Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 17 de 17
Filtrar
1.
Sci Transl Med ; 11(502)2019 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-31341059

RESUMEN

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.


Asunto(s)
Autoinmunidad/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , TYK2 Quinasa/química , Animales , Femenino , Voluntarios Sanos , Compuestos Heterocíclicos/farmacología , Humanos , Interferón alfa-2/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Inhibidores de Proteínas Quinasas/farmacología , TYK2 Quinasa/antagonistas & inhibidores
2.
J Forensic Sci ; 61 Suppl 1: S163-70, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26292990

RESUMEN

Domestic homicide is the most extreme form of domestic violence and one of the most common types of homicide. The objective was to examine differences between spontaneous domestic homicide and nondomestic homicide offenders regarding demographics, psychiatric history, crime characteristics, and neuropsychological status, utilizing neuropsychological test data from forensic examinations of 153 murderers. Using standard crime classification criteria, 33% committed spontaneous domestic homicides (SDH) and 61% committed nondomestic homicides (NDH). SDH offenders were more likely to manifest psychotic disorders, but less likely to be diagnosed with antisocial personality disorder or to have prior felony convictions. SDH offenders manifested significantly worse neuropsychological impairments than NDH offenders. The mean number of victims was lower for the SDH than the NDH group and only 14% of SDH offenders used a firearm, whereas 59% of NDH offenders used a firearm. These findings corroborate the notion that spontaneous domestic homicide may represent a discernible criminological phenotype.


Asunto(s)
Conducta Criminal , Violencia Doméstica , Homicidio , Fenotipo , Víctimas de Crimen , Familia , Femenino , Humanos , Relaciones Interpersonales , Masculino
3.
Bioorg Med Chem Lett ; 23(20): 5571-4, 2013 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-24011644

RESUMEN

A series of heterocyclic glucocorticoid receptor (GR) modulators with 2,2-dimethyl-3-phenyl-N-(thiazol or thiadiazol-2-yl)propanamide core are described. Structure-activity relationships suggest a combination of H-bond acceptor and a 4-fluorophenyl moiety as being important structural components contributing to the glucocorticoid receptor binding and functional activity for this series of GR modulators.


Asunto(s)
Amidas/química , Compuestos Heterocíclicos/química , Receptores de Glucocorticoides/agonistas , Tiadiazoles/química , Tiazoles/química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/metabolismo , Unión Proteica , Receptores de Glucocorticoides/metabolismo , Estereoisomerismo , Relación Estructura-Actividad
4.
Bioorg Med Chem Lett ; 23(19): 5442-7, 2013 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-23953070

RESUMEN

Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure.


Asunto(s)
Amidas/química , Amidas/farmacología , Descubrimiento de Drogas , Receptores de Glucocorticoides/agonistas , Sitios de Unión , Cristalografía por Rayos X , Humanos , Indazoles/química , Indazoles/farmacología , Estructura Molecular , Unión Proteica/efectos de los fármacos , Esteroides/química , Esteroides/farmacología , Relación Estructura-Actividad
5.
Bioorg Med Chem Lett ; 23(19): 5448-51, 2013 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-23916594

RESUMEN

SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors.


Asunto(s)
Indazoles/síntesis química , Indazoles/farmacología , Receptores de Glucocorticoides/agonistas , Amidas/química , Amidas/farmacología , Humanos , Indazoles/química , Modelos Moleculares , Unión Proteica/efectos de los fármacos , Receptores de Glucocorticoides/química , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Urea/química , Urea/farmacología
6.
Behav Sci Law ; 31(2): 286-305, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23613146

RESUMEN

The ability of capital juries to accurately predict future prison violence at the sentencing phase of aggravated murder trials was examined through retrospective review of the disciplinary records of 115 male inmates sentenced to either life (n = 65) or death (n = 50) in Oregon from 1985 through 2008, with a mean post-conviction time at risk of 15.3 years. Violent prison behavior was completely unrelated to predictions made by capital jurors, with bidirectional accuracy simply reflecting the base rate of assaultive misconduct in the group. Rejection of the special issue predicting future violence enjoyed 90% accuracy. Conversely, predictions that future violence was probable had 90% error rates. More than 90% of the assaultive rule violations committed by these offenders resulted in no harm or only minor injuries.


Asunto(s)
Pena de Muerte/estadística & datos numéricos , Derecho Penal/estadística & datos numéricos , Criminales/estadística & datos numéricos , Prisioneros/estadística & datos numéricos , Violencia/estadística & datos numéricos , Femenino , Homicidio , Humanos , Masculino , Prisiones , Probabilidad , Medición de Riesgo
7.
Law Hum Behav ; 36(4): 356-63, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22849420

RESUMEN

This large-scale study (N = 23,277) investigated the relationship between criminal history in the community and serious or assaultive prison misconduct, while controlling for the effects of inmate characteristics, general criminality, and custody level. Community violence variables included the rate of prior violent crime arrests and the types of prior violent crime, as well as a range of specific violent crimes of conviction. Behavioral continuity from community to prison was neither simple nor intuitively discernible, depending on the type, recency, and pattern of community criminality. Application of logistic regression models revealed that the omnibus measure of the rate of prior violent arrests was not related to either serious or assaultive prison misconduct. Prior arrests for assault and current convictions for robbery and/or assault, but not prior or current homicides, were associated with an increased risk for prison violence. Current conviction for a sexual assault had the strongest inverse relationship to prison violence, while prior arrests for sexual assault showed no relationship to prison violence. A more "nuanced" approach in assigning risk ratings based on prior criminal history and seriousness of offense is recommended.


Asunto(s)
Prisiones , Violencia/clasificación , Adulto , Estudios Transversales , Femenino , Humanos , Modelos Logísticos , Masculino , Oregon , Medición de Riesgo , Adulto Joven
8.
Behav Sci Law ; 29(1): 1-22, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21105010

RESUMEN

The accuracy of three decades of Texas jury predictions of future violence by capital defendants was tested through retrospective review of the disciplinary records of former death row (FDR) inmates in Texas (N = 111) who had been sentenced to death under this "special issue" and subsequently obtained relief from their death sentences between 1989 and 2008. FDR inmates typically had extended tenures on death row (M = 9.9 years) and post-relief in the general prison population (M = 8.4 years). FDR prevalence of serious assault was low, both on death row (3.6%) and upon entering the prison population (4.5%). None of the assaults resulted in life-threatening injuries to the victims. Violence among the FDR inmates was not disproportionate compared with life-sentenced capital offenders. Consistent with other research, juror expectations of serious prison violence by these offenders had high error (i.e., false positive) rates. The confidence of legislators and courts in the violence prediction capabilities of capital jurors is misplaced.


Asunto(s)
Pena de Muerte , Prisioneros , Violencia/estadística & datos numéricos , Adolescente , Adulto , Femenino , Predicción , Homicidio/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Prisioneros/psicología , Estudios Retrospectivos , Texas , Violencia/prevención & control
9.
J Am Acad Psychiatry Law ; 38(1): 61-72, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20305077

RESUMEN

The postconviction prison disciplinary records of capital defendants (n = 73) who had been the subject of defense-sponsored violence risk assessments or risk-related testimony (1995-2007) that asserted an improbability of future serious prison violence were analyzed. During postconviction prison tenures averaging 4.4 years, none of the capital defendants was cited for accomplished serious assaults. The prevalence of misconduct was inversely related to severity: 54.8 percent were cited for some disciplinary misconduct, 27.4 percent for potentially violent disciplinary violations, 12.3 percent for assaultive misconduct, and 1.4 percent for attempted serious assault. Rates of misconduct among the capital offenders were equivalent to those among all inmates (n = 18,561, annual average) in high-security federal prisons (2001-2005). The accuracy rate of forecasts of improbability stands in sharp contrast to that of prosecution-sponsored expert testimony at capital sentencing that had asserted high rates of future violence.


Asunto(s)
Pena de Muerte/legislación & jurisprudencia , Testimonio de Experto , Psiquiatría Forense , Prisioneros , Violencia/estadística & datos numéricos , Adulto , Predicción , Humanos , Modelos Logísticos , Persona de Mediana Edad , Medición de Riesgo , Estados Unidos
10.
J Med Chem ; 53(3): 1270-80, 2010 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-20047280

RESUMEN

The first stereoselective synthesis of the hexahydroimidazo[1,5b]isoquinoline (HHII) scaffold as a surrogate for the steroidal A-B ring system is described. The structure-activity relationships of the analogs derived from this scaffold show that the basic imidazole moiety is tolerated by the glucocorticoid receptor (GR) in terms of binding affinity, although the partial agonist activity in the transrepressive assays depends on the substitution pattern on the B-ring. More importantly, most compounds in the HHII series bearing a tertiary alcohol moiety on the B-ring are either inactive or significantly less active in inducing GR-mediated transactivation, thus displaying a "dissociated" pharmacology in vitro.


Asunto(s)
Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Receptores de Glucocorticoides/agonistas , Dexametasona/farmacología , Selectina E/genética , Selectina E/metabolismo , Genes Reporteros , Células HeLa , Humanos , Isoquinolinas/química , Pulmón/citología , Pulmón/efectos de los fármacos , Estructura Molecular , Regiones Promotoras Genéticas , Relación Estructura-Actividad , Transcripción Genética , Activación Transcripcional
11.
Law Hum Behav ; 32(1): 46-63, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17876695

RESUMEN

The federal prison disciplinary records of federal capital inmates (n=145) who were sentenced to life without possibility of release (LWOP) by plea bargain, pre-sentencing withdrawal of the death penalty, or jury determination were retrospectively reviewed (M=6.17 years post-admission). Disaggregated prevalence rates were inversely related to infraction severity: serious infraction =0.324, assaultive infraction =0.207, serious assault =0.09, assault with moderate injury =0.007, assault with major injuries or death =0.00. Frequency rates of misconduct were equivalent to other high-security federal inmates (n=18,561), regardless of infraction severity. Government assertions of "future dangerousness" as a nonstatutory aggravating factor were not predictive of prison misconduct. These findings inform federal capital risk assessments and have public policy implications for procedural reliability in death penalty prosecutions.


Asunto(s)
Pena de Muerte , Prisiones , Violencia , Adulto , Femenino , Humanos , Masculino , Estudios Retrospectivos , Medición de Riesgo , Estados Unidos , Violencia/estadística & datos numéricos
12.
Am Psychol ; 61(8): 828-839, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17115827

RESUMEN

An assertion that a capital offender will engage in future acts of criminal violence is a factor in determining "death worthiness" in many jurisdictions of the United States. The legislative conception and court affirmation of this issue as a capital consideration were products of the parole policy and prison capability of an earlier era as well as of the limitations of risk assessment methodology and findings at that time. The intuitive assumptions that support assertions of future dangerousness as a death penalty issue have been rendered irrelevant by changing prison conditions and parole policies or have been refuted by current findings. This raises important questions for a reasoned public policy in capital sentencing. ((c) 2006 APA, all rights reserved).


Asunto(s)
Pena de Muerte/legislación & jurisprudencia , Conducta Peligrosa , Jurisprudencia , Humanos , Estados Unidos , Violencia
13.
Assessment ; 13(3): 253-65, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16880278

RESUMEN

An investigation and extension of the Risk Assessment Scale for Prison (RASP-Potosi), an actuarially derived scale for the assessment of prison violence, was undertaken through a retrospective review of the disciplinary records of the first 12 months of confinement of a cohort of inmates entering the Florida Department of Corrections in 2002 and remaining throughout 2003 (N=14,088). A near replication of the RASP-Potosi and additional analyses based on other weighted logistic regression models were performed on an inmate subsample for whom all information categories were available (n=13,341). Younger age and shorter sentences were associated with increased violent misconduct. Older age, drug conviction, and higher educational attainment were associated with reduced violent misconduct. Regardless of whether the original RASP-Potosi or its progeny were utilized, or the custody level of the inmate sample, the models were modestly successful in predicting prison violence, with the area under the curve (AUC) ranging from .645 to .707.


Asunto(s)
Análisis Actuarial , Prisioneros , Medición de Riesgo , Violencia , Adulto , Factores de Edad , Escolaridad , Femenino , Florida/epidemiología , Humanos , Modelos Logísticos , Masculino , Estudios Retrospectivos , Factores de Riesgo , Trastornos Relacionados con Sustancias/epidemiología
14.
Behav Sci Law ; 23(3): 307-20, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15968709

RESUMEN

Death-sentenced inmates in Missouri have been integrated or "mainstreamed" into the general population of the Potosi Correctional Center since 1991. By comparing the rate of violent misconduct among these mainstreamed death-sentenced inmates with that of the life-without-parole and parole eligible inmates under fully integrated conditions of confinement, this study provides the first empirical (statistical) evaluation of this innovative alternative to segregated death row confinement. The mainstreamed death-sentenced inmates committed no inmate or staff homicides, or attempted homicides. Comparison of their rates of institutional violence revealed frequencies that were similar to those of life-without-parole inmates, and well below those of fellow inmates who were sentenced to parole eligible terms. These findings cast serious doubt on the security-driven assumptions that have typified the segregation of death-sentenced inmates and have dictated highly restrictive confinement policies for this group. A conclusion that death-sentenced inmates can be safely integrated into a general prison population has significant implications for allocation of scarce fiscal resources and correctional staff, as well as for inmate mental health, particularly given the extended tenure that death-sentenced inmates typically serve between sentencing and relief/execution.


Asunto(s)
Pena de Muerte , Prisioneros/psicología , Violencia/tendencias , Adulto , Humanos , Missouri , Prisiones , Seguridad , Aislamiento Social
15.
Assessment ; 12(1): 40-9, 2005 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15695742

RESUMEN

An experimental scale for the assessment of prison violence risk among maximum security inmates was developed from a logistic regression analysis involving inmates serving parole-eligible terms of varying length (n = 1,503), life-without-parole inmates (n = 960), and death-sentenced inmates who were mainstreamed into the general prison population (n = 132). Records of institutional violent misconduct of these 2,595 inmates were retrospectively examined for an 11-year period (1991 to 2002). Predictors affecting the likelihood of such misconduct included age, type and length of sentence, education, prior prison terms, prior probated sentences, and years served. The scale was modestly successful, as demonstrated by an overall omnibus area under the curve of .719. Double cross-validation demonstrated minimal shrinkage. The authors have termed this experimental scale the Risk Assessment Scale for Prison.


Asunto(s)
Prisioneros/psicología , Medición de Riesgo/métodos , Violencia/psicología , Adulto , Factores de Edad , Escolaridad , Humanos , Modelos Logísticos , Masculino , Missouri , Análisis de Regresión , Estudios Retrospectivos , Factores de Tiempo
16.
Biochem Biophys Res Commun ; 300(2): 403-7, 2003 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-12504098

RESUMEN

The nuclear import of transcription factors involves proteins termed karyopherins. Previously, we described an intracellular targeted dual nuclear localization sequence (NLS) peptide inhibitor of processes dependent upon the transcription factor NF-kappa B. We have now developed a homogeneous solution based assay and show that NF-kappa B interacts with karyopherin alpha and that the dual NLS peptide inhibits this interaction. We also show that both L- and D-amino acid containing peptides bind well to karyopherin alpha 2, whereas, the L-amino acid peptides bind more efficiently than the D-amino acid peptide to karyopherin alpha1.


Asunto(s)
FN-kappa B/metabolismo , Señales de Localización Nuclear/farmacología , alfa Carioferinas/efectos de los fármacos , Animales , Células COS , Citoplasma/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Señales de Localización Nuclear/metabolismo , Transporte de Proteínas , Espectrometría de Fluorescencia , alfa Carioferinas/metabolismo
17.
Behav Sci Law ; 20(1-2): 191-210, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-11979498

RESUMEN

This article reviews and summarizes research on death row inmates. The contributions and weaknesses of death row demographic data, clinical studies, and research based on institutional records are critiqued. Our analysis shows that death row inmates are overwhelmingly male and disproportionately Southern. Racial representation remains controversial. Frequently death row inmates are intellectually limited and academically deficient. Histories of significant neurological insult are common, as are developmental histories of trauma, family disruption, and substance abuse. Rates of psychological disorder among death row inmates are high, with conditions of confinement appearing to precipitate or aggravate these disorders. Contrary to expectation, the extant research indicates that the majority of death row inmates do not exhibit violence in prison even in more open institutional settings. These findings have implications for forensic mental health sentencing evaluations, competent attorney representation, provision of mental health services, racial disparity in death sentences, death row security and confinement policies, and moral culpability considerations. Future research directions on death row populations are suggested.


Asunto(s)
Adaptación Psicológica , Pena de Muerte , Prisioneros/psicología , Prisioneros/estadística & datos numéricos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Trastornos Mentales/epidemiología , Persona de Mediana Edad , Factores Socioeconómicos , Estados Unidos/epidemiología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA