Association of Pesticide Exposure with Neurologic Dysfunction and Disease

Poisoning by acute high-level exposure to certain pesticides has well-known neurotoxic effects, but whether chronic exposure to moderate levels of pesticides is also neurotoxic is more controversial. Most studies of moderate pesticide exposure have found increased prevalence of neurologic symptoms and changes in neurobehavioral performance, reflecting cognitive and psychomotor dysfunction. There is less evidence that moderate exposure is related to deficits in sensory or motor function or peripheral nerve conduction, but fewer studies have considered these outcomes. It is possible that the most sensitive manifestation of pesticide neurotoxicity is a general malaise lacking in specificity and related to mild cognitive dysfunction, similar to that described for Gulf War syndrome. Most studies have focused on organophosphate insecticides, but some found neuro-toxic effects from other pesticides, including fungicides, fumigants, and organochlorine and carbamate insecticides. Pesticide exposure may also be associated with increased risk of Parkinson disease; several classes of pesticides, including insecticides, herbicides, and fungicides, have been implicated. Studies of other neurodegenerative diseases are limited and inconclusive. Future studies will need to improve assessment of pesticide exposure in individuals and consider the role of genetic susceptibility. More studies of pesticides other than organophosphates are needed. Major unresolved issues include the relative importance of acute and chronic exposure, the effect of moderate exposure in the absence of poisoning, and the relationship of pesticide-related neurotoxicity to neurodegenerative disease

Anti-müllerian hormone is not associated with cardiometabolic risk factors in adolescent females

<p>Objectives: Epidemiological evidence for associations of Anti-Müllerian hormone (AMH) with cardiometabolic risk factors is lacking. Existing evidence comes from small studies in select adult populations, and findings are conflicting. We aimed to assess whether AMH is associated with cardiometabolic risk factors in a general population of adolescent females.</p> <p>Methods: AMH, fasting insulin, glucose, HDLc, LDLc, triglycerides and C-reactive protein (CRP) were measured at a mean age 15.5 years in 1,308 female participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Multivariable linear regression was used to examine associations of AMH with these cardiometabolic outcomes.</p> <p>Results: AMH values ranged from 0.16–35.84 ng/ml and median AMH was 3.57 ng/ml (IQR: 2.41, 5.49). For females classified as post-pubertal (n = 848) at the time of assessment median (IQR) AMH was 3.81 ng/ml (2.55, 5.82) compared with 3.25 ng/ml (2.23, 5.05) in those classed as early pubertal (n = 460, P≤0.001). After adjusting for birth weight, gestational age, pubertal stage, age, ethnicity, socioeconomic position, adiposity and use of hormonal contraceptives, there were no associations with any of the cardiometabolic outcomes. For example fasting insulin changed by 0% per doubling of AMH (95%CI: −3%,+2%) p = 0.70, with identical results if HOMA-IR was used. Results were similar after additional adjustment for smoking, physical activity and age at menarche, after exclusion of 3% of females with the highest AMH values, after excluding those that had not started menarche and after excluding those using hormonal contraceptives.</p> <p>Conclusion: Our results suggest that in healthy adolescent females, AMH is not associated with cardiometabolic risk factors.</p&gt

Screening for Parkinson's disease with response time batteries: A pilot study

BACKGROUND: Although significant response time deficits (both reaction time and movement time) have been identified in numerous studies of patients with Parkinson's disease (PD), few attempts have been made to evaluate the use of these measures in screening for PD. METHODS: Receiver operator characteristic curves were used to identify cutoff scores for a unit-weighted composite of two choice response tasks in a sample of 40 patients and 40 healthy participants. These scores were then cross-validated in an independent sample of 20 patients and 20 healthy participants. RESULTS: The unit-weighted movement time composite demonstrated high sensitivity (90%) and specificity (90%) in the identification of PD. Movement time was also significantly correlated (r = 0.59, p < 0.025) with the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS). CONCLUSIONS: Measures of chronometric speed, assessed without the use of biomechanically complex movements, have a potential role in screening for PD. Furthermore, the significant correlation between movement time and UPDRS motor score suggests that movement time may be useful in the quantification of PD severity

Isokinetic muscle function comparison of lower limbs among elderly fallers and non-fallers

O objetivo deste estudo foi identificar se há diferenças entre o desempenho muscular de tornozelo, joelho e quadril em idosos com e sem relato de queda nos últimos seis meses. Foram incluídos 81 idosos com 65 anos ou mais: 56 negaram quedas (G1) e 25 relataram quedas (G2). Utilizou-se o questionário perfil de atividade humana para medir o nível de atividade física, e o dinamômetro isocinético para mensurar os parâmetros físicos da função muscular. Os grupos não diferiram entre si em relação à idade (p=0,925), duração (p=0,065) e frequência (p=0,302) da prática do exercício físico, índice de massa corpórea (p=0,995) e nível de atividade física (p=0,561). O G2 apresentou menor desempenho para as variáveis pico de torque de flexão e extensão de joelho esquerdo (p=0,027 e p=0,030, respectivamente) e trabalho por peso corporal (p=0,040) de flexão de joelho esquerdo a 60°/s; pico de torque e trabalho por peso corporal de flexão e extensão de joelho a 180°/s bilateralmente (p<0,050); e potência média de flexão de joelhos direito e esquerdo (p=0,030). A maioria das variáveis do tornozelo e quadril não apresentou diferenças entre os grupos. Apenas a variável pico de torque de extensão de quadril esquerdo foi significativamente maior no G1 (p=0,035). É importante considerar a função muscular do joelho na avaliação clínica de idosos para direcionar a intervenção terapêutica e a prevenção de quedas.The aim of this study was to identify whether there are differences between the performance of muscular groups of ankle, knee and hip among elderly people who didn't have falls and individuals who reported falls in the last six months. The study included 81 elderly aged 65 or older: 56 non-faller subjects (G1) and 25 faaller subjects (G2). To obtain the level of physical activity, the questionnaire Human Activity Profile was used, and the muscle function of the lower limbs was assessed using isokinetic dynamometer. The groups did not differ regarding age (p=0.925), duration (p=0.065) and frequency (p=0.302) of the practice of physical exercise, body mass index (BMI) (p=0.995) and level of physical activity (p=0.561). The G2 showed a lower performance of peak torque of left knee flexion and extension (p=0.027 and p=0.030, respectively) and work proportional to body weight (p=0.040) of left knee flexion at 60°/s; peak torque and work proportional to body weight of bilaterally knee flexion and extension at 180°/s (p<0.05) and average power of right and left knee extension (p=0.03). Most variables of ankle and hip joints did not differ between groups. Only peak torque of left hip extension was significantly higher in the non-faller group (p=0.035). It is important to consider knee muscle function in the clinical evaluation of elderly in order to make the intervention more assertive and thus to prevent falls

Identification of a novel zinc metalloprotease through a global analysis of clostridium difficile extracellular proteins

Clostridium difficile is a major cause of infectious diarrhea worldwide. Although the cell surface proteins are recognized to be important in clostridial pathogenesis, biological functions of only a few are known. Also, apart from the toxins, proteins exported by C. difficile into the extracellular milieu have been poorly studied. In order to identify novel extracellular factors of C. difficile, we analyzed bacterial culture supernatants prepared from clinical isolates, 630 and R20291, using liquid chromatography-tandem mass spectrometry. The majority of the proteins identified were non-canonical extracellular proteins. These could be largely classified into proteins associated to the cell wall (including CWPs and extracellular hydrolases), transporters and flagellar proteins. Seven unknown hypothetical proteins were also identified. One of these proteins, CD630_28300, shared sequence similarity with the anthrax lethal factor, a known zinc metallopeptidase. We demonstrated that CD630_28300 (named Zmp1) binds zinc and is able to cleave fibronectin and fibrinogen in vitro in a zinc-dependent manner. Using site-directed mutagenesis, we identified residues important in zinc binding and enzymatic activity. Furthermore, we demonstrated that Zmp1 destabilizes the fibronectin network produced by human fibroblasts. Thus, by analyzing the exoproteome of C. difficile, we identified a novel extracellular metalloprotease that may be important in key steps of clostridial pathogenesis

Territoriality and the organization of technology during the Last Glacial Maximum in southwestern Europe

Climate changes that occurred during the Last Glacial Maximum (LGM) had significant consequences in human eco-dynamics across Europe. Among the most striking impacts are the demographic contraction of modern humans into southern refugia and the potential formation of a population bottleneck. In Iberia and southern France transformations also included the occurrence of significant technological changes, mostly marked by the emergence of a diverse set of bifacially-shaped stone projectiles. The rapid dissemination of bifacial technologies and the geographical circumscription of specific projectile morphologies within these regions have been regarded as evidence for: (1) the existence of a system of long-distance exchange and social alliance networks; (2) the organization of human groups into cultural facies with well-defined stylistic territorial boundaries. However, the degree and modes in which cultural transmission have occurred within these territories, and how it may have influenced other domains of the adaptive systems, remains largely unknown. Using southern Iberia as a case-study, this paper presents the first quantitative approach to the organization of lithic technology and its relationship to hunter-gatherers' territorial organization during the LGM. Similarities and dissimilarities in the presence of morphological and metric data describing lithic technologies are used as a proxy to explore modes and degrees of cultural transmission. Statistical results show that similarities in technological options are dependent on the chronology and geographical distance between sites and corroborate previous arguments for the organization of LGM settlement in Southern Iberia into discrete eco-cultural facies.STSM COST action (ref. COST-STSM-TD0902-10855); FCT, contract ref. DL 57/2016/CP1361/ CT0026. Work at Vale Boi is funded by the project ALG-01-0145-FEDER-27833 - PTDC/HAR-ARQ/27833/2017.info:eu-repo/semantics/publishedVersio

Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms

Cancer cells depend on transcription of telomerase reverse transcriptase (TERT). Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3′-oxime (BIO) predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several aspects of TERT regulation including previously unknown mechanisms. An extrapolation suggests that a dominant stimulatory system may programme TERT for transcriptional stability