Toxic neuropathies.

PURPOSE OF REVIEW: Immunotherapy has had a significant impact on the treatment of an increasing number of cancers as well as in inflammatory, rheumatological and gastroenterological conditions.Recreational nitrous oxide use is now a global epidemic. Linezolid is now recommended for the treatment of drug-resistant tuberculosis (TB); neuropathy is a significant cause of morbidity.Global warming will result in increasing toxin exposure, such as ciguatera, in previously unaffected areas. RECENT FINDINGS: With increasing experience, the pathophysiology underlying the neuropathic complications of these drugs has become clear with guidelines now available, for the complications of immune check-point inhibitors and nitrous oxide toxicity. The optimum dose and duration of treatment for resistant TB with regimens, including linezolid, has been ascertained. SUMMARY: Although neuropathic complications with immunotherapy are relatively rare, it is essential that they are recognized and treated early. Nitrous oxide toxicity should be in the differential diagnosis for all patients, particularly those of younger age, presenting with a neuropathy or myleo-neuropathy. Ciguatera toxicity is under recognized and its geographical spread will increase due to global warming. Further research is necessary on the mechanisms and treatment of both acute and chronic effects, which at present, are only symptomatic.

A health-based recommended occupational exposure limit for nitrous oxide using experimental animal data based on a systematic review and dose-response analysis.

BACKGROUND: Nitrous oxide (N2O) is a common inhalation anaesthetic used in medical, paramedical, and veterinary practice. Since the mid 1950's, concerns have been raised regarding occupational exposure to N2O, leading to many epidemiological and experimental animal studies. Previous evaluations resulted in the classification of N2O as a possible risk factor for adverse reproductive health outcomes based on animal data. Human data were deemed inadequate primarily because of simultaneous co-exposures to other risk factors for adverse reproductive and developmental outcomes, including other anaesthetic gases. Since previous evaluations, controversies regarding N2O use remained and new approaches for dose response modelling have been adopted, calling for an update and re-evaluation of the body of evidence. This review aims to assess available animal evidence on N2O reproductive and developmental outcomes to inform a health-based recommended occupational exposure limit (OEL) for N2O with a benchmark dose-response modelling (BMD) approach. METHODS: Comprehensive searches in PubMed, EMBASE, and Web of Science were performed to retrieve all relevant studies addressing reproductive and developmental outcomes related to inhalation of N2O in animals. The articles retrieved were screened based on title-abstract and full text by two independent reviewers. After data extraction, an overview of all studies was created for the different endpoints, namely foetal outcomes (e.g., resorption), female outcomes (e.g. implantations), and male outcomes (e.g. sperm count). A subset of studies reporting on exposure relevant to workplace settings and with a sufficient number of tested doses were included in dose-response modelling using the BMD approach. RESULTS: In total, 15.816 articles were retrieved, of which 47 articles were finally included while 4 of those were used for the quantitative data synthesis. The overall risk of bias was judged to be probably high (using OHAT risk of bias tool) and unclear (using SYRCLE's risk of bias tool). From eligible rat studies, three studies provided an acceptable result by fitting a Hill model to the dose-response data. The resulting benchmark dose lower bounds (BMDLs) from three studies converged to an average (±sd) exposure level of 925 ± 2 mg/m3 at an additional risk of one standard deviation of implantation losses above those observed in the control group (i.e. reduced number of live foetuses/mother). For extrapolation from rats to humans, an uncertainty factor of 10 was used and an additional factor of 5 was applied to account for interindividual variability within the population of workers. CONCLUSION: With this systematic review, all available evidence for reproductive toxicity and adverse developmental outcomes in animals resulting from inhalation exposure to N2O was used to derive a health-based OEL recommendation of 20 mg/m3 as 8-h time-weighted average.

Air pollution and risk of hospitalization for epilepsy: the role of farm use of nitrogen fertilizers and emissions of the agricultural air pollutant, nitrous oxide / Poluição do ar e risco de hospitalização por epilepsia: o papel do uso agrícola de fertilizantes nitrogenados e as emissões de poluente atmosférico agrícola, óxido nitroso

ABSTRACT The link between various air pollutants and hospitalization for epilepsy has come under scrutiny. We have proposed that exposure to air pollution and specifically the pervasive agricultural air pollutant and greenhouse gas, nitrous oxide (N2O), may provoke susceptibility to neurodevelopmental disorders. Evidence supports a role of N2O exposure in reducing epileptiform seizure activity, while withdrawal from the drug has been shown to induce seizure-like activity. Therefore, we show here that the statewide use of anthropogenic nitrogen fertilizers (the most recognized causal contributor to environmental N2O burden) is significantly negatively associated with hospitalization for epilepsy in all three pre-specified hospitalization categories, even after multiple pollutant comparison correction (p<.007), while the other identified pollutants were not consistently statistically significantly associated with hospitalization for epilepsy. We discuss potential neurological mechanisms underpinning this association between air pollutants associated with farm use of anthropogenic nitrogen fertilizers and hospitalization for epilepsy.

RESUMO A ligação entre vários poluentes do ar e a hospitalização por epilepsia tem sido examinada. Propusemos que a exposição à poluição do ar, especificamente ao poluente atmosférico generalizado e ao gás de efeito estufa, o óxido nitroso (N2O), poderiam fomentar a susceptibilidade a distúrbios do desenvolvimento neurológico. A evidência apoia o papel da exposição ao N2O na redução da atividade convulsiva epileptiforme, enquanto mostra que a retirada do fármaco induz atividade pseudo-convulsiva. Portanto, mostramos aqui que o uso a nível estatal de fertilizantes nitrogenados antropogênicos (o agente causal mais reconhecido para a carga ambiental de N2O) está significativa e negativamente associado à hospitalização por epilepsia nas três categorias de hospitalização pré-especificadas, mesmo após a correção de comparação de poluentes múltiplos (p <0,007 ), enquanto os outros poluentes identificados não foram consistentemente associados de forma estatística com a hospitalização por epilepsia. Discutimos possíveis mecanismos neurológicos subjacentes a esta associação entre poluentes atmosféricos associados ao uso agrícola de fertilizantes nitrogenados antropogênicos, e hospitalização por epilepsia.

When the Laughing Stops: Subacute Combined Spinal Cord Degeneration Caused by Laughing Gas Use.

: Here we describe a case of subacute combined spinal cord degeneration caused by nitrous oxide (N2O, laughing gas) use. Because of its euphoric effects, the use of N2O has become increasingly popular in recent years. Unfortunately, the use of N2O leads to inactivation of vitamin B12. Vitamin B12 plays an essential role in the synthesis and maintenance of myelin, a fatty substance that surrounds nerve cells and is crucial for their functioning. Deficiency of vitamin B12 could typically result in degeneration of posterior and lateral columns of the spinal cord. Treatment with intramuscular vitamin B12 injections and abstinence of N2O generally leads to gradual improvement of symptoms. Our case demonstrates the importance of the methyl malonic acid test to detect early or mild vitamin B12 deficiency as a cause of myelopathy while serum vitamin B12 level may be normal. Written consent was obtained from our patient to publish the details of this individual case.

Does environmental exposure to the greenhouse gas, N2O, contribute to etiological factors in neurodevelopmental disorders? A mini-review of the evidence.

BACKGROUND: Neurodevelopmental disorders are increasing in prevalence worldwide. Previous work suggests that exposure to the environmental air pollutant and greenhouse gas - nitrous oxide (N2O) - may be an etiological factor in neurodevelopmental disorders through the targeting of several neural correlates. METHODOLOGY: While a number of recent systematic reviews have addressed the role of general anesthesia in the surgical setting and neurodevelopmental outcomes, a narrative mini-review was conducted to first define and characterize the relevant variables (i.e., N2O, attention-deficit hyperactivity disorder [ADHD] and autism spectrum disorders [ASD]) and their potential interactions into a coherent, hypothesis-generating work. The narrative mini-review merges basic principles in environmental science, anesthesiology, and psychiatry to more fully develop the novel hypotheses that neurodevelopmental impairment found in conditions like ADHD and ASD may be due to exposure to the increasing air pollutant, N2O. RESULTS: The results of the present mini-review indicate that exposure to N2O, even at non-toxic doses, may modulate central neurotransmission and target many neural substrates directly implicated in neurodevelopmental disorders, including the glutamatergic, opioidergic, cholinergic, and dopaminergic systems. Epidemiological studies also indicate that early and repeated exposure to general anesthesia, including N2O, may contribute to later adverse neurodevelopmental outcomes in children. CONCLUSIONS: The current evidence and subsequent hypotheses suggest that a renewed interest be taken in the toxicological assessment of environmental N2O exposure using validated biomarkers and psychiatric endpoints. Given the relevance of N2O as a greenhouse gas, societies may also wish to engage in a more robust monitoring and reporting of N2O levels in the environment for climactic benefit as well.

Impact of nitrous oxide on the haemodynamic consequences of venous carbon dioxide embolism: An experimental study.

BACKGROUND: Nitrous oxide (N2O) is still considered an important component of general anaesthesia. However, should gas embolisation occur as result of carbon dioxide (CO2) pneumoperitoneum, N2O may compromise safety, as the consequences of a gas embolus consisting of a combination of CO2 and N2O may be more severe than CO2 alone. OBJECTIVE: This experimental study was designed to compare the cardiopulmonary consequences of gas embolisation with a N2O/CO2 mixture, or CO2 alone. DESIGN: Experimental study. SETTING: Research Institute Against Digestive Cancer laboratory, Strasbourg, France. ANIMALS: Seven Large-White pigs receiving standardised inhalation anaesthesia. INTERVENTIONS: Each animal, acting as its own control, was studied in two successive experimental conditions - intravenous gas injections of 2 ml kg of 100% CO2 and 2 ml kg of a gas mixture consisting of 10% N2O and 90% CO2. MAIN OUTCOMES MEASURES: Haemodynamic and ventilatory consequences of embolisation with the gases. RESULTS: We found that the haemodynamic (heart rate, mean arterial blood pressure, central venous pressure, mean pulmonary artery pressure, pulmonary artery occlusion pressure and transoesophageal echocardiography parameters) and ventilatory (arterial oxygen saturation, end-tidal CO2 concentration and mixed venous oxygen saturation) consequences of embolisation with either 100% CO2 or 10% N2O with 90% CO2 were similar. CONCLUSION: The findings of this study may alleviate concerns that the use of N2O, as a part of a balanced general anaesthesia technique, may have greater adverse consequences should embolisation of pneumoperitoneal gas containing N2O occur.

DNA damage and antioxidant status in medical residents occupationally exposed to waste anesthetic gases.

PURPOSE: To investigate the effects of occupational exposure to waste anesthetic gases on genetic material and antioxidant status in professionals during their medical residency. METHODS: The study group consisted of 15 medical residents from Anesthesiology and Surgery areas, of both genders, mainly exposed to isoflurane and to a lesser degree to sevoflurane and nitrous oxide; the control group consisted of 15 young adults not exposed to anesthetics. Blood samples were drawn from professionals during medical residency (eight, 16 and 22 months of exposure to waste anesthetic gases). DNA damage was evaluated by comet assay, and antioxidant defense was assessed by total thiols and the enzymes glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase (CAT). RESULTS: When comparing the two groups, DNA damage was significantly increased at all time points evaluated in the exposed group; plasma thiols increased at 22 months of exposure and GPX was higher at 16 and 22 months of exposure. CONCLUSION: Young professionals exposed to waste anesthetic gases in operating rooms without adequate scavenging system have increased DNA damage and changes in redox status during medical residency. There is a need to minimize exposure to inhalation anesthetics and to provide better work conditions.

An alternative gas-phase in vitro exposure system for toxicity testing: the interaction between nitrous oxide and A549 cells.

An original in vitro approach was adopted to expose cells to volatile agents. The anaesthetic nitrous oxide (N(2)O) was chosen as the model agent, and type II pneumocyte-like cells (A549 cells) were used as the target to represent the lungs. A time-lapse microscopy station was equipped with a manual gas mixer that allowed the generation of a mixture of N(2)O/air/CO(2) in the gas phase, to provide a uniform distribution of the volatile agent. The dissolution of N(2)O in the culture medium was monitored by gas chromatography-electron capture detection. Biochemical alterations, in terms of homocysteine accumulation, demonstrated that intracellular methionine synthase had been inactivated by N(2)O absorbed by the cells, a process that also occurs in vivo. Toll-like receptors, which are key molecules in inflammatory lung diseases, were also investigated at the molecular level. Our experiments indicated that biochemical and molecular alterations occurred in the cells, even under conditions where neither morphologic changes nor consistent alterations in cell proliferation were evident. This in vitro exposure system can be efficiently adopted for looking at the repeat-dose effects of volatile agents on respiratory tissues. Moreover, it could be of further benefit for identifying the wide range of specific cell targets, and for monitoring relevant endpoints in the cellular and molecular processes that occur during exposure to volatile compounds.

Nitrous oxide plus isoflurane induces apoptosis and increases beta-amyloid protein levels.

BACKGROUND: Some anesthetics have been suggested to induce neurotoxicity, including promotion of Alzheimer's disease neuropathogenesis. Nitrous oxide and isoflurane are common anesthetics. The authors set out to assess the effects of nitrous oxide and/or isoflurane on apoptosis and beta-amyloid (Abeta) levels in H4 human neuroglioma cells and primary neurons from naïve mice. METHODS: The cells or neurons were exposed to 70% nitrous oxide and/or 1% isoflurane for 6 h. The cells or neurons and conditioned media were harvested at the end of the treatment. Caspase-3 activation, apoptosis, processing of amyloid precursor protein, and Abeta levels were determined. RESULTS: Treatment with a combination of 70% nitrous oxide and 1% isoflurane for 6 h induced caspase-3 activation and apoptosis in H4 naïve cells and primary neurons from naïve mice. The 70% nitrous oxide plus 1% isoflurane, but neither alone, for 6 h induced caspase-3 activation and apoptosis, and increased levels of beta-site amyloid precursor protein-cleaving enzyme and Abeta in H4-amyloid precursor protein cells. In addition, the nitrous oxide plus isoflurane-induced Abeta generation was reduced by a broad caspase inhibitor, Z-VAD. Finally, the nitrous oxide plus isoflurane-induced caspase-3 activation was attenuated by gamma-secretase inhibitor L-685,458, but potentiated by exogenously added Abeta. CONCLUSION: These results suggest that the common anesthetics nitrous oxide plus isoflurane may promote neurotoxicity by inducing apoptosis and increasing Abeta levels. The generated Abeta may further potentiate apoptosis to form another round of apoptosis and Abeta generation. More studies, especially the in vivo confirmation of these in vitro findings, are needed.

DNA damage induced by nitrous oxide: study in medical personnel of operating rooms.

Occupational exposure to anaesthetics such as nitrous oxide (N(2)O) and halogenated hydrocarbons has been suggested to increase risk of genetic damage. However, the dose-dependency of genotoxic effects has not been unequivocally established and their relation to occupational exposure limit (OEL) remain obscure. In this study, the genotoxicity associated with occupational exposure to anaesthetics has been investigated in a group of 55 female nurses and 29 male anaesthesiologists active for at least 5 years in a working environment containing variable concentrations of N(2)O and halogenated hydrocarbons. 83 unexposed health care workers (52 female nurses and 31 male doctors) matched for age, gender, smoking habit and employment duration were included in the control group. Genotoxicity has been assessed using comet test. Concentrations of nitrous oxide, sevoflurane and isoflurane monitored by gas chromatography and mass spectrometry made possible to relate the extent of DNA damage to the level of exposure. Our results for the first time document a positive correlation between the DNA damage and the N(2)O levels in the ambient air. By contrast, no correlation has been observed between genotoxic effects and concentrations of sevoflurane and isoflurane. The extent of genetic injury was especially aggravated among nurses and anaesthesiologists exposed to N(2)O in concentrations exceeding OEL (180 mg/m(3)). We conclude that occupational exposure to N(2)O is associated with increased DNA damage and that the level of exposure plays a critical role in this regard.

Mutagenicity of native cigarette mainstream smoke and its gas/vapour phase by use of different tester strains and cigarettes in a modified Ames assay.

The "Bacterial Reverse Mutation Assay" is generally accepted to analyse the genotoxic capacity of single compounds or complex mixtures such as cigarette-smoke condensates. With an adapted and modified Ames assay, the mutagenicity of native cigarette mainstream whole smoke (WS) and its gas/vapour phase (GVP) was studied. The bacteria were directly exposed to the smoke in a CULTEX1 system closely connected to a smoking robot (VC10). A variety of standard tester strains (TA98, TA100, TA1535, TA1537, TA1538, TA102, WP2uvrApKM101) and descendants of TA98 (YG1021, YG1024, YG1041) and TA100 (YG1026, YG1029 and YG1042) were exposed to whole and filtered smoke of the research cigarette K2R4F to find the most sensitive strains for analysing the mutagenic activity of these test atmospheres. Mutagenicity of WS was detected by TA98, TA100 and their YG descendant strains as well as by WP2uvrApKM101 in the presence of S9 mix. The GVP induced a mutagenic signal in TA100, YG1029 and YG1042 and WP2uvrApKM101 only in the absence of S9 mix. To detect mutagenicity in WS the presence of the plasmid pKM101 is required and a frame-shift mutation is more effective than a missense mutation. To detect mutagenicity in GVP, the presence of the plasmid pKM101 and a missense mutation are required. The differentiating capacity of this modified Ames assay was demonstrated by exposing strain TA98 to WS and TA100 to the GVP of cigarettes with different tar content. The mutagenic activity of WS and the GVP increased with rising tar content of the cigarettes with two exceptions in WS. Thus, the concept of tar content alone is misleading and does not reflect the mutagenic activity of a cigarette.

Indoor air pollution and respiratory function of children in Ashok Vihar, Delhi: an exposure-response study.

The objective of this study was to investigate the effects of indoor air pollution on respiratory function of children (aged 7-15 years). The study took place at Ashok Vihar, an urban locality in the northwest part of Delhi during the summer months of June and July 2004. The team did house visits. The questionnaire, administered at the house itself, asked about the history of smoking in the family, type of cooking fuel used, duration of cooking, ventilation and lighting at the cooking place, and other confounders. In total, 441 children (59% male, 41% female) between ages 7 and 15 years were considered for the study, and a detailed profile was collected. Clinical examination with special reference to respiratory system was done. Pulmonary function tests/peak expiratory flow rates of each child were measured. Indoor air pollutant (suspended particulate matter, SO(2), NO(2)) was measured, and the effect of these pollutants on the children's respiratory function was analyzed. The respiratory health profile suggests that children had cough, sputum production, shortness of breath, wheezing, common cold, and throat congestion. Indoor SO(2) , NO(2), and suspended particulate matter levels were high in houses where there was a family history of smoking. SO(2) level was significantly high according to occupancy per room. NO(2) and suspended particulate matter levels were significantly high in houses where children had respiratory problems. It is concluded that indoor air pollution had an association with respiratory function of children.

The role of antioxidant supplementation in occupational exposure to waste anaesthetic gases.

OBJECTIVES: Although the genotoxicity related to waste anaesthetic gases is controversial, a consistent number of observations have provided evidence for an increased level of DNA strand breaks. The goal of the research was to investigate this hypothesis and estimate the genoprotective role of antioxidant supplementation in technical anaesthesiology staff working in operating theatres. METHODS: Heparinized venous blood samples were collected from 17 exposed technical anaesthesiology staff (mean age 34.3 +/- 3.5 years) and non-exposed control group (mean age 32.2 +/- 3.4 years) and examined in the alkaline comet assay for DNA strand breakage. Vitamin E (300 mg/day) plus vitamin C (500 mg/day) were supplemented to the technical anaesthesiology staff for 12 weeks and blood samples were retaken and evaluated by comet assay. RESULTS: The DNA breakage observed in the lymphocytes of the technical anaesthesiology staff was 21.5 +/- 5.0, as calculated by total comet score (TCS). This score was significantly higher (P<0.001) than in the controls (8.6 +/- 4.7) before antioxidant treatment. Supplementation of vitamins E plus C significantly (P<0.01) reduced the mean TCS as 14.2 +/- 6.1. CONCLUSION: The results of our study indicate that occupational exposure to anaesthetic gases induces oxidative DNA damage. Supplementation of the diet for 12 weeks with vitamin C and vitamin E resulted in a significant decrease in the DNA damage.

Phenotypical and functional characterization of alveolar macrophage subpopulations in the lungs of NO2-exposed rats.

BACKGROUND: Alveolar macrophages (AM) are known to play an important role in the regulation of inflammatory reactions in the lung, e.g. during the development of chronic lung diseases. Exposure of rats to NO2 has recently been shown to induce a shift in the activation type of AM that is characterized by reduced TNF-alpha and increased IL-10 production. So far it is unclear, whether a functional shift in the already present AM population or the occurrence of a new, phenotypically different AM population is responsible for these observations. METHODS: AM from rat and mice were analyzed by flow cytometry for surface marker expression and in vivo staining with PKH26 was applied to characterize newly recruited macrophages. Following magnetic bead separation, AM subpopulations were further analyzed for cytokine, inducible NO synthase (iNOS) and matrix metalloproteinase (MMP) mRNA expression using quantitative RT-PCR. Following in vitro stimulation, cytokines were quantitated in the culture supernatants by ELISA. RESULTS: In untreated rats the majority of AM showed a low expression of the surface antigen ED7 (CD11b) and a high ED9 (CD172) expression (ED7-/ED9high). In contrast, NO2 exposure induced the occurrence of a subpopulation characterized by the marker combination ED7+/ED9low. Comparable changes were observed in mice and by in vivo labeling of resident AM using the dye PKH26 we could demonstrate that CD11b positive cells mainly comprise newly recruited AM. Subsequent functional analyses of separated AM subpopulations of the rat revealed that ED7+ cells showed an increased expression and production of the antiinflammatory cytokine IL-10 whereas TNF-alpha production was lower compared to ED7- AM. However, iNOS and IL-12 expression were also increased in the ED7+ subpopulation. In addition, these cells showed a significantly higher mRNA expression for the matrix metalloproteinases MMP-7, -8, -9, and -12. CONCLUSION: NO2 exposure induces the infiltration of an AM subpopulation that, on the one hand may exert antiinflammatory functions by the production of high amounts of IL-10 but on the other hand may contribute to the pathology of NO2-induced lung damage by selective expression of certain matrix metalloproteinases.

Effectiveness of fixed 50% nitrous oxide oxygen mixture and EMLA cream for insertion of central venous catheters in children.

BACKGROUND: Although the equimolecular mixture of oxygen and nitrous oxide (EMONO) seems a good choice to relieve procedure-related pain in children, it has not been evaluated for insertion of central venous catheters in children. To assess the safety and the effectiveness of this gas mixture for insertion of central venous catheters, we conducted a prospective observational study. PROCEDURE: This study was performed by the "Centre National de Greffe de Moelle Osseuse." Procedure and inhalation characteristics, as well as pain evaluations and side effects, were reported. RESULTS: Fifty central venous catheters were inserted in 50 consecutive children. Median age was 7 (range, 4-13) years. An anesthesiologist was responsible for delivering EMONO, and provided constant surveillance throughout the procedure. EMLA cream was applied 2 hr before EMONO inhalation. No associated drugs were used. All catheters were inserted by the same experienced physician in the operating theater. Median inhalation length was 5 min (range, 3-6) before starting catheter's insertion and 12 min (range, 9-25) for the total inhalation. Median procedural pain evaluations were 10 (range, 0-30) for children on a 0-100 visual analog scale (VAS). Minor side effects were observed during eight (16%) inhalations. These side effects were euphoria (14%), deep sedation (4%), nausea and vomiting (2%), hallucinations (2%). All side effects were transient and resolved within 5 min after removing the inhalation device. CONCLUSIONS: This study which shows that EMONO is effective for insertion of central venous catheters in children and represents a simple and safe alternative to general anesthesia.