RESUMEN
A male preponderance of Parkinson's disease (PD) has been reported in European countries and the USA. To verify this issue in Japanese patients with PD, we examined the age- and gender-specific prevalence of PD in Yamagata Prefecture (population 1,244,040), Japan. The prevalence of PD was 61.3/100,000 men and 91.0/100,000 women, showing that women were significantly more affected by PD than men (p < 0.001). Contrary to the findings in Europe and the USA, the results indicate a female preponderance of PD among the Japanese population.
Asunto(s)
Enfermedad de Parkinson/epidemiología , Razón de Masculinidad , Adulto , Anciano , Anciano de 80 o más Años , Estudios Epidemiológicos , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/etnología , PrevalenciaRESUMEN
The discovery of a series of nonpeptide arginine vasopressin V(2) receptor agonists is described. After identifying the aniline derivative 8 as our lead compound from the metabolites of compound 7 that showed antidiuretic activity by po administration to Brattleboro rats, improvements in the in vitro potency involving evaluations of the structural requirements for agonist action and optimizing the structure of the benzoyl moiety have been intensively undertaken. These studies led to compounds 16g, 19a, and 23b,h,i that show potent agonist activity for the V(2) receptor.
Asunto(s)
Arginina Vasopresina/metabolismo , Benzazepinas/síntesis química , Receptores de Vasopresinas/agonistas , Administración Oral , Animales , Benzazepinas/química , Benzazepinas/farmacología , AMP Cíclico/biosíntesis , Diuresis/efectos de los fármacos , Diseño de Fármacos , Femenino , Células HeLa , Humanos , Modelos Moleculares , Conformación Molecular , Ensayo de Unión Radioligante , Ratas , Receptores de Vasopresinas/metabolismo , Relación Estructura-ActividadRESUMEN
BACKGROUND: Urine contains microscopically observable particles that can indicate certain types of disease in the urinary tract system. Determining these various types of sediments by manual operation is a cumbersome and time-consuming task. To eliminate this labor, we developed an automated urinary sediment analyzer with high-throughput pretreatment system. METHODS: The pretreatment system mainly consists of four reaction vessels for dying samples (urine), a sheath flow chamber, and an unique sample carrier mechanism from the reaction vessel to the flow chamber, which enables overlapped processing, and rapid transfer of samples with small dispersion and a short buildup time. RESULTS: The buildup time was experimentally found to be 1.8 s, and the extra-sample volume beside that for measurement was only 4.9 microl (1/20 of the total sample volume). CONCLUSIONS: Short buildup time results in high throughput of 120 samples per hour, and relatively small extra-volume contributes to reduce carryover.
Asunto(s)
Citometría de Flujo/instrumentación , Orina/química , Automatización , Estudios de Evaluación como Asunto , Citometría de Flujo/métodos , Humanos , Modelos Biológicos , Factores de TiempoRESUMEN
DNA-based mutation analysis on the connexin 32 gene was performed in 49 families with Charcot-Marie-Tooth disease (CMT) type 1 but without duplication involving the chromosomal region, 17p12-p11.2. Mutations were identified in five of the 49 families, and four of the five mutations were hitherto undescribed: Va137Met, Glu57His, Arg142Glu, Val177Ala. X-linked CMT sometimes lacks evidence for X-linked transmission and cannot be differentiated from CMT type 2, especially in females with mildly decreased nerve conduction velocity. Therefore, molecular analysis is useful for molecular pathology of their disease.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Conexinas/genética , Genes/genética , Adolescente , Adulto , Sustitución de Aminoácidos , Análisis Mutacional de ADN , Salud de la Familia , Humanos , Japón , Masculino , Linaje , Mutación Puntual , Polimorfismo Conformacional Retorcido-Simple , Proteína beta1 de Unión ComunicanteRESUMEN
The prognostic value of ubiquitin levels in cerebrospinal fluid (CSF) was studied in human global brain ischemia (anoxic-ischemic encephalopathy). Twenty four samples were collected from 13 patients who were resuscitated from cardio-pulmonary arrest and survived for at least 1 day. The outcome was classified according to the Glasgow Outcome Scale (GOS1-5). The ubiquitin levels (normal: 14.3 +/- 1.1 ng/ml, mean +/- S.E.M.) in neurologically symptomatic patients (GOS1-4) were 151 +/- 32.5 ng/ml on day 1-2 and elevated to 1,960 +/- 849 ng/ml on day 3-4. The Spearman's rank correlation of ubiquitin levels on day 3-4 and the GOS was -0.855, showing a better correlation than CSF neuron-specific enolase levels (r = -0.846). Ubiquitin is a heat shock protein associated with the degradation of abnormal cellular proteins. Thus, the elevation of CSF ubiquitin levels represents both its overproduction by a cytoprotective response to brain ischemia and its leakage from the damaged tissue. The present study suggests that the measurement of CSF ubiquitin level is useful for the early prognostic assessment of global brain ischemia.
Asunto(s)
Isquemia Encefálica/mortalidad , Ubiquinona/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/líquido cefalorraquídeo , Muerte Encefálica/líquido cefalorraquídeo , Isquemia Encefálica/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Persona de Mediana Edad , PronósticoAsunto(s)
Vacunas contra el SIDA/inmunología , Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Adyuvantes Inmunológicos/síntesis química , Anticuerpos Anti-VIH/biosíntesis , Proteína gp120 de Envoltorio del VIH/inmunología , VIH-1/inmunología , Acetilmuramil-Alanil-Isoglutamina/síntesis química , Acetilmuramil-Alanil-Isoglutamina/inmunología , Adyuvantes Inmunológicos/química , Adyuvantes Inmunológicos/farmacología , Secuencia de Aminoácidos , Animales , Especificidad de Anticuerpos , Cromatografía Líquida de Alta Presión , Ensayo de Inmunoadsorción Enzimática , Masculino , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Peso Molecular , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/inmunología , Vacunas Sintéticas/inmunologíaRESUMEN
Mitogenicity and the production of tumor necrosis factor (TNF) by a chemically synthesized lipotetrapeptide analog (KAB-8), S-[2,3-bis(palmitoyloxy)-2R-propyl]-N-[(2,2,2)-trichloro- ethoxycarbonyl: Troc group]-(R)-cysteinyl-(S)-seryl-(S)-seryl-(S)-asparagine, the amino acid sequence of which corresponds to that of the lipopeptide part of lipoprotein in Escherichia coli, and several derivatives (KAB-30-41), which possessed the altered glycerocysteine moiety, were examined. A 1-cysteinyl glycerol skeleton-type compound (KAB-8), a propane-type compound (KAB-31), a homoglycerol-type (KAB-39 and 40) and a 2-cysteinyl glycerol-type (KAB-41) exhibited mitogenic activity on splenocytes from C3H/He mice at various concentrations ranging from 0.4 to 100 micrograms/ml. However, propane-type compounds, except KAB-31, and ethane-type compounds showed lower mitogenic activity than other types of compounds. Compounds KAB-8, 31, 40 and 41 induced the production of TNF in peritoneal exudated macrophages from C3H/He mice at concentrations of 25 and 50 micrograms/ml. The results indicate that the structural differences of the glycerol moiety in the synthetic lipopeptides affect the potency of its biological activities.
Asunto(s)
Proteínas Bacterianas/farmacología , Escherichia coli/química , Lipoproteínas/farmacología , Mitógenos/farmacología , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Macrófagos Peritoneales/metabolismo , Masculino , Ratones , Ratones Endogámicos C3H , Relación Estructura-ActividadRESUMEN
Optically active lipopeptide derivatives have been synthesized by the use of chiral glycerol derivatives. Lipopeptide WS1279 derivatives with (R)-glycerol moieties showed a higher mitogenic activity than those with the (S)-configuration. Various N-protected lipopeptide and N-deprotected derivatives showed increased mitogenic activity.
Asunto(s)
Lipoproteínas/síntesis química , Lipoproteínas/farmacología , Mitógenos/síntesis química , Secuencia de Aminoácidos , Mitógenos/farmacología , Datos de Secuencia Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Clinical characteristics of late deterioration in adult cerebral palsy were reported with detailed neurological evaluations and analyses. 10 adult cases, 9 male and 1 female, with cerebral palsy (CP) were included aged from 24 to 58 years on admission. Without marked mental retardation all had been ambulant and completely independent of ADL with residual spasticity and/or dyskinesia of minimal degree until the second or third decade. Late deterioration of functional abilities starting with numbness or pain in upper extremities at age 24-45 (mean: 36.2 y), associated with profound atrophy of the shoulder girdle and hand muscles. Dyskinesia and spasticity markedly aggravated with urinary and respiratory dysfunctions, resulting in tetraplegia in a couple of years. Mentality is generally unaffected, however, severe dementia occurred in one case. Intensive clinical examinations revealed no particular abnormalities except for mild segmental neurogenic changes by needle EMG. Neuroradiological surveys revealed a marked narrowing of upper to middle cervical spinal canal with deformity and shrinkage of the corresponding cord in most cases. Cranial CT scans and MRI were unremarkable except for diffuse cortical atrophy and ventricular dilation. These studies showed that in adult CP an unexpectedly severe deterioration of sensory, motor and/or mental functions may appear even in previously well achieved cases. These dramatic changes of the clinical features of CP after middle age might be suggestive of the degenerating process and precocious aging of the CNS.
Asunto(s)
Parálisis Cerebral/fisiopatología , Adulto , Envejecimiento , Sistema Nervioso Central/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Proteínas de la Membrana Bacteriana Externa/síntesis química , Escherichia coli/química , Lipoproteínas/síntesis química , Mitógenos , Secuencia de Aminoácidos , Proteínas de la Membrana Bacteriana Externa/química , Proteínas de la Membrana Bacteriana Externa/inmunología , Cromatografía Líquida de Alta Presión , Lipoproteínas/química , Lipoproteínas/inmunología , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/química , Fragmentos de Péptidos/inmunología , Relación Estructura-ActividadRESUMEN
Mitogenicity, lethal toxicity, and antitumor activity against Meth A fibrosarcoma of chemically synthesized lipopeptide analogs, S-[2,3-bis(palmitoyloxy)-2R-propyl]-N-[(2,2,2)-tri- chloroethoxycarbonyl: Troc group]-cysteinyl-seryl-seryl-asparaginyl-alanine (compound KAB-2), which contain the amino acid sequence of lipopeptide in Escherichia coli, S-[2,3-bis(palmitoyloxy)- 2R-propyl]-N-(Troc- or amino-group)-cysteinyl-asparaginyl-seryl-glycyl-glycine (compound KAB-14 or -20), which is found in the amino acid sequence of lipopeptide in Streptomyces, and the compounds binding one to six amino acids, were examined. The analogs showed the mitogenic activity toward splenocytes of C3H/He mice. Low concentrations (0.4 and 2.0 micrograms/ml) of compounds KAB-20 and -21, which have five and six amino acids, respectively, increased the incorporation of [3H]thymidine better than a high concentration (50 micrograms/ml), suggesting that KAB compounds carrying amino groups exert better mitogenicity than KAB compounds carrying Troc group. The decrease of amino acid number in lipopeptide analogs appears to result in a lowering of mitogenicity at low concentrations. KAB-14 and KAB-2 did not exhibit the lethality at a high dose of 50 micrograms/mouse in galactosamine-loaded C57BL/6 mice. By twice intravenous injections of 50 micrograms against Meth A fibrosarcoma in BALB/c mice, KAB-2 showed a higher inhibitory effect than KAB-14. Based on these results, we concluded that the difference of amino acid sequence in the synthetic lipopeptides affects the potency of biologic activities.
Asunto(s)
Antineoplásicos/farmacología , Fibrosarcoma/tratamiento farmacológico , Lipoproteínas/farmacología , Secuencia de Aminoácidos , Animales , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Ensayos de Selección de Medicamentos Antitumorales , Galactosamina/farmacología , Lipoproteínas/síntesis química , Lipoproteínas/toxicidad , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Datos de Secuencia MolecularRESUMEN
The synthesis of optically active lipopeptide derivatives has been accomplished by the use of chiral glycerol derivatives. Lipopeptide derivatives with (R)-glycerol moieties showed higher mitogenic activities than those with the (S)-configuration. N-2,2,2-Trichloroethoxycarbonyl lipopeptide derivatives increased mitogenic activity.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/síntesis química , Escherichia coli/metabolismo , Lipoproteínas/síntesis química , Secuencia de Aminoácidos , Proteínas de la Membrana Bacteriana Externa/farmacología , Cromatografía en Capa Delgada , Lipoproteínas/farmacología , Mitógenos/síntesis química , Mitógenos/farmacología , Datos de Secuencia Molecular , EstereoisomerismoRESUMEN
Mitogenicity, lethal toxicity, induction of tumor necrotizing factor (TNF), and antitumor activity against Meth A fibrosarcoma of four chemically synthesized lipopentapeptide analogs, S-[2,3-bis(palmitoyloxy)-2R (designated as KAB-1), -2S(KAB-3)-propyl]-N-palmitoyl-(R)-cysteinyl-(S)-seryl- (S)-seryl-(S)-asparaginyl-(S)-alanine, S-[2,3-bis(palmitoyloxy)-2R(KAB-2), and -2S(KAB-4)-propyl]-N-[(2,2,2)-trichloroethoxycarbonyl]-(R)- cysteinyl-(S)-seryl-(S)-seryl-(S)-asparaginyl-(S)-alanine, of bacterial lipoprotein were investigated. These four analogs, as well as bacterial lipopolysaccharide (LPS) or synthetic Escherichia coli-type lipid A (506), were capable of increasing of [3H]thymidine into splenocytes of C3H/He mice. Although LPS and 506 did not exhibit the mitogenic activity in C3H/HeJ mice, KAB compounds showed remarkable mitogenicity. These analogs did not show the lethal toxicity at a high dose of 50 micrograms/mouse in galactosamine-loaded C57BL/6 mice. Peritoneal macrophages, stimulated with four analogs, caused the production of TNF which induces the L929 cell lysis in vitro. Twice, intravenous injections of 50 micrograms/mouse of these analogs showed weak growth inhibition of Meth A fibrosarcoma in BALB/c mice. The inhibitory effect of KAB-2 compound, which caused the strong TNF-induction among the four analogs, was the most potent. These results indicate that the biological activity of KAB-2 (R-configuration of the C-2 position in glycerol moiety with dipalmitoyl) is stronger than that of the other three analogs.