Search

This review investigated which patterns of thyroid- and brain-related effects are seen in rats upon gestational/lactational exposure to 14 substances causing thyroid hormone imbalance by four different modes-of-action (inhibition of thyroid peroxidase, sodium-iodide symporter and deiodinase activities, enhancement of thyroid hormone clearance) or to dietary iodine deficiency. Brain-related parameters included motor activity, cognitive function, acoustic startle response, hearing function, periventricular heterotopia, electrophysiology and brain gene expression. Specific modes-of-action were not related to specific patterns of brain-related effects. Based upon the rat data reviewed, maternal serum thyroid hormone levels do not show a causal relationship with statistically significant neurodevelopmental effects. Offspring serum thyroxine together with offspring serum triiodothyronine and thyroid stimulating hormone appear relevant to predict the likelihood for neurodevelopmental effects. Based upon the collated database, thresholds of ≥60%/≥50% offspring serum thyroxine reduction and ≥20% and statistically significant offspring serum triiodothyronine reduction indicate an increased likelihood for statistically significant neurodevelopmental effects; accuracies: 83% and 67% when excluding electrophysiology (and gene expression). Measurements of brain thyroid hormone levels are likely relevant, too. The extent of substance-mediated thyroid hormone imbalance appears more important than substance mode-of-action to predict neurodevelopmental impairment in rats. Pertinent research needs were identified, e.g. to determine whether the phenomenological offspring thyroid hormone thresholds are relevant for regulatory toxicity testing. The insight from this review shall be used to suggest a tiered testing strategy to determine whether gestational/lactational substance exposure may elicit thyroid hormone imbalance and potentially also neurodevelopmental effects. [ABSTRACT FROM AUTHOR]

Abstract The endocrine system is responsible for growth, development, maintaining homeostasis and for the control of many physiological processes. Due to the integral nature of its signaling pathways, it can be difficult to distinguish endocrine-mediated adverse effects from transient fluctuations, adaptive/compensatory responses, or adverse effects on the endocrine system that are caused by mechanisms outside the endocrine system. This is particularly true in toxicological studies that require generation of effects through the use of Maximum Tolerated Doses (or Concentrations). Endocrine-mediated adverse effects are those that occur as a consequence of the interaction of a chemical with a specific molecular component of the endocrine system, for example, a hormone receptor. Non-endocrine-mediated adverse effects on the endocrine system are those that occur by other mechanisms. For example, systemic toxicity, which perturbs homeostasis and affects the general well-being of an organism, can affect endocrine signaling. Some organs/tissues can be affected by both endocrine and non-endocrine signals, which must be distinguished. This paper examines in vitro and in vivo endocrine endpoints that can be altered by non-endocrine processes. It recommends an evaluation of these issues in the assessment of effects for the determination of endocrine disrupting properties of chemicals. This underscores the importance of using a formal weight of evidence (WoE) process to evaluate potential endocrine activity. [ABSTRACT FROM AUTHOR]

Context: The recent recommendations of the European Endocrine Society states that the performance of computed tomography (CT) to characterize 'true' adrenal incidentalomas (AIs) remains debatable. Objective: To determine relevant thresholds for usual CT parameters for the diagnosis of benign tumors using robust reference standard among a large series of 'true' AIs recruited in an endocrinological setting. Design: Retrospective study of 253 AIs in 233 consecutive patients explored in a single university hospital: 183 adenomas, 33 pheochromocytomas, 23 adrenocortical carcinomas, 5 other malignant tumors and 9 other benign tumors. Reference standard was histopathology in 118 AIs, biological diagnosis of pheochromocytoma in 2 AIs and size stability after at least 1 year of follow-up in 133 AIs. Methods: Sensitivity, specificity and positive and negative predictive values were estimated for various thresholds of size, unenhanced attenuation (UA), relative and absolute wash-out (RPW, APW) of contrast media. 197 scans were reviewed independently in a blinded fashion by two expert radiologists to assess inter-observer reproducibility of measurements. Results: Criteria associated with a 100% positive predictive value for the diagnosis of benign AI were: a combination of size and UA: 30 mm and 20 HU or 40 mm and 15 HU, respectively; RPW >53%; and APW >78%. Non-adenomatous AIs with rapid contrast wash-out were exclusively benign pseudocysts and pheochromocytomas, suggesting that classical thresholds of 60% and 40% for APW and RPW, respectively, can be safely used for patients with normal metanephrine values. Inter-observer reproducibility of all parameters was excellent (intra-class correlation coefficients: 0.96-0.99). Conclusions: Our study, the largest conducted in AIs recruited in an endocrinological setting, suggests safe thresholds for quantitative CT parameters to avoid false diagnoses of benignity. [ABSTRACT FROM AUTHOR]

Purpose: The Core Outcome Measure Index (COMI) is a multidimensional questionnaire that investigates five dimensions in low back pain (LBP) patients, but does not address the psychological dimension. As the biopsychosocial perspective is recognized as important to capture the entire clinical picture of these patients, this multicenter prospective cohort study was designed to investigate the psychometric properties of a modified version of the COMI (COMIAD) which included 2 additional items, exploring anxiety and depression, respectively.Methods: 168 subacute or chronic LBP patients recruited in spine clinics completed a set of questionnaires before and after treatment (follow-up at 6 months). Construct validity was explored by comparing each item of the COMIAD to validated full-length questionnaires. Thus two additional questionnaires were included to assess the construct validity of the anxiety and depression measures. The psychometric properties of the COMI and COMIAD were then compared.Results: The two new items showed good internal consistency, high correlations with the corresponding full-length questionnaires, no floor or ceiling effect and good reproducibility (test-retest agreement kappa 0.68 for anxiety, 0.62 for depression). The addition of the 2 items did not alter internal validity (Cronbach's alpha = 0.88 and 0.87, respectively). The smallest detectable difference, the Minimal Clinically Important Improvement and the Patient Acceptable Symptom State were only minimally affected by the changes.Conclusion: The questions exploring anxiety and depression have good intrinsic and psychometric capacities (i.e., no floor or ceiling effects and high correlations with full-length scales) and did not significantly modify the psychometrics of the original COMI questionnaire. The COMIAD offers the possibility to include the psychological dimension in the multidimensional evaluation without significantly affecting questionnaire length. [ABSTRACT FROM AUTHOR]

Purpose: The Dallas Pain Questionnaire (DPQ) assesses the impact of low back pain (LBP) on four components (0-100) of daily life. We estimated the minimal clinically important improvement (MCII) and the patient acceptable symptom state (PASS) values of DPQ in LBP patients.Methods: 142 patients with LBP lasting for at least 4 weeks completed a battery of questionnaires at baseline and 6 months later. Questions for MCII addressed patient-reported response to treatment at 6 months on a five-point Likert scale, while a yes/no question concerning satisfaction with present state was used to determine PASS. MCII was computed as the difference in mean DPQ scores between patients reporting treatment as effective vs. patients reporting treatment as not effective, and PASS was computed as the third quartile of the DPQ score among patients who reported being satisfied with their present state.Results: MCII values were 22, 23, 2 and 10 for daily activities, work and leisure, social interest, and anxiety/depression, respectively. PASS values were 29, 23, 20 and 21 for the four components, respectively. The PASS total score threshold of 24 correctly classified 84.1 % of the patients who reported being unsatisfied with their present state, and 74.7 % of patients reported being satisfied.Conclusions: These values give information of paramount importance for clinicians in interpreting change in DPQ values over time. Authors should be encouraged to report the percentage of patients who reach MCII and PASS values in randomized clinical trials and cohort studies to help clinicians to interpret clinical results. [ABSTRACT FROM AUTHOR]

Pronamide, a selective, systemic, pre- and post-emergence herbicide, caused an increased incidence of thyroid follicular cell adenomas in a rat carcinogenicity study. Thyroid tumors, as well as liver and pituitary changes, were limited only to the high-dose group. The evidence for and against specific potential modes of action (MoAs) for rat thyroid follicular cell adenomas and their relevance to humans is discussed. Pronamide is not mutagenic and therefore, direct DNA reactivity is not relevant as a MoA. The hypothesized MoA for this effect is altered homeostasis of the hypothalamic–pituitary–thyroid (HPT) axis mediated by the induction of hepatic enzymes, including uridine diphosphate glucuronosyltransferase (UGT). Evaluation of data from a series of regulatory guideline and MoA studies aimed at identifying the causative and associated key events supported a UGT-mediated MoA in the development of thyroid follicular tumors. This MoA for pronamide-induced thyroid tumors in rats, which involves increased thyroid hormone metabolism/clearance, altered thyroid hormone homeostasis and HPT stimulation is not considered relevant to humans based on quantitative species differences, making rats markedly more sensitive than humans to thyroid perturbations. [ABSTRACT FROM AUTHOR]

Information on snow depth and its spatial distribution is crucial for numerous applications in snow and avalanche research as well as in hydrology and ecology. Today, snow depth distributions are usually estimated using point measurements performed by automated weather stations and observers in the field combined with interpolation algorithms. However, these methodologies are not able to capture the high spatial variability of the snow depth distribution present in alpine terrain. Continuous and accurate snow depth mapping has been successfully performed using laser scanning but this method can only cover limited areas and is expensive. We use the airborne ADS80 optoelectronic scanner, acquiring stereo imagery with 0.25m spatial resolution to derive digital surface models (DSMs) of winter and summer terrains in the neighborhood of Davos, Switzerland. The DSMs are generated using photogrammetric image correlation techniques based on the multispectral nadir and backward-looking sensor data. In order to assess the accuracy of the photogrammetric products, we compare these products with the following independent data sets acquired simultaneously: (a) manually measured snow depth plots; (b) differential Global Navigation Satellite System (dGNSS) points; (c) terrestrial laser scanning (TLS); and (d) ground-penetrating radar (GPR) data sets. We demonstrate that the method presented can be used to map snow depth at 2m resolution with a vertical depth accuracy of ±30 cm (root mean square error) in the complex topography of the Alps. The snow depth maps presented have an average accuracy that is better than 15% compared to the average snow depth of 2.2m over the entire test site. [ABSTRACT FROM AUTHOR]

Purpose: A systematic search was conducted to study the efficiency of preventive educational interventions mainly focused on a biomechanical/biomedical model. Methods: The Pubmed electronic database and the Cochrane Library were searched based on a combination of keywords related to low back pain (LBP) and posture education. Only randomized controlled trial (RCT) studying the efficiency on outcomes directly related to LBP of a preventive intervention programme mainly based on education of proper care of the back for subjects not seeking treatment were included. References of the articles meeting these inclusion criteria were also checked to identify other potential citations. Besides, a methodological study assessment of the included RCTs was performed. Results: Nine studies, all conducted at the workplace were included in this review. Their mean quality level was low (5.1/12) and among the four studies with a huge sample size ( n > 400 subjects), only one had an acceptable methodological quality score (6/12). The education interventions differed widely from one study to another. No significant differences between the control and education groups were found at the follow-up in eight out of the nine studies on the incidence of back pain, disability and sick leave. Conclusions: The results of the RCTs included in this review suggest that educational interventions mainly focused on a biomechanical/biomedical model are not effective in preventing LBP. However, taking into account the methodological quality level of the RCTs as well as the very short and heterogeneous interventions often proposed, additional high-quality studies with a longer education period are needed to conclude that such interventions are inefficient. [ABSTRACT FROM AUTHOR]

The optimal diagnostic approach and yield for gastrointestinal bleeding (GIB) in patients with ventricular assist devices (VAD) are unknown. We explored the etiology of bleeding and yield of upper and lower endoscopy, balloon-assisted enteroscopy, and video capsule endoscopy in the evaluation of GIB in patients with VADs. Methods. All VAD patients with overt gastrointestinal bleeding and drop in hematocrit from April 1, 2000 to July 31, 2008 were retrospectively reviewed. The endoscopic evaluation of each episode was recorded. Overall yield of EGD, colonoscopy, balloon-assisted, and video capsule endoscopy were evaluated. Results. Thirty-six bleeding episodes occurred involving 20 patients. The site of GIB was identified in 32/36 episodes (88.9%), and the etiology of bleeding was determined in 30/36 cases (83.3%). Five VAD patients underwent VCE. The VCE exams demonstrated a high yield with 80% of exams identifying the etiology of GIB. Endoscopic intervention was successful in 8/9 attempts. No adverse events were recorded. Two patients required surgical intervention for GIB. Conclusion. Upper, lower, video capsule, and balloon-assisted enteroscopies are safe and demonstrate a high yield in the investigation of gastrointestinal bleeding in VAD patients. Medical centers caring for VAD patients should employ a standardized protocol to optimize endoscopic evaluation and intervention. [ABSTRACT FROM AUTHOR]

If p53 is essential to eliminate damaged spermatogenic cells, then mutagen exposure in the absence of p53 would increase sperm containing damaged DNA. p53 knockout (—/—, NULL) and wild-type (+/+, WT) mice (five/group) were exposed to ethylnitrosourea (ENU) or cyclophosphamide (CP). In phase I, mice were exposed by gavage to 0 or 60 mg/kg/day ENU or CP for four days and examined on test day (TD) 4, and in phase II, mice were exposed to 0, 6, 20, or 60 mg/kg/day ENU or CP for four days and evaluated on TD 36 when exposed spermatocytes matured. In phase I, mutagens were not directly cytotoxic to mature sperm. In phase II, WT mice were more sensitive to decreases in reproductive organ weights, whereas both genotypes had decreased sperm counts. Testicular histology revealed similar CP responses, but genotype-specific ENU responses (WT mice had depletion of elongating spermatids; NULL mice had late-stage spermatocyte/early stage spermatid loss). Ethylnitrosourea increased DNA strand breaks in WT mice. Thus, mice responded similarly to CP, suggesting a primarily p53-independent response, whereas the ENU response differed by zygosity, suggesting a role for p53. As DNA damage increased at higher ENU doses, compensatory repair pathways may operate in NULL mice. [ABSTRACT FROM PUBLISHER]

1,3 Butadiene (BD) is an industrial intermediate used primarily in product manufacturing with the greatest exposure potential via inhalation. BD was evaluated for reproductive and developmental effects in a Good Laboratory Practice (GLP)-compliant, extended OECD 421 guideline study (completed 2003). Twelve-week old rats (12/sex/dose) were exposed via whole-body inhalation to BD vapor (0, 300, 1500, 6000 ppm) for 6 h/day, 7 days/week, starting 14 days prior to mating through the day prior to euthanasia (total exposures: 83–84 days for F0 males 60–70 days for F0 females). Select F1 offspring (1/sex/litter) were dosed 7 days (postnatal days 21–27 or 28–34), then necropsied. At 1500 and 6000 ppm, treatment-related facial soiling was seen in F0 males and females with decreased body weights/gains in F0 males. F1 males and females exhibited similar effects at 1500 and 6000 ppm. Importantly, the F0 generation had no evidence of altered sperm production, testicular effects, or ovarian atrophy, which were sensitive responses in mice. The no-observed-adverse-effect-level (NOAEL) is 300 ppm due to decreased body weight/gain and facial soiling at 1500 ppm, whereas 6000 ppm serves as a NOAEL for reproductive and developmental endpoints. This study contributes to the weight-of-evidence of differential BD reproductive toxicity in rats and mice. • 1,3-Butadiene's reproductive and developmental effects in rats. • 1,3-Butadiene's Reference Dose. • Species specific adjustment factors for 1,3-butadiene. • 1,3-Butadiene's non-cancer risk assessment. [ABSTRACT FROM AUTHOR]

Animal experiments and studies in humans clearly show that the relation between pain (acute and chronic) and sleep quality is two-way: sleep disorders can increase pain, which in turn may cause sleep disorders. Sleep disorders and chronic low back pain are frequent health problems and it is unsurprising that the two can co-exist. This study was conducted to evaluate if sleep disorders and chronic pain associated are more frequently than one would expect. The objective of the study was to compare sleep quality in a population of patients with chronic low back pain and a control population. Sleep quality was assessed in 101 patients with chronic low back pain (CLBP) and in 97 sex- and age-matched healthy control subjects using the Pittsburgh Sleep Quality Index [PSQI; score from 0 (no disorder) to 21]. The French version of the Dallas Pain Questionnaire (DPQ) was used to assess the impact of low back pain on patients’ quality of life. This impact was taken as nil in the healthy controls. The patients with CLBP and the controls were comparable in age, sex, and height, but mean bodyweight was higher in the CLBP group (70.3 ± 14.5 vs. 61.8 ± 11.4 kg; P < 0.05). The patients with CLBP were also more frequently on sick leave than the controls (32.3%; n = 31 vs. 0.0% n = 0; P < 0.001). Coffee, tea, and cola intakes were comparable in the two groups. Patients with CLBP had statistically higher scores in all items of the PSQI than the healthy controls. The mean PSQI was 4.7 ± 3.2 for the healthy controls and 10.9 ± 7.9 for the patients with CLBP ( P < 0.0001). Sleep disorders were greater when the impact of CLBP on daily life (the four aspects of the DPQ) was greater [ P < 0.0001]). The sleep of the patients with CLBP was significantly altered compared with that of the healthy controls, in proportion to the impact of low back pain on daily life. Our findings do not indicate whether sleep disorders are a cause or a consequence of CLBP. [ABSTRACT FROM AUTHOR]

Abstract: Over the last fifteen years, pathology underwent significant changes in the field of soft tissue tumours. They were related to considerable advances in molecular biology and genetics. New data led to the revision of the WHO classification. Malignant fibrous histiocytoma is no longer considered as an entity. It has split up into several subgroups belonging to liposarcomas, leiomyosarcomas or undifferentiated sarcomas. Haemangiopericytoma underwent reappraisal and was put in the same category as solitary fibrous tumour. Many tools have improved. Immunohistochemistry performed with new antibodies had its specificity increased, and became appropriate for the prediction of therapeutic response in some cases, e.g. CD117 detecting mutations of the c-kit proto-oncogen in gastro-intestinal stromal tumours. Refinement of the techniques allows accurate diagnoses from core needle biopsies. Surgical specimens are collegially examined by surgeons and pathologists with special attention paid to resection margins. Although bound by some limitations, the grading system of the French Federation of Cancer Centers has currently remained the best predictor of metastasis-free survival and overall survival of patients. It is based on an assessment of three parameters: differentiation, amount of necrosis, and mitotic count of tumours. The pathologist sets up a diagnosis, and actively takes part in the prediction of the prognosis and therapeutic response. He is one of the major participants in decision making for multimodal treatment of sarcomas. [Copyright &y& Elsevier]

Abstract: The objective of the present study was to determine the relative effectiveness of methylmercury (MeHg) to alter divalent cation homeostasis and cause cell death in MeHg-resistant cerebellar Purkinje and MeHg-sensitive granule neurons. Application of 0.5–5 μM MeHg to Purkinje and granule cells grown in culture caused a concentration- and time-dependent biphasic increase in fura-2 fluorescence. At 0.5 and 1 μM MeHg, the elevations of fura-2 fluorescence induced by MeHg were biphasic in both cell types, but significantly delayed in Purkinje as compared to granule cells. Application of the heavy-metal chelator, TPEN, to Purkinje cells caused a precipitous decline in a proportion of the fura-2 fluorescence signal, indicating that MeHg causes release of Ca2+ and non-Ca2+ divalent cations. Purkinje cells were also more resistant than granule cells to the neurotoxic effects of MeHg. At 24.5 h after-application of 5 μM MeHg, 97.7% of Purkinje cells were viable. At 3 μM MeHg there was no detectable loss of Purkinje cell viability. In contrast, only 40.6% of cerebellar granule cells were alive 24.5 h after application of 3 μM MeHg. In conclusion, Purkinje neurons in primary cultures appear to be more resistant to MeHg-induced dysregulation of divalent cation homeostasis and subsequent cell death when compared to cerebellar granule cells. There is a significant component of non-Ca2+ divalent cation released by MeHg in Purkinje neurons. [Copyright &y& Elsevier]

Abstract: Aim. – To compare the actual practice of Bairatric surgery in France with the guidelines of scientific societies regarding surgical indications and followup. Methods. – This a prospective descriptive transversal study performed within a two month period (December 2002 – January 2003) in all patients for which a consent demand has been sent to the Medical Insurance Services (examined by an administrative consultant) and/or patients operated on for morbid obesity (with or without administrative sonsent). Results. – One thousand (and) three patients have been examined by an administrative consultant before obesity surgery and 1238 patients have been operated in 263 centres including 79 public (non-profit) centres and 184 private centres. In 16.7 % of the cases, there were wrong indications according to recognized criteria (BMI<35 kg/m2 or lack of comorbidities for BMI between 35 and 39) or even contraindications because of other diseases. Patient informed consent was retrieved in only 54 % of medical files and follow up protocol was done in only 47 % of the cases. Because of several missing data, the practice of bariatric surgery followed the guidelines in only 34 % of cases. In hospital morbidity rate was 5 %. Two patients died postoperatively (mortality rate 0.2 %). Conclusions. – This study demonstrates that the practice of bariatric surgery needs to be improved in France. [Copyright &y& Elsevier]

A statistical analysis was performed on the patient data collected from two compassionate-use programmes using oxaliplatin (Eloxatin®) + 5-fluorouracil (5-FU) ± folinic acid (FA), to identify predictive factors for oxaliplatin-based salvage treatment in patients with 5-FU-resistant advanced colorectal cancer (ACRC). 481 5-FU-resistant ACRC patients, most with performance status ≤ 2,≥ 3 involved sites, and ≥ 2 prior lines of chemotherapy, received oxaliplatin + 5-FU ± FA. Prognostic factors associated with overall response rate (ORR), time to progression (TTP) and overall survival (OS) were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. The ORR was 16% (95% CI: 13-20), the median TTP was 4.2 months (95% CI: 3.4-4.6), and the median OS was 9.6 months (95% CI: 8.6-10.6). The multivariate analysis indicated poor (≥ 2 WHO) performance status (PS), a large number of prior chemotherapy regimens (≥ 3), a low baseline haemoglobin level (< 10 g/dl), and a triweekly (vs biweekly) treatment administration schedule as significantly associated (P < 0.05) with a lower ORR. Sex (male), number of organs involved (≥3) and alkaline phosphatase (AP) level (≥ 2 × the upper limit of normal) were associated (P < 0.05) with shorter TTP. Poor PS, a large number of organs involved, and elevated AP were independently and significantly correlated with shorter OS. Our analysis identified a relationship between efficacy results of oxaliplatin + 5-FU ± FA treatment in 5-FU-resistant ACRC patients and baseline prognostic factors related to PS, extent of disease and number of prior regimens. [ABSTRACT FROM AUTHOR]

BACKGROUND. The two most frequently used options to reduce the occurrence of acute otitis media (AOM) are tympanostomy tubes and prophylactic antibiotics. The goal of this study was to create a decision model to identify which intervention, if any, is preferred from the perspective of parents with young children. METHODS. We developed a decision analysis model based on probabilities obtained from the literature and outcome disutilities obtained by interviewing parents. These parameters were placed into the model along with the anticipated number of episodes of AOM a child was expected to have in the coming year without intervention. Sensitivity analyses were performed on the effectiveness of the interventions, the disutilities (burdens associated with specific outcomes or interventions) associated with the interventions, and the characteristics of AOM episodes that the child would experience without any intervention. RESULTS. Thirty-seven parents with young children were interviewed for this project. The preferred intervention for a child was sensitive to the number of episodes of AOM the child was anticipated to have in the coming year, the percentage of these episodes predicted to be severe, and how parents rated tympanostomy tubes compared with prophylactic antibiotics. In our base case of four episodes of AOM in the coming year (two mild episodes and two severe episodes), we found that tympanostomy tubes resulted in the best average outcome. Under different patient conditions, however, the preferred strategy could be either the use of prophylactic antibiotics or watchful waiting. CONCLUSIONS. In our base case, the model suggested that typanostomy tubes were preferable to prophylactic antibiotics. However, there is no single preferred preventive intervention for all children with recurrent AOM because of variation in the character of infections and the values parents give to the potential outcomes. [ABSTRACT FROM AUTHOR]

Evaluates the effect of amiloride on cytokine production by respiratory syncytial virus-infected epithelium. Ribavirin; Dose-dependent reduction in interleukin; Therapeutic agent.

Investigates the effect of amiloride and ribavirin on cytokine production by respiratory syncytial virus (RSV)-infected epithelium. Effect of amiloride and ribavirin on interleukin-8 release and messenger ribonucleic acid production in response to RSV infection; Influence of amiloride on RSV replication and infection.

Describes a study to compare ondansetron (GR 38032F), a 5-hydroxytryptamine3-receptor antagonist, with high-dose metoclopramide in the control of cisplantin-induced emesis. Study details; Results; Conclusions.

Rare cancers are better defined by their incidence (< 3/100 000 per year) than by their prevalence. Rare cancers include various types of cancer: intrinsically rare cancers (sarcomas, primary CNS tumours, cancers of the endocrine system, and cancers of the biliary tract); sub-entities of frequent cancers (male breast cancer, non epithelial ovarian cancers, apocrine carcinomas, MALT lymphomas); genetically determined cancers; and cancers occurring during pregnancy or in organ transplant recipients. Although widely different, these cancers raise common questions and problems: 1) the limitation of preclinical studies in relation with insufficient preserved tumour samples, the rarity of preclinical models, and the poor interest for preclinical pharmacology; 2) the limited number of comprehensive “expert” centres (less than 10–15 in Europe), emphasizing the role of networks; 3) the difficulties in conducting clinical and therapeutic studies due to the small number of concerned patients and methods available to run studies in rare populations. Effective support appears necessary to improve both research on these rare cancers and their management (constitution and maintenance of databases on this topic, constitution of virtual tumour banks, harmonization of the diagnostic procedures, especially regarding pathology and imaging, and “academic” support for clinical studies. Paris University Hospitals include more than 20 comprehensive centres dedicated to almost all rare cancers; these centres are useful for the implementation and evaluation of such methodological and logistic support. [ABSTRACT FROM AUTHOR]

The epidermis, in particular epidermal cytokines, have been shown to modulate a number of inflammatory and cellular immune responses. In this study we have demonstrated that the partially purified epidermal cytokine, epidermal thymocyte activating factor (ETAF), a polypeptide released by keratinocytes, is a potent T-cell chemoattractant. Compared to its ability to augment lectin-stimulated thymocyte proliferation, ETAF is much more active as a T-cell chemoattractant. The results of this study give further support to the role of local epidermal factors in immune reactivity. This finding may have particular relevance to pathologic states characterized by T-cell infiltration in the skin, such as cutaneous T-cell lymphoma. [ABSTRACT FROM AUTHOR]

Objective: The ABCB1 gene encodes P‐glycoprotein (P‐gp), a cellular membrane pump. One functional mutation that leads to expression of a less functional form of P‐gp, ABCB1‐1Δ, has been described in dogs. Individuals with this mutation can have severe adverse reactions to common veterinary pharmaceuticals that are known substrates of this pump. We investigated the detection of this mutation in samples submitted to two Australian diagnostic laboratories. Methods: A total of 4842 dogs across 27 breeds were tested for the ABCB1‐1Δ mutation from buccal swabs or EDTA blood using standard PCR, multiplex PCR, or genotyping chip. Statistical analysis was applied to determine the proportions and odds ratios of the ABCB1‐1Δ mutation in herding breeds compared with non‐herding breeds. Results: The ABCB1‐1Δ mutation was detected in nine breeds. The most commonly affected breeds were collies, Australian shepherds, white Swiss shepherds, and Shetland sheepdogs. Of 32 dogs in 18 non‐herding breeds tested, one cocker spaniel and one labradoodle were positive for the mutation, both heterozygous. Conclusion: The most frequently affected breeds for ABCB1‐1Δ mutation are the collie, Australian shepherd, white Swiss shepherd and Shetland sheepdog. As the mutation is associated with an increased incidence of adverse reactions to commonly used pharmaceuticals, veterinarians need to be aware of the breeds at most risk of carrying this mutation and consider testing these individuals prior to administering these medications. [ABSTRACT FROM AUTHOR]

Thyroid hormones (THs; T3 and T4) play a role in development of cardiovascular, reproductive, immune and nervous systems. Thus, interpretation of TH changes from rodent studies (during pregnancy, in fetuses, neonates, and adults) is critical in hazard characterization and risk assessment. A roundtable session at the 2017 Society of Toxicology (SOT) meeting brought together academic, industry and government scientists to share knowledge and different perspectives on technical and data interpretation issues. Data from a limited group of laboratories were compiled for technical discussions on TH measurements, including good practices for reliable serum TH data. Inter-laboratory historical control data, derived from immunoassays or mass spectrometry methods, revealed: 1) assay sensitivities vary within and across methodologies; 2) TH variability is similar across animal ages; 3) laboratories generally achieve sufficiently sensitive TH quantitation levels, although issues remain for lower levels of serum TH and TSH in fetuses and postnatal day 4 pups; thus, assay sensitivity is critical at these life stages. Best practices require detailed validation of rat serum TH measurements across ages to establish assay sensitivity and precision, and identify potential matrix effects. Finally, issues related to data interpretation for biological understanding and risk assessment were discussed, but their resolution remains elusive. • Historical control data (HCD) are useful in evaluating thyroid hormone (TH) results. • Analysis of HCD showed TH assay sensitivities varied within and across methodologies. • HCD laboratories generally achieved sufficiently sensitive TH quantitation levels. • HCD TH variability was lower than EPA/OECD recommendations, regardless of rodent age. • Best practices include validation of rat serum TH assays against a standard. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about the International Study of Insulin and Cancer (ISICA) which addresses thoroughly the association of breast cancer with insulin use.

The article presents a case study of a 55-year-old man with alcohol cirrhosis who was admitted for treatment of Barrett's esophagus with superficial adenocarcinoma by endoscopic mucosal resection (EMR). He underwent a radiofrequency ablation (RFA) following the EMR to remove the remaining Barrett's esophagus mucosa with high grade dysplasia. He developed an esophageal adenocarcinoma in the buried dysplastic glands after the RFA for Barrett's esophagus.

A comprehensive weight-of-the-evidence evaluation of 2,4-dichlorophenoxyacetic acid (2,4-D) was conducted for potential interactions with the estrogen, androgen and thyroid pathways and with steroidogenesis. This assessment was based on an extensive database of high quality in vitro, in vivo ecotoxicological and in vivo mammalian toxicological studies. Epidemiological studies were also considered. Toxicokinetic data provided the basis for determining rational cutoffs above which exposures were considered irrelevant to humans based on exceeding thresholds for saturation of renal clearance (TSRC); extensive human exposure and biomonitoring data support that these boundaries far exceed human exposures and provide ample margins of exposure. 2,4-D showed no evidence of interacting with the estrogen or androgen pathways. 2,4-D interacts with the thyroid axis in rats through displacement of thyroxine from plasma binding sites only at high doses exceeding the TSRC in mammals. 2,4-D effects on steroidogenesis parameters are likely related to high-dose specific systemic toxicity at doses exceeding the TSRC and are not likely to be endocrine mediated. No studies, including high quality studies in the published literature, predict significant endocrine-related toxicity or functional decrements in any species at environmentally relevant concentrations, or, in mammals, at doses below the TSRC that are relevant for human hazard and risk assessment. Overall, there is no basis for concern regarding potential interactions of 2,4-D with endocrine pathways or axes (estrogen, androgen, steroidogenesis or thyroid), and thus 2,4-D is unlikely to pose a threat from endocrine disruption to wildlife or humans under conditions of real-world exposures. [ABSTRACT FROM AUTHOR]

The US Environmental Protection Agency Endocrine Disruptor Screening Program (EDSP) is a tiered screening approach to determine the potential for a chemical to interact with estrogen, androgen, or thyroid hormone systems and/or perturb steroidogenesis. Use of high-throughput screening (HTS) to predict hazard and exposure is shifting the EDSP approach to (1) prioritization of chemicals for further screening; and (2) targeted use of EDSP Tier 1 assays to inform specific data needs. In this work, toxicology data for three triazole fungicides (triadimefon, propiconazole, and myclobutanil) were evaluated, including HTS results, EDSP Tier 1 screening (and other scientifically relevant information), and EPA guideline mammalian toxicology study data. The endocrine-related bioactivity predictions from HTS and information that satisfied the EDSP Tier 1 requirements were qualitatively concordant. Current limitations in the available HTS battery for thyroid and steroidogenesis pathways were mitigated by inclusion of guideline toxicology studies in this analysis. Similar margins (3–5 orders of magnitude) were observed between HTS-predicted human bioactivity and exposure values and betweenin vivomammalian bioactivity and EPA chronic human exposure estimates for these products’ registered uses. Combined HTS hazard and human exposure predictions suggest low priority for higher-tiered endocrine testing of these triazoles. Comparison with the mammalian toxicology database indicated that this HTS-based prioritization would have been protective for any potentialin vivoeffects that form the basis of current risk assessment for these chemicals. This example demonstrates an effective, human health protective roadmap for EDSP evaluation of pesticide active ingredients via prioritization using HTS and guideline toxicology information. [ABSTRACT FROM PUBLISHER]

This study examined omissions, errors, and variability in lexical selection across simultaneous interpretations of President Obama's 2009 inaugural address, in three spoken languages (French, German, Japanese) and in American Sign Language (ASL). Microanalysis of how information conveyed by 39 source speech lexical items was transferred into the target languages assessed to what extent omissions and errors reflected differences in lexical structure (relative frequency of ready lexical correspondents and of shared cognates between the source and target languages; and, for ASL in particular, size of lexicon compared to English). The highest number of errors and omissions was found in ASL, which has the smallest documented vocabulary, fewest lexical correspondents, and no shared cognates with English. If omission/error rates in interpretation of lexical units are taken as a rough indicator of interpreting difficulty, results suggest that it is more difficult to interpret the speech into Japanese than into French or German and, by the same token, more difficult to interpret it into ASL than into the three spoken languages. These findings are consistent with the idea that language structures impact cognitive load during interpreting, and that interpreting effort increases in relation to the degree of difference between the source and target languages. [ABSTRACT FROM AUTHOR]

Dietary exposure to pronamide resulted in higher incidences of Leydig cell tumors (LCT) at 1000 ppm in a 2-year cancer bioassay, but there were no testes effects at 40 or 200 ppm, and no testes effects at 12-months at any concentration. A 90-day mode-of-action (MoA) study was conducted at concentrations of 0, 200, 1000 and 2000 ppm. Standard parameters and stereological and proliferation analyses of LCs, targeted testis and liver gene expression, in vitro metabolism of testosterone by liver microsomes, and quantification of serum hormones and testosterone metabolites were evaluated. Increased testosterone metabolism due to increases in hepatic microsomal activity, alterations in serum hormone levels, and other data suggest that LCTs were mediated through a perturbation of the HPG-axis. Data suggest that this occurs after a threshold of exposure is reached, indicating a nonlinear/threshold dose–response. Pronamide-induced rat LCTs mediated by alterations to the HPG-axis have low relevance to humans due to quantitative differences in sensitivity between rats and humans to LCTs. Pronamide displayed no genotoxicity or direct endocrine effects. A margin of exposure approach for risk assessment and derivation of the chronic reference dose based on a point of departure of 200 ppm is most appropriate and protective of human health. [ABSTRACT FROM AUTHOR]

High throughput (HTS) and high content (HCS) screening methods show great promise in changing how hazard and risk assessments are undertaken, but scientific confidence in such methods and associated prediction models needs to be established prior to regulatory use. Using a case study of HTS-derived models for predicting in vivo androgen (A), estrogen (E), thyroid (T) and steroidogenesis (S) endpoints in endocrine screening assays, we compare classification (fitting) models to cross validation (prediction) models. The more robust cross validation models (based on a set of endocrine ToxCast™ assays and guideline in vivo endocrine screening studies) have balanced accuracies from 79% to 85% for A and E, but only 23% to 50% for T and S. Thus, for E and A, HTS results appear promising for initial use in setting priorities for endocrine screening. However, continued research is needed to expand the domain of applicability and to develop more robust HTS/HCS-based prediction models prior to their use in other regulatory applications. Based on the lessons learned, we propose a framework for documenting scientific confidence in HTS assays and the prediction models derived therefrom. The documentation, transparency and the scientific rigor involved in addressing the elements in the proposed Scientific Confidence Framework could aid in discussions and decisions about the prediction accuracy needed for different applications. [ABSTRACT FROM AUTHOR]

This article summarizes statements and perspectives on breast cancer biology, identification of novel biological targets and optimal drug development with the aim of treatment individualization.Insights into tumour biology of breast cancer have led the path towards the introduction of targeted treatment approaches; still, breast cancer-related mortality remains relatively high. Efforts in the field of basic research revealed new druggable targets which now await validation within the context of clinical trials. Therefore, questions concerning the optimal design of future studies are becoming even more pertinent. Aspects such as the ideal end point, availability of predictive markers to identify the optimal cohort for drug testing, or potential mechanisms of resistance need to be resolved. An expert panel representing the academic community, the pharmaceutical industry, as well as European Regulatory Authorities met in Vienna, Austria, in November 2012, in order to discuss breast cancer biology, identification of novel biological targets and optimal drug development with the aim of treatment individualization. This article summarizes statements and perspectives provided by the meeting participants. [ABSTRACT FROM PUBLISHER]

Abstract: Advances in bioengineering have lead to the possibility to conduct large scale production of monoclonal antibodies (MoAB) and to reduce progressively the murine component from 30% (chimeric MoAB) to 5% (humanized MoAB) to 0% (human MoAB). Three types of extracellular components are targeted in solid tumours : (1) Growth factors with transmembrane tyrosine kinase receptors either of tumour cells (IGF1) or endothelial cells (Bevacizumab). Bevacizumab has activity additive to that of chemotherapy in advanced colorectal, non squamous lung, ovarian, metastatic breast cancers and glioblastomas; (2) Extracellular domain of those transmembrane receptors : EGFR in colorectal cancer if no activating of KRAS with cetuximab and panitumumab, head and neck carcinomas with radiotherapy, and probably squamous lung cancers. Anti-ERBB2 MoAb are now a constitutive part of therapy of ERBB2 positive breast cancers at any stage; (3) Differenciation cluster regulating relationship ot tumour and stromal cells and in particular immunologic effectors. This is the case of anti-CTLA4 MoAB ipilimumab which activates and amplifies immunological cytotoxic response against melanoma with improved survival. These activities are achieved to the expense of class, target related toxicity conditioned by expression of the target on normal cells and or mechanism of action (immunological toxicity with ipilimumab). Of note a synergistic or additive activity with valid treatment regimens of targeted cancers and now targeted small molecules. [Copyright &y& Elsevier]

Purpose: To conduct a cross-cultural adaptation of the Core Outcome Measures Index (COMI) into French according to established guidelines.Methods: Seventy outpatients with chronic low back pain were recruited from six spine centres in Switzerland and France. They completed the newly translated COMI, and the Roland Morris disability (RMQ), Dallas Pain (DPQ), adjectival pain rating scale, WHO Quality of Life, and EuroQoL-5D questionnaires. After ~14 days RMQ and COMI were completed again to assess reproducibility; a transition question (7-point Likert scale; "very much worse" through "no change" to "very much better") indicated any change in status since the first questionnaire.Results: COMI whole scores displayed no floor effects and just 1.5% ceiling effects. The scores for the individual COMI items correlated with their corresponding full-length reference questionnaire with varying strengths of correlation (0.33-0.84, P < 0.05). COMI whole scores showed a very good correlation with the "multidimensional" DPQ global score (Rho = 0.71). 55 patients (79%) returned a second questionnaire with no/minimal change in their back status. The reproducibility of individual COMI 5-point items was good, with test-retest differences within one grade ranging from 89% for 'social/work disability' to 98% for 'symptom-specific well-being'. The intraclass correlation coefficient for the COMI whole score was 0.85 (95% CI 0.76-0.91).Conclusions: In conclusion, the French version of this short, multidimensional questionnaire showed good psychometric properties, comparable to those reported for German and Spanish versions. The French COMI represents a valuable tool for future multicentre clinical studies and surgical registries (e.g. SSE Spine Tango) in French-speaking countries. [ABSTRACT FROM AUTHOR]

In the last decades in industrialized countries, the increase of life expectancy has resulted in an increase in the population of the elderly. However, little is known about the prevalence of allergies in the elderly population. The aim of the study was to investigate the specific relationship of serum IgE and Phadiatop, with asthma, rhinitis, and smoking in a sample of an elderly population. Subjects from the Paquid cohort living in Gironde Department (age 65 years and over) in France were followed up since 1988 (PAQUID cohort). Among the randomized sample of 352 subjects, there were 158 men (45%) and 194 women (55%). The lowest levels of IgE were in subjects with chronic sputum; and in normal subjects (47.1 ± 56.4 vs 56.2 ± 73.9, NS). Multiple linear regression was performed with log10 IgE values as a dependent variable and age, Phadiatop test, smoking, and respiratory symptoms independently in men and in women. In men, a significant relationship was observed between IgE values and Phadiatop test ( P < 0.001), asthma history ( P = 0.002), and smoking ( P = 0.019). Respiratory allergy is present in persons >65 years of age. There is an association between smoking and IgE level independent of allergic reactivity to common allergens in the elderly. [ABSTRACT FROM AUTHOR]

In 1996, Congress passed legislation requiring the U.S. Environmental Protection Agency (EPA) to implement screening/testing strategies for endocrine-active compounds (EACs). In response, EPA convened the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) to advise the agency on a strategy to screen and test xenobiotics for endocrine disruption. EDSTAC completed their charter in 1998 by recommending a tiered screening and testing scheme to evaluate compounds for their potential to act as agonists or antagonists to the estrogen or androgen receptors, steroid biosynthesis inhibitors, or their ability to alter thyroid function. For Tier I, the EDSTAC-recommended screening battery comprised eight different assays, but EDSTAC also proposed two alternative batteries that were deemed worthy of further evaluation. The challenge currently confronting EPA is to choose among the Tier I screening options and then to standardize protocols, validate the assays, and determine the criteria for judging a compound as positive or negative in the battery. The purpose of the current review is to: (1) provide an overview of the three EDSTAC options, (2) evaluate the data currently available for the individual assays of the three EDSTAC options and discuss the strengths and limitations of each, and (3) provide a final recommendation for a Tier I screen based on the experiences of the authors who have used all of the individual assays under consideration by EDSTAC. The goal of this report is not to provide an exhaustive historical review of each assay, but rather to summarize some of the more relevant data from available published reports as it relates to current proposed study designs for those particular assays. Based on the current data, a Tier I screening battery consisting of in vitro receptor binding assays, a 3-day uterotrophic assay, and a 15-day intact male assay are recommended as the preferred approach on which future validation efforts should be focused.... [ABSTRACT FROM AUTHOR]

Our purpose was to evaluate the late physical and psychosocial difficulties of premenpausal patients treated for a localized breast cancer and to weigh the impact of chemotherapy on long-term quality of life. Two self-administered questionnaires, the EORTC core QLQ-C30 and the breast module (BR23) were mailed to 179 premenopausal node-negative women continuously disease-free, previously enrolled in a trial testing the efficacy of adjuvant CMF chemotherapy (Espié et al, 1997). The core questionnaire evaluates the physical, role, emotional, cognitive and social functioning and global health status. The breast module includes four functional scales: body image, sexual functioning, sexual enjoyment and future perspective. It also includes symptom scales such as arm or breast symptoms. Some specific professional and social states were added. 119 (68%) patients (mean age 54 years, range 30-69) participated. Mean follow-up time since diagnosis was 9.6 years (4-16). 68% had conservative and 32% radical surgery (with reconstructive surgery in 50%). CMF was given to 77 (65%) patients. Irradiation was administered in 75% of patients irrespective of adjuvant therapy. QLQ-C30 scale scores were similar in patients who had or had not received chemotherapy. Disturbance in body image, sex life and breast symptoms did not differ between patients who had or had not received adjuvant CMF. No major socioprofessional difficulties were reported except problems in borrowing from banks not related to past chemotherapy. With long follow-up, most premenopausal women treated for a localized breast cancer cope with the disease and its treatments. Adjuvant CMF chemotherapy does not appear to impair quality of life nor social and professional life in these patients. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is an immune-mediated systemic disorder caused by ingestion of the gluten found in wheat, rye, and barley. The currently estimated prevalence in children is about 1%. CD is a chronic enteropathy with gastrointestinal manifestations including diarrhea, abdominal distension and weight loss, but extra-intestinal features are increasingly being reported. Dental and oral manifestations such as dental enamel defects (ED), delay in dental eruption, and recurrent aphthous stomatitis (RAS) are well-recognized manifestations of CD. The aim of this study was to compare the frequency of oral manifestations (ED, RAS and delay in dental eruption) on deciduous and permanent teeth between children with CD and a control population. An oral examination was performed on 28 CD children and 59 control children. All children were younger than 12 years old and had deciduous or mixed dentition. CD children had significantly more ED and RAS than the control group (67.9% vs. 33.9% P = 0.004 and 50.0% vs. 21.8% P = 0.011, respectively). No delay in dental eruption was observed in CD children. ED were mainly grade I and II of Aine's classification (color defects and slight structural defects). ED were more often seen on CD children's deciduous teeth than on permanent teeth (57.1% and 13.6%, respectively; P < 0.001). The main teeth affected by ED are the second molar and canines of the deciduous teeth, and the first molar, central incisor, and lateral incisors of the permanent teeth. RAS and ED that were symmetrical in all quadrants and occurred firstly in teeth that mineralize during the first year of life both seem to be signs of CD. Thus, more information for dentists and pediatricians on these oral manifestations should help improve detection of CD. [ABSTRACT FROM AUTHOR]

The European Society of Toxicologic Pathology organized an expert workshop in May 2018 to address adversity considerations related to thyroid follicular cell hypertrophy and/or hyperplasia (FCHH), which is a common finding in nonclinical toxicity studies that can have important implications for risk assessment of pharmaceuticals, food additives, and environmental chemicals. The broad goal of the workshop was to facilitate better alignment in toxicologic pathology and regulatory sciences on how to determine adversity of FCHH. Key objectives were to describe common mechanisms leading to thyroid FCHH and potential functional consequences; provide working criteria to assess adversity of FCHH in context of associated findings; and describe additional methods and experimental data that may influence adversity determinations. The workshop panel was comprised of representatives from the European Union, Japan, and the United States. Participants shared case examples illustrating issues related to adversity assessments of thyroid changes. Provided here are summary discussions, key case presentations, and panel recommendations. This information should increase consistency in the interpretation of adverse changes in the thyroid based on pathology findings in nonclinical toxicity studies, help integrate new types of biomarker data into the review process, and facilitate a more systematic approach to communicating adversity determinations in toxicology reports. [ABSTRACT FROM AUTHOR]