More pesticides-less children?

A previously presented study investigated the impact of recent pesticide exposure on cytological signs of genotoxicity and on symptoms of intoxication in 71 male coffee workers in the Dominican Republic. An unexpected finding of this study was that conventional farming workers, among other symptoms, reported fewer children than controls working in organic farms without pesticide use. This study set out to investigate possible reasons for the latter difference. One statistical problem of this analysis is that the age of the workers is a strong predictor for the number of children and available data on the exposure determinants "duration of pesticide exposure" as well as "age at first pesticide exposure" are correlated with age. To correctly control statistics for these confounding parameters, different approaches to best control for age were explored. After careful elimination of the age-related confounding factors, a reduced number of children was still observed in exposed workers. The clearest effect is seen in those workers that reported first exposure before the age of 20 years. Socioeconomic factors could still confound that finding, but a direct effect of early life pesticide exposure is the most likely explanation of the observation.

Subjective Symptoms of Male Workers Linked to Occupational Pesticide Exposure on Coffee Plantations in the Jarabacoa Region, Dominican Republic.

Acute and sub-acute effects of pesticide use in coffee farmers have rarely been investigated. In the present field study, self-reported health symptoms from 38 male pesticide users were compared to those of 33 organic farmers. Results of cytological findings have been reported in an accompanying paper in this issue. The present second part of the study comprises a questionnaire based survey for various, potentially pesticide related symptoms among the coffee farmers. Symptom rates were generally higher in exposed workers, reaching significance in nine out of 19 assessed symptoms. Significantly increased symptom frequencies were related to neurotoxicity, parasympathic effects and acetylcholine esterase inhibition, with the highest differences found for excessive salivation, dizziness and stomach ache. We revealed a lack of precautionary measures in the majority of farmers. Better education, regulations, and safety equipment are urgently needed.

TRPC3 contributes to regulation of cardiac contractility and arrhythmogenesis by dynamic interaction with NCX1.

AIM: TRPC3 is a non-selective cation channel, which forms a Ca2+ entry pathway involved in cardiac remodelling. Our aim was to analyse acute electrophysiological and contractile consequences of TRPC3 activation in the heart. METHODS AND RESULTS: We used a murine model of cardiac TRPC3 overexpression and a novel TRPC3 agonist, GSK1702934A, to uncover (patho)physiological functions of TRPC3. GSK1702934A induced a transient, non-selective conductance and prolonged action potentials in TRPC3-overexpressing myocytes but lacked significant electrophysiological effects in wild-type myocytes. GSK1702934A transiently enhanced contractility and evoked arrhythmias in isolated Langendorff hearts from TRPC3-overexpressing but not wild-type mice. Interestingly, pro-arrhythmic effects outlasted TRPC3 current activation, were prevented by enhanced intracellular Ca2+ buffering, and suppressed by the NCX inhibitor 3',4'-dichlorobenzamil hydrochloride. GSK1702934A substantially promoted NCX currents in TRPC3-overexpressing myocytes. The TRPC3-dependent electrophysiologic, pro-arrhythmic, and inotropic actions of GSK1702934A were mimicked by angiotensin II (AngII). Immunocytochemistry demonstrated colocalization of TRPC3 with NCX1 and disruption of local interaction upon channel activation by either GSK1702934A or AngII. CONCLUSION: Cardiac TRPC3 mediates Ca2+ and Na+ entry in proximity of NCX1, thereby elevating cellular Ca2+ levels and contractility. Excessive activation of TRPC3 is associated with transient cellular Ca2+ overload, spatial uncoupling between TRPC3 and NCX1, and arrhythmogenesis. We propose TRPC3-NCX micro/nanodomain communication as determinant of cardiac contractility and susceptibility to arrhythmogenic stimuli.

Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia.

We have investigated the functional consequences of three P/Q-type Ca(2+) channel alpha1A (Ca(v)2.1alpha(1)) subunit mutations associated with different forms of ataxia (episodic ataxia type 2 (EA-2), R1279Stop, AY1593/1594D; progressive ataxia (PA), G293R). Mutations were introduced into human alpha1A cDNA and heterologously expressed in Xenopus oocytes or tsA-201 cells (with alpha(2)delta and beta1a) for electrophysiological and biochemical analysis. G293R reduced current density in both expression systems without changing single channel conductance. R1279Stop and AY1593/1594D protein were expressed in tsA-201 cells but failed to yield inward barium currents (I(Ba)). However, AY1593/1594D mediated I(Ba) when expressed in oocytes. G293R and AY1593/1594D shifted the current-voltage relationship to more positive potentials and enhanced inactivation during depolarizing pulses (3 s) and pulse trains (100 ms, 1 Hz). Mutation AY1593/1594D also slowed recovery from inactivation. Single channel recordings revealed a change in fast channel gating for G293R evident as a decrease in the mean open time. Our data support the hypothesis that a pronounced loss of P/Q-type Ca(2+) channel function underlies the pathophysiology of EA-2 and PA. In contrast to other EA-2 mutations, AY1593/1594D and G293R form at least partially functional channels.