hormones, insulin, PRL, and sex hormone-binding globulin. The low isoflavone diet decreased LH (P = 0.009) and FSH (P = 0.04) levels during the periovulatory phase. The high isoflavone diet decreased free T3 (P = 0.02) and dehydroepiandrosterone sulfate (P = 0.02) levels during the early follicular phase and estrone levels during the midfollicular phase (P = 0.02). No other significant changes were observed in hormone concentrations or in the length of the menstrual cycle, follicular phase, or luteal phase. Endometrial biopsies performed in the luteal phase of cycle 3 of each diet period revealed no effect of isoflavone consumption on histological dating. These data suggest that effects on plasma hormones and the menstrual cycle are not likely to be the primary mechanisms by which isoflavones may prevent cancer in premenopausal women.

Pharmacokinetics of nicotinic acid-salicylic acid interaction.

Both nicotinic acid and salicylic acid undergo glycine conjugation in human beings. Competitive inhibition may therefore be possible when these substances are used concomitantly in patients with hyperlipidemic disorders. The aim of this study was to determine, in six healthy subjects, whether nicotinic acid steady-state levels and total clearance are affected by concomitant aspirin administration. Steady-state nicotinic acid concentrations were obtained in all six volunteers by infusion of nicotinic acid solutions at constant rates (0.075 to 0.100 mg/kg/min) for 6 hours; aspirin (1 gm) was administered orally 120 minutes after the beginning of the infusion of nicotinic acid. Plasma samples were analyzed for nicotinic acid, nicotinuric acid, and salicylic acid. After aspirin administration an immediate marked decrease of nicotinuric acid levels could be observed in all six volunteers, whereas nicotinic acid concentrations increased. We hypothesize that salicylic acid causes a concentration-dependent decrease of total nicotinic acid clearance that results in the saturation (and effective elimination) of the nicotinuric acid conjugation pathway.

Acetylcholine receptors of the Drosophila brain: a 900 bp promoter fragment contains the essential information for specific expression of the ard gene in vivo.

The ard gene encodes a beta-subunit of Drosophila nicotinic acetylcholine receptors specifically expressed in a subset of neurons. To identify the cis-regulatory region responsible for this cell-specific expression, various 5' fragments of the ard gene were fused to a lacZ reporter gene and introduced into the Drosophila genome. A DNA fragment spanning approximately 760 bp upstream and approximately 140 bp downstream of a cluster of putative transcription start sites produced a pattern of beta-galactosidase activity that resembles the distribution of ARD transcripts. Both in embryos and adults the levels of lacZ RNA were similar to those of endogenous ARD transcripts, suggesting that the 900 bp fragment harbors all essential elements for proper expression of the ard gene.

Structure and developmental expression of the D alpha 2 gene encoding a novel nicotinic acetylcholine receptor protein of Drosophila melanogaster.

Nicotinic acetylcholine receptors (nAChRs) represent a heterogeneous group of excitatory neurotransmitter receptors in the insect brain. We have characterized the D alpha 2 gene of Drosophila melanogaster, a new member of the nAChR gene family. The protein coding region is interrupted by six introns. The positions of three of these introns are shared with all other nAChR genes. The deduced D alpha 2 protein shows the structural features of ligand-binding nAChR alpha-subunits. Cytogenetically, the D alpha 2 gene maps at position 96A of the 3rd chromosome, close to the ALS gene which also encodes an alpha-like nAChR subunit. D alpha 2 transcripts are predominantly expressed in late embryos and in fly heads.

Effects of soy isoflavones on estrogen and phytoestrogen metabolism in premenopausal women.

Isoflavones and lignans are soy phytoestrogens that have been suggested to be anticarcinogenic. The mechanisms by which they exert cancer-preventive effects may involve modulation of estrogen synthesis and metabolism. To evaluate this hypothesis, a randomized, cross-over soy isoflavone feeding study was performed in 12 healthy premenopausal women. The study consisted of three diet periods, each separated by a washout of approximately 3 weeks. Each diet period lasted for three menstrual cycles plus 9 days (averaging approximately 100 days), during which subjects consumed their habitual diets supplemented with soy protein powder providing 0.16 (control diet), 1.01, or 2.01 mg of total isoflavones per kg of body weight per day (10+/-1.1, 65+/-9.4, or 129+/-16 mg/day, respectively). A 72-h urine sample was collected during the midfollicular phase (days 7-9) of the fourth menstrual cycle in each diet period. Urine samples were analyzed for 10 phytoestrogens and 15 endogenous estrogens and their metabolites by a capillary gas chromatography-mass spectrometry method. Urinary excretion of isoflavonoids and lignans significantly increased with increased isoflavone consumption. Compared with the control diet, increased isoflavone consumption decreased urinary excretion of estradiol, estrone, estriol, and total estrogens, as well as excretion of the hypothesized genotoxic estrogen metabolites, 16alpha-hydroxyestrone, 4-hydroxyestrone, and 4-hydroxyestradiol. Of importance are the observations of a significant increase in the 2-hydroxyestrone/16alpha-hydroxyestrone ratio and a decrease in the genotoxic/total estrogens ratio. These data suggest that soy isoflavone consumption may exert cancer-preventive effects by decreasing estrogen synthesis and altering metabolism away from genotoxic metabolites toward inactive metabolites.

Implant metastasis of gallbladder carcinoma in situ in a cholecystectomy scar: a case report.

A subcutaneous mass within the scar left by cholecystectomy with common bile duct exploration and T-tube drainage developed 6 years after surgery. Pathologic examination of this mass showed features of atypical villous hyperplasia, similar to that identified within the previously removed gallbladder, but with additional foci of carcinoma in situ. Since excision of the mass, the patient has had persistent fluid collections requiring frequent aspiration. Cytologic analysis of the fluid has revealed tumor cells. The cause of this spread has been unclear. Few literature reports have identified biliary drainage techniques as a source for metastatic seeding. The malignant or metastatic potential of severe dysplasia or carcinoma in situ of the gallbladder associated with T-tube drainage and implantation in the drainage tract is previously unreported.

Effect of the menstrual cycle on creatinine clearance in normally cycling women.

OBJECTIVE: We assessed changes in creatinine clearance during the menstrual cycle of normally cycling women. METHODS: We used a design that precisely identified the day of ovulation. Creatinine clearance was measured in 14 subjects on each of three days: cycle day 2 or 3, 1 or 2 days before the day of ovulation, and 6 or 7 days after ovulation. RESULTS: Creatinine clearance was affected significantly by the menstrual cycle (P=.02), but the degree of this effect was modest. Mean (+/-standard error of mean) early follicular, preovulatory, and midluteal creatinine clearance values were 135+/-4, 131+/-5, and 142+/-5 mL/min, respectively, and only the difference between the preovulatory and midluteal values was significant. These changes in creatinine clearance were attributable largely to changes in creatinine excretion and not to changes in plasma creatinine concentrations. CONCLUSION: Despite the statistically significant luteal phase increase, creatinine clearance does not change in a clinically important manner during the normal menstrual cycle. Specifically, there is no substantial decrease in creatinine clearance around the time of ovulation.

Perioperative stroke risk in 173 consecutive patients with a past history of stroke.

During an 8-year period ending in 1988, 173 consecutive patients with a history of previous cerebrovascular accident underwent general anesthesia for surgery. Five patients (2.9%) had documented postoperative cerebrovascular accidents from 3 to 21 days (mean, 12.2 days) after surgery. The risk of postoperative cerebrovascular accident did not correlate with age, sex, history of multiple cerebrovascular accidents, poststroke transient ischemic attacks, American Society for Anesthesia physical status, aspirin use, coronary artery disease, peripheral vascular disease, intraoperative blood pressure, time since previous cerebrovascular accident, or cause of previous cerebrovascular accident. Postoperative stroke was more common in patients given preoperative heparin sodium. We conclude that the risk of perioperative stroke is low (2.9%) but not easily predicted and that the risk continues beyond the first week of convalescence. Unlike myocardial infarction, cerebral reinfarction risk does not seem to depend on time since previous infarct.

Mechanical implications of humero-ulnar incongruity--finite element analysis and experiment.

Previous studies show that the humero-ulnar joint is physiologically incongruous [Eckstein et al. (1995a) Anat. Rec. 243, 318-326] and exhibits a bicentric (ventro-dorsal) distribution of subchondral mineralization [Eckstein et al. (1995b) J. Orthop. Res. 13, 286-278]. We therefore asked: (1) Does humero-ulnar incongruity bring about a bicentric distribution of contact pressure? (2) Do tensile stresses occur in the subchondral bone of the trochlear notch that are in the same order of magnitude as the compressive stresses? (3) Do ventral and dorsal maxima of subchondral bone density correlate with a bicentric distribution of strain energy density? To that end, a two-dimensional finite element model was designed. The shape and material properties of the bones were based on CT and the boundary conditions selected to agree with resisted elbow extension at 90 degrees of flexion. The incongruity and contact areas were determined experimentally from casts, and the pressure distribution with Fuji Prescale film. In the model and the experiment contact stresses above 2 MPa were recorded in the ventral and dorsal parts of the joint, and values below 0.5 MPa in the depth of the notch. In the model, tensile stresses of 2.9 MPa were observed in the subchondral bone of the ulna, but not in the humerus. The subchondral strain energy density yielded a bicentric pattern in a model with homogeneous subchondral bone properties. It is shown that humero-ulnar incongruity brings about a bicentric distribution of contact pressure, a tensile stress in the notch that is in the same order of magnitude as the compressive stress, and a distribution of strain energy density that correlates with subchondral density patterns.

The influence of geometry on the stress distribution in joints--a finite element analysis.

The incongruity of human joints is a phenomenon which has long been recognized, and recent CT-osteoabsorptiometric findings suggest that this incongruity influences the distribution of stress in joints during their normal physiological use. The finite element method (FEM) was therefore applied to five different geometric configurations consistent with the anatomy of articular surfaces, and a program with variable contact areas (Marc) was used to calculate the stress distribution for loads of 100 to 6,900 N. The assumption of congruity between head and socket results in a "bell-shaped" distribution of stress with a maximum value of 61.5 N/mm2 in the depths of the socket, decreasing towards zero at its edges. In the model with a flatter socket the von Mises stresses are higher (max. 101.3 N/mm2); with a deeper socket, lower (max. 53.0 N/mm2). If the diameter of the head is greater, the stresses build up from the periphery of the socket and move towards its depths as the load increases. The combination of an oversized head and a deeper socket results in the most satisfactory stress distribution (max. 43.2 N/mm2). These results extend previous photoelastic findings with incongruous joint surfaces. The calculated mechanical conditions show a relationship to the location of osteoarthritic changes, and are reflected by the distribution pattern of subchondral bone density. A more satisfactory stress distribution is found with functionally advantageous, incongruous joint surfaces (oversized head and deepened socket) than in the congruous joint, and a better nutritive situation for the articular cartilage seems likely.(ABSTRACT TRUNCATED AT 250 WORDS)

Tension and bending, but not compression alone determine the functional adaptation of subchondral bone in incongruous joints.

In the present study, we tested the hypothesis that tension and bending, rather than compression alone, determine the functional adaptation of subchondral bone in incongruous joints. We investigated whether tensile stresses in the subchondral bone of the humero-ulnar articulation are affected by the direction of muscle and joint forces, and whether the tensile stresses are large enough to cause microstructural adaptation, specifically a preferential alignment of the trabeculae and the subchondral collagen fibres. Using a previously validated finite element model of the human humero-ulnar joint, we calculated the contact pressure, the principal compressive and tensile stresses, and the strain energy density in the subchondral bone for various flexion angles. A bicentric (ventro-dorsal) pressure distribution was found in the joint at 30 degrees to 120 degrees of flexion, with contact pressures of up to between 2.5 and 3 MPa in the ventral and dorsal aspects of the ulnar joint surface, but less than 0.5 MPa in the centre. The principal tensile stress in the subchondral bone of the trochlear notch quantitatively exceeded the principal compressive stress at low flexion angles (maximum 8.2 MPa), and the distribution of subchondral strain energy density differed substantially from that of the contact stress (r=-0.72 at 30 degrees and r=+0.58 at 90 degrees of flexion). No important tensile stress was computed in the trochlea humeri. On contact radiography, we found sagittally orientated subarticular trabeculae in the notch, running tangential to the surface. Furthermore, we observed sagittally orientated split lines in the subchondral bone of the notch of 20 cadaver joints, suggesting a ventro-dorsal orientation of the collagen fibres. The trochlea humeri, on the other hand, did not show a preferential direction of the subchondral split lines, these findings confirming the predictions of tensile stresses in the model. We conclude that, due to the important contribution of tension to subchondral bone stress, the distribution of subchondral density cannot be directly employed for assessing the long term distribution of joint pressure at the cartilage surface. The magnitude of the tensional stress varies considerably with the direction of the muscle and joint forces, and it appears large enough to cause functional adaptation of the subchondral bone on a microstructural level.

Time and knowledge barriers to recognizing occupational disease.

Traditionally, inadequate training has been considered the major barrier to recognition of occupational disease. A survey of 136 practitioners was conducted to determine which barriers were actually considered most relevant. The sample included three subgroups: primary care, occupational medicine-oriented, and Mexican. Four aggregate indices were derived: Knowledge, Time, Unpleasant aspects, and Importance. Inadequate Time was as important as inadequate Knowledge, whereas perceived lack of Importance and Unpleasant aspects were less relevant. Patterns among the subgroups were generally comparable. This study implies that training more occupational medicine specialists in increasing recognition is not sufficient unless specific strategies to overcome time constraints are also implemented. For example, emphasizing a "complete occupational history" may be counterproductive. Limiting histories to selected patients; use of focused, brief histories; and, perhaps, computer-based methods are needed.

Decision model for optimizing respirator protection.

Respirators are widely used for protection against inhaled toxins. The emphasis of research and implementation effort has evolved through several stages: the respirator device itself, use situation, respirator program factors under employer control, individual worker factors not under employer control, and occupational health systems. For this study, a computer-simulation decision assistance model was developed to assess the impact of various factors on the number of workers receiving adequate protection. Factors include the respirator protection factor, identification of sites needing respirator protection, selection of proper device, availability when needed, frequency of ever use, regularity of use among users, and variability in personal susceptibility or other factors. This analysis demonstrates that for both moderate-risk and high-risk (i.e., IDLH, immediately dangerous to life and health) exposures under current circumstances, the actual protection afforded depends upon the optimization of program factors and detection of atypical outlier persons and worksites. Therefore, programs and research must focus on these areas. Occupational medicine specialists should help optimize these areas and, in addition, use each case of respiratory protection failure as an index case to improve the overall programs.

Frequency of occupational health concerns in general clinics.

Studies have suggested that occupational disease and injury are under-recognized by clinicians. To estimate the frequency of occupational factors in disease and injury, 108 patients in a general (not occupational) health care facility were interviewed about the frequency and types of workplace-health interactions. Thirty-nine percent reported possible causation by work, and 66% reported a possible increase in symptoms by work, even if not caused by work. Twenty-seven percent reported changing jobs and/or tasks because of work-health interactions. The majority of men and women reported that worksite changes could improve their functional ability at work. This study therefore indicates that (1) occupational health concerns are common in primary care clinics, even if not addressed by clinicians; (2) the definition of occupational health concerns should be broadened to include disease caused by work, disease symptoms worsened by work, and the need for occupational accommodation even if the disease itself is not caused by work; and (3) inquiring about patient concerns about workplace-health interactions can provide clinicians with significant opportunities for primary, secondary, and tertiary prevention.

Intelligent database generated occupational questionnaire system.

Obtaining an adequate occupational history requires special expertise to "ask the right questions" that are relevant to a particular patient's specific health conditions and potential exposures. This article describes a way to systematically accomplish this by means of a computer system that can overcome limited availability of necessary clinical occupational health expertise. The Intelligent Questionnaire system is a computer-based system for generating case-specific questionnaires about the influence of work on respiratory disease. Intelligent Questionnaire includes three databases: Questions, Responses, and Calls (clues to identify questions). The Questionnaire also arranges questions in a logical manner and provides a customized data entry screen for each subject. This approach provides primary practitioners with expertise on a case-by-case basis. It also facilitates occupational health surveillance because it allows acquiring detailed case-specific information in a systematic fashion. A computer-based system can facilitate obtaining occupational histories with high specificity and consistency without depending on general availability of a human occupational health clinical expertise.

Use of a computerized respiratory care record system to study utilization of IPPB therapy.

Increases in the utilization of respiratory therapy and the need to avoid its misuse have placed increasing management responsibilities on medical and technical supervisors of respiratory care services. To improve our managerial capabilities we designed a computerized respiratory care record system. Respiratory therapists use specially designed forms to record initial respiratory assessments and subsequent progress notes. A computer program allows secretaries to enter information from the forms into a data base. Another program tabulates information from the data base. As an example of the usefulness of this system we present a study of the utilization of intermittent positive-pressure breathing (IPPB) therapy in patients undergoing intrathoracic or upper abdominal surgery. Although all such patients were routinely educated preoperatively in the use of IPPB, chest physiotherapy, and incentive spirometry, the study revealed that only 14% of the patients received IPPB postoperatively, whereas more than 90% received chest physiotherapy and incentive spirometry. As a result of our findings we are saving time and money by discontinuing routine IPPB education for this population.