Barriers in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) management: perspectives from health practitioners.

OBJECTIVES: Chronic prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a complex condition which causes a significant burden on the diagnosed individuals. Assessment and management are perplexing, often resulting in unsatisfactory outcomes. Existing research has only focused on patients' perspectives of pain experiences, but scant evidence is available to understand the barriers that undermine effective pain management. Using an exploratory approach, this study examined these barriers from practitioners' perspectives. METHODS: Twelve semi-structured interviews were conducted with practitioners across disciplines who have experience in chronic pelvic pain management in males. Practitioners expressed their views and experiences in supporting men with CP/CPPS and what barriers they perceived when providing treatment for patients. Data were analysed using reflexive thematic analysis supported by NVivo software. RESULTS: Five broad and interrelated themes were identified: (1) Where to Start, (2) Insufficient Resources, (3) Prioritisation, (4) Training and Confident Practice and (5) Constraints in Help-Seeking. CONCLUSIONS: Practitioners value multimodal management using a biopsychosocial approach; however, practical challenges prevent practitioners from choosing and applying this approach in clinical practice. The findings also identified some unique challenges faced by men with CP/CPPS consistent with previous evidence from patient perspective. Refining terminology, developing specific resources, and increasing psychosocial treatment options are urgently needed.

The influence of the BDNF Val66Met genotype on emotional recognition memory in post-traumatic stress disorder.

Dysregulated consolidation of emotional memories is a core feature of posttraumatic stress disorder (PTSD). Brain Derived Neurotrophic Factor (BDNF) influences synaptic plasticity and emotional memory consolidation. The BDNF Val66Met polymorphism has been associated with PTSD risk and memory deficits respectively, although findings have been inconsistent, potentially due to a failure to control for important confounds such as sex, ethnicity, and the timing/extent of previous trauma experiences. Furthermore, very little research has examined the impact of BDNF genotypes on emotional memory in PTSD populations. This study investigated the interaction effects of Val66Met and PTSD symptomatology in an emotional recognition memory task in 234 participants divided into healthy control (n = 85), trauma exposed (TE: n = 105) and PTSD (n = 44) groups. Key findings revealed impaired negative recognition memory in PTSD compared to control and TE groups and in participants with the Val/Met compared to the Val/Val genotype. There was a group × genotype interaction showing no Met effect in the TE group despite significant effects in PTSD and controls. Results suggest that people previously exposed to trauma who do not develop PTSD may be protected from the BDNF Met effect, however more research is needed to replicate findings and to explore the epigenetic and neural processes involved.

Psychological management of patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS): a systematic review.

OBJECTIVES: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a complex condition. Despite recommendations for the inclusion of non-pharmacological treatment in the management of CP/CPPS, the focus has predominantly been on the inclusion of physical therapies with minimal discussion of psychological interventions. Therefore, this systematic review aimed to evaluate peer-reviewed studies of psychological interventions for men with CP/CPPS to determine their therapeutic efficacy and quality of intervention. METHODS: The review was registered in PROSPERO and based on PRISMA 2020 protocol. The systematic literature search was conducted in six databases. Quantitative studies of psychological intervention for adult men with CP/CPPS that provided outcome measures of pain, quality of life and/or psychological symptoms were reviewed. The Oxford level of evidence and Quality Assessment Tool for Quantitative Studies developed by the Effective Public Health Practice were employed. RESULTS: A total of 4,503 studies were reviewed; seven met the inclusion criteria. The included studies were randomised controlled trials, cohort, repeated measures, and case-series studies, with most including combined treatment for CP/CPPS. Cognitive therapy, cognitive behavioural therapy, or paradoxical relaxation training were found to be effective. However, high risks of bias were found in all included studies, limiting the generalisability and reliability of findings. CONCLUSIONS: Evidence is preliminary but shows promise for psychological treatment either as a combined or standalone treatment for CP/CPPS. However, there is a need to develop research with a more rigorous methodology to evaluate psychological treatments for men with CP/CPPS.

Subthreshold repetitive transcranial magnetic stimulation drives structural synaptic plasticity in the young and aged motor cortex.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive tool commonly used to drive neural plasticity in the young adult and aged brain. Recent data from mouse models have shown that even at subthreshold intensities (0.12 T), rTMS can drive neuronal and glial plasticity in the motor cortex. However, the physiological mechanisms underlying subthreshold rTMS induced plasticity and whether these are altered with normal ageing are unclear. OBJECTIVE: To assess the effect of subthreshold rTMS, using the intermittent theta burst stimulation (iTBS) protocol on structural synaptic plasticity in the mouse motor cortex of young and aged mice. METHODS: Longitudinal in vivo 2-photon microscopy was used to measure changes to the structural plasticity of pyramidal neuron dendritic spines in the motor cortex following a single train of subthreshold rTMS (in young adult and aged animals) or the same rTMS train administered on 4 consecutive days (in young adult animals only). Data were analysed with Bayesian hierarchical generalized linear regression models and interpreted with the aid of Bayes Factors (BF). RESULTS: We found strong evidence (BF > 10) that subthreshold rTMS altered the rate of dendritic spine losses and gains, dependent on the number of stimulation sessions and that a single session of subthreshold rTMS was effective in driving structural synaptic plasticity in both young adult and aged mice. CONCLUSION: These findings provide further evidence that rTMS drives synaptic plasticity in the brain and uncovers structural synaptic plasticity as a key mechanism of subthreshold rTMS induced plasticity.

Cognitive outcomes associated with long-term, regular, recreational cannabis use in adults: A meta-analysis.

Despite research advances, it remains unclear if long-term, regular cannabis use harms cognition once intoxication has passed. Our meta-analysis aimed to investigate the association between cognitive functioning and long-term (mean ≥2 years), regular (mean ≥4 days/week), recreational cannabis use in adults during abstinence (mean ≥12 hr). We searched PubMed, PsycINFO, CINAHL, Scopus, and Dissertations and Theses International for English-language articles from the date each database began until May 22, 2019. We identified study inclusion by completing abstract and full text screening using predetermined criteria and Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. We classified cognitive performance into 6 cognitive domains (attention, executive function, learning and memory, decision making, information processing, and working memory), and included a global measure. Effect sizes were calculated for each domain using univariate meta-analyses. There were 30 studies with a total 849 participants who used cannabis (M = 30.7-years-old, SD = 5.5-years-old) and 764 control participants (M = 30.3-years-old, SD = 5.9-years-old). Cannabis was associated with significant but small-magnitude deficits in executive function, learning and memory, and global cognition, while decision making had moderate deficits. There were small-magnitude and nonsignificant group differences for information processing, working memory, and attention. Cannabis use duration, age of onset, and prolonged abstinence (≥25 days) did not influence outcomes, except group differences in executive function were nonsignificant in analyses of prolonged abstinence. Our results suggest that long-term, regular cannabis use is associated with small to moderate deficits in some cognitive domains. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Critical Review of Exposure and Effects: Implications for Setting Regulatory Health Criteria for Ingested Copper.

Decades of study indicate that copper oral exposures are typically not a human health concern. Ingesting high levels of soluble copper salts can cause acute gastrointestinal symptoms and, in uncommon cases, liver toxicity in susceptible individuals with repeated exposure. This focused toxicological review evaluated the current literature since the last comprehensive reviews (2007-2010). Our review identified limitations in the existing United States and international guidance for determining an oral reference dose (RfD) for essential metals like copper. Instead, an alternative method using categorical regression analysis to develop an optimal dose that considers deficiency, toxicity, and integrates information from human and animal studies was reviewed for interpreting an oral RfD for copper. We also considered subchronic or chronic toxicity from genetic susceptibility to copper dysregulation leading to rare occurrences of liver and other organ toxicity with elevated copper exposure. Based on this approach, an oral RfD of 0.04 mg Cu/kg/day would be protective of acute or chronic toxicity in adults and children. This RfD is also protective for possible genetic susceptibility to elevated copper exposure and allows for background dietary exposures. This dose is not intended to be protective of patients with rare genetic disorders for copper sensitivity within typical nutritional intake ranges, nor is it protective for those with excessive supplement intake. Less soluble mineral forms of copper in soil have reduced bioavailability as compared with more soluble copper in water and diet, which should be considered in using this RfD for risk assessments of copper.

A systematic literature review of epidemiologic studies of developmental manganese exposure and neurodevelopmental outcomes.

BACKGROUND: Neurotoxic effects of high-level occupational exposure to manganese (Mn) are well established; however, whether lower-level environmental exposure to Mn in early life causes neurodevelopmental toxicity in children is unclear. METHODS: A systematic literature review was conducted to identify and evaluate epidemiologic studies of specific Mn biomarkers assessed during gestation, childhood, or adolescence in association with neurodevelopmental outcomes, focusing on quantitative exposure-response estimates with specific endpoints that were assessed in multiple independent study populations. Study quality was evaluated using the revised RTI item bank and the Cochrane Risk of Bias tool, and the overall weight of epidemiologic evidence for causality was evaluated according to the Bradford Hill considerations. RESULTS: Twenty-two epidemiologic studies were identified that estimated associations between early-life Mn biomarkers and neurodevelopmental outcomes. Seven of these studies provided adjusted estimates for the association with child intelligence assessed using versions of the Wechsler Intelligence Scales for Children; no other specific neurodevelopmental endpoints were assessed in more than three independent study populations each. Among the studies of child intelligence, five studies in four independent populations measured blood Mn, three studies measured hair Mn, and one measured dentin Mn. Overall, cross-sectional associations between Mn biomarkers and measures of child intelligence were mostly statistically nonsignificant but in a negative direction; however, the lone prospective cohort study found mostly null results, with some positive (favorable) associations between dentin Mn and child intelligence. Studies were methodologically limited by their cross-sectional design and potential for confounding and selection bias, as well as unaddressed questions on exposure assessment validity and biological plausibility. CONCLUSIONS: The statistical associations reported in the few studies of specific Mn biomarkers and specific neurodevelopmental endpoints do not establish causal effects based on the Bradford Hill considerations. Additional prospective cohort studies of Mn biomarkers and validated neurodevelopmental outcomes, and a better understanding of the etiologic relevance of Mn biomarkers, are needed to shed light on whether environmental exposure to Mn causes adverse neurodevelopmental effects in children.

Mania Associated With Herbal Medicines, Other Than Cannabis: A Systematic Review and Quality Assessment of Case Reports.

Background: DSM-5 introduced the diagnostic category of substance/medication-induced bipolar and related disorder. This systematic review examines published reports linking mania with the consumption of herbal medicines (HM), excluding cannabis. Putative pathophysiological mechanisms that may account for the reported HM being associated with mania are discussed. Methods: A systematic search of EMBASE, CINAHL, Health Source, PsychINFO, and PubMed. The quality of case reports meeting inclusion criteria was assessed using the modified Quality Assessment Scale by Agbabiaka. Results: Nineteen single and seven multiple-case reports met inclusion criteria. These yielded a study sample of 35 case reports, 28 of herbal medicine associated mania, 5 of hypomania, and two mixed states, in 17 females [age in years M(SD) = 43.1(13.2)] and 18 males [40.7(18.1)]. A total of 11 herbal medicines were implicated. Case reports by herbal medicine (number of reports) comprised: St John's wort (Hypericum perforatum) (14); Ginseng (Panax ginseng) (5); brindleberry (Garcinia cambogia) (4); ma-huang (Ephedra sinica) (3); "herbal slimming pills" (2); Herbalife products (2); Hydroxycut (1); horny goat weed (Epimedium grandiflorum) (1); "herbal body tonic" (1); celery root (Apium graveolans) (1), and a "herbal mixture" (1). All case reports were associated with use rather than withdrawal of herbal medicines. Only one case report was rated for probability of association using a standardized algorithm. Laboratory assays to confirm composition of the herbal preparation were reported in only one article describing two cases and indicating admixture of a likely causal pharmaceutical in the herbal preparation. Conclusions: Causal attributions are problematic given the limited number of reports, antidepressant co-prescribing in 7 cases, insufficient data regarding pattern and type of herbal medicine use, and lack of a reference frequency for spontaneous mania.The quality assessment scores across the 26 papers (35 case reports) were as follows: low quality (0), lower-medium quality (9), upper-medium quality (10) and high quality (7). Putative pathophysiological mechanisms were postulated for nine of the 11 herbal medicines and centered on HPA-axis activation and increased monoamine activity. Systematic study of the association between herbal medicines and the course of bipolar disorder may contribute to defining targets for pathophysiological research.

Application of a weight of evidence approach to evaluating risks associated with subsistence caribou consumption near a lead/zinc mine.

Overland transport of ore concentrate from the Red Dog lead/zinc mine in northwest Alaska to its seaport has historically raised concerns among local subsistence users regarding the potential impacts of fugitive dust from the operation, including the potential uptake of metals into caribou meat. Caribou are an integral part of life for northern Alaska Natives for both subsistence and cultural reasons. The Western Arctic caribou herd, whose range includes the Red Dog mine, transportation corridor, and port site, sometimes overwinter in the vicinity of mine operations. A weight of evidence approach using multiple lines of evidence was used to evaluate potential risks associated with subsistence consumption of caribou harvested near the road and mine. Data from a long-term caribou monitoring program indicate a lack of consistent trends for either increasing or decreasing metals concentrations in caribou muscle, liver, and kidney tissue. Lead, cadmium, and zinc from all tissues were within the range of reference concentrations reported for caribou elsewhere in Northern Alaska. In addition, a site use study based on data from satellite-collared caribou from the Western Arctic Herd showed that caribou utilize the area near the road, port, and mine approximately 1/20th to 1/90th of the time assumed in a human health risk assessment conducted for the site, implying that risks were significantly overestimated in the risk assessment. The results from multiple lines of evidence consistently indicate that fugitive dust emissions from Red Dog Operations are not a significant source of metals in caribou, and that caribou remain safe for human consumption.

Low intensity repetitive transcranial magnetic stimulation modulates skilled motor learning in adult mice.

Repetitive transcranial magnetic stimulation (rTMS) is commonly used to modulate cortical plasticity in clinical and non-clinical populations. Clinically, rTMS is delivered to targeted regions of the cortex at high intensities (>1 T). We have previously shown that even at low intensities, rTMS induces structural and molecular plasticity in the rodent cortex. To determine whether low intensity rTMS (LI-rTMS) alters behavioural performance, daily intermittent theta burst LI-rTMS (120 mT) or sham was delivered as a priming or consolidating stimulus to mice completing 10 consecutive days of skilled reaching training. Relative to sham, priming LI-rTMS (before each training session), increased skill accuracy (~9%) but did not alter the rate of learning over time. In contrast, consolidating LI-rTMS (after each training session), resulted in a small increase in the rate of learning (an additional ~1.6% each day) but did not alter the daily skill accuracy. Changes in behaviour with LI-rTMS were not accompanied with long lasting changes in brain-derived neurotrophic factor (BDNF) expression or in the expression of plasticity markers at excitatory and inhibitory synapses for either priming or consolidation groups. These results suggest that LI-rTMS can alter specific aspects of skilled motor learning in a manner dependent on the timing of intervention.

Risks of Allergic Contact Dermatitis Elicited by Nickel, Chromium, and Organic Sensitizers: Quantitative Models Based on Clinical Patch Test Data.

Risks of allergic contact dermatitis (ACD) from consumer products intended for extended (nonpiercing) dermal contact are regulated by E.U. Directive EN 1811 that limits released Ni to a weekly equivalent dermal load of ≤0.5 µg/cm2 . Similar approaches for thousands of known organic sensitizers are hampered by inability to quantify respective ACD-elicitation risk levels. To help address this gap, normalized values of cumulative risk for eliciting a positive ("≥+") clinical patch test response reported in 12 studies for a total of n = 625 Ni-sensitized patients were modeled in relation to observed ACD-eliciting Ni loads, yielding an approximate lognormal (LN) distribution with a geometric mean and standard deviation of GMNi = 15 µg/cm2 and GSDNi = 8.0, respectively. Such data for five sensitizers (including formaldehyde and 2-hydroxyethyl methacrylate) were also ∼LN distributed, but with a common GSD value equal to GSDNi and with heterogeneous sensitizer-specific GM values each defining a respective ACD-eliciting potency GMNi /GM relative to Ni. Such potencies were also estimated for nine (meth)acrylates by applying this general LN ACD-elicitation risk model to respective sets of fewer data. ACD-elicitation risk patterns observed for Cr(VI) (n = 417) and Cr(III) (n = 78) were fit to mixed-LN models in which ∼30% and ∼40% of the most sensitive responders, respectively, were estimated to exhibit a LN response also governed by GSDNi . The observed common LN-response shape parameter GSDNi may reflect a common underlying ACD mechanism and suggests a common interim approach to quantitative ACD-elicitation risk assessment based on available clinical data.

Systematic Review of Cognitive Function in Euthymic Bipolar Disorder and Pre-Surgical Temporal Lobe Epilepsy.

BACKGROUND: Bipolar disorder (BD) and temporal lobe epilepsy (TLE) overlap in domains including epidemiology, treatment response, shared neurotransmitter involvement and temporal lobe pathology. Comparison of cognitive function in both disorders may indicate temporal lobe mediated processes relevant to BD. This systematic review examines neuropsychological test profiles in euthymic bipolar disorder type I (BD-I) and pre-surgical TLE and compares experimental designs used. METHODS: A search of PubMed, PsychINFO, and Scopus using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted. Inclusion criteria were comparison group or pre- to post-surgical patients; reported neuropsychological tests; participants aged 18-60 years. Fifty six studies met criteria: 27 BD-I; 29 TLE. RESULTS: Deficits in BD-I compared to healthy controls (HC) were in executive function, attention span and verbal memory. Deficits in TLE compared to HC were in executive function and memory. In the pre- to post-surgical comparisons, verbal memory in left temporal lobe (LTL) and, less consistently, visuospatial memory in right temporal lobe (RTL) epilepsy declined following surgery. BD-I studies used comprehensive test batteries in well-defined euthymic patients compared to matched HC groups. TLE studies used convenience samples pre- to post-surgery, comparing LTL and RTL subgroups, few included comparisons to HC (5 studies). TLE studies typically examined a narrow range of known temporal lobe-mediated neuropsychological functions, particularly verbal and visuospatial memory. CONCLUSION: Both disorders exhibit deficits in executive function and verbal memory suggestive of both frontal and temporal lobe involvement. However, deficits in TLE are measured pre- to post-surgery and not controlled at baseline pre-surgery. Further research involving a head-to-head comparison of the two disorders on a broad range of neuropsychological tests is needed to clarify the nature and extent of cognitive deficits and potential overlaps.

Construction and Evaluation of Rodent-Specific rTMS Coils.

Rodent models of transcranial magnetic stimulation (TMS) play a crucial role in aiding the understanding of the cellular and molecular mechanisms underlying TMS induced plasticity. Rodent-specific TMS have previously been used to deliver focal stimulation at the cost of stimulus intensity (12 mT). Here we describe two novel TMS coils designed to deliver repetitive TMS (rTMS) at greater stimulation intensities whilst maintaining spatial resolution. Two circular coils (8 mm outer diameter) were constructed with either an air or pure iron-core. Peak magnetic field strength for the air and iron-cores were 90 and 120 mT, respectively, with the iron-core coil exhibiting less focality. Coil temperature and magnetic field stability for the two coils undergoing rTMS, were similar at 1 Hz but varied at 10 Hz. Finite element modeling of 10 Hz rTMS with the iron-core in a simplified rat brain model suggests a peak electric field of 85 and 12.7 V/m, within the skull and the brain, respectively. Delivering 10 Hz rTMS to the motor cortex of anaesthetized rats with the iron-core coil significantly increased motor evoked potential amplitudes immediately after stimulation (n = 4). Our results suggest these novel coils generate modest magnetic and electric fields, capable of altering cortical excitability and provide an alternative method to investigate the mechanisms underlying rTMS-induced plasticity in an experimental setting.

Age-Specific Effects of Mirror-Muscle Activity on Cross-Limb Adaptations Under Mirror and Non-Mirror Visual Feedback Conditions.

Cross-limb transfer (CLT) describes the observation of bilateral performance gains due to unilateral motor practice. Previous research has suggested that CLT may be reduced, or absent, in older adults, possibly due to age-related structural and functional brain changes. Based on research showing increases in CLT due to the provision of mirror visual feedback (MVF) during task execution in young adults, our study aimed to investigate whether MVF can facilitate CLT in older adults, who are known to be more reliant on visual feedback for accurate motor performance. Participants (N = 53) engaged in a short-term training regime (300 movements) involving a ballistic finger task using their dominant hand, while being provided with either visual feedback of their active limb, or a mirror reflection of their active limb (superimposed over the quiescent limb). Performance in both limbs was examined before, during and following the unilateral training. Furthermore, we measured corticospinal excitability (using TMS) at these time points, and assessed muscle activity bilaterally during the task via EMG; these parameters were used to investigate the mechanisms mediating and predicting CLT. Training resulted in significant bilateral performance gains that did not differ as a result of age or visual feedback (both p > 0.1). Training also elicited bilateral increases in corticospinal excitability (p < 0.05). For younger adults, CLT was significantly predicted by performance gains in the trained hand (ß = 0.47), whereas for older adults it was significantly predicted by mirror activity in the untrained hand during training (ß = 0.60). The present study suggests that older adults are capable of exhibiting CLT to a similar degree to younger adults. The prominent role of mirror activity in the untrained hand for CLT in older adults indicates that bilateral cortical activity during unilateral motor tasks is a compensatory mechanism. In this particular task, MVF did not facilitate the extent of CLT.

Fish consumption as a driver of risk-management decisions and human health-based water quality criteria.

The use and interpretation of fish consumption surveys and interviews, the application of fish consumption rates for sediment evaluation and cleanup, and the development of human health water quality criteria (HH WQC) are complex and interrelated issues. The present article focuses on these issues using examples from the United States, although the issues may be relevant for other countries. Some key considerations include the fact that there are many types of fish consumption surveys (e.g., 24-h recall surveys, food frequency questionnaires, creel surveys), and these surveys have different advantages and limitations. Identification of target populations for protection, identification of the species and quantities of fish consumed, and determination of bioaccumulation assumptions are important factors when developing water quality and sediment screening levels and standards. Accounting for the cultural importance of fish consumption for some populations is an even more complex element. Discussions about HH WQC often focus only on the fish consumption rate and may not have broad public input. Some states are trying to change this through extensive public participation efforts and use of probabilistic approaches to derive HH WQC. Finally, there are limits to what WQC can achieve. Solutions beyond the establishment of WQC that target toxics reduction from other sources may provide the greatest improvements to water quality and reductions in human health risks in the future.

The Influence of Mirror-Visual Feedback on Training-Induced Motor Performance Gains in the Untrained Hand.

The well-documented observation of bilateral performance gains following unilateral motor training, a phenomenon known as cross-limb transfer, has important implications for rehabilitation. It has recently been shown that provision of a mirror image of the active hand during unilateral motor training has the capacity to enhance the efficacy of this phenomenon when compared to training without augmented visual feedback (i.e., watching the passive hand), possibly via action observation effects [1]. The current experiment was designed to confirm whether mirror-visual feedback (MVF) during motor training can indeed elicit greater performance gains in the untrained hand compared to more standard visual feedback (i.e., watching the active hand). Furthermore, discussing the mechanisms underlying any such MVF-induced behavioural effects, we suggest that action observation and the cross-activation hypothesis may both play important roles in eliciting cross-limb transfer. Eighty participants practiced a fast-as-possible two-ball rotation task with their dominant hand. During training, three different groups were provided with concurrent visual feedback of the active hand, inactive hand or a mirror image of the active hand with a fourth control group receiving no training. Pre- and post-training performance was measured in both hands. MVF did not increase the extent of training-induced performance changes in the untrained hand following unilateral training above and beyond those observed for other types of feedback. The data are consistent with the notion that cross-limb transfer, when combined with MVF, is mediated by cross-activation with action observation playing a less unique role than previously suggested. Further research is needed to replicate the current and previous studies to determine the clinical relevance and potential benefits of MVF for cases that, due to the severity of impairment, rely on unilateral training programmes of the unaffected limb to drive changes in the contralateral affected limb.

Low-level arsenic exposure and developmental neurotoxicity in children: A systematic review and risk assessment.

UNLABELLED: Risk assessments of arsenic have focused on skin, bladder, and lung cancers and skin lesions as the sensitive cancer and non-cancer health endpoints, respectively; however, an increasing number of epidemiologic studies that can inform risk assessment have examined neurodevelopmental effects in children. We conducted a systematic review and risk assessment based on the epidemiologic literature on possible neurodevelopmental effects at lower arsenic exposures. Twenty-four cross-sectional, case-control, and cohort studies were identified that report on the association between low-level arsenic exposure (i.e., largely <100 µg/L of arsenic in drinking water) and neurological outcomes in children. Although the overall evidence does not consistently show a causal dose-response relationship at low doses, the most rigorously conducted studies from Bangladesh indicate possible inverse associations with cognitive function, predominantly involving concurrent arsenic exposure as measured by biomarkers (i.e., arsenic in urine or blood) and raw verbal test scores at ages 5-11 years. Issues such as non-comparability of outcome measures across studies; inaccuracies of biomarkers and other measures of inorganic arsenic exposure; potential effect modification by cultural practices; insufficient adjustment for nutritional deficiencies, maternal IQ, and other important confounders; and presence of other neurotoxicants in foreign populations limit generalizability to U.S. POPULATIONS: Of the few U.S. studies available, the most rigorously conducted study did not find a consistent dose-response relationship between arsenic concentrations in tap water or toenails and decrements in IQ scores. Assuming that the strongest dose-response relationship from the most rigorous evidence from Bangladesh is generalizable to U.S. populations, possible reference doses were estimated in the range of 0.0004-0.001 mg/kg-day. These doses are higher than the U.S. Environmental Protection Agency reference dose for chronic lifetime exposure, thus indicating protectiveness of the existing value for potential neurotoxicity in children. This reference dose is undergoing revision as EPA considers various health endpoints in the reassessment of inorganic arsenic health risks.

In utero arsenic exposure in mice and early life susceptibility to cancer.

In its review of the U.S. Environmental Protection Agency's toxicological review of inorganic arsenic (iAs), the National Academy of Sciences identified carcinogenic endpoints among the highest priority health effects of concern and stated the need to consider evidence that early life exposures may increase the risk of adverse health effects. Recent studies in mice suggest that in utero exposure to arsenic increases susceptibility to cancer later in life. These data are striking in light of the general lack of evidence for carcinogenicity in rodents exposed to iAs. To evaluate the transplacental carcinogenic potential of iAs, a detailed analysis of the toxicology literature evaluating the role of in utero arsenic exposure in carcinogenesis was conducted. Bladder, lung, and skin tumors, which are the tumor types most consistently reported in humans exposed to high arsenic levels, were not consistently increased in mouse studies. There was also a lack of concordance across studies for other tumor types not typically reported in humans. Therefore, we considered methodological and other critical issues that may have contributed to variable results and we suggest additional studies to address these issues. It was concluded that the available data do not provide evidence of a causal link between in utero arsenic exposure and cancer or indicate early life-stage susceptibility to arsenic-induced cancer, particularly at environmentally relevant doses.

Comparison of precipitating factors for mania and partial seizures: Indicative of shared pathophysiology?

OBJECTIVES: Mania in bipolar disorder (BD) and partial (focal) seizures (PS) arising from the temporal lobes, have a number of similarities. Typically, a chronic course of the disorders is punctuated by acute illness episodes. Common features of episodes may include sensory, perceptual, cognitive and affective changes. Both respond to anticonvulsant treatment. Common mechanisms imputed include neurotransmitters and kindling processes. Further investigation may improve understanding of the occurrence of both mania and PS, casting light on the relevance of temporal lobe mediated processes and pathology. One avenue of investigation is to compare aetiological factors and determine the extent of overlap which may indicate shared brain localization or pathophysiology. Aetiology includes predisposing, precipitating or perpetuating factors. This paper examines the literature on precipitating factors of mania, first or subsequent episode, and of PS in diagnosed epilepsy, which is the second or subsequent seizure, to identify the extent and nature of their overlap. METHOD: Narrative review based on a literature search of PubMed and Google Scholar. RESULTS: Precipitating factors for both mania and PS were stress, sleep deprivation, antidepressant medication and, tentatively, emotion. For mania alone, goal-attainment events, spring and summer season, postpartum, and drugs include steroids and stimulants. For PS alone, winter season, menstruation and specific triggers in complex reflex epilepsies. Those not substantiated include lunar phase and menopause. A wide range of chemicals may provoke isolated seizures but by definition epilepsy requires at least two seizures. CONCLUSIONS: The overlap of precipitating factors in mania and PS imply that common brain processes may contribute to both, consistent with findings from neuroscience research.