RESUMEN
PURPOSE: Mepirapim is a new synthetic cannabinoid. We previously reported that the concentrations of unchanged mepirapim in whole blood and urine were much higher than those of other synthetic cannabinoids. To determine the postmortem distribution of mepirapim and acetyl fentanyl in the deceased individual, we established a standard addition method for detailed analysis by liquid chromatography-mass spectrometry (LC-MS) for quantification of these drugs. METHODS: The LC-MS method was fully validated for linearity, extraction recovery, matrix effect and repeatability. RESULTS: Good linearities, extraction recoveries, matrix effects and repeatabilities were shown for both target compounds in all specimens. The concentrations of mepirapim and acetyl fentanyl in three body fluid specimens and 12 solid tissue specimens were measured. For mepirapim, the highest concentrations were found in the liver and kidney, and the concentrations in the blood and urine specimens were one order of magnitude lower than the high concentrations in the solid tissues except the psoas major muscle. For acetyl fentanyl, the highest concentrations were found in the myocardium, spleen and kidney, and the concentrations in the body fluid specimens were also one order of magnitude lower than the highest concentrations in the solid tissues. There were concentration differences of mepirapim and acetyl fentanyl among the regions of the brain. CONCLUSIONS: The concentration of unchanged mepirapim in urine was much higher than those of other synthetic cannabinoids; the higher dosage, urinary excretion, metabolisms and/or pharmacokinetics of mepirapim may be quite different from those of other synthetic cannabinoids.
RESUMEN
BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is described as a clinical-radiological disease entity with good prognosis. In brain MRI, PRES generally presents with vasogenic edema. Although PRES is induced by various causes, a small number of PRES cases have occurred after red cell blood transfusion. It is unclear whether there are characteristic features in PRES after blood transfusion. CASE PRESENTATION: Here, we report a case of 75-year-old Japanese woman who had acute exacerbation of subacute anemia by bleeding from gastric ulcer. After receiving a red cell blood transfusion, she showed disturbance of consciousness with extensive cytotoxic and small vasogenic edema in the occipitoparietal area on brain MRI. She was diagnosed as PRES and suffered irreversible impairments of visual acuity and fields in both eyes. We summarized and discussed clinical features of cases with PRES after blood transfusion. CONCLUSIONS: A total of 21 cases including the present one have been reported as PRES after blood transfusion. Of the cases, 20 of 21 were female, and 15 of 17 developed PRES in the course of chronic anemia lasting over 1 month. Anemia was severe in 15 of 20 cases, with hemoglobin levels < 3.5 g/dl. In 14 of 17 cases, hemoglobin levels increased to 5 g/dl by red cell blood transfusion until the onset of PRES. On brain MRI, 2 of 21 cases showed cytotoxic edema and 3 of 21 cases showed irreversible neurological disturbance. In this patient, the occurrence of PRES in subacute anemia and the presence of extensive cytotoxic brain edema with irreversible neurological deficits were characteristic points. When treating severe anemia, even with a subacute progression, we should consider a possibility that PRES occurs after blood transfusion with extensive cytotoxic brain edema and irreversible neurological changes.
Asunto(s)
Síndrome de Leucoencefalopatía Posterior/etiología , Reacción a la Transfusión/complicaciones , Anciano , Anemia/terapia , Edema Encefálico/etiología , Transfusión de Eritrocitos/efectos adversos , Femenino , Humanos , Imagen por Resonancia MagnéticaRESUMEN
PURPOSE: We encountered a curious case in which two male subjects self-administered mepirapim plus acetyl fentanyl by different routes, i.e., intravenously and by inhalation. We have thus established a detailed procedure for quantification of mepirapim and acetyl fentanyl in whole blood and urine specimens using gas chromatography (GC)-tandem mass spectrometry (MS/MS). METHODS: The GC-MS/MS method was validated for linearity, extraction recovery, accuracy, and precision. Liquid chromatography-MS/MS was also used for identification of the target compounds. RESULTS: Good linearity and reproducibility were achieved in the range of 20-1000 ng/g for both target compounds in both matrices. The concentrations of mepirapim in heart whole blood, femoral vein whole blood, and urine of the deceased individual with administration by intravenous injection were 593, 567, and 527 ng/g, respectively; those of acetyl fentanyl were 155, 125, and 126 ng/g, respectively. The mepirapim and acetyl fentanyl concentrations in the urine specimen of the surviving individual who had administered them by inhalation were 4900 and 570 ng/g, respectively. CONCLUSIONS: To our knowledge, with the exception of a brief mention of a mepirapim concentration in a serum sample in emergency medicine, there are no reported data on the identification and quantification of mepirapim in biological samples. Mepirapim is a new synthetic cannabinoid. The concentration profiles of unchanged mepirapim in whole blood and urine were quite different and unique. A detailed clarification of such uniqueness is under way in our laboratory.
RESUMEN
An aqueous suspension of polystyrene (PS) particles gave rise to a distinct color when a water-soluble volatile solvent, such as methanol or acetone, was added and left to evaporate. The color was caused by the formation of a colloidal crystal film of PS particles at the air-suspension interface. The colloidal crystal formation was possibly induced by the shear flow of particles and condensation of the suspension due to evaporation of the solvent. The colloidal crystal was estimated to consist of about 120 layers of PS particles. PS particles in the colloidal crystals formed a periodic array among the dispersion media, and the interparticle distance of the particles depended on the conductivity of the suspension. Further, the color of the colloidal crystal film as observed by the naked eye was complementary to the direct reflection peak.
RESUMEN
Nitric oxide (NO) production during hyposmotic stimulation in outer hair cells (OHCs) of the guinea pig cochlea was investigated using the NO sensitive dye DAF-2. Simultaneous measurement of the cell length and NO production showed rapid hyposmotic-induced cell swelling to precede NO production in OHCs. Hyposmotic stimulation failed to induce NO production in the Ca2+-free solution. L-NG-nitroarginine methyl ester (L-NAME), a non-specific NO synthase inhibitor and gadolinium, a stretch-activated channel blocker inhibited the hyposmotic stimulation-induced NO production whereas suramin, a P2 receptor antagonist did not. S-nitroso-N-acetylpenicillamine (SNAP), a NO donor inhibited the hyposmotic stimulation-induced increase in the intracellular Ca2+ concentrations ([Ca2+]i) while L-NAME enhanced it. 1H-[1,2,4]oxadiazole[4,3a]quinoxalin-1-one, an inhibitor of guanylate cyclase and KT5823, an inhibitor of cGMP-dependent protein kinase (PKG) mimicked effects of L-NAME on the Ca2+ response. Transient receptor potential vanilloid 4 (TRPV4), an osmo- and mechanosensitive channel was expressed in the OHCs by means of immunohistochemistry. 4alpha-phorbol 12,13-didecanoate, a TRPV4 synthetic activator, induced NO production in OHCs. These results suggest that hyposmotic stimulation can induce NO production by the [Ca2+]i increase, which is presumably mediated by the activation of TRPV4 in OHCs. NO conversely inhibits the Ca2+ response via the NO-cGMP-PKG pathway by a feedback mechanism.
Asunto(s)
Tamaño de la Célula , Células Ciliadas Auditivas Externas/metabolismo , Óxido Nítrico/metabolismo , Órgano Espiral/metabolismo , Transducción de Señal , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Animales , Calcio/metabolismo , Carbazoles/farmacología , Tamaño de la Célula/efectos de los fármacos , Células Cultivadas , GMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Inhibidores Enzimáticos/farmacología , Gadolinio/farmacología , Guanilato Ciclasa/antagonistas & inhibidores , Guanilato Ciclasa/metabolismo , Cobayas , Células Ciliadas Auditivas Externas/efectos de los fármacos , Soluciones Hipotónicas , Indoles/farmacología , Cinética , Potenciales de la Membrana , NG-Nitroarginina Metil Éster/farmacología , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Órgano Espiral/citología , Órgano Espiral/efectos de los fármacos , Presión Osmótica , Ésteres del Forbol/farmacología , Potasio/metabolismo , Antagonistas del Receptor Purinérgico P2 , Receptores Purinérgicos P2/metabolismo , S-Nitroso-N-Acetilpenicilamina/farmacología , Transducción de Señal/efectos de los fármacos , Cloruro de Sodio/metabolismo , Suramina/farmacología , Canales Catiónicos TRPV/agonistas , Canales Catiónicos TRPV/metabolismoRESUMEN
Nitric oxide (NO) production during hyposmotic stimulation in outer hair cells (OHCs) of the guinea pig cochlea was investigated using the NO sensitive dye DAF-2. Simultaneous measurement of the cell length and NO production showed rapid hyposmotic-induced cell swelling to precede NO production in OHCs. Hyposmotic stimulation failed to induce NO production in the Ca(2+)-free solution. L-N(G)-nitroarginine methyl ester (L-NAME), a non-specific NO synthase inhibitor and gadolinium, a stretch-activated channel blocker inhibited the hyposmotic stimulation-induced NO production whereas suramin, a P2 receptor antagonist did not. S-nitroso-N-acetylpenicillamine (SNAP), a NO donor inhibited the hyposmotic stimulation-induced increase in the intracellular Ca(2+) concentrations ([Ca(2+)](i)) while L-NAME enhanced it. 1H-[1,2,4]oxadiazole[4,3a]quinoxalin-1-one, an inhibitor of guanylate cyclase and KT5823, an inhibitor of cGMP-dependent protein kinase (PKG) mimicked effects of L-NAME on the Ca(2+) response. Transient receptor potential vanilloid 4 (TRPV4), an osmo- and mechanosensitive channel was expressed in the OHCs by means of immunohistochemistry. 4alpha-phorbol 12,13-didecanoate, a TRPV4 synthetic activator, induced NO production in OHCs. These results suggest that hyposmotic stimulation can induce NO production by the [Ca(2+)](i) increase, which is presumably mediated by the activation of TRPV4 in OHCs. NO conversely inhibits the Ca(2+) response via the NO-cGMP-PKG pathway by a feedback mechanism.
Asunto(s)
Cóclea/metabolismo , Células Ciliadas Auditivas Externas/metabolismo , Óxido Nítrico/metabolismo , Transducción de Señal , Equilibrio Hidroelectrolítico , Animales , Calcio/metabolismo , Carbazoles/farmacología , Tamaño de la Célula , Células Cultivadas , Cóclea/citología , Cóclea/efectos de los fármacos , Proteínas Quinasas Dependientes de GMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Inhibidores Enzimáticos/farmacología , Gadolinio/farmacología , Guanilato Ciclasa/metabolismo , Cobayas , Células Ciliadas Auditivas Externas/efectos de los fármacos , Soluciones Hipotónicas/metabolismo , Indoles/farmacología , Mecanorreceptores/efectos de los fármacos , Mecanorreceptores/metabolismo , NG-Nitroarginina Metil Éster/farmacología , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Ésteres del Forbol/farmacología , Potasio/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , S-Nitroso-N-Acetilpenicilamina/farmacología , Transducción de Señal/efectos de los fármacos , Canales Catiónicos TRPV/agonistas , Canales Catiónicos TRPV/metabolismo , Regulación hacia Arriba , Equilibrio Hidroelectrolítico/efectos de los fármacosRESUMEN
Recently, a negative feedback effect of nitric oxide (NO) on the adenosine 5'-triphosphate (ATP)-induced Ca2+ response has been described in cochlear inner hair cells. We here investigated the role of NO on the ATP-induced Ca2+ response in outer hair cells (OHCs) of the guinea pig cochlea using the NO-sensitive dye DAF-2 and Ca2+ -sensitive dye fura-2. Extracellular ATP induced NO production in OHCs, which was inhibited by L-NG-nitroarginine methyl ester (L-NAME), a non-specific NO synthase (NOS) inhibitor, and suramin, a P2 receptor antagonist. ATP failed to induce NO production in the Ca2+ -free solution. S-nitroso-N-acetylpenicillamine (SNAP), a NO donor, enhanced the ATP-induced increase of the intracellular Ca2+ concentrations ([Ca2+]i), while L-NAME inhibited it. SNAP accelerated ATP-induced Mn2+ quenching in fura-2 fluorescence, while L-NAME suppressed it. 8-Bromoguanosine-cGMP, a membrane permeable analog of cGMP, mimicked the effects of SNAP. 1H-[1,2,4]oxadiazole[4,3-a] quinoxalin-1-one, an inhibitor of guanylate cyclase and KT5823, an inhibitor of cGMP-dependent protein kinase inhibited the ATP-induced [Ca2+]i increase. Selective neuronal NOS inhibitors, namely either 7-nitro-indazole or 1-(2-trifluoromethylphenyl) imidazole, mimicked the effects of L-NAME regarding both ATP-induced Ca2+ response and NO production. Immunofluorescent staining of neuronal nitric oxide synthase (nNOS) in isolated OHCs showed the localization of nNOS in the apical region of OHCs. These results suggest that the ATP-induced Ca2+ influx via a direct action of P2X receptors may be the principal source for nNOS activity in the apical region of OHCs. Thereafter, NO can be produced while conversely enhancing the Ca2+ influx via the NO-cGMP-PKG pathway by a feedback mechanism.
Asunto(s)
Adenosina Trifosfato/farmacología , Señalización del Calcio/efectos de los fármacos , Calcio/metabolismo , Cóclea/citología , Células Ciliadas Auditivas Externas/metabolismo , Óxido Nítrico/fisiología , Análisis de Varianza , Animales , Western Blotting/métodos , Señalización del Calcio/fisiología , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacología , Diagnóstico por Imagen/métodos , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Técnica del Anticuerpo Fluorescente/métodos , Cobayas , Donantes de Óxido Nítrico/farmacología , Penicilamina/análogos & derivados , Penicilamina/farmacología , Factores de TiempoRESUMEN
We recently demonstrated that extracellular adenosine 5'-triphosphate (ATP) induced nitric oxide (NO) production in the inner hair cells (IHCs) of the guinea pig cochlea, which inhibited the ATP-induced increase in the intracellular Ca(2+) concentrations ([Ca(2+)](i)) by a feedback mechanism [Shen, J., Harada, N. & Yamashita, T. (2003) Neurosci. Lett., 337, 135-138]. We herein investigated the role of the NO-cGMP pathway and neuronal NO synthase (nNOS) in the ATP-induced Ca(2+) signalling in IHCs using the Ca(2+)-sensitive dye fura-2 and the NO-sensitive dye DAF-2. Fura-2 fluorescence-quenching experiments with Mn(2+) showed that ATP triggered a Mn(2+) influx. L-N(G)-nitroarginine methyl ester (L-NAME), a nonspecific NOS inhibitor, accelerated the ATP-induced Mn(2+) influx while S-nitroso-N-acetylpenicillamine (SNAP), a NO donor, suppressed it. 1H-[1,2,4]oxadiazole[4,3-a] quinoxalin-1-one, an inhibitor of guanylate cyclase, and KT5823, an inhibitor of cGMP-dependent protein kinase, enhanced the ATP-induced [Ca(2+)](i) increase. 8-Bromoguanosine-cGMP, a membrane-permeant analogue of cGMP mimicked the effects of SNAP. Moreover, the effects of 7-nitroindazole, a selective nNOS inhibitor, mimicked the effects of L-NAME regarding both the enhancement of the ATP-induced Ca(2+) response and the attenuation of NO production. Immunofluorescent staining of nNOS using a single IHC revealed that nNOS was distributed throughout the IHCs, but enriched in the apical region of the IHCs as shown by intense staining. In conclusion, the ATP-induced Ca(2+) influx may be the principal source for nNOS activity, which may interact with P2X receptors in the apical region of IHCs. Thereafter, NO can be produced and conversely inhibits the Ca(2+) influx via the NO-cGMP-PKG pathway by a feedback mechanism.
Asunto(s)
Adenosina Trifosfato/metabolismo , Señalización del Calcio/fisiología , Calcio/metabolismo , GMP Cíclico/metabolismo , Células Ciliadas Auditivas Internas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico/metabolismo , Adenosina Trifosfato/farmacología , Animales , Señalización del Calcio/efectos de los fármacos , GMP Cíclico/análogos & derivados , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Inhibidores Enzimáticos/farmacología , Retroalimentación Fisiológica/fisiología , Fluoresceínas , Fura-2 , Cobayas , Células Ciliadas Auditivas Internas/efectos de los fármacos , Inmunohistoquímica , Manganeso/metabolismo , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I , Receptores Purinérgicos P2/efectos de los fármacos , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
The adverse health effects caused by indoor air pollution are termed "sick building syndrome". We report such a patient whose symptoms appeared in the workplace. A 36-year-old female office worker developed nausea and headache during working hours in a refurbished office. After eight months of seeking help at other clinics or hospitals without improvement, she was referred to our hospital. At that time she reacted to the smells of various chemicals outside of the office building. Biochemical findings were all within normal ranges. Specific IgE antibody to cedar pollen was positive and the ratio of TH1/TH2 was 4.5. In the Eye Tracking Test (ETT), vertical eye movement was saccadic. Her anxiety level was very high according to the State-Trait Anxiety Inventory (STAI) questionnaire. Subjective symptoms, ETT findings and anxiety levels on STAI gradually improved during two years of follow-up. One year after the onset of her illness, the formaldehyde concentrations in the building air ranged from 0.017-0.053 ppm. Even though relatively low, chemical exposure from building materials such as formaldehyde induced a range of symptoms. Also, lack of recognition by superiors and doctors that sick building syndrome might have been the source of her illness coupled with her high state of anxiety may have exacerbated her symptoms and led to the onset of multiple chemical sensitivity. Thus psychosocial factors may contribute to sick building syndrome in the workplace.