Systematic update to the mammalian relative potency estimate database and development of best estimate toxic equivalency factors for dioxin-like compounds.

The World Health Organization (WHO) assesses potential health risks of dioxin-like compounds using Toxic Equivalency Factors (TEFs). This study systematically updated the relative potency (REP) database underlying the 2005 WHO TEFs and applied advanced methods for quantitative integration of study quality and dose-response. Data obtained from fifty-one publications more than doubled the size of the previous REP database (∼1300 datasets). REP quality and relevance for these data was assessed via application of a consensus-based weighting framework. Using Bayesian dose-response modeling, available data were modeled to produce standardized dose/concentration-response Hill curves. Study quality and REP data were synthesized via Bayesian meta-analysis to integrate dose/concentration-response data, author-calculated REPs and benchmark ratios. The output is a prediction of the most likely relationship between each congener and its reference as model-predicted TEF uncertainty distributions, or the 'best estimate TEF' (BE-TEF). The resulting weighted BE-TEFs were similar to the 2005 TEFs, though provide more information to inform selection of TEF values as well as to provide risk assessors and managers with information needed to quantitatively characterize uncertainty around TEF values. Collectively, these efforts produce an updated REP database and an objective, reproducible approach to support development of TEF values based on all available data.

Measuring interoception: The phase adjustment task.

Interoception, perception of one's bodily state, has been associated with mental health and socio-emotional processes. However, several interoception tasks are of questionable validity, meaning associations between interoception and other variables require confirmation with new measures. Here we describe the novel, smartphone-based Phase Adjustment Task (PAT). Tones are presented at the participant's heart rate, but out of phase with heartbeats. Participants adjust the phase relationship between tones and heartbeats until they are synchronous. Data from 124 participants indicates variance in performance across participants which is not affected by physiological or strategic confounds. Associations between interoception and anxiety, depression and stress were not significant. Weak associations between interoception and mental health variables may be a consequence of testing a non-clinical sample. A second study revealed PAT performance to be moderately stable over one week, consistent with state effects on interoception.

Assessing children's exposure to manganese in drinking water using a PBPK model.

A previously published human PBPK model for manganese (Mn) in infants and children has been updated with Mn in drinking water as an additional exposure source. Built upon the ability to capture differences in Mn source-specific regulation of intestinal uptake in nursing infants who are breast-fed and formula-fed, the updated model now describes the bioavailability of Mn from drinking water in children of ages 0-18. The age-related features, including the recommended age-specific Mn dietary intake, age-specific water consumption rates, and age-specific homeostasis of Mn, are based on the available human data and knowledge of the biology of essential-metal homeostasis. Model simulations suggest that the impact of adding drinking-water exposure to daily Mn exposure via dietary intake and ambient air inhalation in children is not greater than the impacts in adults, even at a drinking-water concentration that is 2 times higher than the USEPA's lifetime health advisory value. This conclusion was also valid for formula-fed infants who are considered at the highest potential exposure to Mn from drinking water compared to all other age groups. Our multi-route, multi-source Mn PBPK model for infants and children provides insights about the potential for Mn-related health effects on growing children and will thereby improve the level of confidence in properly interpreting Mn exposure-health effects relationships in children in human epidemiological studies.

Feature analysis of ultrasound elastography image for quantitative assessment of cutaneous carcinoma.

BACKGROUND: To evaluate the feasibility of using quantitative texture features computed from high frequency ultrasound and ultrasound elastography (USE) images in the discrimination of benign from malignant skin lesions. METHODS: A commercial ultrasound system with a 14 MHz transducer was used to visualize skin lesions requiring biopsy on clinical evaluation. Patients were enrolled over a 6-month period and imaged prospectively by operators blind to the histopathologic diagnosis. Anatomic ultrasound and USE imaging of the skin lesions was performed using a 2-4 mm gel standoff pad before biopsy and histopathologic evaluation. The ElastoAnalysis software developed for the texture analysis of USE images was provided by Hitachi. The software computes thirteen texture features within a region of interest (ROI), which have demonstrated promise in diagnostic characterization of liver fibrosis staging and in quantitative elastography of breast cancer. This approach has not yet been studied in the quantitative assessment of skin cancer. Results were retrospectively compared to the histopathologic diagnosis and a diagnostic criteria with the goal of maximizing sensitivity was evaluated for each textural feature. RESULTS: Of the 37 lesions included, among 30 patients who participated, 12 lesions were malignant and 25 were benign. Eleven out of thirteen textural metrics computed by the software were useful in differentiating benign from malignant lesions with 100% sensitivity and specificities ranging from 28% to 85%. CONCLUSIONS: This feasibility study demonstrated that feature analysis of USE may be useful in quantitatively differentiating cancerous from benign primary solitary skin lesions prior to biopsy.

Prospective analysis of visual outcomes using apodized, diffractive multifocal intraocular lenses following phacoemulsification for cataract or clear lens extraction.

BACKGROUND: To evaluate efficacy, safety and predictability of apodized, diffractive multifocal intraocular lenses. DESIGN: Prospective, observational study. PARTICIPANTS OR SAMPLE: Two hundred three patients (363 eyes) underwent surgery for cataract (54.8%) or clear lens extraction (45.2%). METHODS: A study of consecutive patients undergoing lens extraction with insertion of the AcrySof Natural ReSTOR intraocular lens (SN60D3). Assessment included: refraction, corneal topography, biometry, monocular and binocular uncorrected and best spectacle corrected distance and near visual acuity. MAIN OUTCOME MEASURES: Visual acuity, spectacle dependence. RESULTS: Mean preoperative best corrected visual acuity was 6/12 (cataract) and 6/6 (clear lens extraction). One hundred sixty-one (98.2%) of the clear lens extraction group were hyperopic and presbyopic (mean spherical equivalent +4.25±3.5D). Postoperatively uncorrected visual acuity was ≥6/12 in 96.5% of eyes (51.9% ≥6/6) and ≥ N5 in 95% of eyes. At 6 months, 182 eyes (91.4%) (cataract) and 137 eyes (83.5%) (clear lens extraction) were ≤0.50 D of target spherical equivalent. Spectacle independence was reported in 81.9% (n=168). Minor halos or other visual phenomena were reported in 10.2%. No subjects required intraocular lens exchange. Safety index at 6 months was 2.5 and 1.17 for cataract and clear lens extraction, respectively. CONCLUSIONS: The apodized, diffractive multifocal intraocular lens predictably provided excellent near uncorrected visual acuity and good distance uncorrected visual acuity following cataract and clear lens extraction surgery with a high rate of spectacle independence. A minority of subjects note halos and other visual phenomena that may be related to intraocular lens design.

rKv1.2 overexpression in the central medial thalamic area decreases caffeine-induced arousal.

The voltage-gated potassium channel Kv1.2 belongs to the shaker-related family and has recently been implicated in the control of sleep profile on the basis of clinical and experimental evidence in rodents. To further investigate whether increasing Kv1.2 activity would promote sleep occurrence in rats, we developed an adeno-associated viral vector that induces overexpression of rat Kv1.2 protein. The viral vector was first evaluated in vitro for its ability to overexpress rat Kv1.2 protein and to produce functional currents in infected U2OS cells. Next, the adeno-associated Kv1.2 vector was injected stereotaxically into the central medial thalamic area of rats and overexpression of Kv1.2 was showed by in situ hybridization, ex vivo electrophysiology and immunohistochemistry. Finally, the functional effect of Kv1.2 overexpression on sleep facilitation was investigated using telemetry system under normal conditions and following administration of the arousing agent caffeine, during the light phase. While no differences in sleep profile were observed between the control and the treated animals under normal conditions, a decrease in the pro-arousal effect of caffeine was seen only in the animals injected with the adeno-associated virus-Kv1.2 vector. Overall, our data further support a role of the Kv1.2 channel in the control of sleep profile, particularly under conditions of sleep disturbance.

Do early stages of lumbar intervertebral disc degeneration really cause instability? Evaluation of an in vitro database.

Early stages of intervertebral disc degeneration are postulated to cause instability. In the literature, however, some authors report the opposite. These contradictory positions are probably supported by the mostly small number of segments which are investigated. The aim of this project therefore was to investigate the influence of intervertebral disc degeneration on lumbar spine rotational stability using a large data set. The flexibility data from all spine specimens tested in our institute so far were collected in a large in vitro database. From this database, all lumbar spine specimens were selected, which had been tested for flexibility under pure moment loads of ±7.5 N m and for which radiographs were accessible. 203 segments met these criteria. Their radiographic degree of disc degeneration was determined on a scale from 0 (no degeneration) to 3 (severe degeneration) and their influence on the respective range of motion and neutral zone was examined. The different lumbar levels differ in flexibility, which increases the variability of the data if pooled together. To minimise this effect a statistical model was fitted. The model-based mean estimates showed a decrease of the range of motion from grade 0 to 3 in flexion/extension (by 3.1°, p < 0.05) and lateral bending (by 3.4°, p < 0.05). In contrast, in axial rotation the range of motion tended to increase; however, not only from grade 0 to 1 but also towards grade 3 (by 0.2°) (p > 0.05). The neutral zone was affected in a similar way but to a smaller degree (p > 0.05). In conclusion, the results indicated that early stages of intervertebral disc degeneration do not necessarily cause rotational instability. In contrast, stability increased in flexion/extension and lateral bending. Only in axial rotation stability tended to decrease.

Transgene expression and effective gene silencing in vagal afferent neurons in vivo using recombinant adeno-associated virus vectors.

Vagal afferent fibres innervating thoracic structures such as the respiratory tract and oesophagus are diverse, comprising several subtypes of functionally distinct C-fibres and A-fibres. Both morphological and functional studies of these nerve subtypes would be advanced by selective, effective and long-term transduction of vagal afferent neurons with viral vectors. Here we addressed the hypothesis that vagal sensory neurons can be transduced with adeno-associated virus (AAV) vectors in vivo, in a manner that would be useful for morphological assessment of nerve terminals, using enhanced green fluorescent protein (eGFP), as well as for the selective knock-down of specific genes of interest in a tissue-selective manner. We found that a direct microinjection of AAV vectors into the vagal nodose ganglia in vivo leads to selective, effective and long-lasting transduction of the vast majority of primary sensory vagal neurons without transduction of parasympathetic efferent neurons. The transduction of vagal neurons by pseudoserotype AAV2/8 vectors in vivo is sufficiently efficient such that it can be used to functionally silence TRPV1 gene expression using short hairpin RNA (shRNA). The eGFP encoded by AAV vectors is robustly transported to both the central and peripheral terminals of transduced vagal afferent neurons allowing for bright imaging of the nerve endings in living tissues and suitable for structure-function studies of vagal afferent nerve endings. Finally, the AAV2/8 vectors are efficiently taken up by the vagal nerve terminals in the visceral tissue and retrogradely transported to the cell body, allowing for tissue-specific transduction.

Sensory detection thresholds are modulated across the cardiac cycle: evidence that cutaneous sensibility is greatest for systolic stimulation.

The visceral afferent feedback hypothesis proposes that sensorimotor function is impaired by cortical inhibition associated with increased baroreceptor activation. This study is the first to examine the effects of naturally occurring variations in baroreceptor activity across the cardiac cycle on cutaneous sensory detection thresholds. In each trial, an electrocutaneous stimulus was delivered to the index finger at one of three intervals (0, 300, 600 ms) after the R-wave of the electrocardiogram. Separate interleaving up-down staircases were used to determine the 50% detection threshold for each R-wave to stimulation interval. Cutaneous sensory detection thresholds were lower for stimuli presented at R+300 ms than R+0 ms or R+600 ms. The finding that cutaneous sensibility was greater when stimulated during systole than diastole may be accounted for by a modified afferent feedback hypothesis.

[Improvement of anxiety and depression in women with breast cancer during inpatient oncological rehabilitation-- results of a prospective study]. / Verbesserung von Angst und Depression bei Brustkrebspatientinnen während stationärer onkologischer Rehabilitation-- Ergebnisse einer prospektiven Studie.

PURPOSE: Investigation of the influence of an oncological inpatient rehabilitation programme on anxiety and depression in women with breast cancer. PATIENTS AND METHOD: 198 women with breast cancer, aged 25 to 75 years, filled in the Hospital Anxiety and Depression Scale (HADS) German version at the beginning and end of inpatient rehabilitation. Focus was set on the frequency of anxiety and depression. Therefore proportions with 95 % confidence intervals (CI) were built. The before-after comparison of HADS-scores was made using the signed rank test with two-sided level of significance of alpha = 5 %. In addition effect sizes were calculated. Possible relations between the scores at the beginning of rehabilitation and the patients' age or the interval since diagnosis were analysed by calculating correlation coefficients. RESULTS: At the beginning of rehabilitation a state of anxiety was probable in 23.2 % (CI [17.3 %; 29.1 %] of the women and one of depression in 9.1 % (CI [5.8 %; 13.9 %]). In other words, they reached a level of >or= 11 score points on each scale. No correlation was found with the age of the patients or the time interval since diagnosis (|r|

[Prediction of premature pension after stationary rehabilitation due to adipositas--a prognostic model based on routinely collected data of the State Insurance Institution of Baden-Württemberg]. / Vorhersage vorzeitiger Berentung nach stationärer Rehabilitation wegen Adipositas -- ein Prognosemodell basierend auf Routinedaten der Landesversicherungsanstalt Baden-Württemberg.

Up to 60 % of the German population can be marked as obese. Due is to its frequency and its associated diseases like cardiovascular disorders and disorders of the musculoskeletal system adipositas is a severe burden on the German health care system. This burden is caused by costs of the disease and costs due to premature pensioning. In this study logistic regression modelling has been performed by means of routinely collected data of patients of the regional statutory pension insurance institute Landesversicherungsanstalt Baden-Württemberg (LVA-BW) rehabilitated due to adipositas (n = 599). The aim was to detect influential variables for the prognosis of premature pensioning (n = 135). The data of the patients were obtained from a research database of the "RehaNet" project which includes data of the standardized discharge report of the Federation of German Pension Insurance Institutes and quality assurance questionnaires of the LVA-BW. Three variables remain in the model after a step-down procedure for modelling by logistic regression. The selected variables are age (in years), the physician's statement about the patients limitations of movement after rehabilitation (yes/no) and about the patients ability to work in future (more/less than half-day). After internal validation of the model by bootstrap methods the model achieves a sensitivity of 73 %, a specificity of 87 %, a positive and a negative predictive value of 57 and 93 % respectively. The area under the curve (AUC) of the ROC analysis is 0.87, so the model achieves a good prognostic value. Thus, this model is a valuable test for the exclusion of possible premature pension while or after rehabilitation due to adipositas. It was found that the situation of "no premature pensioning" of patients rehabilitated due to adipositas can be predicted quite accurately with little information (three variables). This reveals a perspective for further research in the possibility of an early, risk-adapted and individualised intervention after stationary rehabilitation for adipositas to keep employment.

A randomized trial of Korodin Herz-Kreislauf-Tropfen as add-on treatment in older patients with orthostatic hypotension.

In a randomized, double-blind, placebo-controlled, parallel group, phase III clinical trial efficacy and safety of Korodin, a combination of natural D-camphor and an extract from fresh crataegus berries, was investigated in patients 50 years and older with orthostatic hypotension. At visit 1 eligibility of patients was checked and a placebo medication was given to all patients. At visit 2 orthostatic hypotension had to be reconfirmed, then the patient was randomized either to Korodin or placebo, study medication (25 drops) was applied once and then outcome was measured. After 7 days of home treatment with daily 3 x 25 drops outcome was measured at visit 3. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were documented 10, 5, 2 and 0 min before as well as 1, 3, 5, 8, and 10 min after getting in the upright position at visit 1, at visit 2 before and after application of study medication and at visit 3. Primary outcome was the change of mean arterial blood pressure (MAP) from just before standing up to the nadir within the first 3 min after standing up. Secondary outcome variables were SBP, DBP, HR, quality of life (SF-12) and seven typical signs and symptoms of orthostatic hypotension. The study was performed in a rehabilitation clinic and in two doctor's practices in Germany from November 2002 to May 2003. During this time, 57 patients were admitted to the study, 39 patients were eligible and randomized, 38 patients were treated according to protocol and evaluated, 21 patients with Korodin and 17 patients with placebo. After a single application the median decrease of MAP was 11.4 mmHg for Korodin and 14.0 mmHg for placebo. Compared to baseline, the median MAP improved 4.3 mmHg for Korodin and 0.3 mmHg for placebo. After 1 week of treatment the decrease of median MAP after standing up was 9.3 mmHg for Korodin and 13.3 mmHg for placebo. Compared to baseline, the improvement was 5.9 mmHg for Korodin and 1.6 mmHg for placebo. Efficacy of 1 week treatment was significant. For the single application a superiority of Korodin over placebo was seen; however, it was not significant. All secondary outcome variables confirmed these findings, except for the physical summary score in the quality of life evaluation (SF-12 questionnaire). Only one adverse event occurred, but this was not serious and without relationship to the study medication. The other safety variables (SBP, DBP, HR, ECG, physical examination) did not show any problems. This study demonstrates that Korodin is efficacious for orthostatic hypotension in patients over 50 years.

Increased C reactive protein in response to acute stress in patients with rheumatoid arthritis.

OBJECTIVE: To assess the effects of acute stress on inflammatory, haemostatic, rheological, and haemodynamic activity in patients with rheumatoid arthritis (RA) in comparison with patients with osteoarthritis (OA). METHODS: 21 patients with RA and 10 with OA underwent a brief mental stress task while standing. Inflammatory, haemostatic, rheological, and haemodynamic variables were measured at baseline, during the task, and at recovery. RESULTS: At baseline, erythrocyte sedimentation rate and fibrinogen were higher in RA than OA. White blood cell count, fibrinogen, blood pressure, and pulse rate increased, whereas prothrombin time and plasma volume decreased during the task in both patient groups. The stress task increased C reactive protein (CRP) only in patients with RA, and more specifically in those patients with RA with high disease activity. CONCLUSIONS: The increase in the inflammatory marker CRP, which was specific to patients with RA, combined with the haemostatic, rheological, and haemodynamic reactions to the stress task, over and above the already high baseline levels, could underlie the increased risk for myocardial infarction in this vulnerable patient group.

Design and performance testing of quantitative real time PCR assays for influenza A and B viral load measurement.

BACKGROUND: The antiviral effect of anti-influenza drugs such as zanamivir may be demonstrated in patients as an increased rate of decline in viral load over a time course of treatment as compared with placebo. Historically this was measured using plaque assays, or Culture Enhanced Enzyme Linked Immunosorbent Assay (CE-ELISA). OBJECTIVES: to develop and characterise real time quantitative PCR (qPCR) assays to measure influenza A and B viral load in clinical samples, that offer improvements over existing methods, in particular virus infectivity assays. STUDY DESIGN: The dynamic range and robustness were established for the real time qPCR assays along with stability of the assay components. Cross validation of the real time PCR assays with CE-ELISA was performed by parallel testing of both serial dilutions of three different subtypes of cultured virus and a panel of influenza positive throat swab specimens. RESULTS: the assays were specific for influenza A and B and the dynamic ranges were at least seven logs. The assay variability was within acceptable limits but increased towards the lower limit of quantification, which was 3.33 log(10) viral cDNA copies/ml of virus transport medium (ten viral RNA copies/PCR). The components of the assay were robust enough to withstand extended storage and several freeze-thaw cycles. For the real time PCR assays the limit of quantification was equivalent to the virus infectivity cut off, which equates to a 93-fold increase in sensitivity. CONCLUSION: Well characterised real time PCR assays offer significant improvements over the existing methods for measuring the viral load of strains of influenza A and B in clinical specimens.

[Osteoporosis in inflammatory bowel disease - results of a survey among members of the German Crohn's and Ulcerative Colitis Association]. / Osteoporose bei chronisch entzündlichen Darmerkrankungen - Ergebnisse einer Umfrage an Mitgliedern der Deutschen M. Crohn und Colitis ulcerosa Vereinigung (DCCV).

INTRODUCTION: Osteoporosis is a frequent and clinically important complication in inflammatory bowel disease (IBD). Prevalence and risk factors have been examined in small numbers of patients. With a nationwide survey of members of the German Crohn's and Ulcerative Colitis Association (DCCV) we wanted to evaluate the situation in a larger group of patients. METHODS: Questionnaires were sent with the autumn issue of the members journal to approx. 14,620 affected members of the DCCV. Items covered osteoporosis, clinical symptoms, anamnesis and sociodemographic topics. Results are presented as descriptive analysis and in a logistic regression analysis of factors contributing to the osteoporosis risk. RESULTS: 2,536 questionnaires could be used (17.3 %). Mean age and distribution concerning diagnosis and gender were comparable to the DCCV members in total. The prevalence of pathologic bone density was 62.3 % in those 1,265 patients (50.1 %) who underwent bone densitometry in the course of their disease. The analysis led to the following possible risk factors: disease activity (high chronic activity or more than 1 acute flare annually vs. remission, p < 0.001), lifetime steroid dosage > 10 g (p = 0.002), Crohn's disease vs. ulcerative colitis (p = 0.02), multiple bowel resection (p = 0.032), age (p = 0.018) and low body mass index (p = 0.034). 83.4 % of the patients with pathologic bone density received specific therapy, but most of those (63.5 %) were solely substituted with calcium and vitamin D. CONCLUSION: This is the first study looking at epidemiology and risk factors of osteoporosis in a large study population of patients with inflammatory bowel disease. Although the prevalence may be overestimated due to selection bias in our study, osteoporosis is confirmed as a frequent and clinically relevant complication in IBD. Bone densitometry is recommended in those patients with one or more risk factors.

Elevated heels and adaptation to new shoes in frail elderly women.

Footwear is supposed to have influence on postural control and is a potential aspect to address in the prevention of falls in the elderly. This study aimed to show whether measurements of static balance and gait are different with habitual shoes compared to new special senior shoes with different heel height and whether these results change after adaptation. In a randomized controlled intervention study, 26 subjects (median age 87 years) were recruited from two nursing homes and one facility of assisted living. Measurements of static balance and gait were performed with habitual shoes and two types of new special senior shoes differing in heel height. Measurements were repeated after five weeks. There was no difference in static balance and gait with habitual shoes compared to either of the new footwear offered. Results of performance with higher heels were not different compared to lower heels. No further effect of adaptation after wearing a new shoe over five weeks could be demonstrated. With respect to static and dynamic balance, there seems to be a wide range of acceptable footwear as long as the heel height is below a critical value. A standardized shoe can be used in the assessment of balance because the effect of adaptation can be neglected.

The influence of diabetes mellitus on postoperative infections.

Clinicians and researchers are linking elevated glucose levels with potential infectious outcomes. Physiologic processes to fight foreign agents are potentially impaired during periods of hyperglycemia. Some of these responses, such as immune function and the inflammatory response, are impaired when they are needed most, such as during the recovery from surgical procedures. Investigators have demonstrated the importance of control of serum glucose postoperatively. Outcomes are improved when tighter glycemic control is practiced. The current literature challenges practitioners to become more cognizant of serum glucose in surgical patients and patients who are critically ill, implementing protocols to gain tighter control of serum glucose in any patient may be appropriate. Further investigation of glycemic control in surgical and other populations will reinforce research findings in this area. Studies should be performed on surgical patients who are particularly vulnerable to DM, glycemic alterations, and postoperative infections, such as patients undergoing peripheral vascular surgery. Further investigations are also needed on the role of hyperglycemia and outcomes in nondiabetic individuals, and on the similarities or differences in glycemic control in types 1 and 2 DM. To increase the generalizability of the study findings, definitions used across studies, such as the type of diabetes, should be standardized. When these studies determine optimal glycemic control practices in a variety of patient populations, clinicians will be able to determine the best practice guidelines to optimize patient care and limit adverse infectious outcomes.

Predictors of attendance at cardiac rehabilitation after myocardial infarction.

OBJECTIVE: The purpose of this study was to determine predictors of attendance at cardiac rehabilitation after myocardial infarction (MI). METHODS: Various demographic, behavioural, and clinical variables were measured during hospitalisation in 288 MI patients. Of these, 263 were available to attend outpatient-based cardiac rehabilitation: 108 actually attended. RESULTS: Multiple logistic regression analyses indicated that nonattenders lived in more deprived areas and were less likely to have paid employment. Nonattenders also registered more symptoms of depression and anxiety and exercised less frequently prior to their MI, although only the last of these variables were predicted in a multivariate model. In terms of clinical status, whether patients had been thrombolysed or not was the strongest predictor of attendance. CONCLUSIONS: Attendance at cardiac rehabilitation is not an arbitrary matter. Strategies should be developed for encouraging greater attendance among those not in paid employment, those from deprived areas, and those who exercise infrequently.