Functional neurologic disorder as a rare complication of dental local anaesthetics: two contrasting cases.

Adverse reactions to dental local anaesthetics are fortunately rare. However, when they occur, they can be severe and debilitating to the patient. Adverse reactions may be either prolonged anaesthesia, with or without dysaesthesia, or systemic reactions. Although these systemic reactions are commonly thought to be allergies, this is rarely the case. Much more commonly, these adverse systemic reactions are either cardiovascular or from the central nervous system. This paper describes two contrasting cases of functional neurologic disorder which illustrates the consequences and appropriate management. The responsibilities of the dentist who injected the local anaesthetic are outlined.

Neurological Manifestations Induced by Nitrous Oxide Abuse: A Case Series and Review of Literature.

INTRODUCTION: Nitrous oxide (NO) abuse is increasing among young people. This can result in severe neurological disorders such as myelopathy and/or peripheral neuropathy. We report the clinical presentations, biological, radiologic and electrophysiological findings of 5 patients hospitalized with neurological symptoms consecutive to NO abuse. In addition, a literature review was conducted to describe the neurological characteristics and to identify factors associated with a poor recovery. CASE REPORT: Among the 5 patients included, 2 had a myeloneuropathy, 2 had a sensorimotor neuropathy, and 1 had a normal spinal cord magnetic resonance imaging and electromyography despite neurological manifestations consistent with myeloneuropathy. After vitamin B 12 supplementation, recovery was reported in 4 patients, and 1 was lost to follow-up.From the literature review, 154 patients were included [94 males; median age 22 (19 to 26) y; NO exposure 9 (3 to 18) mo]. A myelopathy was identified in 116 patients (75%) and a peripheral neuropathy was documented in 89 patients (58%). Compared with patients who recovered, those with sequelae were more likely to have a motor deficit at presentation ( P <0.001), to use NO regularly ( P <0.001), to have a lower vitamin B 12 level ( P =0.04), and a higher concentration of homocysteine ( P =0.04). A less extensive myelopathy was more frequently found in the group with favorable outcomes ( P =0.002). CONCLUSION: Neurological disorders caused by NO may be challenging with severe clinical patterns. We identified several factors associated with a poor recovery, to make clinicians aware of NO-induced neurotoxicity.

Network pharmacology and molecular docking approaches predict the mechanisms of Corididius chinensis in treating manganese-induced nervous system diseases: A review.

Neurotoxicity could be induced by long exposure to manganese (Mn). The traditional Chinese medicine, Corididius chinensis (Cc) has been proven to have a certain curative effect on Mn poisoning. Therefore, network pharmacology was performed to explore potential therapeutic targets and pharmacological mechanisms of Cc. We found ingredients by building our own database through literature, (which is the first to screen traditional Chinese medicine without traditional Chinese medicine systems pharmacology database and analysis platform databases and it is applicable whenever a Chinese medicine is not found in the traditional Chinese medicine systems pharmacology database and analysis platform database) and potential targets of Mn-induced nervous system diseases from the OMIM, GeneCards, and DrugBank database were identified. A protein-protein interaction network was constructed using Cytoscape. Gene ontology and Kyoto encyclopedia of genes and genomes pathway enrichment analysis was performed for the treatment of Mn-induced nervous system disease, and molecular docking was carried out to verify the results of network pharmacology analysis. After screening disease-related genes, 12 intersecting genes overlapped between 284 target proteins of the active compound and 195 potential disease targets. The pathways of neurodegeneration_multiple diseases and Alzheimer disease pathway may be the most potential pathway of Cc treating Mn-induced nervous system diseases. CASP9 and PTGS2 in neurodegeneration_multiple diseases, NOS1, NOS2 in Alzheimer disease pathway were identified as core targets. Especially, molecule docking analysis unveil that aspongpyrazine A docking NOS2 is the most potential therapeutic drug and target, which primarily involved in the processes of oxidative stress and inflammation.

Risk of longer-term neurological conditions in the Deepwater Horizon Oil Spill Coast Guard Cohort Study - Five years of follow-up.

BACKGROUND: Long-term neurological health risks associated with oil spill cleanup exposures are largely unknown. We aimed to investigate risks of longer-term neurological conditions among U.S. Coast Guard (USCG) responders to the 2010 Deepwater Horizon (DWH) oil spill. METHODS: We used data from active duty members of the DWH Oil Spill Coast Guard Cohort Study (N=45224). Self-reported oil spill exposures were ascertained from post-deployment surveys. Incident neurological outcomes were classified using International Classification of Diseases, 9th Revision, codes from military health encounter records up to 5.5 years post-DWH. We used Cox Proportional Hazards regression to calculate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for various incident neurological diagnoses (2010-2015). Oil spill responder (n=5964) vs. non-responder (n= 39260) comparisons were adjusted for age, sex, and race, while within-responder comparisons were additionally adjusted for smoking. RESULTS: Compared to those not responding to the spill, spill responders had reduced risks for headache (aHR=0.84, 95% CI: 0.74-0.96), syncope and collapse (aHR=0.74, 95% CI: 0.56-0.97), and disturbance of skin sensation (aHR=0.81, 95% CI: 0.68-0.96). Responders reporting ever (n=1068) vs. never (n=2424) crude oil inhalation exposure were at increased risk for several individual and grouped outcomes related to headaches and migraines (aHR range: 1.39-1.83). Crude oil inhalation exposure was also associated with elevated risks for an inflammatory nerve condition, mononeuritis of upper limb and mononeuritis multiplex (aHR=1.71, 95% CI: 1.04-2.83), and tinnitus (aHR=1.91, 95% CI: 1.23-2.96), a condition defined by ringing in one or both ears. Risk estimates for those neurological conditions were higher in magnitude among responders reporting exposure to both crude oil and oil dispersants than among those reporting crude oil only. CONCLUSION: In this large study of active duty USCG responders to the DWH disaster, self-reported spill cleanup exposures were associated with elevated risks for longer-term neurological conditions.

Neuroprotective effect of hesperidin against emamectin benzoate-induced neurobehavioral toxicity in rats.

Emamectin Benzoate (EMB) is an avermectin insecticide widely used in agriculture and veterinary medicine. Hesperidin (HSP) is a flavanone glycoside predominantly found in citrus fruits and has various beneficial health effects. The current research was conducted to study the neurobehavioral toxic effects of EMB in rats and also to evaluate the protective effect of HSP against these toxic effects. Sixty Sprague-Dawley rats were randomly divided into 4 equal groups: control group, EMB group, HSP group, and EMB + HSP group. EMB (8.8. mg/kg) and/or HSP (100 mg/kg) were administered daily by gavage for 8 weeks. The behavioral assessment demonstrated the adverse effects of EMB on the behavioral, motor, and cognitive brain functions. Exposure to EMB also decreased the activity of antioxidants (catalase and reduced glutathione) and increased the malondialdehyde level in nervous tissue. Moreover, EMB increased the level of inflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) and decreased brain-derived neurotrophic factor (BDNF) levels in rats' brains. On the other hand, concurrent administration of HSP ameliorated the toxic effects of EMB as indicated by improvements in neural functions and reduction of oxidative stress and inflammation. The study concluded that exposure to EMB induces toxic effects in the brain of rats and that HSP has a protective effect against these toxic effects.

Sex and Adverse Events of Adjuvant Chemotherapy in Colon Cancer: An Analysis of 34 640 Patients in the ACCENT Database.

BACKGROUND: Adjuvant chemotherapy is a standard treatment option for patients with stage III and high-risk stage II colon cancer. Sex is one of several factors responsible for the wide inter-patient variability in drug responses. Amalgamated data on the effect of sex on the toxicity of current standard adjuvant treatment for colorectal cancer are missing. METHODS: The objective of our study was to compare incidence and severity of major toxicities of fluoropyrimidine- (5FU or capecitabine) based adjuvant chemotherapy, with or without oxaliplatin, between male and female patients after curative surgery for colon cancer. Adult patients enrolled in 27 relevant randomized trials included in the ACCENT (Adjuvant Colon Cancer End Points) database, a large, multi-group, international data repository containing individual patient data, were included. Comparisons were conducted using logistic regression models (stratified by study and treatment arm) within each type of adjuvant chemotherapy (5FU, FOLFOX, capecitabine, CAPOX, and FOLFIRI). The following major toxicities were compared (grade III or IV and grade I-IV, according to National Cancer Institute Common Terminology Criteria [NCI-CTC] criteria, regardless of attribution): nausea, vomiting, nausea or vomiting, stomatitis, diarrhea, leukopenia, neutropenia, thrombocytopenia, anemia, and neuropathy (in patients treated with oxaliplatin). RESULTS: Data from 34 640 patients were analyzed. Statistically significant and clinically relevant differences in the occurrence of grade III or IV nonhematological {especially nausea (5FU: odds ratio [OR] = 2.33, 95% confidence interval [CI] = 1.90 to 2.87, P < .001; FOLFOX: OR = 2.34, 95% CI = 1.76 to 3.11, P < .001), vomiting (5FU: OR = 2.38, 95% CI = 1.86 to 3.04, P < .001; FOLFOX: OR = 2.00, 95% CI = 1.50 to 2.66, P < .001; CAPOX: OR = 2.32, 95% CI = 1.55 to 3.46, P < .001), and diarrhea (5FU: OR = 1.35, 95% CI = 1.21 to 1.51, P < .001; FOLFOX: OR = 1.60, 95% CI = 1.35 to 1.90, P < .001; FOLFIRI: OR = 1.57, 95% CI = 1.25 to 1.97, P < .001)} as well as hematological toxicities (neutropenia [5FU: OR = 1.55, 95% CI = 1.37 to 1.76, P < .001; FOLFOX: OR = 1.96, 95% CI = 1.71 to 2.25, P < .001; FOLFIRI: OR = 2.01, 95% CI = 1.66 to 2.43, P < .001; capecitabine: OR = 4.07, 95% CI = 1.84 to 8.99, P < .001] and leukopenia [5FU: OR = 1.74, 95% CI = 1.40 to 2.17, P < .001; FOLFIRI: OR = 1.75, 95% CI = 1.28 to 2.40, P < .001]) were observed, with women being consistently at increased risk. CONCLUSIONS: Our analysis confirms that women with colon cancer receiving adjuvant fluoropyrimidine-based chemotherapy are at increased risk of toxicity. Given the known sex differences in fluoropyrimidine pharmacokinetics, sex-specific dosing of fluoropyrimidines warrants further investigation.

Repressive effect of Rhus coriaria L. fruit extracts on microglial cells-mediated inflammatory and oxidative stress responses.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhus coriaria L. represents a herbal shrub that is used widely in traditional medicine in the Middle East region to treat different diseases including inflammation-related disorders. R. coriaria extracts have been well characterized in terms of their biological activities, pharmacological potential and phytochemical components. However, the effect of R. coriaria on neuro-inflammation has not been studied previously in detail. AIM OF THE STUDY: In the present study, we performed a qualitative phytochemical analysis and investigated the antioxidant and anti-neuro-inflammatory potential of R. coriaria extracts on BV-2 microglial cells. MATERIALS AND METHODS: R. coriaria extracts were prepared using two different solvents: distilled water and ethanol. Phytochemical screening was performed to determine the principal bioactive components. The radical scavenging activity was assessed by DPPH method (2,2-diphenyl-1-picrylhydrazyl). The effect of R. coriaria on neuro-inflammation was studied upon measuring the production of oxidative stress and inflammatory factors using DCF (2',7'-dichlorofluorescein) and Nitric oxide (NO) assays respectively, and by analyzing the mRNA (TNFα, IL-10, iNOS and COX-2) and protein (NFκß) levels of genes involved BV-2 microglia cells-mediated inflammation using quantitative Real Time PCR and Western blot, respectively. RESULTS: We found that R. coriaria extracts contain high phenolic and flavonoid contents. Interestingly, the ethanolic extract exerted a potent anti-inflammatory potential on insulted BV-2 cells manifested by: i) inhibition of Reactive Oxygen species (ROS) production and nitric oxide (NO) release; ii) suppressing TNFα, iNOS and COX-2 mRNA levels; iii) reducing NFκß activation; and iiii) enhancing IL-10 transcription levels. CONCLUSION: Our results indicate that the neuro-inflammation inhibitory activity of R. coriaria extracts involves the inhibition of NF-κB signaling pathway. These findings suggest that R. coriaria might carry therapeutic potential against neurodegenerative diseases.

Ceguera y trastornos neurológicos por monóxido de carbono: tratamiento efectivo con oxígeno hiperbárico en dos pacientes pediátricos / Blindness and neurological sequelae following carbon monoxide poisoning: effective treatment with hyperbaric oxygen

Se presentan dos pacientes que desarrollaron deterioro visual debido a una intoxicación por monóxido de carbono. Ellos fueron tratados con oxígeno hiperbárico y recuperaron no solo su visión, sino que, además, mejoraron su signo-sintomatología neurológica. Se cree que la implementación de oxígeno hiperbárico, incluso en un período tardío, será efectiva para revertir las secuelas neurológicas.

We present two patients who developed visual deterioration due to carbon monoxide poisoning. They were treated with hyperbaric oxygen and recovered not only their vision but also they improved neurological signs and symptoms. We believe that implementation of hyperbaric oxygen, even in a late period of time will be effective in reversing neurological sequela

Non-clinical toxicity of (+)-limonene epoxide and its physio-pharmacological properties on neurological disorders.

The compound (+)-limonene epoxide has antioxidant, anxiolytic, and antihelminthic properties. However, investigations to determine its long-term exposure were not performed. We investigated the systemic toxicological profile after chronic exposure as well as the antidepressant and antiepileptic potentialities of (+)-limonene epoxide on mice. Initially, we evaluated acute toxicity on Artemia salina nauplii and cytotoxicity on mice erythrocytes and peripheral blood mononuclear cells (PBMC). Aftterwards, mice were chronically treated for 120 days by gavage with (+)-limonene epoxide (25, 50, and 75 mg/kg/day) and this exposure was assessed by pathophysiological measurements. For antidepressant and anticonvulsivant analysis, we performed the forced swimming and tail suspension protocols and pentylenetetrazol- and picrotoxin-induced seizures, respectively. (+)-Limonene epoxide showed a LC50 value of 318.7 µg/mL on A. salina shrimps, caused lysis of red blood cells at higher concentrations only but did not show cytotoxicity on PMBC, which suggests pharmacological safety if plasma concentrations do not exceed 100 µg/mL. Macroscopic, hematological, clinical chemistry, and nutritional changes were not detected, though focal areas of hepatic necrosis, inflammatory infiltrate, and karyolysis have been detected at 75 mg/kg/day. The compound inhibited the developing of pentylenetetrazol- and picrotoxin-induced seizures, decreased deaths, and reduced immobility times, mainly at 75 mg/kg. So, it reversed reserpine effects, suggesting antidepressant effects should be linked to serotonergic and/or adrenergic transmission. It is feasible that (+)-limonene epoxide plays a benzodiazepine-like anticonvulsive action and may be also recommended as an antidote for poisonings caused by central depressants.

Preclinical and clinical research on the toxic and neurological effects of cassava (Manihot esculenta Crantz) consumption.

Cassava (Manihot esculenta Crantz) is a tropical plant that is used as fresh food, processed food, or raw material for the preparation of flours with high nutritional value. However, cassava contains cyanogenic glycosides, such as linamarin and lotaustralin, that can trigger severe toxic effects and some neurological disorders, including motor impairment, cognitive deterioration, and symptoms that characterize tropical ataxic neuropathy and spastic epidemic paraparesis (Konzo). These alterations that are associated with the consumption of cassava or its derivatives have been reported in both humans and experimental animals. The present review discusses and integrates preclinical and clinical evidence that indicates the toxic and neurological effects of cassava and its derivatives by affecting metabolic processes and the central nervous system. An exhaustive review of the literature was performed using specialized databases that focused on the toxic and neurological effects of the consumption of cassava and its derivatives. We sought to provide structured information that will contribute to understanding the undesirable effects of some foods and preventing health problems in vulnerable populations who consume these vegetables. Cassava contains cyanogenic glycosides that contribute to the development of neurological disorders when they are ingested inappropriately or for prolonged periods of time. Such high consumption can affect neurochemical and neurophysiological processes in particular brain structures and affect peripheral metabolic processes that impact wellness. Although some vegetables have high nutritional value and ameliorate food deficits in vulnerable populations, they can also predispose individuals to the development of neurological diseases.

Modulation of key enzymes linked to Parkinsonism and neurologic disorders by Antiaris africana in rotenone-toxified rats.

Background The physiopathologies of many neurologic diseases are characterized by related biochemical dysfunctions that could be explored as drug targets. This study evaluated the effect of a methanol leaf extract of Antiaris africana (MEA) on critical bioindices of Parkinsonism and related neurologic dysfunctions in rats with rotenone-induced neurotoxicity. Methods Animals were administered 50 or 100 mg/kg MEA for 14 consecutive days. Rotenone (1.5 mg/kg) was administered three times per day on days 13 and 14. Coenzyme Q10 (5 mg/kg) was the reference drug. Complex I activity, dopamine level, activities of acetylcholinesterase, myeloperoxidase, Na+/K+ ATPase and glutamine synthetase, as well as oxidative stress indices were evaluated at the end of the period of treatment. Results Rotenone-intoxicated group showed disruption of complex 1 activity, dopamine level, and glutamine synthetase activity with negative alterations to activities of acetylcholinesterase, myeloperoxidase, and Na+/K+ ATPase as well as heightened cerebral oxidative stress. MEA restored brain mitochondria functionality, mitigated altered neurochemical integrity, and ameliorated cerebral oxidative stress occasioned by rotenone neurotoxicity. The activity of A. Africana was comparable with that of 5 mg/kg coenzyme Q10. Conclusions These results indicated that A. africana displayed therapeutic potential against Parkinsonism and related neurologic dysfunctions and support its ethnobotanical use for the treatment of neurologic disorders.

Environmental Selenium and Human Health: an Update.

PURPOSE OF REVIEW: Selenium, a trace element, is ubiquitous in the environment. The main source of human exposure is diet. Despite its nutritional benefits, it is one of the most toxic naturally occurring elements. Selenium deficiency and overexposure have been associated with adverse health effects. Its level of toxicity may depend on its chemical form, as inorganic and organic species have distinct biological properties. RECENT FINDINGS: Nonexperimental and experimental studies have generated insufficient evidence for a role of selenium deficiency in human disease, with the exception of Keshan disease, a cardiomyopathy. Conversely, recent randomized trials have indicated that selenium overexposure is positively associated with type 2 diabetes and high-grade prostate cancer. In addition, a natural experiment has suggested an association between overexposure to inorganic hexavalent selenium and two neurodegenerative diseases, amyotrophic lateral sclerosis and Parkinson's disease. Risk assessments should be revised to incorporate the results of studies demonstrating toxic effects of selenium. Additional observational studies and secondary analyses of completed randomized trials are needed to address the uncertainties regarding the health risks of selenium exposure.

The Irwin Test and Functional Observational Battery (FOB) for Assessing the Effects of Compounds on Behavior, Physiology, and Safety Pharmacology in Rodents.

The modified Irwin procedure or functional observational battery (FOB) can be used to achieve several goals. New chemical entities (NCEs) can be behaviorally screened for nervous system effects at a variety of doses to identify potential therapeutic uses and in the selection of appropriate doses for subsequent assays. NCEs can also be evaluated in the behavioral battery and compared with reference standards to assess liabilities in a new compound class, with an estimated therapeutic index being suggested by the doses used in comparison to therapeutic doses. For the assessment of neurotoxicology, the FOB is often used. The differences between the two assays are subtle. The procedures used are essentially the same, but when considering neurotoxicology, the FOB is often conducted using GLP guidelines, with more animals being used per group, and doses that are low enough to determine a no effect level and high enough to induce marked nervous system behaviors. © 2018 by John Wiley & Sons, Inc.

Phase I trial of selenium plus chemotherapy in gynecologic cancers.

PURPOSE: Preclinical studies performed in our laboratory have shown that high-dose selenium inhibits the development of carboplatin drug resistance in an ovarian cancer mouse xenograft model. Based on these data, as well as the potential serious toxicities of supranutritional doses of selenium, a phase I trial of a combination of selenium/carboplatin/paclitaxel was designed to determine the maximum tolerated dose, safety, and effects of selenium on carboplatin pharmacokinetics in the treatment of chemo-naive women with gynecologic cancers. Correlative studies were performed to identify gene targets of selenium. METHODS: Chemo-naïve patients with gynecologic malignancy received selenious acid IV on day 1 followed by carboplatin IV and paclitaxel IV on day 3. A standard 3 + 3 dose-escalating design was used for addition of selenium to standard dose chemotherapy. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed. RESULTS: Forty-five patients were enrolled and 291 treatment cycles were administered. Selenium was administered as selenious acid to 9 cohorts of patients with selenium doses ranging from 50 µg to 5000 µg. Grade 3/4 toxicities included neutropenia (66.7%), febrile neutropenia (2.2%), pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The maximum tolerated dose of selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. Correlative studies showed post-treatment downregulation of RAD51AP1, a protein involved in DNA repair, in both cancer cell lines and patient tumors. CONCLUSION: Overall, the addition of selenium to carboplatin/paclitaxel chemotherapy is safe and well tolerated, and does not alter carboplatin pharmacokinetics. A 5000 µg dose of elemental selenium as selenious acid is suggested as the dose to be evaluated in a phase II trial.

Effect of Choline Supplementation on Neurological, Cognitive, and Behavioral Outcomes in Offspring Arising from Alcohol Exposure During Development: A Quantitative Systematic Review of Clinical and Preclinical Studies.

Prenatal alcohol exposure results in cognitive, behavioral, and neurological deficits in offspring. There is an urgent need for safe and effective treatments to overcome these effects. Maternal choline supplementation has been identified as a potential intervention. Our objective was to review preclinical and clinical studies using choline supplementation in known cases of fetal alcohol exposure to determine its effectiveness in ameliorating deficits in offspring. A systematic search of 6 electronic databases was conducted and studies selected by reviewing titles/abstracts against specific inclusion/exclusion criteria. Study characteristics, population demographics, alcohol exposure, and intervention methods were tabulated, and quality of reporting was assessed. Data on cognitive, behavioral, and neurological outcomes were extracted and tabulated. Quantitative analysis was performed to determine treatment effects for individual study outcomes. A total of 189 studies were retrieved following duplicate removal. Of these, 22 studies (2 randomized controlled trials, 2 prospective cohort studies, and 18 preclinical studies) met the full inclusion/exclusion criteria. Choline interventions were administered at different times relative to alcohol exposure, impacting on their success to prevent deficits for specific outcomes. Only 1 clinical study showed significant improvements in information processing in 6-month-old infants from mothers treated with choline during pregnancy. Preclinical studies showed significant amelioration of deficits due to prenatal alcohol exposure across a wide variety of outcomes, including epigenetic/molecular changes, gross motor, memory, and executive function. This review suggests that choline supplementation has the potential to ameliorate specific behavioral, neurological, and cognitive deficits in offspring caused by fetal alcohol exposure, at least in preclinical studies. As only 1 clinical study has shown benefit, we recommend more clinical trials be undertaken to assess the effectiveness of choline in preventing deficits across a wider range of cognitive domains in children.

Cannabinoids for Treatment of MS Symptoms: State of the Evidence.

PURPOSE OF REVIEW: Cannabis and cannabinoids have been used medically and recreationally for thousands of years and recently there has been a growing body of research in this area. With increased access now that medical marijuana is available in many jurisdictions, patients and providers want to know more about the evidence for benefits and risks of cannabinoid use. This paper provides an overview of the available cannabinoid-based formulations, a summary of the highest quality evidence for the use of cannabinoids for treating spasticity and pain associated with multiple sclerosis (MS), and a discussion of possible dosing regimens based on information from these studies. RECENT FINDINGS: Two recent high-quality systematic reviews concluded that the only strong evidence for medical marijuana in neurological disorders was for reducing the symptoms of patient-reported spasticity and central pain in MS and that the only complementary and alternative medicine (CAM) intervention in MS with strong supportive evidence was cannabinoids. Based on this review, they concluded that nabiximols (Sativex oral spray), oral cannabis extract (OCE), and synthetic tetrahydrocannabinol (THC) are probably effective at reducing patient-reported symptoms of spasticity in people with MS, but OCE and synthetic THC were not found to be effective for reducing physician-administered measures of spasticity. In addition, nabiximols, OCE, and synthetic THC are probably effective at reducing MS-related pain. Cannabinoids were generally well-tolerated. However, cannabis use has been associated with an increased risk of psychosis and schizophrenia in at-risk individuals, there is growing evidence that cannabis can increase the risk for cardiovascular diseases, including myocardial infarction (MI), hypertension, heart failure, and stroke, and a recently recognized adverse effect of cannabis is cannabinoid hyperemesis syndrome. The medical use of cannabinoids remains controversial. While cannabinoids have been studied for a variety of neurologic disorders, there is strongest evidence to indicate benefits in treatment of spasticity and neuropathic pain in multiple sclerosis. Although the best dose for an individual remains uncertain, most participants in the studies discussed in this paper used between 20 and 40 mg of THC a day in divided doses. Adverse events in studies were generally more common in the groups using cannabinoid products but serious adverse events were rare and cannabis products were generally well-tolerated. Cannabis use does appear to be associated with increased risk of certain adverse events, including psychosis, cardiovascular diseases, and cannabinoid hyperemesis syndrome.

Atropa belladonna neurotoxicity: Implications to neurological disorders.

Atropa belladonna, commonly known as belladonna or deadly nightshade, ranks among one of the most poisonous plants in Europe and other parts of the world. The plant contains tropane alkaloids including atropine, scopolamine, and hyoscyamine, which are used as anticholinergics in Food and Drug Administration (FDA) approved drugs and homeopathic remedies. These alkaloids can be very toxic at high dose. The FDA has recently reported that Hyland's baby teething tablets contain inconsistent amounts of Atropa belladonna that may have adverse effects on the nervous system and cause death in children, thus recalled the product in 2017. A greater understanding of the neurotoxicity of Atropa belladonna and its modification of genetic polymorphisms in the nervous system is critical in order to develop better treatment strategies, therapies, regulations, education of at-risk populations, and a more cohesive paradigm for future research. This review offers an integrated view of the homeopathy and neurotoxicity of Atropa belladonna in children, adults, and animal models as well as its implications to neurological disorders. Particular attention is dedicated to the pharmaco/toxicodynamics, pharmaco/toxicokinetics, pathophysiology, epidemiological cases, and animal studies associated with the effects of Atropa belladonna on the nervous system. Additionally, we discuss the influence of active tropane alkaloids in Atropa belladonna and other similar plants on FDA-approved therapeutic drugs for treatment of neurological disorders.

Duration of Adjuvant Chemotherapy for Stage III Colon Cancer.

BACKGROUND: Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. METHODS: We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. RESULTS: After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority). CONCLUSIONS: Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).

Jobelyn® attenuates inflammatory responses and neurobehavioural deficits associated with complete Freund-adjuvant-induced arthritis in mice.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects the physical and psychosocial wellbeing of the patients and a major cause of work disability. Current drugs for its treatment only provide palliative effect, as cure for the disease still remains elusive. Jobelyn® (JB), a potent anti-oxidant and anti-inflammatory dietary supplement obtained from Sorghum bicolor, has been claimed to relieve arthritic pain. Thus, this study was designed to evaluate its effect on inflammatory and biochemical changes as well as neurobehavioural deficits associated with complete Freund-adjuvant (CFA)-induced arthritis in mice. The effect of JB (50, 100 and 200 mg/kg) on inflammatory oedema, neurobehavioural deficits, levels of biomarkers of oxidative stress and inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) induced by 0.1 mL of CFA (10 mg/mL) was evaluated in male Swiss mice. Oral administration of JB (100 and 200 mg/kg) reduced inflammatory paw volume and reversed sensorimotor deficits induced by CFA. JB also reduced pain episodes, anxiety and depressive-like symptoms in CFA-mice. The increased level of oxidative stress in the joint and brain tissues of CFA-mice was reduced by JB. It also decreased tumor necrosis factor-alpha and interleukin-6 levels induced by CFA in the joint tissue of mice. These findings suggest that Jobelyn® attenuates inflammatory responses induced by CFA in mice via inhibition of oxidative stress and release of inflammatory cytokines. The ability of JB to attenuate CFA-induced nociception, sensorimotor deficits and depressive-like symptom suggests it might improve the quality of life of patients with arthritic conditions.

Health Symptoms Associated with Pesticides Exposure among Flower and Onion Pesticide Applicators in Arusha Region.

INTRODUCTION: Pesticides are extensively used in agriculture to control harmful pests and prevent crop yield losses or product damage. In Tanzania several studies have been conducted on health effects of pesticides on agricultural workers. However, there are few studies on neurological health symptoms associated with pesticide exposure in flower and onion farms. OBJECTIVE: The objective of this cross-sectional study was to assess health symptoms associated with pesticide exposure among flower and onion pesticide applicators in the Arusha region, Tanzania. METHODS: Data on demographic variables and health symptoms associated with pesticide exposure were collected from 140 males who were employed in spraying pesticides on flower and onion farms in Arusha, Meru and Karatu districts between April and May 2017. The study participants were interviewed using a structured questionnaire with questions focusing sociodemographic characteristics, occupation, pesticide exposure, common type of pesticide used in the area and neurological symptoms experienced during and after pesticide spraying. To determine the intensity of pesticide exposure, acetylcholinesterase assay was done by using the Test-mate Model 400 device with a photometric sensor. RESULTS: Ninety-five percent of pesticide applicators reported handling organophosphate pesticides. Body weakness was the most frequently reported neurological symptom (57.1%) followed by perspiration and headache (40.7%), poor appetite and depression (29.3%) and irritation (26.4%). About 27% of pesticide applicators had an acetylcholinesterase level below the limit value. CONCLUSION: A high proportion of neurological health symptoms and cholinesterase test depression was noted among pesticide applicators in both farms. There is a need to conduct further studies to ascertain causality for such high instances of neurological symptoms.