Organophosphates and their impact on the global environment

Serious intoxications and incidences due to misuse of organophosphorus insecticides (OP) have been reported for over three decades. In this meeting I am talking about the following three topics. (1) Epidemiological studies on the use of OP in Japan, Taiwan and Thailand. The National Research Institute of Police Science (NRIPS) in Japan has published the annual report of the epidemiological studies on the criminal and suicide events. The numbers of the incidence of pesticides are approximately 22%-30% of the total incidences, during 1991 and 1996. The incidence of pesticides has been gradually reduced for past six years. This seems to be influenced by the decrease of the incidences of paraquat having extremely high toxicity. According to the epidemiological data in the National Poison Center in Taiwan, unlike the prevalence of drug poisoning exposures in most western countries, pesticides poisoning exposures are numerous in Taiwan. The number of pesticide intoxication cases is 6,872 out of 23,436 of total case numbers of various intoxications during the 1985 and 1997. The fatality rate is much higher in Taiwan than in most western countries, with 5.65% of all poisoning exposures resulted in death. Paraquot is the leading cause of death in Taiwan. The ratio of death to total OP intoxication cases is 11.5% including accidental exposure and suicide. According to the report of the Division of Epidemiology, Ministry of Public Health, Thailand during the 1990-1995, the overall morbidity due to poisoning was 30 per 100,000 population with 300 deaths per year. The morbidity rate of reported pesticide poisoning in the whole country was 10 per 100,000 population. (2) Sarin victims in Tokyo. On March 20, 1995, a terrorist attack using sarin (isopropylmethylphosphonofluoridate) occurred on the Tokyo subway. Many people inhaled the sarin gas and collapsed in the train. Eventually, 12 people died and over 5,000 were injured. The results of the forensic studies showed that methylphosphonic acid, the hydrolysis product of sarin, bound to AChE in the cerebellums of the victims was separated and identified using GCMS. (3) A sensitive and rapid biomarker of OP-poisoning. Beta-glucuronidase (beta-G) is loosely bound to egasyn which is one of carboxylesterase isozymes in the liver microsomes. The oxon formed from OP in the liver microsomes is covalently bound to egasyn and causes the cleavage of the egasyn-glucuronidase complex, leading to the release of beta-G into the blood. In fact, plasma beta-G activities is a much more sensitive and rapid biomarker than the blood cholinesterase inhibition. In conclusion, OPs cause serious toxicity in both acute and chronic exposures. The epidemiological data in Taiwan and Thailand show that paraquat intoxication cause the most serious irreversible damage in the patients. In 1995, terrorists attack using sarin which is one of the most toxic OP, on the Tokyo subway, and 12 people died. This is an example of the acute intoxication of OP and some people have been still in hospitalized. Recently, the present authors have reported that the plasma beta-G activity is a novel biomarker of OP intoxication. The plasma beta-G is rapidly and significantly increased after OP exposure, and this is a much more sensitive to OP intoxication than ChE inhibition.     

A Young Patient with Microscopic Polyangiitis Requiring Hemodialysis with Complications of Repeated Episodes of Posterior Reversible Encephalopathy Syndrome Probably Due to Different Etiologies

A young woman with microscopic polyangiitis (MPA) requiring hemodialysis showed repeated posterior reversible encephalopathy syndrome (PRES) with spatiotemporal multiple lesions over a period of two months. The first PRES episode with confusion and the second PRES episode with vertigo and nausea were caused by MPA, hypertension and renal failure. These symptoms were improved by the reinforcement of MPA treatment and blood pressure management. The third PRES episode with nausea, headache, seizure and visual changes was induced by rituximab infusion and hypertension. The PRES was improved with blood pressure and convulsant management. These conditions are challenging to diagnose and treat.     

Hypoxia-induced fetoplacental vasoconstriction in perfused human placental cotyledons

Effects of maternal hypoxia on fetoplacental vascular resistance in the human placenta were investigated in an in vitro model in which single anatomic subunits (cotyledons) from term placentas were perfused at constant flow through both fetal and maternal circuits by means of a physiologic salt solution containing dextran. Acute reduction of oxygen tension in the maternal perfusate induced prompt fetoplacental vasoconstriction that recovered rapidly on restoration of oxygen to the perfusate. The response, hypoxic fetoplacental vasoconstriction, could be repeatedly demonstrated in the same cotyledon. The time course of hypoxic fetoplacental vasoconstriction was inversely related to oxygen tension of maternal arterial and maternal and fetal venous perfusates. Maternal and fetal venous perfusate pH and PCO2 did not change during the response. It is concluded that hypoxic fetoplacental vasoconstriction is triggered by decreased oxygen availability. It is suggested that hypoxic fetoplacental vasoconstriction may play a role in local regulation of human fetoplacental blood flow in vivo and may contribute to poor fetal prognosis in preeclampsia.     

Rhabdomyolysis Caused by Gefitinib Overdose

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are common therapeutic agents for EGFR mutation-positive advanced non-small-cell lung cancer. There has been no report of rhabdomyolysis caused by an overdose of EGFR-TKIs. We herein review the existing literature on the subject and report a rare case of rhabdomyolysis due to an overdose of gefitinib, an EGFR-TKI.     

Branched-Chain Fatty Acids Alter the Expression of Genes Responsible for Lipid Synthesis and Inflammation in Human Adipose Cells

Recently, we have demonstrated a decreased level of iso-branched-chain fatty acids (iso-BCFAs) in patients with excessive weight. However, it is still unclear whether BCFAs may influence lipid metabolism and inflammation in lipogenic tissues. To verify this, human visceral adipocytes were cultured with three different concentrations of selected iso-BCFA (14-methylpentadecanoic acid) and anteiso-BCFA (12-methyltetradecanoic acid), and then the expression of genes associated with lipid metabolism (FASN—fatty acid synthase; SREBP1—sterol regulatory element-binding protein 1; SCD1—stearoyl-CoA desaturase; ELOVL4—fatty acid elongase 4; ELOVL6—fatty acid elongase 6; FADS2—fatty acid desaturase 2; FADS1–fatty acid desaturase 1) and inflammation (COX-2—cyclooxygenase 2; ALOX-15—lipoxygenase 15; IL-6—interleukin 6) were determined. This study demonstrates for the first time that incubation with iso-BCFA decreases the expression of adipocyte genes that are associated with lipid metabolism (except FASN) and inflammation. These findings suggest that changes in the iso-BCFA profile in obese patients may contribute to adipose inflammation and dyslipidemia. Further studies should evaluate whether iso-BCFA supplementation in obese patients would be beneficial.     

Effects of Five Amino Acids (Serine,Alanine, Glutamate,Aspartate, and Tyrosine) on Mental Health in Healthy Office Workers: A Randomized,Double-Blind,Placebo-Controlled Exploratory Trial

Background: The importance of maintaining good mental health with overall well-being has recently drawn attention from various spheres of academics and the working population. Amino acid intake has been reported to reduce depression symptoms and other mental health problems. However, the effectiveness of amino acid intake (i.e., single or combined) remains unknown. In this study, we assessed a combination of five amino acids (serine, alanine, glutamate, aspartate, and tyrosine; SAGAT) reported to regulate mental health. Methods: A randomized, double-blind, placebo-controlled exploratory trial was conducted. Participants, aged between 20 and 65 years with fatigue sensation, were randomized to receive either SAGAT or the placebo and ingested them for four weeks. A transient mental work was loaded at day 0 and after four weeks of intervention. As the primary outcomes, the fatigue sensation was assessed. The mood status, cognitive function, work efficiency, and blood marker were also measured as secondary outcomes. Results: The number of participants analyzed for the efficacy evaluation were 20 in SAGAT and 22 in the placebo. There were no significant differences in the primary outcomes. However, as the secondary outcomes, the SAGAT group showed a significant improvement in motivation and cognitive function in the recovery period after mental work loaded in a four-week intervention compared to the placebo. Conclusion: The current findings suggest that SAGAT contributes to maintaining proper motivation and cognitive function. Clinical Trial Registration: University Hospital Medical Information Network Clinical Trial Registry (ID: UMIN 000041221).     

Determination of diagnostic threshold in harmonization and comparison of clinical utility for five major antiphospholipid antibody assays used in Japan

BackgroundAnticardiolipin antibodies (aCL) and anti‐β₂‐glycoprotein I antibodies (aβ₂GPI) are essential in diagnosing antiphospholipid syndrome (APS) according to the international APS guideline. Five commercial assays for aCL and aβ₂GPI are available in Japan, but their test results are quite discordant. For harmonization of diagnosing APS, upper reference limit (URL) and diagnostic accuracy of each assay were evaluated and compared by testing common sets of specimens across all assays.MethodsWe evaluated two manual and three automated assays for aCL and aβ₂GPI of IgG‐ and IgM classes. 99%URL (the upper limit of reference interval: as per guideline) together with 97.5%URL were determined by testing sera from 198 to 400 well‐defined healthy subjects. Both URLs were compared with the cutoff values, which were determined based on ROC analysis by testing 50 each of plasma specimens from patients with/without APS. Diagnostic accuracy was evaluated as area under curve (AUC) of the ROC curve.ResultsA variable degree of discrepancy between URLs and the cutoff values was observed, which was partly attributable to between‐year assay variability. 97.5%URLs were set lower and closer to the cutoff values than 99%URLs. For all assays, diagnostic accuracies of both aβ₂GPI‐IgG and aCL‐IgG were generally high (AUC: 0.84−0.93); whereas those for IgM‐class assays were low (AUC: 0.57−0.67), implicating its utility is limited to rare IgG negative APS cases.ConclusionTo ensure harmonized APS diagnosis, the diagnostic thresholds of the five assays were evaluated by common procedures. Contrary to the guideline, 97.5%URL is rather recommended for diagnosing APS, which showed a closer match to the cutoff value.     

Effect of Surface Tooling Techniques of Medical Titanium Implants on Bacterial Biofilm Formation In Vitro

The aim of this study was to assess the biofilm formation of Streptococcus mutans, Staphylococcus aureus, Enterococcus faecalis, and Escherichia coli on titanium implants with CAD-CAM tooling techniques. Twenty specimens of titanium were studied: Titanium grade 2 tooled with a Planmeca CAD-CAM milling device (TiGrade 2), Ti₆Al₄V grade 5 as it comes from CAD-DMLS device (computer aided design-direct metal laser sintering device) (TiGrade 5), Ti₆Al₄V grade 23 as it comes from a CAD-CAM milling device (TiGrade 23), and CAD-DMLS TiGrade 5 polished with an abrasive disc (TiGrade 5 polished). Bacterial adhesion on the implants was completed with and without saliva treatment to mimic both extraoral and intraoral surgical methods of implant placement. Five specimens/implant types were used in the bacterial adhesion experiments. Autoclaved implant specimens were placed in petri plates and immersed in saliva solution for 30 min at room temperature and then washed 3× with 1× PBS. Bacterial suspensions of each strain were made and added to the specimens after saliva treatment. Biofilm was allowed to form for 24 h at 37 °C and the adhered bacteria was calculated. Tooling techniques had an insignificant effect on the bacterial adhesion by all the bacterial strains studied. However, there was a significant difference in biofilm formation between the saliva-treated and non-saliva-treated implants. Saliva contamination enhanced S. mutans, S. aureus, and E. faecalis adhesion in all material types studied. S. aureus was found to be the most adherent strain in the saliva-treated group, whereas E. coli was the most adherent strain in the non-saliva-treated group. In conclusion, CAD-CAM tooling techniques have little effect on bacterial adhesion. Saliva coating enhances the biofilm formation; therefore, saliva contamination of the implant must be minimized during implant placement. Further extensive studies are needed to evaluate the effects of surface treatments of the titanium implant on soft tissue response and to prevent the factors causing implant infection and failure.