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Changing customer requirements, regulations, technology and regulations, shift to automated assembly and product variety are common challenges faced by many manufacturing industries and alignment between product and production system is critical for business success. Design engineers should be aware of production constraints and capabilities to ensure efficient manufacture and assembly of products that are developed. This requires different and detailed support to guide the work, evaluate different design solutions, enable continuous and concurrent work with design for producibility and production preparation. A study was conducted in three companies to understand alignment and integration of product development and production preparation processes. Also, utilization of production requirements, design for manufacture and assembly (DFMA) and failure modes and effect analysis (FMEA) to support design for producibility (DFP) was studied. Currently, production preparation is done through discussions between design and production engineers. Production preparation and work with DFMA and FMEA is skill and experience dependent. Definition, structuring and sharing of production requirements on different system levels, from production and product perspectives are identified as critical to supporting design for producibility and production preparation. The work with FMEA and DFMA can be developed and improved with systematic and structured way of working with production requirements.

Preclinical efforts to improve medical countermeasures against organophosphate (OP) chemical threat agents have largely focused on adult male models. However, age and sex have been shown to influence the neurotoxicity of repeated low-level OP exposure. Therefore, to determine the influence of sex and age on outcomes associated with acute OP intoxication, postnatal day 28 Sprague-Dawley male and female rats were exposed to the OP diisopropylfluorophosphate (DFP; 3.4 mg/kg, s.c.) or an equal volume of vehicle (∼80 µL saline, s.c.) followed by atropine sulfate (0.1 mg/kg, i.m.) and pralidoxime (2-PAM; 25 mg/kg, i.m.). Seizure activity was assessed during the first 4 h post-exposure using behavioral criteria and electroencephalographic (EEG) recordings. At 1 d post-exposure, acetylcholinesterase (AChE) activity was measured in cortical tissue, and at 1, 7, and 28 d post-exposure, brains were collected for neuropathologic analyses. At 1 month post-DFP, animals were analyzed for motor ability, learning and memory, and hippocampal neurogenesis. Acute DFP intoxication triggered more severe seizure behavior in males than females, which was supported by EEG recordings. DFP caused significant neurodegeneration and persistent microglial activation in numerous brain regions of both sexes, but astrogliosis occurred earlier and was more severe in males compared to females. DFP males and females exhibited pronounced memory deficits relative to sex-matched controls. In contrast, acute DFP intoxication altered hippocampal neurogenesis in males, but not females. These findings demonstrate that acute DFP intoxication triggers seizures in juvenile rats of both sexes, but the seizure severity varies by sex. Some, but not all, chronic neurotoxic outcomes also varied by sex. The spatiotemporal patterns of neurological damage suggest that microglial activation may be a more important factor than astrogliosis or altered neurogenesis in the pathogenesis of c

Preclinical efforts to improve medical countermeasures against organophosphate (OP) chemical threat agents have largely focused on adult male models. However, age and sex have been shown to influence the neurotoxicity of repeated low-level OP exposure. Therefore, to determine the influence of sex and age on outcomes associated with acute OP intoxication, postnatal day 28 Sprague-Dawley male and female rats were exposed to the OP diisopropylfluorophosphate (DFP; 3.4 mg/kg, s.c.) or an equal volume of vehicle (∼80 µL saline, s.c.) followed by atropine sulfate (0.1 mg/kg, i.m.) and pralidoxime (2-PAM; 25 mg/kg, i.m.). Seizure activity was assessed during the first 4 h post-exposure using behavioral criteria and electroencephalographic (EEG) recordings. At 1 d post-exposure, acetylcholinesterase (AChE) activity was measured in cortical tissue, and at 1, 7, and 28 d post-exposure, brains were collected for neuropathologic analyses. At 1 month post-DFP, animals were analyzed for motor ability, learning and memory, and hippocampal neurogenesis. Acute DFP intoxication triggered more severe seizure behavior in males than females, which was supported by EEG recordings. DFP caused significant neurodegeneration and persistent microglial activation in numerous brain regions of both sexes, but astrogliosis occurred earlier and was more severe in males compared to females. DFP males and females exhibited pronounced memory deficits relative to sex-matched controls. In contrast, acute DFP intoxication altered hippocampal neurogenesis in males, but not females. These findings demonstrate that acute DFP intoxication triggers seizures in juvenile rats of both sexes, but the seizure severity varies by sex. Some, but not all, chronic neurotoxic outcomes also varied by sex. The spatiotemporal patterns of neurological damage suggest that microglial activation may be a more important factor than astrogliosis or altered neurogenesis in the pathogenesis of c

Preclinical efforts to improve medical countermeasures against organophosphate (OP) chemical threat agents have largely focused on adult male models. However, age and sex have been shown to influence the neurotoxicity of repeated low-level OP exposure. Therefore, to determine the influence of sex and age on outcomes associated with acute OP intoxication, postnatal day 28 Sprague-Dawley male and female rats were exposed to the OP diisopropylfluorophosphate (DFP; 3.4 mg/kg, s.c.) or an equal volume of vehicle (∼80 µL saline, s.c.) followed by atropine sulfate (0.1 mg/kg, i.m.) and pralidoxime (2-PAM; 25 mg/kg, i.m.). Seizure activity was assessed during the first 4 h post-exposure using behavioral criteria and electroencephalographic (EEG) recordings. At 1 d post-exposure, acetylcholinesterase (AChE) activity was measured in cortical tissue, and at 1, 7, and 28 d post-exposure, brains were collected for neuropathologic analyses. At 1 month post-DFP, animals were analyzed for motor ability, learning and memory, and hippocampal neurogenesis. Acute DFP intoxication triggered more severe seizure behavior in males than females, which was supported by EEG recordings. DFP caused significant neurodegeneration and persistent microglial activation in numerous brain regions of both sexes, but astrogliosis occurred earlier and was more severe in males compared to females. DFP males and females exhibited pronounced memory deficits relative to sex-matched controls. In contrast, acute DFP intoxication altered hippocampal neurogenesis in males, but not females. These findings demonstrate that acute DFP intoxication triggers seizures in juvenile rats of both sexes, but the seizure severity varies by sex. Some, but not all, chronic neurotoxic outcomes also varied by sex. The spatiotemporal patterns of neurological damage suggest that microglial activation may be a more important factor than astrogliosis or altered neurogenesis in the pathogenesis of c

Approximately 33% of U.S. soldiers from the first Gulf War suffer from a multi-system disorder known as the Gulf War Illness (GWI). GW veterans suffer from a cluster of symptoms that prominently include fatigue and can include mood-related symptoms. Compared to traditional antidepressants, ketamine (KET) produces a fast-onset and long-lasting antidepressant response, but assessments of KET for GWI-related depression are lacking. The etiology of GWI is multi-factorial and exposure to organophosphates (OP) during deployment is one of the factors underlying GWI development. Here, male Sprague-Dawley rats were repeatedly exposed to an OP DFP and three months later these rats, when assessed on a battery of rodent behavioral assays, displayed signs consistent with aspects of GWI characteristics. When treated with a sub-anesthetic dose of KET (3, 5, or 10 mg/kg, i.p.), DFP-treated rats exhibited a significant improvement in immobility time, open-arm exploration, and sucrose consumption as early as 1 h and much of these effects persisted at 24-h post-KET injection. KET’s stereoisomers, R-KET and S-KET, also exhibited such effects in DFP rats, with R-KET being the more potent isomer. Our studies provide a starting point for further assessment of KET for GWI depression.

Approximately 33% of U.S. soldiers from the first Gulf War suffer from a multi-system disorder known as the Gulf War Illness (GWI). GW veterans suffer from a cluster of symptoms that prominently include fatigue and can include mood-related symptoms. Compared to traditional antidepressants, ketamine (KET) produces a fast-onset and long-lasting antidepressant response, but assessments of KET for GWI-related depression are lacking. The etiology of GWI is multi-factorial and exposure to organophosphates (OP) during deployment is one of the factors underlying GWI development. Here, male Sprague-Dawley rats were repeatedly exposed to an OP DFP and three months later these rats, when assessed on a battery of rodent behavioral assays, displayed signs consistent with aspects of GWI characteristics. When treated with a sub-anesthetic dose of KET (3, 5, or 10 mg/kg, i.p.), DFP-treated rats exhibited a significant improvement in immobility time, open-arm exploration, and sucrose consumption as early as 1 h and much of these effects persisted at 24-h post-KET injection. KET’s stereoisomers, R-KET and S-KET, also exhibited such effects in DFP rats, with R-KET being the more potent isomer. Our studies provide a starting point for further assessment of KET for GWI depression.

Approximately 33% of U.S. soldiers from the first Gulf War suffer from a multi-system disorder known as the Gulf War Illness (GWI). GW veterans suffer from a cluster of symptoms that prominently include fatigue and can include mood-related symptoms. Compared to traditional antidepressants, ketamine (KET) produces a fast-onset and long-lasting antidepressant response, but assessments of KET for GWI-related depression are lacking. The etiology of GWI is multi-factorial and exposure to organophosphates (OP) during deployment is one of the factors underlying GWI development. Here, male Sprague-Dawley rats were repeatedly exposed to an OP DFP and three months later these rats, when assessed on a battery of rodent behavioral assays, displayed signs consistent with aspects of GWI characteristics. When treated with a sub-anesthetic dose of KET (3, 5, or 10 mg/kg, i.p.), DFP-treated rats exhibited a significant improvement in immobility time, open-arm exploration, and sucrose consumption as early as 1 h and much of these effects persisted at 24-h post-KET injection. KET’s stereoisomers, R-KET and S-KET, also exhibited such effects in DFP rats, with R-KET being the more potent isomer. Our studies provide a starting point for further assessment of KET for GWI depression.

Approximately 33% of U.S. soldiers from the first Gulf War suffer from a multi-system disorder known as the Gulf War Illness (GWI). GW veterans suffer from a cluster of symptoms that prominently include fatigue and can include mood-related symptoms. Compared to traditional antidepressants, ketamine (KET) produces a fast-onset and long-lasting antidepressant response, but assessments of KET for GWI-related depression are lacking. The etiology of GWI is multi-factorial and exposure to organophosphates (OP) during deployment is one of the factors underlying GWI development. Here, male Sprague-Dawley rats were repeatedly exposed to an OP DFP and three months later these rats, when assessed on a battery of rodent behavioral assays, displayed signs consistent with aspects of GWI characteristics. When treated with a sub-anesthetic dose of KET (3, 5, or 10 mg/kg, i.p.), DFP-treated rats exhibited a significant improvement in immobility time, open-arm exploration, and sucrose consumption as early as 1 h and much of these effects persisted at 24-h post-KET injection. KET’s stereoisomers, R-KET and S-KET, also exhibited such effects in DFP rats, with R-KET being the more potent isomer. Our studies provide a starting point for further assessment of KET for GWI depression.

Organophosphates (OPs), a class of phosphorus-containing chemicals that act by disrupting cholinergic transmission, include both toxic and fast-acting chemical warfare agents as well as less toxic but more easily accessible OP pesticides. The classical atropine/2-PAM antidote fails to protect against long-term symptoms following acute intoxication with OPs at levels that trigger status epilepticus. Acute OP intoxication also causes a robust neuroinflammatory response, which is implicated in the pathogenesis of long-term effects. In this study, we characterized the profiles of lipid mediators, important players in neuroinflammation, in the rat model of acute DFP intoxication. The profiles of lipid mediators were monitored in three different regions of the brain (cortex, hippocampus, and cerebellum) at 0, 1, 3, 7, 14, and 28 days post-exposure. The distribution pattern of lipid mediators was distinct in the three brain regions. In the cerebellum, the profile is dominated by LOX metabolites, while the lipid mediator profiles in cortex and hippocampus are dominated by COX metabolites followed by LOX and CYP 450 metabolites. Following acute DFP intoxication, most of the pro-inflammatory lipid mediators (e.g., PGD2 and PGE2) increased rapidly from day 1, while the concentrations of some anti-inflammatory lipid mediators (e.g. 14,15 EpETrE) decreased after DFP intoxication but recovered by day 14 post-exposure. The lipidomics results suggest two potential treatment targets: blocking the formation of prostaglandins by inhibiting COX and stabilizing the anti-inflammatory lipid mediators containing epoxides by inhibiting the enzyme soluble epoxide hydrolase (sEH).

Organophosphates (OPs), a class of phosphorus-containing chemicals that act by disrupting cholinergic transmission, include both toxic and fast-acting chemical warfare agents as well as less toxic but more easily accessible OP pesticides. The classical atropine/2-PAM antidote fails to protect against long-term symptoms following acute intoxication with OPs at levels that trigger status epilepticus. Acute OP intoxication also causes a robust neuroinflammatory response, which is implicated in the pathogenesis of long-term effects. In this study, we characterized the profiles of lipid mediators, important players in neuroinflammation, in the rat model of acute DFP intoxication. The profiles of lipid mediators were monitored in three different regions of the brain (cortex, hippocampus, and cerebellum) at 0, 1, 3, 7, 14, and 28 days post-exposure. The distribution pattern of lipid mediators was distinct in the three brain regions. In the cerebellum, the profile is dominated by LOX metabolites, while the lipid mediator profiles in cortex and hippocampus are dominated by COX metabolites followed by LOX and CYP 450 metabolites. Following acute DFP intoxication, most of the pro-inflammatory lipid mediators (e.g., PGD2 and PGE2) increased rapidly from day 1, while the concentrations of some anti-inflammatory lipid mediators (e.g. 14,15 EpETrE) decreased after DFP intoxication but recovered by day 14 post-exposure. The lipidomics results suggest two potential treatment targets: blocking the formation of prostaglandins by inhibiting COX and stabilizing the anti-inflammatory lipid mediators containing epoxides by inhibiting the enzyme soluble epoxide hydrolase (sEH).

Organophosphates (OPs), a class of phosphorus-containing chemicals that act by disrupting cholinergic transmission, include both toxic and fast-acting chemical warfare agents as well as less toxic but more easily accessible OP pesticides. The classical atropine/2-PAM antidote fails to protect against long-term symptoms following acute intoxication with OPs at levels that trigger status epilepticus. Acute OP intoxication also causes a robust neuroinflammatory response, which is implicated in the pathogenesis of long-term effects. In this study, we characterized the profiles of lipid mediators, important players in neuroinflammation, in the rat model of acute DFP intoxication. The profiles of lipid mediators were monitored in three different regions of the brain (cortex, hippocampus, and cerebellum) at 0, 1, 3, 7, 14, and 28 days post-exposure. The distribution pattern of lipid mediators was distinct in the three brain regions. In the cerebellum, the profile is dominated by LOX metabolites, while the lipid mediator profiles in cortex and hippocampus are dominated by COX metabolites followed by LOX and CYP 450 metabolites. Following acute DFP intoxication, most of the pro-inflammatory lipid mediators (e.g., PGD2 and PGE2) increased rapidly from day 1, while the concentrations of some anti-inflammatory lipid mediators (e.g. 14,15 EpETrE) decreased after DFP intoxication but recovered by day 14 post-exposure. The lipidomics results suggest two potential treatment targets: blocking the formation of prostaglandins by inhibiting COX and stabilizing the anti-inflammatory lipid mediators containing epoxides by inhibiting the enzyme soluble epoxide hydrolase (sEH).

Green Health herbal mixture is a pharmacological pure herb product of Green Healthcare Limited, Aboha, Ohii, Imo State, Nigeria, approved by National Agency for Food and Drug Administration and Control (NAFDAC) used orally and topically in the treatment of muscular ache/pain, scalp, warts, inflammation, skin infection due to bacteria/fungi, and lumps and to relieve high fever. However, its oral lethal dose is yet to be reported. Thus, this work was aimed at assessing its oral acute toxicity in wistar albino rats. The results of phase one and phase two of the study showed no mortality in any of the groups of rats in 24 hours, 72 hours and up to two weeks after oral administration of 5000 mg per kg body weight (b.w) of the herbal mixture, but the histology (photomicrograph) of the liver sections revealed multiple dose-dependent necrosis, histological lesions, and abnormal sinusoids. Therefore, oral intake of the herbal mixture at dose less than or equal to 5000 mg/kg b.w. is safe, but may not be advisable, having noted its deleterious effects on the hepatocytes via the photomicrograph (H and E 400). That is oral LD 50 > 5000 mg/kg b.w. Hence, topical usage is recommended.

Green Health herbal mixture is a pharmacological pure herb product of Green Healthcare Limited, Aboha, Ohii, Imo State, Nigeria, approved by National Agency for Food and Drug Administration and Control (NAFDAC) used orally and topically in the treatment of muscular ache/pain, scalp, warts, inflammation, skin infection due to bacteria/fungi, and lumps and to relieve high fever. However, its oral lethal dose is yet to be reported. Thus, this work was aimed at assessing its oral acute toxicity in wistar albino rats. The results of phase one and phase two of the study showed no mortality in any of the groups of rats in 24 hours, 72 hours and up to two weeks after oral administration of 5000 mg per kg body weight (b.w) of the herbal mixture, but the histology (photomicrograph) of the liver sections revealed multiple dose-dependent necrosis, histological lesions, and abnormal sinusoids. Therefore, oral intake of the herbal mixture at dose less than or equal to 5000 mg/kg b.w. is safe, but may not be advisable, having noted its deleterious effects on the hepatocytes via the photomicrograph (H and E 400). That is oral LD 50 > 5000 mg/kg b.w. Hence, topical usage is recommended.

Green Health herbal mixture is a pharmacological pure herb product of Green Healthcare Limited, Aboha, Ohii, Imo State, Nigeria, approved by National Agency for Food and Drug Administration and Control (NAFDAC) used orally and topically in the treatment of muscular ache/pain, scalp, warts, inflammation, skin infection due to bacteria/fungi, and lumps and to relieve high fever. However, its oral lethal dose is yet to be reported. Thus, this work was aimed at assessing its oral acute toxicity in wistar albino rats. The results of phase one and phase two of the study showed no mortality in any of the groups of rats in 24 hours, 72 hours and up to two weeks after oral administration of 5000 mg per kg body weight (b.w) of the herbal mixture, but the histology (photomicrograph) of the liver sections revealed multiple dose-dependent necrosis, histological lesions, and abnormal sinusoids. Therefore, oral intake of the herbal mixture at dose less than or equal to 5000 mg/kg b.w. is safe, but may not be advisable, having noted its deleterious effects on the hepatocytes via the photomicrograph (H and E 400). That is oral LD 50 > 5000 mg/kg b.w. Hence, topical usage is recommended.

[EN] Gold nanoparticles functionalized with a triarylcarbinol derivative have been used as colorimetric molecular probes for the naked-eye detection of the nerve agent simulants DCNP and DFP. The detection process is based on the compensation of charges at the surface of the nanoparticles which triggers their aggregation in solution with the resulting change in their plasmon band. (C) 2014 Elsevier Ltd. All rights reserved.

[EN] Gold nanoparticles functionalized with a triarylcarbinol derivative have been used as colorimetric molecular probes for the naked-eye detection of the nerve agent simulants DCNP and DFP. The detection process is based on the compensation of charges at the surface of the nanoparticles which triggers their aggregation in solution with the resulting change in their plasmon band. (C) 2014 Elsevier Ltd. All rights reserved.

Organophosphate (OP) poisoning can result in status epilepticus (SE), a medical emergency which can become pharmacoresistant if treatment is delayed. Little to no data exists on pediatric models of OP-induced SE, even though the immature brain is likely to respond differently to OPs, and the optimal therapies are also likely to differ from adults. Our aim is to identify novel drugs that block pharmacoresistant OP-induced SE in children. In the past year, we have provided USAMRICD investigators with the miniature telemetry devices and recording apparatus for recording from P7 and P14 rats. We have developed rat models for DPF exposure for ages P7, P14, P21, and P28. We have found that P7 and P14 rat pups have brief (minutes) seizure behavior in response to DFP, while P21 and P28 animals develop SE which is robust and lasts for several hours. We see extensive neuronal injury in P28 rats using Fluoro-Jade B as a marker. We have developed an electrographic profile for the EEG activity of DFP-treated P21 and P28 animals, and are working on profiles for P7 and P14 DFP-treated rat pups. We have begun characterizing the effects of midazolam on DFP-induced SE in P21 and P28 rat pups, and we find that midazolam ameliorates the SE triggered by the organophosphate., The original document contains color images.

The photocatalytic decomposition of diisopropylfluorophosphate (DFP) over nanostructured anatase and rutile TiO2 powder was investigated by FTIR and XPS. Upon irradiation with artificial solar light DFP decomposed on both polymorphs as evidenced by FTIR. For both crystalline structures acetone and subsequently coordinated formate and carbonate were observed on the surface during the photocatalytic reaction is the isopropyl groups dissociated from DFP. XPS revealed that small amounts of phosphates and inorganic fluoride (Ti-F) gradually built up on both TiO2 surfaces, while organic F was present only on the rutile phase. From repeated cycles of intermittent DFP adsorption and irradiation measurements, the decomposition rates and formation of residuals on the surface were deduced. It was found that the overall oxidation yield is higher on anatase than rutile. The oxidation rate decreases with increasing irradiation time. an effect that is more pronounced on rutile. We find that both the difference between the polymorphs and the initial decrease of the oxidation yield can largely be explained by variations in surface area rather than poisoning by POx or F species. In particular, we observe a dramatic decrease of the specific area or rutile as a function of photocatalytic oxidation cycle. (c) 2005 Elsevier B.V. All rights reserved.

The photocatalytic decomposition of diisopropylfluorophosphate (DFP) over nanostructured anatase and rutile TiO2 powder was investigated by FTIR and XPS. Upon irradiation with artificial solar light DFP decomposed on both polymorphs as evidenced by FTIR. For both crystalline structures acetone and subsequently coordinated formate and carbonate were observed on the surface during the photocatalytic reaction as the isopropyl groups dissociated from DFP. XPS revealed that small amounts of phosphates and inorganic fluoride (TiF) gradually built up on both TiO2 surfaces, while organic F was present only on the rutile phase. From repeated cycles of intermittent DFP adsorption and irradiation measurements, the decomposition rates and formation of residuals on the surface were deduced. It was found that the overall oxidation yield is higher on anatase than rutile. The oxidation rate decreases with increasing irradiation time, an effect that is more pronounced on rutile. We find that both the difference between the polymorphs and the initial decrease of the oxidation yield can largely be explained by variations in surface area rather than poisoning by POx or F species. In particular, we observe a dramatic decrease of the specific area of rutile as a function of photocatalytic oxidation cycle.

The use of large volume injections has been studied for the verification of intact organophosphorus chemical warfare agents in water samples. As the use of ethyl acetate caused severe detection problems new potential solvents were evaluated. With the developed procedure, the nerve agents sarin, tabun, soman, DFP and VX can be determined in freshly prepared water samples at ppt levels. Except for the nerve agent tabun all other agents added to the water samples were still present after 8 days at 20-60% levels, if the pH of the water sample is adjusted to ca. 5 shortly after sampling and adjusted to pH 7 for analysis.

The objective of this research is to investigate feasibility of immobilizing squid-type DFPase on fabrics such as nylon, polyester, cotton and polyester-cotton blends and on polyethylene glycol. Large quantities (about 15, 000 units) on of the enzyme was prepared from the hepatopancreas tissues of East Coast (ECHP) and West Coast (WCHP) squid belonging to the species, Loligo Pealii and Loligo Opalescens. The purified enzyme preparations were characterized by their activities against diisopropylphosphorofluoridate (DFP), isopropylmethylphosphonofluoridate (SARIN) and pinacolylmethyl phosphonofluoridate (SOMAN) and their kinetic constants (KM and VMAX). The enzyme-immobilization study included the exploration of different preactivation methods involving treatment with (1) glutaraldehyde, (2) triethyloxoniumtetrafluoroborate (TTFB), (3) tresylchloride, (4) isocyanide, (5) cyanuric chloride and (6) KMnO4-oxidation. Results of examination of the DFPase- immobilized matrices showed agent-specific activities (DFP, SOMAN and SARIN) in the range 3.5 to 17.7 units/gram. A number of them retained up to 90% of their initial enzyme activity over a 90-day period. This is indicative of a good potential for this technical approach squid-type DFPase.