RESUMO
OBJECTIVE: This study aimed to examine whether, on the basis of the relationship between sensors attached on the upper limbs and energy expenditure (EE) at the time of wheelchair propulsion, there are differences in the measurement of EE depending on the sensor attachment site and whether addition of the angular velocity information to the acceleration value is advantageous. We also aimed to clarify the variables used to estimate EE as well as the estimated error. SETTING: Laboratory of the National Hospital Organization Murayama Medical Center, Japan. METHODS: Six male subjects with spinal cord injuries participated in the study. Each wore sensors at the wrist and the middle upper arm on both sides while driving a wheelchair on a treadmill at three levels: very, very light; very light; and fairly light. Triaxial acceleration, triaxial angular velocity and EE were measured during driving. We analyzed the correlation between EE and acceleration, angular velocity and synthesized values of acceleration and angular velocity at each location using regression, multiple regression and Bland-Altman analyses. RESULTS: The determination coefficients between EE and the acceleration, angular velocity and synthesized values of acceleration and angular velocity varied from 0.68 to 0.87 at each location. The mean difference between the measured and estimated EE varied from 0.0028 (s.d., 0.0027) kcal min(-1) kg(-1) on the right upper arm. CONCLUSION: These findings suggest that combining the synthesized values of angular velocity and acceleration of the motion sensors on the upper limbs might reflect EE during a wheelchair driving activity on a treadmill.
Assuntos
Teste de Esforço/métodos , Atividade Motora/fisiologia , Paraplegia/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Cadeiras de Rodas , Adulto , Antropometria , Metabolismo Energético/fisiologia , Teste de Esforço/instrumentação , Humanos , Japão , Masculino , Paraplegia/diagnóstico , Paraplegia/etiologia , Análise de Regressão , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/diagnóstico , Extremidade Superior/fisiopatologiaRESUMO
In 195 parotid saliva samples collected at random from a Japanese population, two phenotypes were observed by electrophoresis in acid-urea starch gels. The protein showing polymorphisms was detected in the middle zone between Pa and Pb, and was tentatively designated Pm. Inheritance was controlled by a dominant allele at an autosomal locus. The frequencies of the genes determining these phenotypes were, for the Japanese population studied, Pm+=.38+/-.03, Pm-=.62+/-.03.
Assuntos
Povo Asiático , Polimorfismo Genético , Proteínas/análise , Saliva/análise , China/etnologia , Eletroforese , Frequência do Gene , Humanos , Japão/etnologia , FenótipoRESUMO
Conjugated linoleic acid (CLA) is a naturally occurring group of dienoic derivatives of linoleic acid found in beef and dairy products. CLA has been reported to reduce body fat. To examine the mechanism(s) of CLA reduction of fat mass, female C57BL/6J mice were fed standard semipurified diets (10% fat of total energy) with or without CLA (1% wt/wt). Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick endlabeling (TUNEL) and DNA fragmentation analysis revealed that fat-mass decrease by CLA was mainly due to apoptosis. Tumor necrosis factor (TNF)-alpha and uncoupling protein (UCP)-2 mRNA levels increased 12- and 6-fold, respectively, in isolated adipocytes from CLA-fed mice compared with control mice. Because it is known that TNF-alpha induces apoptosis of adipocytes and upregulates UCP2 mRNA, a marked increase of TNF-alpha mRNA with an increase of UCP2 in adipocytes caused CLA-induced apoptosis. However, with a decrease of fat mass, CLA supplementation resulted in a state resembling lipoatrophic diabetes: ablation of brown adipose tissue, a marked reduction of white adipose tissue, marked hepatomegaly, and marked insulin resistance. CLA supplementation decreased blood leptin levels, but continuous leptin infusion reversed hyperinsulinemia, indicating that leptin depletion contributes to the development of insulin resistance. These results demonstrate that intake of CLA reduces adipose tissue by apoptosis and results in lipodystrophy, but hyperinsulinemia by CLA can be normalized by leptin administration.
Assuntos
Tecido Adiposo/patologia , Apoptose/efeitos dos fármacos , Ácidos Linoleicos/farmacologia , Ácidos Linoleicos/toxicidade , Lipodistrofia/induzido quimicamente , Proteínas de Membrana Transportadoras , Proteínas Mitocondriais , Proteínas/genética , Tecido Adiposo/citologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/patologia , Animais , Peso Corporal , Suplementos Nutricionais , Feminino , Canais Iônicos , Ácidos Linoleicos/administração & dosagem , Lipodistrofia/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Tamanho do Órgão/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Proteína Desacopladora 2RESUMO
BACKGROUND: The studies on the association of deletion/ insertion (D/I) polymorphism of angiotensin converting enzyme (ACE) gene with blood pressure and hypertension reported contradictory results. Because there was no population-based study in Japan, we examine the hypothesized association in a cross-sectional sample of a Japanese cohort. METHODS AND RESULTS: The blood pressure of 464 men and 876 women aged 40-80 years was measured, and their DNA was analyzed for ACE D/I genotypes. The prevalence of the D allele was 38.7 and 39.2% in men and women, respectively (overall 39%). There was a tendency for higher covariate (age, body mass index, albuminuria, hematocrit, alcohol consumption, smoking, diabetes mellitus, ischemic heart disease and antihypertensive medication) adjusted mean levels of diastolic blood pressure for the DD genotype in men but not in women. However, this tendency disappeared after dichotomization of blood pressure into diagnostic categories (normotension and hypertension). Results did not differ when the subjects were divided into two age groups (< or = 59 and > or = 60 years). Covariate-adjusted odds ratios for hypertension for presence of the D allele were close to the null value of one. ACE genetic variation accounted for only 0.1 and 0.7% of the inter-individual variation in systolic and diastolic blood pressure in men. These estimates were 0.2 and 0.1%, respectively, in women. CONCLUSION: Although there is a tendency of higher diastolic blood pressure in men with DD genotypes, there is no convincing evidence that ACE genotypes are associated with hypertension in this Japanese population.
Assuntos
DNA/genética , Hipertensão/enzimologia , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Pressão Sanguínea , Feminino , Genótipo , Humanos , Hipertensão/epidemiologia , Hipertensão/genética , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Peptidil Dipeptidase A/sangue , Prevalência , Estudos Retrospectivos , População RuralRESUMO
The ventral striatum appears to play a critical role in mediating motoric effects (i.e. ambulatory activity and rearing) of psychostimulants such as cocaine. We evaluated whether sub-regions of the ventral striatum play differential roles in locomotion and rearing induced by various dopaminergic drugs. Injections of D-amphetamine and dopamine stimulated locomotion and rearing with a similar potency at each of the sub-regions: the core, medial shell or medial tubercle. However, injections of mixtures of the D(1)- and D(2)-type agonists SKF 38393 and quinpirole or cocaine into the medial olfactory tubercle or the medial shell of the nucleus accumbens induced marked locomotion and rearing, while these injections into the core induced little or no locomotion or rearing. Furthermore, cocaine injections into the lateral or posterior tubercle produced marginal locomotion and rearing, while cocaine injections into regions just dorsal to these tubercle sites, the lateral portion of the shell or the ventral pallidum, did not produce any stimulating effect. We conclude that dopaminergic compounds induce vigorous locomotion and rearing in both core and shell; the relative roles of the core and shell differ depending on chemical compounds. Similar to the nucleus accumbens, the olfactory tubercle, particularly the medial portion, also mediates these behaviors induced by dopaminergic compounds. The medial ventral striatum (i.e. the medial tubercle and medial shell) plays a more important role in cocaine-induced locomotion and rearing than the lateral ventral striatum (i.e. the core, lateral shell and lateral tubercle). Moreover, the differential effects of cocaine between the medial and lateral portions of the shell on locomotion and rearing suggest more than two functional units (the core vs. the shell) within the accumbens.
Assuntos
Gânglios da Base/efeitos dos fármacos , Cocaína/farmacologia , Dextroanfetamina/farmacologia , Agonistas de Dopamina/farmacologia , Dopamina/farmacologia , Atividade Motora/efeitos dos fármacos , Animais , Gânglios da Base/anatomia & histologia , Gânglios da Base/fisiologia , Relação Dose-Resposta a Droga , Masculino , Atividade Motora/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/fisiologiaRESUMO
We studied the antimutagenic effects of urine on the SOS-inducing activity of mutagenic substances by using a novel test system (umu-test) for detecting DNA damaging agents, which uses a new tester strain (Salmonella typhimurium TA1535/pSK1002). The SOS-inducing activity of chemicals was detected in terms of the level of umu operon expression by measuring beta-galactosidase activity. We first examined the effects of various amounts of urine on SOS responses caused by mitomycin C (MMC). As a result, the urine suppressed beta-galactosidase activity of MMC dose-dependently. A urine concentration of 50 microliters/ml in the medium also suppressed 89.9% of SOS response induced by 0.1 microgram/ml of PEP, 75.6% of that induced by 0.02 microgram/ml of AF2 and 60.9% of that induced by 0.1 microgram/ml of AFB1. In addition, a urine concentration of 50 microliters/ml in the medium also suppressed 85.6% of SOS response by 5 J/m2 of UV irradiation. The observed suppression seemed to be directly related to the SOS responses at a cellular level, rather than to interaction between urine and mutagens, because the urine suppressed SOS responses induced not only by various mutagens but also by UV irradiation. These results suggest that urine works as a strong antimutagen against UV and chemical substances.
Assuntos
Antimutagênicos/farmacologia , Resposta SOS em Genética , Urina/fisiologia , Antimutagênicos/análise , Humanos , Mitomicinas/antagonistas & inibidores , Raios Ultravioleta , Urina/química , beta-Galactosidase/metabolismoRESUMO
Significant sex differences exist among cases of bladder cancer in humans as well as in experimental animals such as rats. Aromatic amines such as benzidine and 2-naphthylamine are known to induce bladder cancer. These carcinogenic amines are activated to genotoxic substances by cytochrome P 450 CYP4B1, which is present in bladder mucosa. In this study, regulation of CYP4B1 was investigated to elucidate sex difference in bladder carcinogenesis. Competitive reverse transcription-polymerase chain reaction was used to investigate the expression of rat CYP4B1 mRNA occurring in small amounts of tissue such as bladder tissue. Expression of CYP4B1 in the bladder of male rats increased with development but not in that of female rats. Moreover, mature male rats exhibited higher expression of CYP4B1 in the bladder than did mature female rats. Castration of male rats decreased CYP4B1 levels and treatment with testosterone led to a partial recovery of CYP4B1 levels. These results indicate that CYP4B1 levels in the rat bladder are partly regulated by androgens. Furthermore, the present findings suggest that the sex difference observed in bladder carcinogenesis was due to sex-different expression of CYP4B1 in bladder tissue.
Assuntos
Androgênios/fisiologia , Hidrocarboneto de Aril Hidroxilases , Sistema Enzimático do Citocromo P-450/metabolismo , Bexiga Urinária/metabolismo , Fatores Etários , Animais , Carcinógenos/metabolismo , Sistema Enzimático do Citocromo P-450/análise , Sistema Enzimático do Citocromo P-450/genética , Feminino , Masculino , Mucosa/enzimologia , Mucosa/metabolismo , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores Sexuais , Bexiga Urinária/enzimologia , Neoplasias da Bexiga Urinária/etiologiaRESUMO
5'-Deoxy-5-fluorouridine (5'-dFUrd) is a prodrug of 5-fluorouracil (5-FUra) activated by pyrimidine nucleoside phosphorylase (PyN Pase), mainly by uridine phosphorylase (Urd Pase) in rodents and by thymidine phosphorylase (TdR Pase) in humans, which is preferentially located in tumor tissues compared to normal tissues. It has been reported that PyN Pase is induced by cytokines such as tumor necrosis factor (TNF), interleukin-1alpha (IL-1alpha) and interferon (IFN). Thymosin is a glycoprotein extract obtained from the calf thymus and is a potent immunopotentiating preparation. In this study, the antiproliferative activity of 5'-dFUrd used in combination with thymosin fraction 5 (TF5) was investigated in mouse bladder cancer cell line MBT-2 in vitro and in vivo. In vitro TF5 enhanced the activity of 5'-dFUrd by up to 4.11-fold, whereas the activity of other cytostatics such as 5-FUra, mitomycin C, adriamycin, cis-platinum, etoposide, vinblastine and methotrexate was not changed. In vivo when the effects of combination therapy with 5'-dFUrd and TF5 in C3H/HeN mice implanted with MBT2 were studied, tumor growth was not suppressed by TF5 alone while tumor growth was suppressed to some degree by 5'-dFUrd alone. However, tumor growth suppression was enhanced when 5'-dFUrd was used in combination with TF5. In order to investigate this mechanism, Urd Pase in MB2 was measured, and it was found that TF5 increased enzyme activity by up to 1.8-fold in MBT2. This increased susceptibility might be a result of the induction of Urd Pase, which is the essential enzyme for the conversion of 5'-dFUrd to 5-FUra. These results suggested that the therapeutic benefit of 5'-dFUrd would be improved by its use in combination with TF5 and the modulation of converting enzymes for antitumor prodrugs could be a novel therapeutic strategy for treating human cancers.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunossupressores/uso terapêutico , Pró-Fármacos/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Divisão Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Floxuridina/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C3H , Timosina/administração & dosagem , Timosina/análogos & derivados , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/patologiaRESUMO
The proportions of different hepatic microsomal cytochrome P450s expressed in uremic rats were studied with specific antibodies and with a steroid hydroxylase assay. In male uremic rats, the hepatic levels of P450 2C11, a male-specific form, and 3A2, a male-dominant form, were decreased to about 30% at 5 weeks after the induction of uremia. These changes were paralleled by decreases in the activities of testosterone 2 alpha-, 16 alpha-, and 6 beta-hydroxylation. The level of P450 2A1, abundant in immature rats, was increased 2-fold by uremia and accompanied by an increase in testosterone 7 alpha-hydroxylation activity. The levels of P450 2C6 and 2E1 were not changed by uremia. The levels of male-specific and male-dominant forms such as P450 2C11 and 3A2 are affected by the serum level of testosterone, which was decreased in the male rats with uremia. Therefore, castrated rats were prepared to compare the effects of testosterone on hepatic cytochrome P450s in uremic rats with those in castrated rats. When testosterone was administered to the castrated rats, the decreased levels of both P450 2C11 and 3A2 returned to normal. However, the administration of testosterone to the uremic rats did not prevent the decrease in the levels of these P450s. In female rats, changes in the levels of cytochrome P450s were not as great during uremia as those in male uremic rats. The level of P450 2C12, a female-specific form, was not changed; the level of P450 2A1 was increased by 50%, that of 3A2 which is barely detected in female rats was increased by 60%, and that of 2E1 was increased by 25%. These results suggested that the changes in the hepatic levels of cytochrome P450s were affected by factors other than testosterone in uremic rats.
Assuntos
Hidrocarboneto de Aril Hidroxilases , Sistema Enzimático do Citocromo P-450/metabolismo , Isoenzimas/metabolismo , Microssomos Hepáticos/enzimologia , Uremia/enzimologia , Animais , Nitrogênio da Ureia Sanguínea , Castração , Creatinina/sangue , Feminino , Masculino , Ratos , Ratos Endogâmicos , Fatores Sexuais , Esteroide Hidroxilases/metabolismo , Testosterona/sangueRESUMO
Gc-system typing by isoelectric focusing polyacrylamide gel electrophoresis and quantitative assays were carried out on a patient with a karyotype of 46,XY,del(4)(q12q21.1) and on his parents with normal chromosomes. Although a father-child incompatibility within the Gc-system suggested that its locus is on segment 4q12-13, the serum concentration of vitamin D binding protein in the patient and his father were only about half of that of his mother and control individuals. The possibility of interference of a silent allele in the child could not be excluded. Associated congenital partial leukodermia appeared to be an expression of a partial piebald trait.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 4 , Mecanismo Genético de Compensação de Dose , Proteína de Ligação a Vitamina D/genética , Bandeamento Cromossômico , Mapeamento Cromossômico , Dermatoglifia , Pai , Feminino , Marcadores Genéticos , Humanos , Lactente , Focalização Isoelétrica , Cariotipagem , Masculino , Fenótipo , Polimorfismo Genético , Gravidez , Pigmentação da Pele/genética , Proteína de Ligação a Vitamina D/sangue , Proteína de Ligação a Vitamina D/imunologiaRESUMO
Appetitive behaviors of rats were monitored in a runway situation following central infusions of neuroactive substances into brain areas implicated in electrical self-stimulation. Microinjections of the dopamine antagonist cis-flupentixol or the cholinergic antagonist atropine into the nucleus accumbens (Acb) severely reduced the approach speed and anticipatory shuttlebox activity while leaving the consumption of the 20% sucrose reward intact. Microinjections of GABA into the ventral tegmental area (VTA), pedunculopontine tegmental nucleus (PPTg), and oral pontine reticular nucleus (PnO) also severely disrupted approach without decreasing consumption. The highest doses of atropine into the VTA, PPTg, and PnO disrupted both consummatory and approach responses equally. The results indicate that modulation of various neurochemistries along the trajectory of the self-stimulation system has stronger effects on appetitive approach than consummatory motivation. The implications for understanding appetitive-approach motivation in the brain are discussed.
Assuntos
Comportamento Apetitivo/fisiologia , Encéfalo/fisiologia , Comportamento Consumatório/fisiologia , Motivação , Neurotransmissores/fisiologia , Autoestimulação/fisiologia , Acetilcolina/fisiologia , Animais , Comportamento Apetitivo/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Mapeamento Encefálico , Comportamento Consumatório/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Estimulação Elétrica , Flupentixol/farmacologia , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Ponte/efeitos dos fármacos , Ponte/fisiologia , Ratos , Formação Reticular/efeitos dos fármacos , Formação Reticular/fisiologia , Autoestimulação/efeitos dos fármacos , Tegmento Mesencefálico/efeitos dos fármacos , Tegmento Mesencefálico/fisiologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologia , Ácido gama-Aminobutírico/farmacologia , Ácido gama-Aminobutírico/fisiologiaRESUMO
The authors have hypothesized that, in adult rats, 50-kHz ultrasonic vocalizations (USVs) index a state characterized by high arousal and expectations of reward. This study was conducted to investigate whether dopamine agonism of the nucleus accumbens (NAcc) could evoke such an appetitive state, by examining the effects of NAcc amphetamine (AMPH) microinjections on USVs. Intra-NAcc AMPH injections (0.3, 1.0, 3.0, 10.0 microg unilaterally) produced robust, dose-dependent increases in 50-kHz USVs, which could not be accounted for by concomitant increases in locomotor activity (LA). However, AMPH injections into dorsal control caudate putamen sites produced a modest, dose-dependent increase in LA without significant increases in 50-kHz USVs. These findings indicate that NAcc AMPH microinjections selectively evoke 50-kHz USVs in rats, supporting the notion that dopamine elevations in the NAcc may unconditionally elicit a state of reward anticipation.
Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Dopaminérgicos/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Vocalização Animal/efeitos dos fármacos , Anfetamina/administração & dosagem , Animais , Comportamento Apetitivo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Dopaminérgicos/administração & dosagem , Masculino , Microinjeções , Núcleo Accumbens/patologia , Núcleo Accumbens/fisiologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , UltrassomRESUMO
This study used an intracerebral self-administration paradigm in rats to determine if blockade of GABA(A) receptors in the ventral tegmental area (VTA) has a reinforcing effect. Rats quickly learned to self-infuse a picrotoxin solution into the anterior VTA; rats discriminated the lever that produced picrotoxin infusions from the lever without consequences; and when the response requirement was increased, rats increased response levels for picrotoxin infusion. The reinforcing effect of picrotoxin was site-specific: Anterior VTA regions supported vigorous self-infusions, but not the posterior VTA, substantia nigra, or lateral hypothalamus. Muscimol, a GABA(A) agonist, disrupted picrotoxin self-infusion, but bicuculline, a GABA(A) antagonist, was self-infused into the VTA. The results suggest that blockade of GABA(A) receptors in the anterior VTA is reinforcing and that functional organization of the GABA systems within the VTA is heterogeneous.
Assuntos
Condicionamento Clássico/efeitos dos fármacos , Antagonistas GABAérgicos/farmacologia , Antagonistas de Receptores de GABA-A , Motivação , Picrotoxina/farmacologia , Autoestimulação/efeitos dos fármacos , Tegmento Mesencefálico/efeitos dos fármacos , Animais , Mapeamento Encefálico , Condicionamento Clássico/fisiologia , Feminino , Ratos , Ratos Wistar , Receptores de GABA-A/fisiologia , Autoadministração , Autoestimulação/fisiologia , Tegmento Mesencefálico/fisiologiaRESUMO
This paper examines noradrenergic hyperactivity in response to stress in the development of spontaneous recurrences of methamphetamine (MAP) psychosis, a phenomenon known as flashbacks, in studies of psychedelic drug use. We studied predictors of flashbacks in 36 subjects with flashbacks, along with 80 subjects with a history of MAP psychosis who did not experience flashbacks. Plasma monoamine metabolite levels were assayed in 26 of the 36 subjects with flashbacks, 16 of the 80 subjects without flashbacks, nine subjects with persistent MAP psychosis, and 28 normal controls. None of the 28 controls became psychotic. A square root transformation was applied to all monoaminergic values, resulting in data nearly normally distributed. The subjects with flashbacks had been exposed to stressful events or threatening paranoid-hallucinatory states or both during previous MAP use. Most flashbacks occurred under conditions that provoked a mild fear of other people. Plasma norepinephrine levels were markedly increased during flashbacks. Thus, stressful experiences together with MAP use may have induced noradrenergic hyperreactivity to a mild stress, which in turn may elicit memories of MAP psychosis associated with stressful experiences. A mild fear of other people precipitated the flashbacks, including markedly increased noradrenergic activity. The results of this study suggest that noradrenergic hyperreactivity to a mild stress is a precipitating factor in spontaneous recurrences of MAP psychosis.
Assuntos
Inibidores da Captação de Dopamina , Metanfetamina , Psicoses Induzidas por Substâncias/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adulto , Ansiedade/psicologia , Monoaminas Biogênicas/metabolismo , Feminino , Humanos , Recidiva , Estresse Psicológico/psicologiaRESUMO
Increased sensitivity to stress associated with noradrenergic hyperactivity and dopaminergic changes may precipitate stress-related psychiatric disorders. The present study examines the relation between this increased sensitivity and vulnerability to subsequent spontaneous recurrences of methamphetamine (MAP) psychosis (i.e. flashbacks). Plasma monoamine metabolite levels were assayed in 18 subjects with flashbacks, of whom ten experienced a single flashback and eight experienced further subsequent flashbacks; in 21 subjects with a history of MAP psychosis who did not experience flashbacks; and 33 controls. A square-root transformation was applied to monoaminergic values, rendering the distribution normal. The subjects with flashbacks had undergone frightening stressful experiences during previous MAP use. The dominant factor triggering flashbacks was a mild fear of other people. During flashbacks, plasma noradrenaline levels markedly increased and 3-methoxytyramine levels, an indicator of dopamine release, were elevated. Among the 18 subjects with flashbacks, the ten with subsequent flashbacks had markedly increased noradrenaline levels during flashbacks, whereas the eight with a single flashback displayed small increases in noradrenaline levels as well as 3-methoxytyramine levels. Thus, a mild fear of other people may have elicited memories of MAP psychosis, related to frightening stressful experiences through increased sensitivity to stress associated with noradrenergic hyperactivity, involving increased dopamine release. Robust noradrenergic hyperreactivity to mild stress may predispose subjects to subsequent flashbacks.
Assuntos
Estimulantes do Sistema Nervoso Central/efeitos adversos , Metanfetamina/efeitos adversos , Psicoses Induzidas por Substâncias/complicações , Estresse Fisiológico/complicações , Adulto , Monoaminas Biogênicas/sangue , Feminino , Humanos , Psicoses Induzidas por Substâncias/sangue , RecidivaRESUMO
There exist clinical characteristics of methamphetamine (MAP) psychosis in the Japanese population. MAP psychosis involves paranoid-hallucinatory states indistinguishable from paranoid schizophrenia, with residual volitional disturbances (e.g., loss of spontaneity and idleness). Paranoid-hallucinatory states persist after the pharmacological effects of MAP have worn off and readily reappear upon a reinjection of MAP. Individuals with a history of MAP psychosis further undergo spontaneous recurrence of their paranoid-hallucinatory states in response to stress. The development of MAP psychosis might therefore be related to persisting brain damage or changes in brain metabolism induced by repeated MAP use, and thus studies of the clinical course and neurological basis of MAP psychosis could provide insights into the pathophysiology of schizophrenia. Accordingly, psychiatrists have studied the clinical characteristics of MAP psychosis and examined the neurobiological basis of MAP-induced behavioral sensitization, using animals. MAP-induced behavioral sensitization might well be related to dopamine supersensitivity; however, the contribution of presynaptic autoreceptors remains controversial, and other hypotheses should be considered. Recently, the process that triggers spontaneous recurrence of MAP psychosis (flashbacks) and corresponding peripheral neurotransmitter functions has been studied. Stress sensitization associated with noradrenergic hyperactivity, involving increased dopamine release, appears to be crucial in the development of flashbacks. Overall, MAP-induced susceptibility to paranoid-hallucinatory states and to abnormal behavior (e.g., stereotyped behavior) in animals is examined as a model for predicting relapses of paranoid schizophrenia. Further extensive studies on the neurobiological and molecular mechanisms of this susceptibility are required.
Assuntos
Estimulantes do Sistema Nervoso Central , Psicoses Induzidas por Substâncias/etiologia , Esquizofrenia/etiologia , Transtornos Relacionados ao Uso de Substâncias/complicações , Anfetaminas , Animais , Comportamento Animal , Modelos Animais de Doenças , Humanos , Japão/epidemiologia , Metanfetamina , Pesquisa , Transtornos Relacionados ao Uso de Substâncias/classificação , Transtornos Relacionados ao Uso de Substâncias/epidemiologiaRESUMO
The relation is examined between increased sensitivity to stress associated with noradrenergic hyperactivity and dopaminergic changes, and susceptibility to subsequent spontaneous recurrences of methamphetamine (MAP) psychosis (i.e., flashbacks). Plasma monoamine metabolite levels were assayed in 23 flashbackers, 19 nonflashbackers with a history of MAP psychosis, 10 subjects with persistent MAP psychosis, and 21 MAP user and 9 nonuser controls. All 23 flashbackers had undergone frightening stressful experiences during previous MAP use. Mild psychosocial stressors then triggered flashbacks. The 12 flashbackers with further episodes had markedly increased norepinephrine levels and slightly increased plasma levels of 3-methoxytyramine, an index of dopamine release. While the 11 flashbackers with a single episode displayed small increases in norepinephrine and 3-methoxytyramine levels. Thus, robust noradrenergic hyperreactivity, involving increased dopamine release in response to mild stress may predispose to further episodes of flashbacks.
Assuntos
Estimulantes do Sistema Nervoso Central/efeitos adversos , Metanfetamina/efeitos adversos , Psicoses Induzidas por Substâncias/etiologia , Psicoses Induzidas por Substâncias/fisiopatologia , Análise de Variância , Ansiedade/etiologia , Monoaminas Biogênicas/sangue , Estudos de Casos e Controles , Suscetibilidade a Doenças , Feminino , Humanos , Psicoses Induzidas por Substâncias/sangue , Prevenção Secundária , Estresse Fisiológico/etiologiaRESUMO
The process that triggered spontaneous recurrence of methamphetamine (MAP)-induced paranoid-hallucinatory psychosis, a phenomenon known as flashbacks, was studied in 41 subjects with flashbacks, along with 84 subjects with a history of previous MAP psychosis but no flashbacks. Plasma levels of norepinephrine (NE), dopamine, and 5-hydroxytryptamine, and their respective metabolites were assayed in 28 of the 41 flashbackers, 16 of the 84 non-flashbackers, 9 subjects with persistent MAP psychosis, and 28 healthy controls comprised of 20 MAP users and 8 non-users. None of the 28 controls had become psychotic. The 41 flashbackers had experienced significantly greater frequencies of threatening events and frightening paranoid-hallucinatory states during previous MAP use than the 84 non-flashbackers. The dominant factor that triggered flashbacks was a mild fear of other persons. The 41 flashbackers may have encoded threatening experiences as frightening images. Repeated MAP use with threatening experiences may induce sensitization to frightening images. Plasma NE levels during flashbacks were significantly higher than the levels during periods of normalcy, and the NE levels in the 20 user and 8 non-user controls. The 9 subjects with persistent MAP psychosis had significant higher levels of NE than the user and non-user controls. The 16 non-flashbackers had significantly higher MHPG levels than the user controls. The findings suggest that MAP use may induce changes at pharmacological levels in the process underlying sensitization to frightening images. We suggested that when the flashbackers experienced a mild fear of other persons, MAP-induced sensitization to frightening images may have been actualized. Thus, the flashbacks may have been caused through increased noradrenergic hyperactivity.
Assuntos
Monoaminas Biogênicas/fisiologia , Metanfetamina/toxicidade , Psicoses Induzidas por Substâncias/fisiopatologia , Adulto , Ansiedade , Monoaminas Biogênicas/sangue , Feminino , Humanos , Metanfetamina/sangue , Psicoses Induzidas por Substâncias/psicologia , RecidivaRESUMO
Monotherapy with sulfonylurea may result in the exhaustion of pancreatic beta-cell function, fat accumulation, and dyslipidemia. We examined the possibility of dose reduction by administering sulfonylurea together with troglitazone, and investigated changes in insulin secretion and fat deposition. Seventy-eight patients with type 2 diabetes adequately controlled with glibenclamide were randomly allocated to a troglitazone (400 mg/d)-added group (n = 40) or a control group without placebo (n = 38) and monitored for 24 weeks. The daily dose of glibenclamide was adjusted to maintain stable HbA(1c) levels. Fat accumulation to the liver and thigh muscle were measured in mean Hounsfield units determined on computed tomography (CT) scan. Visceral fat accumulation (V), subcutaneous fat accumulation (S), and the V/S ratio were also determined by CT scan. The daily dose of glibenclamide and serum fasting insulin level in the troglitazone-added group significantly decreased (from 4.05 +/- 2.50 mg/d to 1.84 +/- 1.65 mg/d and from 8.47 +/- 4.62 microU/mL to 6.49 +/- 3.28 microU/mL, respectively) during the observation period compared with the control group (P < .01 and P < .01, respectively). Serum triglyceride and homeostasis model insulin resistance index (HOMA-R) in the troglitazone-added group decreased significantly in comparison to the control group (P < .05 and P < .01, respectively). The mean Hounsfield units of liver significantly decreased in the control group compared with the troglitazone-added group (P < .05). Visceral fat area and the V/S ratio significantly increased in the control group compared with the troglitazone-added group (P < .01 and P < .01, respectively). Glibenclamide monotherapy resulted in fat accumulation accompanied by dyslipidemia. An alternate conclusion is that troglitazone reversed type 2 diabetes (not sulfonylurea)-associated fat accumulation. The addition of troglitazone decreased daily doses of glibenclamide, preserved fasting insulin secretion, improved fat accumulation in liver, and prevented dyslipidemia.
Assuntos
Cromanos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus/prevenção & controle , Fígado Gorduroso/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Obesidade , Compostos de Sulfonilureia/efeitos adversos , Tiazóis/uso terapêutico , Tiazolidinedionas , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/crescimento & desenvolvimento , Idoso , Diabetes Mellitus/sangue , Diabetes Mellitus Tipo 2/sangue , Quimioterapia Combinada , Fígado Gorduroso/sangue , Fígado Gorduroso/induzido quimicamente , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Compostos de Sulfonilureia/uso terapêutico , TroglitazonaRESUMO
Mice fed a high-fat diet develop hyperglycemia and obesity. Using non-insulin-dependent diabetes mellitus (NIDDM) model mice, we investigated the effects of seven different dietary oils on glucose metabolism: palm oil, which contains mainly 45% palmitic acid (16:0) and 40% oleic acid (18:1); lard oil, 24% palmitic and 44% oleic acid; rapeseed oil, 59% oleic and 20% linoleic acid (18:2); soybean oil, 24% oleic and 54% linoleic acid; safflower oil, 76% linoleic acid; perilla oil, 58% alpha-linolenic acid; and tuna fish oil, 7% eicosapentaenoic acid and 23% docosahexaenoic acid. C57BL/6J mice received each as a high-fat diet (60% of total calories) for 19 weeks (n = 6 to 11 per group). After 19 weeks of feeding, body weight induced by the diets was in the following order: soybean > palm > or = lard > or = rapeseed > or = safflower > or = perilla > fish oil. Glucose levels 30 minutes after a glucose load were highest for safflower oil (approximately 21.5 mmol/L), modest for rapeseed oil, soybean oil, and lard (approximately 17.6 mmol/L), mild for perilla, fish, and palm oil (approximately 13.8 mmol/L), and minimal for high-carbohydrate meals (approximately 10.4 mmol/L). Only palm oil-fed mice showed fasting hyperinsulinemia (P < .001). By stepwise multiple regression analysis, body weight (or white adipose tissue [WAT] weight) and intake of linoleic acid (or n-3/n-6 ratio) were chosen as independent variables to affect glucose tolerance. By univariate analysis, the linoleic acid intake had a positive correlation with blood glucose level (r = .83, P = .02) but not with obesity (r = .46, P = .30). These data indicate that (1) fasting blood insulin levels vary among fat subtypes, and a higher fasting blood insulin level in palm oil-fed mice may explain their better glycemic control irrespective of their marked obesity; (2) a favorable glucose response induced by fish oil feeding may be mediated by a decrease of body weight; and (3) obesity and a higher intake of linoleic acid are independent risk factors for dysregulation of glucose tolerance.