Catalytic and structural effects of flexible loop deletion in organophosphorus hydrolase enzyme: A thermostability improvement mechanism

Thermostability improvement of enzymes used industrially or commercially would develop their capacity andcommercial potential due to increased enzymatic competence and cost-effectiveness. Several stabilizing factorshave been suggested to be the base of thermal stability, like proline replacements, disulfide bonds, surface looptruncation and ionic pair networks creation. This research evaluated the mechanism of increasing the rigidity oforganophosphorus hydrolase enzyme by flexible loop truncation. Bioinformatics analysis revealed that themutated protein retains its stability after loop truncation (five amino acids deleted). The thermostability of thewild-type (OPH-wt) and mutated (OPH-D5) enzymes were investigated by half-life, DGi, and fluorescence andfar-UV CD analysis. Results demonstrated an increase half-life and DGi in OPH-D5 compared to OPH-wt.These results were confirmed by extrinsic fluorescence and circular dichroism (CD) spectrometry experiments,therefore, as rigidity increased in OPHD5 after loop truncation, half-life and DGi also increased. Based onthese findings, a strong case is presented for thermostability improvement of OPH enzyme by flexible looptruncation after bioinformatics analysis.

Effect of hemoperfusion on ChE activity and toxicant clearance in patients with organophosphorus poisoning / 中国基层医药

Objective@#To investigate the effect of hemoperfusion (HP) on the activity of ChE in blood of patients with organophosphorus poisoning, and its toxicant clearance effect.@*Methods@#From January 2017 to January 2019, 60 patients with organophosphorus poisoning in Shengjing Hospital Affiliated to China Medical University were divided into observation group and control group according to random number table method, with 30 cases in each group.The control group was treated with routine treatment, while the observation group was treated with HP on the basis of routine treatment.The therapeutic effects of the two groups were compared.@*Results@#The duration of mechanical ventilation and conscious awakening in the observation group were (3.07±1.14) d and (1.42±0.37) d, respectively, which were significantly shorter than those in the control group[(4.15±1.22) d, (2.01±0.58)d](t=3.543, 4.697, all P<0.05). The dosage of atropine in the observation group[(252.57±28.44)mg]was significantly less than that in the control group[(282.61±29.82)mg](t=3.993, P<0.05). The activity of cholinesterase after 12 h and 24 h of treatment was significantly higher than those before treatment (all P<0.05). After 12 h and 24 h of treatment, the cholinesterase activities in the observation group were (1 128.64±152.49)U/L and (1 422.08±184.68)U/L, respectively, which were higher than those in the control group[(912.73±144.61)U/L and (1 165.32±173.27)U/L](t=5.627, 5.553, all P<0.05). After 1 d and 3 d of treatment, the concentrations of organophosphorus poisons in the observation group were (1.08±0.30)mg/L and (0.62±0.18)mg/L, respectively, which were significantly lower than those in the control group[(1.32±0.35)mg/L and (0.84±0.27)mg/L](t=2.852, 3.713, all P<0.05). The incidences of rebound, intermediate syndrome and multiple organ failure in the observation group were 3.33% (1/30), 6.67% (2/30) and 13.33% (4/30), respectively, which were lower than those in the control group[23.33% (7/30), 23.33% (7/30), 36.67% (11/30)](χ2=5.192, 3.278, 4.356, all P<0.05).@*Conclusion@#HP has obvious effect on the activity of ChE and the concentration of blood poisons in patients with organophosphorus poisoning.It is worthy of popularizing and applying in clinic.

Effect of hemoperfusion on ChE activity and toxicant clearance in patients with organophosphorus poisoning / 中国基层医药

Objective To investigate the effect of hemoperfusion (HP) on the activity of ChE in blood ofpatients with organophosphorus poisoning,and its toxicant clearance effect.Methods From January 2017 to January 2019,60 patients with organophosphorus poisoning in Shengjing Hospital Affiliated to China Medical University were divided into observation group and control group according to random number table method , with 30 cases in each group.The control group was treated with routine treatment ,while the observation group was treated with HP on the basis of routinetreatment.Thetherapeuticeffectsof thetwogroupswerecompared.Results Thedurationof mechanical ventilation and conscious awakening in the observation group were (3.07 ±1.14) d and (1.42 ±0.37) d,respectively, which were significantly shorter than those in the control group [(4.15 ±1.22) d,(2.01 ±0.58)d](t=3.543, 4.697,all P<0.05).The dosage of atropine in the observation group [(252.57 ±28.44) mg] was significantly less than that in the control group [(282.61 ±29.82)mg](t=3.993,P<0.05).The activity of cholinesterase after 12 h and 24 h of treatment was significantly higher than those before treatment (all P<0.05).After 12 h and 24 h of treatment,the cholinesterase activities in the observation group were (1128.64 ±152.49) U/L and (1422.08 ± 184.68)U/L,respectively,which were higher than those in the control group[(912.73 ±144.61) U/L and (1165.32 ± 173.27)U/L](t=5.627,5.553,all P<0.05).After 1 d and 3 d of treatment,the concentrations of organophosphorus poisons in the observation group were (1.08 ±0.30) mg/L and (0.62 ±0.18) mg/L,respectively,which were significantly lower than those in the control group[(1.32 ±0.35)mg/L and (0.84 ±0.27)mg/L](t =2.852, 3.713,all P<0.05).The incidences of rebound ,intermediate syndrome and multiple organ failure in the observation group were 3.33％(1/30),6.67％(2/30) and 13.33％(4/30),respectively,which were lower than those in the control group［23.33％(7／30),23.33％(7／30),36.67％(11／30)］(χ2 ＝5.192,3.278,4.356,all P ＜0.05).Conclusion HP has obvious effect on the activity of ChE and the concentration of blood poisons in patients with organophosphorus poisoning.It is worthy of popularizing and applying in clinic.

Clinicoepidemiological Profile of Organophosphorus Poisoning in a Tertiary Care Center

Introduction: Organophosphorus compounds are widelyused as insecticides. Organophosphorus poisoning hasa significant morbidity and mortality and is a commonoccurrence due to their easy accessibility. Study aimed toassess clinicoepidemiological profile of organophosphoruspoisoning.Material and methods: Our study was a hospital basedprospective study conducted over a period of two yearsinvolving all the patients of organophosphorus (OP)poisoning, admitted in the medical emergency of the hospital.These patients were evaluated for demographic and clinicalprofile and followed till the time of discharge or death.Results: 102 cases of OP poisoning were admitted, majoritybelonged to the age group of 15-25 years (54.9%) and were ofrural origin (84.3%). Females (67.64%) outnumbered males.97 cases had taken it with suicidal intent. Miosis was themost consistent clinical feature (93.13%). 64 patients (62.7%)needed admission in ICU. Respiratory failure was the mostcommon complication. Mortality rate of 14.7% was observed.Conclusion: OP compounds are ingested mostly with suicidalintent due to their easy availability mostly by young andproductive population. Initial management and resuscitationin periphery is invaluable

Intoxicación por organofosforados / Organophospate poisoning

Resumen La intoxicación por organofosforados es de gran importancia en el campo de la medicina, debido a su uso frecuente en la actividad agrícola, las intoxicaciones producidas por estos agentes pueden ser ocupacionales, accidentales, y con mayor frecuencia por ingesta voluntaria. Una de las mayores repercusiones de los organofosforados es la inhibición del acetil colinesterasa, enzima encargada de hidrolizar el acetil colina. Las manifestaciones clínicas de la intoxicación aguda se deben a la estimulación de receptores muscarínicos y nicotínicos, entre ellas broncorrea, salivación, lagrimeo, broncoespasmo, defecación, emesis, miosis, entre otros. El diagnóstico se realiza mediante la historia clínica y examen físico, de manera adicional con la detección de los niveles en sangre eritrocitaria de acetil colinesterasa o de los metabolitos de los organofosforados. El manejo incluye la descontaminación del agente, la revisión del estado respiratorio y el acceso al soporte ventilatorio, posteriormente se procede con el tratamiento farmacológico que incluye el uso de la atropina, pralidoxima y diazepam. El presente artículo constituye una revisión bibliográfica sobre la intoxicación por organofosforados, sus manifestaciones clínicas, diagnóstico y tratamiento.

Abstract Organophosphorus poisoning is of great importance in the field of medicine due to its frequent use in agriculture, the poisoning by exposure to these agents can be occupational, accidental, and frequently due to voluntary intake. Organophosphorus' intake most notable effects are produced by the inhibition of the acetyl cholinesterase, responsible for hydrolyzing acetyl choline. Clinical manifestations of acute intoxication typically include bronchorrhea, salivation, lacrimation, bronchospasm, defecation, emesis, miosis, among others and they occur due to the stimulation of muscarinic and nicotinic receptors. Diagnosis is made through the interrogation and physical examination, in addition to the detection of acetyl cholinesterase levels or the organophosphates' metabolites in blood testing. Management includes decontamination of the agent, review of respiratory status and access to ventilatory support, followed by pharmacological treatment that includes the use of atropine, pralidoxime and diazepam. The present article constitutes a bibliographic review about the organopho sphorus intoxication, its clinical manifestations, diagnosis and treatment.

Antitumor activities of new iso(thio)cyanates and their nitrogen and sulphur heterocyclic phosphorus derivatives

The cytotoxic activity of Iso(thio)cyanate derivatives and some new organophosphorus compounds were determined,using MTT assay against human hepatocellular carcinoma (HepG2) and adenocarcinoma breast (MCF-7) incomparison with the reference drug 5-flurouracil. All the selected products have been tested and showed concentrationdependent increase in the growth inhibition percentage against HepG2 and MCF-7. Where, the thietane derivativesrevealed anticancer activity with IC50 (20, 8.9 µg/ml) against HepG2 and (20, 10.3 µg/ml) against MCF-7; while,thiazinane compounds showed IC50 (12.7, 32.5 µg/ml) against HepG2 and (20 and 20 µg/ml) against MCF7. The newly synthesized azetidines showed anticancer activity with IC50 (13.5 and 32.5 µg/ml) against HepG2and IC50 (10 and 25.9 µg/ml) against MCF-7 cancer. Moreover, azetidinedione compound exhibited more potentactivity than the azetidinone with both types of cancer cell lines. In addition, the cytotoxic activity of the iso(thio)cyanates, and malonamic acid methyl ester compound were also investigated. 4-Methoxyphenyl isothiocyanate andmethylisothiocyanate, with IC50 (25.9, 12.3 and 40, 20 µg/ml), respectively, against HepG2 and MCF-7 cancer cells.1, 2-Dichloro-4-isocyanato-benzene was similar in potency to the known anticancer drug 5-flurouracil with IC50 (5.3µg/ml) versus 5 µg/ml for 5-flurouracil against MCF-7. While, malonamic acid methyl ester compound had no effecton both types of cancer cell lines.

A study of clinical profile of patients with organophosphorus poisoning

Background: Depression, a common mental disorder characterized by persistent unhappiness and lack of interest in daily activities, is one of the major important public health problems that are often comorbid with other chronic diseases like diabetes and can worsen the effect of the disease outcomes. Depression alone and/or as a comorbidity with diabetes is a common condition in the community. Aim of the study: To identify the prevalence of Depression among Type 2 Diabetes Mellitus patients and relationship between Depression and its effect on Drug Compliance among Type 2 Diabetes Mellitus patients, to determine the severity of Depression among Type 2 Diabetes Mellitus patients and the extent to which it affects Drug compliance. Materials and methods: The study was to be conducted in Rajah Muthiah Medical College and Hospital, Chidambaram in the year 2018-2019. A hundred patients with diagnosis of T2DM attending Diabetic OPD above 20 years of age were randomly selected. The Hamilton rating scale for depression by Hamilton is the most widely used rating scale to assess the symptoms of depression. The Ham-D is an observer-rated scale consisting of 17-21 items. Ratings are based on clinical interview. The items are rated on either a 0 to 4 spectrum or a 0 to 2 spectrum. The HAM-D also relies quite heavily on the clinical interviewing skills and the experience of rater in evaluating individuals with depressive illness. The strength of HAM-D is its excellent validation/research base, K.H. Mohamed Ibrahim, R. Gandhi Babu, M. Senthil Velan. Prevalence of psychiatric morbidity (depression) and its effect on drug compliance among patients attending diabetic outpatient clinic. IAIM, 2019; 6(11): 19-28. Page 20 and case of administration. Its use is limited in individuals who have psychiatric disorders other than primary depression. Results: Analyzing with HAMD score, 40 had no depression, mild depression in 24 cases, moderate depression in 21 cases, severe depression in 15 cases. MAQ score scale- low adherence in 41 cases, medium adherence in 37 cases, high adherence in 22 cases. MMAQ score scale and HAMD scorelow adherence with no depression were 9 cases (22.5%) mild depression were 6 cases (25%) moderate were 11(52.4%) severe depression were 15 cases (100%). MMAQ score scale and HAMD score - medium adherence with no depression were 23 cases (57.5%) mild depression were 9 cases (37.5%) moderate were 5(23.8%) severe depression were not seen. MMAQ score scale and HAMD score - Medium adherence with no depression were 8 cases (20%) Mild depression were 9 cases (37.5%) Moderate were 5(23.8%) severe depression was not seen. Pearson Chi-Square = 35.344**, p<0.001. Conclusion: Further, there was a significant association between the depression in Type 2 diabetes patients and medication adherence, where patients with depression had poor medication adherence as compared to those without depression and severity of depression correlates with worse adherence to diabetic medications

A study of 50 cases of Organophosphorus poisoning and its complications

Background: In developing countries, the widespread use of organophosphorus compounds (OPCs) has been accompanied by increasing incidence of poisoning with these agents, both suicidal and accidental. This is attributed mainly to their easy availability, indiscriminate handling, storage and lack of knowledge about the serious consequences of poisoning. Of the various substance used for suicidal attempts in India, OPCs form a significant group. Since the clinical manifestation of OPC poisoning is diverse ranging from mild symptoms to fatal complications in the course of time, we need proper management of the situation. Materials and methods: We studied 50 patients of organophosphorus poisoning. We checked vital parameters, general examination and systemic examination. We also checked for various parameters on like cholinesterase level, complete blood counts, renal function test with electrolytes, liver function test. Results: In this study majority of patients fell in 20-30 years of age group with male predominance from lower and middle socio-economical class and most common reason was suicidal. Precipitating event were domestic problem, marital friction and financial problem. Most common clinical features were vomiting, miosis and giddiness. Majority of the patients belonged to mild grade. The average S.cholinesterase level was low as severity increases. More doses of PAM and atropine are required in severe poisoning. Most common complication was respiratory paralysis. Death was more in severe poisoning. Conclusion: OPC is one of the most common poisoning in India. Reason for poisoning is most commonly suicidal. It is common in male with low socio-economical class mainly due to domestic Janak Chokshi, Kothi Zuber Suleman, Bhavikkumar Prajapati. A study of 50 cases of Organophosphorus poisoning and its complications. IAIM, 2019; 6(1): 16-22. Page 17 problems, financial issue and unhappy married life. In patients of OP poisoning presenting symptoms and S.ChE level directly correlated with severity. Therapeutic required dose of PAM and atropine are different in different grade of severity. Survival amongst patients is definitely better if atropine and PAM are being given with Mechanical ventilator support in cases of respiratory insufficiency.

Next-generation ALK-TKI in NSCLC patients / 中国医师杂志

Objective The aim of the study is to investigate the therapeutic efficacy of next-generation anaplastic lynphoma kinase-tyrosine kinase inhibitor (ALK-TKI) in advanced non-small cell lung cancer (NSCLC).Methods The clinical data and outcomes of 22 patients with advanced non-small cell lung cancer who received the next generation of ALK-TKI from 2014 to 2017 in our hospital were retrospectively analyzed.Results 22 patients were included for survival analysis with 15 males and 7 females.The median age was 48 and all of them were adenocarcinoma patients.There were 12,2,7 and 1 patients received ceritinib,alectinib,brigatinib and lorlatinib,respectively.A total of 14 patients could be evaluated,including complete response (CR) in 2 cases,partial response (PR) in 3 cases,stable disease (SD) in 6 cases,progressive disease (PD) in 3 cases.The ORR and DCR were 35.7％ and 78.6％,respectively.The median progression free survival (PFS) of the 22 NSCLC patients was 8.7 months.Progression pattern can be analyzed in 17 patients.Among them,10 patients underwent primary progression (lung),occurring at the leading frequency (accounting for 58.8％) and followed by central nerve system (CNS) progression (accounting for 29.4％).Conclusions Next-generation ALK-TKI provide a reasonable choice for crizotinib-resistant patients.Primary progression (lung) is the leading cause for treatment failure.Multi-disciplinary integration may provide a potential choice for prolonging administration of next-generation ALK-TKI.

Tremor essencial em guardas de endemias expostos a agrotóxicos: estudo caso-controle / Essential tremor in endemic disease control agents exposed to pesticides: a case-control study / Temblor esencial en empleados públicos del sector de vigilancia y control de endemias expuestos a pesticidas: estudio caso-control

Resumo: Tremor é o distúrbio do movimento mais frequente na população, e pode estar associado a exposição a agrotóxicos. O objetivo foi avaliar a chance de tremor essencial em 442 guardas de endemias do Estado do Rio de Janeiro, Brasil, expostos a agrotóxicos. Foram selecionados 51 casos e 204 controles (1:4). Todos os participantes responderam a um questionário sobre aspectos sociodemográficos, ocupacionais e toxicológicos. A influência da exposição a agrotóxicos sobre o desenvolvimento do tremor foi estimada por regressão logística não condicional, ajustada por covariáveis selecionadas. A idade média da população estudada foi de 49 (DP = 7) anos, sendo a diferença entre casos (média = 50,8; DP = 6,9) e controles (média = 48,5; DP = 6,9) estatisticamente significativa (p = 0,03). Além disso, aqueles com 16 a 16,9 anos de aplicação de agrotóxicos foram os que estiveram sob maior chance de apresentar a doença (OR ajustada = 4,60; IC95%: 1,29-16,41). Nossos resultados sugerem que o período entre 16 e 16,9 anos de aplicação de agrotóxicos teve impacto importante para o desenvolvimento dessa doença.

Abstract: Tremor is the most frequent movement disorder in the population and can be associated with pesticide exposure. The aim was to assess the odds of essential tremor in 442 endemic disease control agents in Rio de Janeiro State, Brazil, exposed to pesticides. Fifty-one cases and 204 controls were selected (1:4). All participants answered a questionnaire on socio-demographic, occupational, and toxicological items. The influence of pesticide exposure on the development of tremor was estimated by non-conditional logistic regression, adjusted for selected covariables. Mean age of the study population was 49 (SD = 7) years, and the difference between cases (mean = 50.8; SD = 6.9) and controls (mean = 48.5; SD = 6.9) was statistically significant (p = 0.03). Those with 16 to 16.9 years of pesticide use showed the highest odds of essential tremor (adjusted OR = 4.60; 95%CI: 1.29-16.41). Our results suggest that 16 to 16.9 years of pesticide exposure had a major impact on the development of essential tremor.

Resumen: El temblor es el disturbio de movimiento más frecuente en la población y puede estar asociado a la exposición a pesticidas. El objetivo fue evaluar la oportunidad del temblor esencial en 442 empleados públicos del sector de endemias del estado de Río de Janeiro, Brasil, expuestos a pesticidas. Se seleccionaron 51 casos y 204 controles (1:4). Todos los participantes respondieron a un cuestionario sobre aspectos sociodemográficos, ocupacionales y toxicológicos. La influencia de la exposición a pesticidas sobre el desarrollo del temblor fue estimada por regresión logística no condicional, ajustada por covariables seleccionadas. La edad media de la población estudiada fue de 49 (DP = 7) años, siendo la diferencia entre casos (media = 50,8; DP = 6,9) y controles (media = 48,5; DP = 6,9) estadísticamente significativa (p = 0,03). Además, aquellos de 16 a 16,9 años de servicio de fumigación con pesticidas fueron los que estuvieron bajo la mayor oportunidad de presentar la enfermedad (OR ajustada = 4,60; IC95%: 1,29-16,41). Nuestros resultados sugieren que el período entre 16 y 16,9 años de fumigación con pesticidas tuvo un impacto importante para el desarrollo de esa enfermedad.

Assessment of hematological parameters in workers exposed to organophosphorus pesticides, carbamates and pyrethroids in Cundinamarca 2016-2017 / Evaluación de parámetros hematológicos en trabajadores expuestos a pesticidas organofosforados, carbamatos y piretroides, Cundinamarca 2016-2017

ABSTRACT Objective To establish hematotoxic alterations through clinical and paraclinical exploration in workers who are exposed to organophosphorus pesticides, carbamates and pyrethroids (OPCP) due to their work in production, packaging, distribution and fumigation processes in Cundinamarca-Colombia between 2016 and 2017. Materials and Methods A cross-sectional descriptive epidemiological study was carried out on a sample of 92 workers from six companies, mostly aged between 18 and 30 years, of which 61 % were males and 39 % females, and 71 % were workers in the operational area and 29 % in the administrative area. Univariate, bivariate and multivariate analyses were performed. Results Clinical exploration reported findings in 17 % of the sample group, of which only 2 % presented with erythrocyte cholinesterase outside the reference range. The values of hematological parameters such as peripheral blood smear (PBS) and complete blood count (CBC) were outside the range in 15 % and 47 % of the sample, respectively. Discussion The results suggest that there are hematological alterations in this group that could possibly be associated with chronic exposure to OPCP.

RESUMEN Objetivo Determinar las alteraciones hematotóxicas a través de una exploración clínica y paraclínica, en trabajadores que por su oficio se exponen a pesticidas organofosforados, carbamatos y piretroides (POCP), en procesos de producción, envase, distribución y fumigación, en el departamento de Cundinamarca Colombia. Metodología Se realizó un estudio epidemiológico descriptivo de corte transversal. Se realizó un análisis univariado, bivariado y multivariado. La muestra se conforma por 92 trabajadores de seis empresas, la mayoría entre los 18 y 30 años, de los cuales el 61 % son hombres y el 39 % mujeres, 71 % se desempeñan en el área operativa y 29 % en el área administrativa. Resultados Es de resaltar que se tienen hallazgos en la exploración clínica en el 17 % del grupo participante, solo el 2 % presenta la colinesterasa eritrocitaria por fuera del rango de referencia. Los parámetros hematológicos como el frotis de sangre periférica (FSP) presentan valores por fuera de los rangos en el 15 % y el cuadro hemático (CH) tiene valores por fuera de los rangos en el 47 % de las personas. Discusión Los resultados sugieren que existen alteraciones hematológicas en este grupo y que posiblemente podrían estar asociadas con la exposición crónica a POCP.

Observation of the effect of blood perfusion combined with penehyclidine hydrochloride injection in the treatment of acute severe organophosphorus pesticide poisoning / 中国基层医药

Objective To explore the clinical effect of blood perfusion combined with penehyclidine hydrochloride injection in the treatment of acute severe organophosphorus pesticide poisoning.Methods 58 patients with severe organophosphorus pesticide poisoning were selected as the research subjects.By using digital table method,they were randomly divided into observation group and control group,29 cases in each group.The two groups were given conventional treatment and blood perfusion treatment after admission,the observation group was treated with penehyclidine hydrochloride injection on this base.Before and after treatment,the myocardial enzymes,liver,kidney function index,blood gas analysis,cholinesterase activity,as well as other treatment of the two groups were observed,and the results were compared.Results Compared with the control group,after treatment,the myocardial enzyme,transaminase,serum amylase and creatinine levels in the observation group were significantly lower,cholinesterase level was significantly increased,the oxygen partial pressure increased,the partial pressure of carbon dioxide decreased obviously,the differences were statistically significant(all P<0.05).The hospitalization time and cholinesterase activity recovery time of the observation group were significantly shorter than those of the control group[(12.57±2.14)d vs.(16.35±2.73)d,(5.46±2.29)d vs.(7.61±3.47)d],and the cure rate of the observation group was significantly higher than that of the control group(100.00% vs.82.76%),the differences were statistically significant(t=2.139,2.208,x2=5.472,all P<0.05).Conclusion Blood perfusion can directly adsorb organophosphorus pesticide,shorten the recovery time of cholinesterase and reduce the case fatality rate,and it combined with penehyclidine hydrochloride injection not only can improve the clinical curative effect of blood perfusion,but also can protect the organ.

Metabolomics study of tris(2-chloroethyl) phosphate induced hepaotoxicity and nephrotoxicity in Sprague-Dawley rats / 中华预防医学杂志

Objective@#To discuss the potential toxic target organ and the toxic effects and mechanisms of tris (2-chloroethyl) phosphate (TCEP) on SD rats.@*Methods@#40 female SD rats weaning from milk for 21 days, weighted (50±2.3)g were selected as subjects and marked by the weight. They were randomly divided into 4 groups, namely control group, 50 (L), 100 (M) and 250 (H) mg·kg-1·d-1 dose of TCEP group. Each group has 10 rats, and administrated the corresponding dose of drug or vehicle by mouth, quaque die for 60 days. All rats were sacrificed after the last administration. The livers and kidneys were dyed by HE for pathological observation; and the blood samples were collected to analyze the biochemical index. H1-Nuclear Magnetic Resonance (1H-NMR)-based metabolomics methods coupling with histopathogy examination were used to investigate the toxic effects of TCEP.@*Results@#Inflammatory cell infiltration and hepatic necrosis were observed in the liver of TCEP-treated rats. Inflammatory cells invaded and calcification/ossification foci were also found in renal of TCEP-treated rats and tumor hyperplasia were existed in renal tubule in H group. The level of HDL-C in the L, M and H group were separately (1.7±0.09) , (1.5±0.07) and (1.3±0.1) µmol/L, which were all significantly lower than that of control group ( (1.9±0.2) µmol/L) (P<0.05) . The activity of cholinesterase (CHE) in the L, M and H group were separately (918±14.8) , (828±28.6) and (674±36.5) U/L, which were all significantly lower than that of control group ((1056±28.8) µmol/L) (P<0.05). Moreover, The level of creatinine (CRE) in the L, M and H group were separately (29.8±4.6) , (28.9±5.3) and (25.8±6.2) µmol/L, which were all significantly lower than that of control group ((30.2±3.9) µmol/L) (P<0.05). In the H group, the enzyme activities of alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatine kinase (CK), alkaline phosphatase (ALP) and the contents of total bilirubin (TBIL), glucose (GLU) and uric acid (UA) were all significantly higher than the results in control group. The results of 1H-NMR metabolomics showed that the contents of lactate, glycine, high-density lipoprotein, low-density lipoprotein and phosphatidylcholine in blood of rats would decrease by TCEP exposure, while N-acetylglycoprotein, acetate, alanine, glucose, lipids, lipoproteins and fatty acids would increase.@*Conclusion@#TCEP caused disorders in endogenous energy metabolism, leading to the pathological changes of inflammatory cells infiltration and necrosis in liver and kidney, caused enzyme activity changes of ALT, ALP and the content changes of other liver and kidney injury-related markers.

Progress in environmental exposure of organophosphate flame retardants / 中华预防医学杂志

Organophosphate flame retardants (OPFRs), which have both great properties of flame retardation and plasticization, are currently widely used as additive flame retardants. Due to the restriction and phase-out of brominated flame retardants (BFRs), the market demand for OPFRs as excellent alternatives of BFRs has been rapid increasing. OPFRs can be slowly released into the environment during production and application. Some OPFRs might be persistent in the environment. As a result, OPFRs have been detected in various matrices in the environment and are expected to accumulate in human body through various pathways. OPFRs may cause adverse effects to human health as some of them have been identified as neurotoxicants, reproductive toxicants and potential carcinogens. The article summarized the occurrence and patterns of OPFRs in various environmental matrices such as air, dust, water, food and so on, and in human specimens, estimates the exposure status through different pathways and body burdens of OPFRs. The expected hotspots of OPFRs were also discussed in the future.

Evidence-based practice of standardized gastric lavage for acute organophosphorus pesticide poisoning / 中华护理杂志

Objective To formulate standardized program of gastric lavage for acute organophosphorus pesticide poisoning(AOPP) and evaluate the effects.Methods Evidence was obtained via evidence-based approach,and recommendations were formed.The standardized program of gastric lavage for AOPP was formulated and then applied to clinical practice.The effects were evaluated by examining indicators of success rate of catheterization,the first time of gastric lavage,the time of atropinization and total usage of atropine,ChE recovery time,hospital stay,rebound rate,adverse event rate.Results After implementation,the first time of gastric lavage,the time of atropinization,total usage of atropine,ChE recovery time,and hospital stay were significantly lower than the control group (P＜0.05).Conclusion Evidence-based practice of gastric lavage for AOPP can improve therapeutic effects,reduce adverse reactions,improve quality of nursing,and promote safety of medical care.

Diagnóstico diferencial de cetoacidosis hiperglicémica: Intoxicación por plaguicidas. Caso clínico / Differential diagnosis from hyperglycemic ketoacidosis: Pesticide poisoning. Clinical case

La cetoacidosis diabética en niños puede ser una causa de morbilidad grave y mortalidad, especialmente si no se reconoce en el momento del primer diagnóstico. Sin embargo, existen otras patologías que pueden aparentar una alteración metabólica de este tipo y pasarse por alto si no se tiene sospecha clínica. A continuación, se describe un caso clínico que presenta cetoacidosis hiperglicémica debido al contacto con organofosforado, en el cual fue necesario el uso de insulina en infusión continua para el control del trastorno metabólico, sin repercusiones después del alta.

Diabetic ketoacidosis in children causes serious morbidity and mortality, especially if it is not recognized on time in the initial diagnosis. However, there are other diseases that can appear to be a metabolic disorder of this kind and be ignored if it is not suspected. We present a clinical case with hyperglycemic ketoacidosis due to the contact with organophosphate; we had to use a continuous infusion of insulin to control the metabolic disorder without repercussions after the girl came home.

Laboratory genetic-based reference values for cholinesterase activity in a Colombian population: A step forward in personalized diagnostics / Valores de referencia basados en el contexto genético de la actividad enzimática de la colinesterasa en una población colombiana: un paso hacia el diagnóstico personalizado

Introduction: The determination of cholinesterase (ChE) activity has been commonly applied in the biomonitoring of exposure to organophosphate and carbamate pesticides. However, ChE activity is influenced by genetic factors. Integrating genotype and phenotype information in clinical laboratory tests would increase the accuracy of the reference values in well-defined populations. Objective: To establish genetic-based reference values for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity in a Colombian population. Materials and methods: A total of 397 healthy adults from Bucaramanga were included in the study. AChE and BChE activities were measured in blood samples by potentiometry and spectrophotometry, respectively. Genotyping for ACHE rs17880573 and BCHE rs1803274 was performed using the TaqMan allelic discrimination assay. The statistical analyses to obtain the reference values were performed with the MedCalc® software. Results: Allele frequencies were 10.58% for rs17880573 A and 8.82% for rs1803274 A. People with genotypes rs1803274 AA and AG showed a reduction of 20.69% and 10.92% respectively in mean BChE activity compared to people with genotype GG. No significant differences were identified in AChE activity between rs17880573 alleles or genotypes. In the overall sample, the corresponding reference values were as follows: for AChE activity, 0.62-0.98 D pH/h and for BChE activity, 4796.3-10321.1 U/L for people carrying the allele rs1803274A and 5768.2-11180.4 U/L for people carrying the genotype rs1803274 GG. Conclusion: We strongly recommend using these genetic-based reference values for ChE enzymes in our well-defined population in daily clinical practice.

Introducción. La determinación de la actividad enzimática de la colinesterasa se utiliza comúnmente en la vigilancia biológica de la exposición a pesticidas organofosforados y carbamatos. Sin embargo, los factores genéticos afectan la actividad de la colinesterasa, por lo que la integración de la información sobre genotipos y fenotipos en las pruebas de laboratorio clínico, incrementaría la precisión de los valores de referencia. Objetivo. Establecer los valores de referencia basados en el contexto genético para la actividad enzimática de la acetilcolinesterasa (AChE) y la butirilcolinesterasa (BChE), en una población colombiana. Materiales y métodos. Se incluyeron 397 adultos sanos. La actividad de la acetilcolinesterasa y la de la butirilcolinesterasa, se determinaron en muestras de sangre por potenciometría y espectrofotometría, respectivamente. Los genotipos de los ACHE rs17880573 y BCHE rs1803274 se obtuvieron mediante el ensayo TaqMan y los valores de referencia se estimaron con el programa MedCalc®. Resultados. La frecuencia alélica fue de 10,58 % para rs17880573 A y de 8,82 % para rs1803274 A. Las personas con los genotipos rs1803274 AA y AG, mostraron una reducción en el promedio de la actividad de la butirilcolinesterasa de 20,69 % y de 10,92 %, respectivamente, comparados con aquellas con el genotipo GG. No se encontraron diferencias significativas en la actividad de la acetilcolinesterasa con respecto a los alelos y genotipos del rs17880573. Los valores de referencia determinados para esta población fueron de 0,62-0,98 D pH/h para acetilcolinesterasa y de 4796,3-10321,1 U/L para butirilcolinesterasa, en las personas portadoras del alelo rs1803274 A, y de 5768,2-11180,4 U/L, en las portadoras del genotipo rs1803274 GG. Conclusión. Se recomienda el uso de estos valores de referencia basados en el contexto genético para las colinesterasas, en la práctica clínica diaria en esta población.

Research progress in antidotes of nerve agents in the USA / 军事医学

Nerve agent not only inhibit acetylcholinesterase ( AChE) at an early stage, but also induce prolonged and progressive neuroinflammation and delayed neurodegeneration.Recently, the US National Institute of Health ( NIH) has sponsored some major programs of toxic mechanisms and treatment of nerve agents, which aims at the development of quick and effective treatment to acute intoxication and delayed effect.The experimentally effective new antidotes mainly include AChE-targeting drugs, broad-spectrum reactivators and scavengers, antiinflamatory and nerve protection drugs.

Neurotoxicología de plaguicidas prevalentes en la región Andina Colombiana / Neurotoxicology of prevalent pesticides in Colombian Andean region

Introducción: según la Organización Mundial de la Salud, hay tres millones de casos al año por intoxicaciones con plaguicidas, de estas, una décima parte son letales. La mayoría de estas intoxicaciones ocurren en países del tercer mundo, a pesar que menos de un quinto de los plaguicidas disponibles son usados en estas regiones. Objetivo: describir la sintomatología clínica de las intoxicaciones por plaguicidas neurotóxicos prevalentes en la región Andina colombiana. Materiales y Métodos: se realizó una búsqueda sistemática en bases de datos como Medline (PubMed), Scielo y Latindex desde marzo a diciembre de 2013. Debido al objetivo de la presente revisión, los descriptores estrictamente utilizados fueron: mancozeb, profanofos, carbofurán, cymoxanil y parathion. La búsqueda obtenida comprendió aproximadamente 700 artículos, de los cuales fueron seleccionados 72 de acuerdo a los criterios de inclusión previamente definidos. Resultados: los efectos más prevalentes inducidos por los pesticidas estudiados son alteraciones en la salivación, lagrimeo, trastornos de la micción y la defecación, emesis, broncorrea, broncoespasmo, bradicardia, etc. Sin embargo, según el pesticida, existen implicaciones particulares ya sea de tipo endocrino, inmunológico o neoplásico. Conclusión: las manifestaciones clínicas de la toxicidad aguda se dan por un exceso de estimulación colinérgica, sin embargo es relevante continuar investigando la fisiopatología molecular de su intoxicación. MÉD.UIS. 2014;27(3):57-67.

Introduction: according to the World Health Organization, there are three million cases per year related to pesticide poisoning, of these, one-tenth are lethal. Most of these poisonings occur in third-world countries, even when there are less than a fifth of them available in these regions. Objective: to describe clinical symptoms of poisoning caused by prevalent neurotoxic pesticides in Colombian Andes. Materials and Methods: a systematic review was performed in databases such as Medline (PubMed), SciELO and Latindex from March to December 2013. Descriptors used were mancozeb, profanofos, carbofuran, parathion and cymoxanil. The review obtained 700 articles from which 72 were selected according to the inclusion criteria previously defined. Results: the effects induced by these pesticides are changes in salivation, lacrimation, abnormal urination and defecation, emesis, broncorrea, bronchospasm, bradycardia, etc. However, according to the pesticide, there are particular implications either endocrine, immune or neoplastic. Conclusion: clinical manifestations of acute toxicity occur by excessive cholinergic stimulation. However, it is important to continue researching the molecular pathophysiology of this kind of intoxications. MÉD.UIS. 2014;27(3):57-67.

Prevalencia de signos y síntomas asociados a la exposición directa a plaguicidas neurotóxicos en una población rural colombiana en 2013 / Prevalence of signs and symptoms associated with direct exposition to neurotoxic plaguicides in a Colombian rural population in 2013

Introducción: los plaguicidas son agentes tóxicos para la salud humana. En el año 2000, Colombia era el país latinoamericano con la mayor prevalencia de intoxicaciones por pesticidas. Samacá es uno de los municipios caracterizados por su alta producción agrícola, en donde se desconoce la correlación entre la exposición directa a plaguicidas neurotóxicos y la presencia de sintomatología específica. Objetivo: determinar la presencia de sintomatología neurológica compatible con la exposición a plaguicidas usados en los cultivos de Samacá, Boyacá. Materiales y Métodos: estudio observacional analítico de corte transversal con muestreo por conveniencia de casos consecutivos. Como muestra se encuestaron 49 habitantes, por medio de un instrumento de evaluación toxicológica. Se realizó la descripción de variables sociodemográficas y clínicas de la población. Para la determinación de la asociación entre plaguicidas y síntomas, se usaron razones de prevalencia con un IC del 95%. Resultados: el 38,77% de la población encuestada reportó exposición directa a plaguicidas neurotóxicos. Se encontraron razones de prevalencia que proponían asociación para irritabilidad (RP 1,78 IC 95% 1,13-2,83; p=0,01), vértigo (RP 2,28 IC 95% 1,07-4,86; p=0,02), fosfenos (RP 2,61 IC 95% 1,03-6,64; p=0,03), epistaxis (RP 2,90 IC 95% 1,01-8,34; p=0,03), fasciculaciones, (RP 8,70 IC 95% 1,13-66,94; p=0,01) y en general por sistemas, para órganos de los sentidos (RP 1,45 IC 95% 1,05-2,00; p=0,03). Conclusiones: la irritabilidad, el vértigo, los fosfenos y los episodios de epistaxis están asociados a la exposición directa a plaguicidas neurotóxicos. Se hace necesaria una nueva visita para completar la muestra y futuros estudios que permitan ampliar el panorama neurotoxicológico colombiano. (MÉD.UIS. 2014;27(2):41-49).

Background: pesticides are toxic agents to humans. In 2000, Colombia was the Latin American country with the highest prevalence of pesticide poisoning. Samacá is one of the municipalities characterized by high agricultural production, where there is no known association between direct exposure to neurotoxic pesticides and the presence of specific symptoms. Objective: to determine the presence of neurological symptoms compatible with exposure to pesticides commonly used on crops among the inhabitants of Samacá, Boyacá. Materials and Methods: observational cross-sectional analytical study with nonrandom sampling of consecutive cases. Preliminary sample included 49 individuals, who were surveyed using a toxicological assessment tool. It was described all sociodemographic and clinical variables of the population. For the study of the association between pesticides and symptoms, prevalence ratios were used with CI 95%. Results: 38.77% reported direct exposure to neurotoxic pesticides. Prevalence ratios found association for irritability (OR 1.78 95% CI 1.13 to 2.83; p=0.01), dizziness (OR 2.28 95% CI 1.07 to 4.86; p=0.02), phosphenes (RP 2.61 95 % 1.03 to 6.64; p=0.03), epistaxis (OR 2.90 95% CI 1.01 to 8.34; p=0.03), fasciculations, (RP 8.70 IC95% 1.13-66.94; p=0.01), and special senses symptoms (OR 1.45 95% CI 1.05 to 2.00; p=0.03). Conclusions: Irritability, vertigo, phosphenes and episodes of epistaxis are associated with direct exposure to neurotoxic pesticides. It is necessary a new visit to complete the sample, and future studies to expand the neurotoxicological situation. (MÉD.UIS. 2014;27(2):41-49).