RESUMEN
Quantitative structure-activity relationship (QSAR) models are powerful in silico tools for predicting the mutagenicity of unstable compounds, impurities and metabolites that are difficult to examine using the Ames test. Ideally, Ames/QSAR models for regulatory use should demonstrate high sensitivity, low false-negative rate and wide coverage of chemical space. To promote superior model development, the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Japan (DGM/NIHS), conducted the Second Ames/QSAR International Challenge Project (2020-2022) as a successor to the First Project (2014-2017), with 21 teams from 11 countries participating. The DGM/NIHS provided a curated training dataset of approximately 12,000 chemicals and a trial dataset of approximately 1,600 chemicals, and each participating team predicted the Ames mutagenicity of each trial chemical using various Ames/QSAR models. The DGM/NIHS then provided the Ames test results for trial chemicals to assist in model improvement. Although overall model performance on the Second Project was not superior to that on the First, models from the eight teams participating in both projects achieved higher sensitivity than models from teams participating in only the Second Project. Thus, these evaluations have facilitated the development of QSAR models.
Asunto(s)
Mutágenos , Relación Estructura-Actividad Cuantitativa , Mutágenos/toxicidad , Mutágenos/química , Pruebas de Mutagenicidad , Mutagénesis , JapónRESUMEN
Use of antipsychotic medications has been associated consistently with weight gain and metabolic disturbances, and a subsequent increased risk for diabetes and cardiovascular disease. Two experiments tested whether CORT 108297, a newly identified selective glucocorticoid antagonist could (i) reduce and (ii) prevent olanzapine-induced weight gain in rats. In the first experiment, rats dosed only with olanzapine gained a statistically significant amount of weight. When vehicle was added to their olanzapine dose, they continued to gain weight; when CORT 108297 was added to their regimen, they lost a significant amount of weight. Rats administered CORT 108297 plus olanzapine had significantly less abdominal fat than those who received olanzapine alone. In the second experiment, rats receiving olanzapine plus CORT 108297 gained significantly less weight than rats receiving only olanzapine. Increasing doses of CORT 108297 were associated with less weight gain.
Asunto(s)
Antipsicóticos/efectos adversos , Compuestos Aza/farmacología , Benzodiazepinas/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Receptores de Glucocorticoides/antagonistas & inhibidores , Aumento de Peso/efectos de los fármacos , Animales , Peso Corporal , Femenino , Olanzapina , RatasRESUMEN
BACKGROUND: FG syndrome (FGS) is an X-linked disorder characterised by mental retardation, hypotonia, particular dysmorphic facial features, broad thumbs and halluces, anal anomalies, constipation, and abnormalities of the corpus callosum. A behavioural phenotype of hyperactivity, affability, and excessive talkativeness is very frequent. The spectrum of clinical findings attributed to FGS has widened considerably since the initial description of the syndrome by Opitz and Kaveggia in 1974 and has resulted in clinical variability and genetic heterogeneity. In 2007, a recurrent R961W mutation in the MED12 gene at Xq13 was found to cause FGS in six families, including the original family described by Opitz and Kaveggia. The phenotype was highly consistent in all the R961W positive patients. METHODS: In order to determine the prevalence of MED12 mutations in patients clinically diagnosed with FGS and to clarify the phenotypic spectrum of FGS, 30 individuals diagnosed previously with FGS were evaluated clinically and by MED12 sequencing. RESULTS: The R961W mutation was identified in the only patient who had the typical phenotype previously associated with this mutation. The remaining 29 patients displayed a wide variety of features and were shown to be negative for mutations in the entire MED12 gene. A definite or possible alternative diagnosis was identified in 10 of these patients. CONCLUSION: This report illustrates the difficulty in making a clinical diagnosis of FGS given the broad spectrum of signs and symptoms that have been attributed to the syndrome. Individuals with a phenotype consistent with FGS require a thorough genetic evaluation including MED12 mutation analysis. Further genetic testing should be considered in those who test negative for a MED12 mutation to search for an alternative diagnosis.
Asunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Discapacidad Intelectual Ligada al Cromosoma X/genética , Anomalías Múltiples/patología , Adolescente , Sustitución de Aminoácidos , Niño , Preescolar , Femenino , Humanos , Masculino , Complejo Mediador , Discapacidad Intelectual Ligada al Cromosoma X/patología , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Mutación , Fenotipo , Receptores de Hormona Tiroidea/genética , SíndromeRESUMEN
3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) stimulates the transporter-mediated release of monoamines, including 5-HT. High-dose exposure to MDMA causes persistent 5-HT deficits (e.g. depletion of brain 5-HT) in animals, yet the functional and clinical relevance of such deficits are poorly defined. Here we examine functional consequences of MDMA-induced 5-HT depletions in rats. Male rats received binges of three i.p. injections of MDMA or saline, one injection every 2 h; MDMA was given at a threshold pharmacological dose (1.5 mg/kgx3, low dose) or at a fivefold higher amount (7.5 mg/kgx3, high dose). One week later, jugular catheters and intracerebral guide cannulae were implanted. Two weeks after binges, rats received acute i.v. challenge injections of 1 and 3 mg/kg MDMA. Neuroendocrine effects evoked by i.v. MDMA (prolactin and corticosterone secretion) were assessed via serial blood sampling, while neurochemical effects (5-HT and dopamine release) were assessed via microdialysis in brain. MDMA binges elevated core temperatures only in the high-dose group, with these same rats exhibiting approximately 50% loss of forebrain 5-HT 2 weeks later. Prior exposure to MDMA did not alter baseline plasma hormones or dialysate monoamines, and effects of i.v. MDMA were similar in saline and low-dose groups. By contrast, rats pretreated with high-dose MDMA displayed significant reductions in evoked hormone secretion and 5-HT release when challenged with i.v. MDMA. As tolerance developed only in rats exposed to high-dose binges, hyperthermia and 5-HT depletion are implicated in this phenomenon. Our results suggest that MDMA tolerance in humans may reflect 5-HT deficits which could contribute to further dose escalation.
Asunto(s)
Encéfalo/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Tolerancia a Medicamentos , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Serotoninérgicos/toxicidad , Serotonina/deficiencia , Animales , Temperatura Corporal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Líquido Extracelular/efectos de los fármacos , Líquido Extracelular/metabolismo , Fiebre/inducido químicamente , Fiebre/metabolismo , Fiebre/fisiopatología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Infusiones Intravenosas , Infusiones Parenterales , Masculino , Microdiálisis , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Transmisión Sináptica/efectos de los fármacosRESUMEN
This study reviews use of video exposure monitoring (VEM, also known as PIMEX) as an occupational hygiene tool since its inception in the mid-1980s. VEM involves the combination of real-time monitoring instruments, usually for gases/vapours and dust, with video of the worker's activities. VEM is an established method used by practitioners in different countries. The technical aspects of these VEM systems are described, then applications of VEM are discussed, focussing on task analysis, training (risk communication), encouraging worker participation in and motivation for improvements in the workplace environment and occupational hygiene research. The experiences from these applications are used to illustrate how exposure visualization with video can act as a catalyst, initiating a change process in the workplace. Finally, the role of VEM as a workplace improvement tool, now and in the future, is discussed.
Asunto(s)
Monitoreo del Ambiente/instrumentación , Exposición Profesional/análisis , Grabación en Video/instrumentación , Monitoreo del Ambiente/métodos , Gases/análisis , Humanos , Salud Laboral , Análisis y Desempeño de Tareas , Interfaz Usuario-ComputadorRESUMEN
A video-visualization technique, using a combination of a fast-response, direct-reading, personal gas monitor (photo-ionization detector) and synchronized video monitoring (with a standard camcorder), has been applied to assess exposure to solvents in various industries. The objective is to understand how short-term peaks occur and how they can be controlled to minimise both short-term exposure and their contribution to long-term exposure. The technique was employed to identify peaks associated with work activities and their contribution to total exposure arising from use of tetrachloroethene in a dry cleaning establishment. The exposure and video data are simultaneously displayed on computer and the information is disseminated on CD (and video), forming the basis of a detailed occupational hygiene assessment or training material.
RESUMEN
Electronic medical records (EMRs) offer many advantages. However, there are also risks involved with adopting a full commercial EMR. These include high cost, the disruption of clinic routines, and poor or no vendor support. We created and implemented a partial, or miniature EMR (mini EMR) based on Microsoft Access 97 (Microsoft Corporation; Redmond, Wash). This program serves as an electronic front sheet for the patient chart that records International Classification of Diseases--9th revision codes and chronic medications and allergies, and provides reminders for prevention procedures. The mini EMR has been inexpensive, adaptable, easy to maintain, and very well accepted, and it has caused little interruption of our clinical activities. We believe the program can serve as a bridge to a future commercial EMR once that market has matured.
Asunto(s)
Sistemas de Registros Médicos Computarizados/economía , Sistemas de Registros Médicos Computarizados/instrumentación , Análisis Costo-Beneficio , Diseño de Equipo , Medicina Familiar y Comunitaria/educación , Medicina Familiar y Comunitaria/métodos , Humanos , North Carolina , Sensibilidad y EspecificidadRESUMEN
A series of indole- and carbazole-substituted pyridinium iodide salts has been synthesized and characterized. X-ray analysis revealed that the iodide salt of the indole-substituted cation (E)-4-(1H-indol-3-ylvinyl)-N-methylpyridinium (IMPE(+)), C(16)H(15)N(2)(+) x I(-), (I), has two polymorphic modifications, (Ia) and (Ib), and a hemihydrate structure, C(16)H(15)N(2)(+) x I(-) x 0.5H(2)O, (II). Until now, only one crystal modification has been identified for the (E)-4-(9-ethyl-9H-carbazol-3-ylvinyl)-N-methylpyridinium (ECMPE(+)) iodide salt, C(22)H(21)N(2)(+) x I(-), (III). Crystals of (Ia) and (Ib) comprise stacks of antiparallel cations with iodide anions located in the channels between the stacks. Due to the presence of the water molecules, the packing in (II) is quite different to that found in (Ia) and (Ib), and positional disorder involving a statistical superposition of two rotamers of IMPE(+), with different orientations of the indole fragment, was found. Crystals of (III) contain two independent ECMPE(+) rotamers with different orientations of their carbazole substituents. The cations are packed in stacks, with the iodide anions located in the channels between the stacks. In (III), the iodide was found to be disordered over two sites, with occupancies of 0.83 and 0.17.
RESUMEN
OBJECTIVE: To evaluate the consistency of pediatric asthma care with the National Asthma Education and Prevention Program Guidelines. DESIGN: Cross-sectional survey at 2 managed care organizations in the United States (winter 1997-1998). The participants were parents of children (n = 318) age 5 to 17 years with asthma. There were no interventions. The outcome measures were indicators of care in 4 domains: (1) periodic physiologic assessment, (2) proper use of medications, (3) patient education, and (4) control of factors contributing to asthma severity. RESULTS: Of 533 eligible patients with asthma, 318 (60%) parents responded; 59% of children were male, 76% were white, and 60% were aged 5 to 10 years. Deficiencies in care were identified in all care domains including, for patients with moderate and severe persistent symptoms, only 55% used long-term control medication daily, 49% had written instructions for handling asthma attacks, 44% had instructions for adjustment of medication before exposures, 56% had undergone allergy testing, and 54% had undergone pulmonary function testing. CONCLUSIONS: There are significant opportunities to improve the quality of care for children with asthma enrolled in managed care. A comprehensive approach to improving care may be necessary to address multiple aspects of care where opportunities exist.
Asunto(s)
Asma/terapia , Adhesión a Directriz/normas , Programas Controlados de Atención en Salud/normas , Pediatría/normas , Guías de Práctica Clínica como Asunto , Calidad de la Atención de Salud , Adolescente , Asma/diagnóstico , Asma/etiología , Actitud Frente a la Salud , Niño , Preescolar , Estudios Transversales , Femenino , Adhesión a Directriz/estadística & datos numéricos , Investigación sobre Servicios de Salud , Humanos , Masculino , Programas Controlados de Atención en Salud/estadística & datos numéricos , Medio Oeste de Estados Unidos , Evaluación de Necesidades/organización & administración , New England , Evaluación de Resultado en la Atención de Salud , Padres/educación , Padres/psicología , Educación del Paciente como Asunto/normas , Pediatría/métodos , Pediatría/estadística & datos numéricos , Indicadores de Calidad de la Atención de Salud , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Gestión de la Calidad Total/organización & administraciónRESUMEN
We studied the pharmacological properties of twenty-four 5-hydroxytryptamine (5-HT)(4) receptor ligands known to act as antagonists on 5-HT(4) receptors positively coupled to adenylyl cyclase endogenously expressed in mouse colliculi neurons. In COS-7 cells expressing human or mouse 5-HT(4(a)) receptors (100-8000 fmol/mg of protein), we found neutral antagonists, partial agonists, and inverse agonists. The majority of neutral antagonists belong to the benzodioxanyl ketone class, whereas partial agonists belong to different chemical classes. We found only two inverse agonists, GR 125487 and SB 207266, which are both indoles. Analysis of pharmacological characteristics of the constitutively active wild-type and constitutively active mutated receptors revealed that 1) the ratio between the efficiencies of the full agonist 5-HT and the partial agonist RS 23597 was invariable when the receptor density increased, but was dependent on receptor structure; 2) similarly, the efficacy of the inverse agonist SB 207266 was not dependent on receptor density but was dependent on receptor structure; 3) when the receptor concentration increased, the EC(50) values of the full agonist 5-HT were not modified and the increase in basal constitutive activity, as well as its stimulation by 5-HT, followed a parallel evolution; and 4) the stimulation of basal constitutive activity by 5-HT was not modified by the overexpression of Galphas. All these results indicate that in COS-7 cells, the coupling of the 5-HT(4) receptor to adenylyl cyclase was linear with no indication of spare receptors even at high receptor density (8 pmol/mg). These results are also in accordance with a precoupling between the activated receptor (f(R*)) and adenylyl cyclase. Such observations allowed us to use the two-state model to calculate the constant J, i.e., the equilibrium allosteric constant denoting the ratio of the receptor in the inactive versus active state (J = [R]/[R*]). We found that J was a receptor structural characteristic, independent of receptor density.
Asunto(s)
AMP Cíclico/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Adenilil Ciclasas/metabolismo , Regulación Alostérica , Aminobenzoatos/farmacología , Animales , Células COS , Relación Dosis-Respuesta a Droga , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Humanos , Indoles/farmacología , Ratones , Modelos Biológicos , Mutación , Piperidinas/farmacología , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/genética , Receptores de Serotonina 5-HT4 , Sulfonamidas/farmacología , Transfección , para-AminobenzoatosRESUMEN
Carbon-11 labelled RS-15385-197 and its ethylsulphonyl analogue, RS-79948-197, were evaluated in rats as potential radioligands to image central alpha2-adrenoceptors in vivo. The biodistributions of both compounds were comparable with that obtained in an earlier study using tritiated RS-79948-197 and were consistent with the known localisation of alpha2-adrenoceptors. The maximal signals (total to non-specific binding) were, however, reduced, in the order [11C]RS-79948-197 < [11C]RS-15385-197 < [3H]RS-79948-197, primarily due to the difference in radiolabel position (O-methyl for carbon- 11 compared with S-ethyl for tritium). This resulted in the in-growth of radiolabelled metabolites in plasma, which, in turn, contributed to the non-specific component of brain radioactivity. Nonetheless, the signal ratio of approximately 5 for a receptor-dense tissue compared with the receptor-sparse cerebellum, at 90-120 min after radioligand injection, encouraged the development of [O-methyl-11C]RS-15385-197 for human positron emission tomography (PET). Unfortunately, in two human PET scans (each of 90 min), brain extraction of the radioligand was minimal, with volumes of distribution more than an order of magnitude lower than that measured in rats. Following intravenous injection, radioactivity was retained in plasma and metabolism of the radiolabelled compound was very low. Retrospective measurements of in vitro plasma protein binding and in vivo brain uptake index (BUI) in rats demonstrated a higher protein binding of the radioligand in human compared with rat plasma and a lower BUI in the presence of human plasma. It is feasible that a higher affinity of RS-15385-197 for human plasma protein compared with receptor limited the transport of the radioligand. Although one of the PET scans showed a slight heterogeneity in biodistribution of radioactivity which was consistent with the known localisation of alpha2-adrenoceptors in human brain, it was concluded that [O-methyl-11C]RS-15385-197 showed little promise for routine quantification of alpha2-adrenoceptors in man.
Asunto(s)
Isoquinolinas , Naftiridinas , Radiofármacos , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Adulto , Animales , Proteínas Sanguíneas/metabolismo , Encéfalo/diagnóstico por imagen , Cerebelo/diagnóstico por imagen , Humanos , Ligandos , Masculino , Unión Proteica , Ratas , Ratas Sprague-Dawley , Estudios Retrospectivos , Tomografía Computarizada de EmisiónRESUMEN
A computer-aided video exposure monitoring system was used to record exposure information. The system comprised a handheld camcorder, portable video cassette recorder, radio-telemetry transmitter/receiver, and handheld or notebook computers for remote data logging, photoionization gas/vapor detectors (PIDs), and a personal aerosol monitor. The following workplaces were surveyed using the system: dry cleaning establishments--monitoring tetrachoroethylene in the air and in breath; printing works--monitoring white spirit type solvent; tire manufacturing factory--monitoring rubber fume; and a slate quarry--monitoring respirable dust and quartz. The system based on the handheld computer, in particular, simplified the data acquisition process compared with earlier systems in use by our laboratory. The equipment is more compact and easier to operate, and allows more accurate calibration of the instrument reading on the video image. Although a variety of data display formats are possible, the best format for videos intended for educational and training purposes was the review-preview chart superimposed on the video image of the work process. Recommendations for reducing exposure by engineering or by modifying work practice were possible through use of the video exposure system in the dry cleaning and tire manufacturing applications. The slate quarry work illustrated how the technique can be used to test ventilation configurations quickly to see their effect on the worker's personal exposure.
Asunto(s)
Contaminantes Ocupacionales del Aire/análisis , Contaminación del Aire Interior/análisis , Exposición a Riesgos Ambientales/análisis , Microcomputadores , Programas Informáticos , Grabación en Video , Aerosoles , Humanos , Exposición Profesional/análisis , VolatilizaciónRESUMEN
Substructural fingerprints have proven very useful for chemical library and diversity analysis, but their high dimensionality makes them poorly suited to principal components analysis and to standard nonlinear mapping methods. By using a combination of optimizable K-dissimilarity selection (OptiSim) and a modified stress function that suppresses effects of distances that fall beyond a characteristic horizon, it is possible to relax principal components analysis coordinates into more consistently meaningful projections from fingerprint space into two dimensions. The nonlinear maps so obtained are useful for characterizing combinatorial libraries, for comparing sublibraries, and for exploring the distribution of biological properties across structural space.
Asunto(s)
Diseño de Fármacos , Técnicas Químicas Combinatorias , Bases de Datos Factuales , Estructura Molecular , Dinámicas no Lineales , Estadística como AsuntoRESUMEN
BACKGROUND: Overuse of inhaled beta-agonists and underuse of inhaled corticosteroids by patients with asthma may have adverse consequences. This study was performed to identify factors associated with misuse of these types of asthma medication. METHODS: We examined baseline data from a longitudinal survey of adult patients with asthma. The setting was a consortium of 15 national managed care organizations serving 11 large employers. Baseline surveys were completed by 6612 health plan enrollees at least 18 years old who had had at least 2 visits with a diagnostic code for asthma in the preceding 2 years. The main outcome measures were the overuse of inhaled beta-agonists and the underuse of inhaled corticosteroids. Independent variables were patient and process of care factors. RESULTS: Among patients with moderate or severe asthma, 16% of users of inhaled beta-agonists reported overuse (>8 puffs per day on days of use), and 64% of users of inhaled corticosteroids reported underuse (use on < or =4 days/wk or < or =4 puffs per day). Overuse of inhaled beta-agonists was most strongly associated with concomitant treatment with inhaled corticosteroids or anticholinergic agents, increased asthma symptom severity, problems in obtaining asthma medication, and male sex. Underuse of inhaled corticosteroids was associated with nonwhite race, younger age (18 to 34 years), lower use of inhaled beta-agonist, lower symptom severity, and not possessing a peak flow meter. Rates of misuse of medication also varied by speciality of the patient's provider (generalist, allergist, or pulmonologist). CONCLUSIONS: Overuse of inhaled beta-agonists may be caused by symptom severity, while underusers of corticosteroids may interrupt use as symptoms abate. This study demonstrated an important opportunity to improve medication use among patients with asthma.
Asunto(s)
Agonistas Adrenérgicos beta/administración & dosificación , Antiasmáticos/administración & dosificación , Antiinflamatorios/administración & dosificación , Asma/tratamiento farmacológico , Administración por Inhalación , Adulto , Estudios de Cohortes , Esquema de Medicación , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Estudios Longitudinales , Masculino , Programas Controlados de Atención en Salud/estadística & datos numéricos , Análisis Multivariante , Nebulizadores y Vaporizadores , Cooperación del Paciente , EsteroidesRESUMEN
To study the behavioral style or temperament of 45 boys, aged 47 to 88 months, with full-mutation fragile X syndrome (FXS), 102 parent ratings on the Behavioral Style Questionnaire (McDevitt and Carey 1978) were recorded. These ratings were analysed with a variety of statistical techniques. Considerable variability was evident in temperament profiles; consequently, a characteristic profile was not identified for FXS. Boys with FXS differed significantly from the reference sample on five of nine temperament dimensions. They were more active and less intense, approachable, adaptable, and persistent. No significant differences were found in distractibility, rhythmicity, mood, or sensory threshold. Only 16 of the 45 boys in the sample could be classified as easy, difficult, or slow to warm up. There was no link between severity of developmental disability and temperament ratings. This supports the theory that intelligence and temperament are separate constructs. Scores on temperament dimensions were stable over time. Our results suggest that many of the behaviors observed in boys with FXS may be related to temperament. Consequently, parent counseling and environmental modifications should be considered as first line treatment. The question of whether the behavior problems observed in boys with FXS are innate or whether they result from poorness of fit between child and environment is an important issue that needs further study.
Asunto(s)
Trastornos de la Conducta Infantil/etiología , Trastornos de la Conducta Infantil/psicología , Síndrome del Cromosoma X Frágil/complicaciones , Niño , Trastornos de la Conducta Infantil/diagnóstico , Preescolar , Síndrome del Cromosoma X Frágil/genética , Humanos , Masculino , Mutación Puntual/genética , Índice de Severidad de la Enfermedad , Temperamento/fisiologíaRESUMEN
Monilethrix, a rare human hair disorder with autosomal dominant transmission, can be caused by mutations in hair keratins. Up to now, causative mutations have only been found in two type II cortex keratins, hHb6 and hHb1. In these hair keratins, the helix termination motif, HTM, was the only site in which mutations were located. The most frequent mutation, which has been found in 22 cases, was a Glu413Lys substitution in hHb6, whereas other mutations, i.e., hHb6 Glu413Asp, hHb1 Glu413Lys, and hHb1 Glu402Lys, have been reported in a distinctly lower number of cases. In this study, we describe the equivalent of the hHb1 Glu402Lys mutation in the HTM of cortex keratin hHb6. The mutation occurred in an American family in which it could only be detected in one clinically affected individual. Thus the underlying G-->A transition represents a spontaneous germ-line mutation in the hHb6 gene. This new mutation indicates that both the hHb6/hHb1 Glu413Lys substitution and the hHb6/hHb1 Glu402Lys substitution, represent mutational hotspots in the HTM of type II cortex keratins. However, we also describe a monilethrix-causing mutation in the helix initiation motif, HIM, of the cortex keratin hHb6. The critical Asn114Asp substitution was only found in affected members of a large Swedish three-generation family. Considering that since childhood, half of the affected individuals suffer from complete baldness and follicular keratosis, the new HIM mutation seems to be associated with a rather severe disease phenotype. In conclusion, our data strongly suggest that monilethrix is a disease of the hair cortex, whose etiology is interesting in that causative mutations seem to be restricted to type II hair keratins.
Asunto(s)
Enfermedades del Cabello/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Femenino , Secuencias Hélice-Giro-Hélice/genética , Humanos , Queratinas/química , Queratinas/genética , Masculino , Linaje , Mutación PuntualRESUMEN
Posttraumatic stress disorder (PTSD) is characterized by intrusive, avoidance, and hyperarousal symptoms. This study was conducted to investigate the effectiveness of divalproex in reducing PTSD symptoms, depression, and anxiety in patients with PTSD. Sixteen patients with a DSM-IV diagnosis of PTSD at the Albuquerque VAMC outpatient PTSD treatment program received an open-label trial of divalproex. The patients were evaluated at baseline and at 8 weeks by a trained rater using the Clinician Administered PTSD Scale (CAPS), the Hamilton Rating Scale for Depression (HAM-D) and the Hamilton Rating Scale for Anxiety (HAM-A). Plasma valproate levels were measured at the 8-week post-treatment assessment. Three patients stopped the medications due to side effects. Intrusion and hyperarousal symptoms decreased significantly, while no significant change was seen in avoidance/numbing symptoms. Depressive symptoms, as measured by the HAM-D, unexpectedly decreased at post-treatment assessment. HAM-A scores also decreased significantly. Controlled trials are needed to further study the efficacy of divalproex in the treatment of PTSD.
Asunto(s)
Antimaníacos/uso terapéutico , Trastornos por Estrés Postraumático/tratamiento farmacológico , Ácido Valproico/uso terapéutico , Adulto , Anciano , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Trastornos por Estrés Postraumático/diagnóstico , Trastornos por Estrés Postraumático/psicología , Factores de Tiempo , Ácido Valproico/sangreRESUMEN
This study was designed to investigate the efficacy of the antidepressant drug bupropion in the treatment of posttraumatic stress disorder (PTSD). Seventeen male combat veterans with chronic PTSD were treated with bupropion in an open-label fashion for 6 weeks. Patients were evaluated with the Clinical Global Impressions Scale for Improvement (CGI-I) at follow-up and rated blindly at baseline and posttreatment with the Clinician Administered PTSD Scale (CAPS), the Hamilton Rating Scale for Depression (HAM-D), and the Hamilton Rating Scale for Anxiety. Three patients discontinued bupropion prematurely because of side effects. Of the remaining 14 patients, 10 were classified as treatment responders by the CGI-I. HAM-D scores decreased significantly from baseline to follow-up. The improvement seen in hyperarousal symptoms was significant but was less significant than the change in depressive symptoms. There was no significant change in Intrusion, Avoidance, or total CAPS scores. It was concluded that bupropion was well tolerated. Patients who had experienced sexual dysfunction with selective serotonin reuptake inhibitors reported no complaints during bupropion treatment. Bupropion decreased depressive symptoms and most patients reported global improvement, although PTSD symptoms remained mostly unchanged. Controlled trials should further clarify the role of bupropion in the treatment of PTSD.