RESUMEN
An assay to detect the on-target effects of mGlu2/3 receptor antagonists in vivo would be valuable in guiding dosing regimens for the exploration of biological effects of potential therapeutic import. Multiple approaches involving blockade of mGlu2/3 receptor agoinist-driven behavioral effects in mice and rats were investigated. Most of these methods failed to provide a useful method of detection of antagonists in vivo (e.g., locomotor activity). In contrast, the mGlu2/3 receptor agonist LY379268 produced dose-dependent increases in body temperature of mice. The hyperthermic effects of LY379268 was abolished in mGlu2 and in mGlu2/3 receptor null mice but not in mGlu3 null mice. Hyperthermia was not produced by an mGlu8 receptor agonist. Agonist-induced hyperthermia was prevented in a dose-dependent manner by structurally-distinct mGlu2/3 receptor antagonists. The blockade was stereo-specific. Moreover, this biological readout was responsive to both orthosteric and to negative allosteric modulators of mGlu2/3 receptors. Antagonism of agonist-induced hyperthermia predicted antidepressant-like efficacy in the mouse forced swim test. As with the hyperthermic response, the antidepressant-like effects of mGlu2/3 receptor antagonists were shown to be due to mGlu2 and not to mGlu3 or mGlu8 receptors through the use of receptor knock-out mice. The ability to rapidly assess on-target activity of mGlu2/3 receptor antagonists enables determination of parameters for setting efficacy doses in vivo. In turn, efficacy-related data in the preclinical laboratory can help to set expectations of therapeutic potential and dosing in humans.
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Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Fármacos actuantes sobre Aminoácidos Excitadores/uso terapéutico , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/metabolismo , Análisis de Varianza , Animales , Condicionamiento Operante/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Fármacos actuantes sobre Aminoácidos Excitadores/química , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Conducta Exploratoria/efectos de los fármacos , Técnicas In Vitro , Masculino , Ratones , Ratones Noqueados , Movimiento/efectos de los fármacos , Ratas , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/deficienciaRESUMEN
OBJECTIVE: To evaluate the evidence for pre-death grief in caregivers (CGs) of persons with Parkinson's disease (PD) and to compare non-motor PD symptoms (cognitive decline, depression, hallucinations) versus motor symptoms (fluctuations of mobility) for associations with CG grief reactions. BACKGROUND: Prolonged grief in response to loss has been associated with negative outcomes and decreased well-being in caregivers (i.e. spouse or adult child) of relatives with dementia. In Parkinson's disease (PD) the negative impact of providing care has been referred to as caregiver strain. Grief has not been explored in PD caregivers, and understanding grief may offer new insights for future intervention. METHODS: Volunteer caregivers (n = 74) filled out the Marwit and Meuser Caregiver Grief Inventory (MM-CGI-SF) which measures 3 types (i.e. subscales) of grief: Personal Sacrifice and Burden, Heartfelt Sadness and Longing, Worry and Felt Isolation. This scale also provided a total grief score. Volunteer caregivers also responded to self-reported UPDRS questions about the motor and non-motor symptoms of their PD relative (i.e. spouse or parent). T-tests were used to correlate CG subscales of grief with patient variables. A hierarchical regression analysis was used to determine the predictive contribution of motor and nonmotor symptoms to grief. RESULTS: Grief based on the total score was found in 17% of CGs. Grief was significantly higher in CG's whose relative had more severe symptoms. The type of grief experienced was similar across all three subscales. Hierarchical regression analysis revealed that nonmotor symptoms explained slightly more of the variance (14-23%) than motor symptoms (11-17%). CONCLUSIONS: This study revealed that pre-death grief is a significant finding in PD caregivers. The severity of symptoms and the presence of nonmotor symptoms, especially cognitive decline, predict caregivers who are at greatest risk of prolonged grief; however it should be kept in mind that motor symptoms also contribute.
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Actitud Frente a la Muerte , Cuidadores/psicología , Recolección de Datos/métodos , Pesar , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/psicología , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/terapia , Proyectos PilotoRESUMEN
T lymphocytes from patients with sarcoidosis respond weakly when stimulated with mitogen or antigen. However, the mechanisms responsible for this anergy are not fully understood. Here, we investigated the protein levels of nuclear transcription factor NF-κB (p50, p65, and p105), IκBα (inhibitor of NF-κB), T-cell receptor (TCR) CD3ζ-chain, tyrosine kinase p56(LCK), and nuclear factor of activated T cells c2 (NF-ATc2) in peripheral blood CD4(+) T cells from patients with sarcoidosis. Baseline expression of p65 in these lymphocytes was reduced in 50% of patients. The reduced levels of p65 in sarcoid CD4(+) T cells concurred with decreased levels of p50, p105, CD3ζ, p56(LCK), IκBα, and NF-ATc2. Polyclonal stimulation of NF-κB-deficient sarcoid T cells resulted in reduced expression of CD69 and CD154, decreased proliferation, and cytokine (i.e., interleukin 2 [IL-2] and gamma interferon [IFN-γ]) production. The clinical significance of these findings is suggested by the association between low p65 levels and the development of more severe and active sarcoidosis. Although correlative, our results support a model in which multiple intrinsic signaling defects contribute to peripheral T-cell anergy and the persistence of chronic inflammation in sarcoidosis.
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Linfocitos T CD4-Positivos/inmunología , Anergia Clonal , Sarcoidosis/inmunología , Sarcoidosis/patología , Índice de Severidad de la Enfermedad , Factor de Transcripción ReIA/biosíntesis , Adulto , Antígenos CD/biosíntesis , Antígenos de Diferenciación de Linfocitos T/biosíntesis , Ligando de CD40/biosíntesis , Proliferación Celular , Citocinas/metabolismo , Perfilación de la Expresión Génica , Humanos , Interferón gamma/metabolismo , Lectinas Tipo C/biosíntesis , Persona de Mediana EdadRESUMEN
Symptomatic endobronchial recurrence after treatment failure is common in advanced non-small cell lung cancer. Optimal palliation has yet to be defined. We examined the combination of near-simultaneous, high-dose-rate (HDR) brachytherapy with stenting in this cohort of patients. Informed consent for intervention was obtained for 10 patients experiencing severely symptomatic (hemoptysis and oxygen-dependent shortness of breath), biopsy-proven endobronchial recurrence. All patients (eight men, two women, aged 52-77 years) had failed to respond to chemoradiotherapy for stage IIIB non-small cell lung cancer. Intervention consisted of placement of a self-expanding metallic stent (Nitinol/Ultraflex stent, Boston Scientific Co., Natick, MA) into the obstructing region. During that same bronchoscopy, HDR catheters were introduced. A dose of 6 Gy at 0.5 cm from the catheter was then delivered via an HDR unit. Two additional HDR sessions followed at weekly intervals for a total dose of 18 Gy. Patients under went follow-up bronchoscopes 1 month after the last HDR and when clinically indicated. All patients completed the prescribed therapy. No morbidity was noted from bronchoscopy, HDR, or stenting. All patients had rapid relief of signs and symptoms. At 1 week after stenting/first HDR, a statistically significant improvement in Karnofsky status was noted. Pulmonary palliation was maintained for the duration of their survival. The radio-opaque stent also offered significant advantages for catheter placement and verification during the HDR procedure. Although this series is small, the beneficial outcome obtained deserves further evaluation.
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Braquiterapia , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Calidad de Vida , Stents , Anciano , Obstrucción de las Vías Aéreas/etiología , Obstrucción de las Vías Aéreas/psicología , Obstrucción de las Vías Aéreas/cirugía , Broncoscopía , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/psicología , Terapia Combinada , Disnea/etiología , Disnea/psicología , Disnea/cirugía , Femenino , Hemoptisis/etiología , Hemoptisis/psicología , Hemoptisis/cirugía , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/psicología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/complicaciones , Recurrencia Local de Neoplasia/psicología , Recurrencia Local de Neoplasia/terapia , Dosificación RadioterapéuticaRESUMEN
OBJECTIVES: To assess the ability of selective bronchography to predict which patients with neoplastic postobstructive atelectasis will respond to interventional therapies directed at the reexpansion of the affected lung. Furthermore, to compare the utility of selective bronchography with the current predictive standard that reversal of postobstructive atelectasis is unlikely when it is > or = 4 weeks in duration (ie, the 4-week rule). DESIGN: A prospective observational study. SETTING: A tertiary care referral center/medical school. PATIENTS: Twenty-seven consecutive patients with advanced lung cancer or other malignancy, with documented neoplastic postobstructive atelectasis involving a total of 44 lobes. INTERVENTIONS: Lobar collapse was documented radiographically. The duration of atelectasis was investigated and quantified as accurately as possible. Prior to the use of interventional therapies, selective bronchography was performed on each collapsed lobe, and the results were documented. Bronchography results did not influence the decision to proceed with interventional therapies. Patients had each of their collapsed lobes manipulated by interventional techniques that were directed at reexpansion of the lung. One week after the patient underwent the intervention, the degree of reexpansion was assessed radiographically. RESULTS: Interventional therapies leading to significant reversal of airway narrowing were completed in all 44 lobes. These were successful in reexpanding 28 of 44 collapsed lobes (64%). Selective bronchography demonstrated the following two distinct patterns: an intact bronchial tree (ie, tree pattern); or the absence of a distinguishable, distal bronchial tree (ie, blush pattern). The sensitivity of selective bronchography to predict reexpansion is 1.00 (95% confidence interval [CI], 0.90 to 1.00), and its specificity is 0.56 (95% CI, 0.30 to 0.80). There were no complications attributable to selective bronchography. The sensitivity of the 4-week rule to predict reexpansion is 0.61 (95% CI, 0.41 to 0.78), and its specificity is 0.75 (95% CI, 0.48 to 0.93). The results of selective bronchography and use of the 4-week rule were significantly different in predicting which lobes would reexpand and which would not (p = 0.0026). Using selective bronchography to predict the reversal of lobar atelectasis, the positive predictive value of the tree pattern was 0.80 and the negative predictive value of the blush pattern was 1.00. The values for the 4-week rule are 0.81 and 0.52, respectively. CONCLUSIONS: Selective bronchography is a useful tool for predicting whether patients with neoplastic postobstructive atelectasis would benefit from interventional techniques that are directed at lobar reexpansion. Selective bronchography appears to be superior to the 4-week rule in this regard.
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Obstrucción de las Vías Aéreas/complicaciones , Broncografía/métodos , Neoplasias Pulmonares/complicaciones , Atelectasia Pulmonar/diagnóstico por imagen , Anciano , Obstrucción de las Vías Aéreas/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Atelectasia Pulmonar/etiología , Atelectasia Pulmonar/patología , Atelectasia Pulmonar/terapia , Sensibilidad y EspecificidadRESUMEN
PURPOSE: Arachidonate release contributes to prostate tumor progression as arachidonate is metabolized into prostaglandins and leukotrienes, potent mediators of immune suppression, cellular proliferation, tumor motility, and invasion. The group IIa sPLA2 (sPLA2-IIa) can facilitate arachidonate release from cellular phospholipids. We therefore sought to determine whether sPLA2-IIa expression might be related to the development or progression of prostatic adenocarcinoma (CaP). EXPERIMENTAL DESIGN: sPLA2-IIa expression was examined by Western blot analyses of CaP cells and xenografts and by immunohistochemistry of benign prostatic hyperplasias and primary human CaPs (n = 101) using a sPLA2-IIa-specific polyclonal antibody. RESULTS: sPLA2-IIa expression was increased dramatically in the androgen-independent CWR-22R and LNAI CaP cells versus the androgen-dependent CWR-22 and LNCaP cells. Immunohistochemical analyses revealed that sPLA2-IIa expression was also significantly increased with CaP development and advancing disease (trend analysis; Pearson correlation coefficient, P = 0.016). High-grade CaPs showed intense, uniform staining for sPLA2-IIa that was significantly different from that in adjacent benign prostatic hyperplasias (Fisher's exact test, P = 0.021) or low-grade CaP (P = 0.013), both of which showed only focal or weak sPLA2-IIa staining. Further, uniform sPLA2-IIa expression was directly related to the increased proliferative index that typifies advancing disease (P = 0.001). Most significantly, enhanced sPLA2-IIa expression was inversely related to 5-year patient survival (P = 0.015). CONCLUSIONS: These data show that sPLA2-IIa expression increases with progression to androgen-independence and is highest in the most poorly-differentiated, highest-grade primary human CaP samples.
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Fosfolipasas A/metabolismo , Neoplasias de la Próstata/enzimología , Andrógenos/farmacología , Ácido Araquidónico/metabolismo , División Celular , Progresión de la Enfermedad , Humanos , Inmunohistoquímica , Isoenzimas/metabolismo , Masculino , Fosfolipasas A2 , Hiperplasia Prostática/enzimología , Hiperplasia Prostática/patología , Neoplasias de la Próstata/patología , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
OBJECTIVE: To quantify the effects of deep brain stimulation (DBS) of globus pallidus interna (GPi) and subthalamic nucleus (STN) on motor fluctuations and dyskinesia in PD and to determine how the response to levodopa was modified by DBS. BACKGROUND: Patients report that DBS reduces levodopa-induced motor fluctuations and dyskinesia throughout the day, but this has not been objectively measured. Further, the means by which DBS alters the response to levodopa to improve motor fluctuations is unknown. METHODS: Twelve subjects, six with bilateral GPi electrodes and six with bilateral STN electrodes, were studied 12 to 33 months after surgery. To quantify motor fluctuations and dyskinesia, subjects were monitored hourly throughout 2 waking days with their usual oral medications, 1 day with DBS on and 1 day with DBS off, with subjects and nurse raters blinded to DBS status. To examine the effects of DBS on levodopa pharmacodynamics, the effects of a 2-hour levodopa infusion were examined, 1 day with DBS on and 1 day with DBS off, again under double-blind conditions. Time course of variations in parkinsonism was evaluated by tapping speed, arising and walking speed, tremor scores, and dyskinesia scores. RESULTS: DBS raised the mean tapping speed and reduced the coefficient of variation during the waking day. This was achieved by increasing the lowest or trough tapping speed between doses of antiparkinson medications. Mean walking speed was modestly increased and mean tremor scores were reduced. DBS increased the drug-off tapping speed, but neither the peak response nor the duration of response to levodopa was affected by DBS. The study was not powered to detect differences between GPi and STN stimulation and the only difference that approached significance was that GPi reduced peak dyskinesia and STN tended to increase peak dyskinesia. CONCLUSION: DBS objectively reduces motor fluctuations. This is achieved by reduction of drug-off disability and not by alterations in levodopa pharmacodynamics. This finding suggests alleviation of interdose trough disability as an alternative strategy to prolonging the effects of each dose of levodopa as a means to reduce motor fluctuations.
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Terapia por Estimulación Eléctrica , Levodopa/administración & dosificación , Enfermedad de Parkinson/terapia , Adulto , Anciano , Carbidopa/administración & dosificación , Carbidopa/efectos adversos , Terapia Combinada , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Femenino , Globo Pálido/efectos de los fármacos , Globo Pálido/fisiopatología , Humanos , Levodopa/efectos adversos , Masculino , Persona de Mediana Edad , Destreza Motora/efectos de los fármacos , Destreza Motora/fisiología , Examen Neurológico/efectos de los fármacos , Enfermedad de Parkinson/fisiopatología , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Núcleo Subtalámico/efectos de los fármacos , Núcleo Subtalámico/fisiopatología , Caminata/fisiologíaRESUMEN
PURPOSE: Integrin-linked kinase (ILK) overexpression can suppress anoikis, promote anchorage-independent cell cycle progression, and induce tumorigenesis and invasion. Inhibition of ILK in prostatic adenocarcinoma (CaP) cells elicits cell cycle arrest and induces apoptosis. Furthermore, ILK expression increases with androgen-independent progression of human CaP cell lines, suggesting that increased ILK expression may be associated with CaP progression. EXPERIMENTAL DESIGN: To assess whether ILK expression may be related to CaP development and/or progression, we have evaluated ILK expression by immunohistochemistry in 100 human prostate tissues. RESULTS: We show that ILK expression increases significantly with CaP progression. ILK immunostaining is specifically increased in high-grade, primary human CaP relative to adjacent benign prostatic hyperplasia (P < 0.001), benign prostatic hyperplasia from patients without cancer (P < 0.002), and low-grade CaP (P = 0.003). ILK overexpression is specifically associated with the increased proliferative index (P = 0.001) that typifies CaP progression. Strikingly, intense uniform ILK immunostaining was inversely related to 5-year patient survival (P = 0.004). CONCLUSIONS: ILK expression increases dramatically with CaP progression. ILK expression is also specifically related to the disproportionately increased proliferative index that contributes to the net gain of CaP cells during progression. Finally, enhanced ILK expression is inversely related to 5-year patient survival. These data therefore implicate increased ILK expression in prostate tumor progression.
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Adenocarcinoma/patología , Neoplasias de la Próstata/patología , Proteínas Serina-Treonina Quinasas/biosíntesis , Adenocarcinoma/enzimología , Apoptosis , División Celular , Progresión de la Enfermedad , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Antígeno Ki-67/análisis , Masculino , Índice Mitótico , Neoplasias de la Próstata/enzimologíaRESUMEN
Ovarian carcinomas (OCs), particularly recurrent OCs, are frequently resistant to transforming growth factor (TGF)-beta-mediated growth inhibition. Mutations in the TGF-beta receptor type II (TbetaR-II) gene are only evident in a minority of OCs, suggesting that other alterations of the TGF-beta signaling pathway may be involved in OC. Using PCR, cold single-strand conformation polymorphism, and DNA sequencing, we now show that 33% of primary OCs (10 of 30) harbor somatic changes in exons 2, 3, 4, and 6 of the TGF-beta receptor I (TbetaR-I) gene. Most of the changes are missense mutations and clustered largely in the catalytic domain of the receptor kinase. Interestingly, seven additional cases (23.3%) showed heterozygous carriers of an allelic variant [a 9-nucleotide deletion, del(GGC)(3)] in exon 1 of the TbetaR-I gene. This is in contrast with 10.6% of del(GGC)(3) heterozygous carriers in a recent report of a large normal population (n = 735; B. Pasche et al., Cancer Res., 59: 5678-5682, 1999). These results indicate that TbetaR-I is frequently mutated in OC and suggest that resistance to TGF-beta-mediated growth inhibition may frequently involve alterations of the TbetaR-I gene.
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Mutación , Neoplasias Ováricas/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Exones , Femenino , Eliminación de Gen , Mutación de Línea Germinal , Humanos , Persona de Mediana Edad , Mutación Missense , Adhesión en Parafina , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Estructura Terciaria de Proteína/genéticaRESUMEN
BACKGROUND: Dyskinesias are a frequent adverse effect of long-term levodopa therapy. The relative contribution of dopamine D(1) and D(2) receptor function to the pathophysiology of levodopa-induced dyskinesias remains a matter of controversy. OBJECTIVE: To establish whether a selective D(1) dopamine agonist induces more or less dyskinesia than levodopa in primed dyskinetic patients with Parkinson disease. METHODS: We studied ABT-431, the prodrug of a fully selective D(1) agonist, in 20 subjects with advanced Parkinson disease and a fluctuating response to levodopa complicated by dyskinesias. Eight patients were studied in a double-blind, randomized design (French centers); 12, in an open, randomized design (US centers). We assessed and compared the antiparkinsonian (Unified Parkinson's Disease Rating Scale) and dyskinetic (response induced by an acute challenge of a suprathreshold dose of levodopa and by 4 different ascending doses (5, 10, 20, and 40 mg) of ABT-431 during the 6 hours after the challenge. RESULTS: The separate analysis of the double-blind and open data led to the same findings, ie, the antiparkinsonian and dyskinetic responses induced by ABT-431 were dose related. At the most effective doses (20 and 40 mg), ABT-431 exhibited similar antiparkinsonian benefit and produced similar dyskinesias as levodopa. CONCLUSION: Dopamine D(1) agonists can induce a full antiparkinsonian response but do not support previous hypotheses suggesting that D(1) agonists are more or less likely to produce dyskinesias than levodopa.
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Antiparkinsonianos/uso terapéutico , Discinesia Inducida por Medicamentos , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Profármacos/administración & dosificación , Piridinas/administración & dosificación , Receptores de Dopamina D1/efectos de los fármacos , Tetrahidronaftalenos/administración & dosificación , Adulto , Anciano , Agonistas de Dopamina/administración & dosificación , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Profármacos/efectos adversos , Piridinas/efectos adversos , Tetrahidronaftalenos/efectos adversosRESUMEN
Health care is an ever-present concern for homeless individuals. Health-Seeking Behaviors within this population are examined from a nursing perspective. Complex Relationship Building, considered essential in addressing Health-seeking Behaviors for the homeless, is examined in regard to access, trust, and follow-up. It is believed that access and follow-up are related to convenience of site and the matter of trust. A pilot study of how to measure the concept of trust was conducted. Factor analysis for the Gibson Trust Instrument shows two factors: (1) interpersonal attributes and (2) behavior attributes. The Gibson Trust Instrument can be used to measure trust, which is crucial for Complex Relationship Building.
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Personas con Mala Vivienda/psicología , Aceptación de la Atención de Salud , Análisis Factorial , Femenino , Accesibilidad a los Servicios de Salud , Necesidades y Demandas de Servicios de Salud , Humanos , Relaciones Interpersonales , Masculino , Proyectos Piloto , Reproducibilidad de los ResultadosRESUMEN
The authors investigated the ability of daytime infusions of apomorphine, a D-1 and D-2 dopamine agonist, to sustain the long-duration response (LDR) in seven subjects with fluctuating PD in whom L-DOPA was discontinued for 3 days. Apomorphine maintained the LDR to the extent that it kept the subjects "on" during the day. This observation suggests that the LDR can be a postsynaptic effect, independent of dopamine storage.
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Antiparkinsonianos/uso terapéutico , Apomorfina/uso terapéutico , Agonistas de Dopamina/uso terapéutico , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Anciano , Esquema de Medicación , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Humanos , Levodopa/administración & dosificación , Masculino , Persona de Mediana Edad , Movimiento/efectos de los fármacos , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: To design a pattern recognition engine based on concepts derived from mammalian immune systems. DESIGN: A supervised learning system (Immunos-81) was created using software abstractions of T cells, B cells, antibodies, and their interactions. Artificial T cells control the creation of B-cell populations (clones), which compete for recognition of "unknowns." The B-cell clone with the "simple highest avidity" (SHA) or "relative highest avidity" (RHA) is considered to have successfully classified the unknown. MEASUREMENT: Two standard machine learning data sets, consisting of eight nominal and six continuous variables, were used to test the recognition capabilities of Immunos-81. The first set (Cleveland), consisting of 303 cases of patients with suspected coronary artery disease, was used to perform a ten-way cross-validation. After completing the validation runs, the Cleveland data set was used as a training set prior to presentation of the second data set, consisting of 200 unknown cases. RESULTS: For cross-validation runs, correct recognition using SHA ranged from a high of 96 percent to a low of 63.2 percent. The average correct classification for all runs was 83.2 percent. Using the RHA metric, 11.2 percent were labeled "too close to determine" and no further attempt was made to classify them. Of the remaining cases, 85.5 percent were correctly classified. When the second data set was presented, correct classification occurred in 73.5 percent of cases when SHA was used and in 80.3 percent of cases when RHA was used. CONCLUSIONS: The immune system offers a viable paradigm for the design of pattern recognition systems. Additional research is required to fully exploit the nuances of immune computation.
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Inteligencia Artificial , Enfermedad Coronaria/clasificación , Sistema Inmunológico , Reconocimiento de Normas Patrones Automatizadas , Algoritmos , Animales , Linfocitos B/fisiología , Bases de Datos como Asunto , Estudios de Evaluación como Asunto , Humanos , Mamíferos/inmunología , Programas Informáticos , Linfocitos T/fisiologíaRESUMEN
Studies in animal models show a selective D1 receptor agonist with full functional efficacy compared with dopamine to have antiparkinsonian efficacy of similar magnitude to levodopa, without the same propensity for inducing dyskinesia. To date, no such agent has been tested in humans. ABT-431 is the prodrug of A-86929, a full, selective D1 receptor agonist. Subjects (n = 14) with levodopa-responsive Parkinson's disease received five doses of ABT-431 (5, 10, 20, 30, and 40 mg) and one of placebo after a 12-hour levodopa holiday. Response was assessed by using the Unified Parkinson's Disease Rating Scale motor subsection. Dyskinesia was separately graded. ABT-431 showed efficacy significantly superior to placebo at doses of 10 mg and more, and of similar magnitude to that seen with levodopa. Dyskinesia was reduced in several patients after receiving ABT-431. There were no serious adverse events, the most common minor events being nausea and emesis, dizziness, and hypotension. Assuming that ABT-431 is not transformed in humans into an unknown active D2 metabolite, and remains selective for D1 receptors, it is the first dopamine D1 receptor agonist to demonstrate a full antiparkinsonian effect in patients with Parkinson's disease. These preliminary findings also suggest that it may exhibit a reduced tendency to provoke dyskinesia. The emergence of a well-tolerated D1 agonist should allow for the development of a better understanding of the relation between motor efficacy and dyskinesia in Parkinson's disease.
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Enfermedad de Parkinson/tratamiento farmacológico , Profármacos/farmacología , Piridinas/farmacología , Tetrahidronaftalenos/farmacología , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Profármacos/efectos adversos , Profármacos/uso terapéutico , Piridinas/efectos adversos , Piridinas/uso terapéutico , Tetrahidronaftalenos/efectos adversos , Tetrahidronaftalenos/uso terapéuticoAsunto(s)
Laringoscopios , Diseño de Equipo , Lateralidad Funcional , Humanos , Intubación IntratraquealRESUMEN
Id genes encode members of the helix-loop-helix (HLH) family of transcription factors that inhibit transcription by forming inactive heterodimers with basic HLH (bHLH) proteins. There are four members of the Id gene family recognized in mammals, and the proteins they encode share homology primarily in their HLH domain. bHLH proteins typically form heterodimers with other bHLH proteins, and their basic domain binds to a DNA sequence element, the E-box, activating transcription. Products of Id genes lack the basic DNA binding domain of the bHLH transcription factors, and when they heterodimerize with bHLH proteins, the complexes are inactive. Generally, high levels of Id mRNA are detected in proliferative undifferentiated, embryonal cells and lower levels are detected in well-differentiated, mature, adult tissues. In vitro, these genes are generally expressed at lower levels in cells after the induction of differentiation. Recently, high levels of expression of Id genes have been identified in cell lines derived from a wide variety of different tumors and in tumor tissues as well. These findings suggest that not only the inappropriate proliferation of tumors but also the anaplastic characteristics that contribute to their malignant behavior may be regulated by Id gene expression.
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Regulación Neoplásica de la Expresión Génica/fisiología , Secuencias Hélice-Asa-Hélice/genética , Neoplasias/genética , Proteínas Represoras , Factores de Transcripción/genética , Diferenciación Celular/fisiología , División Celular/fisiología , Humanos , Proteína 1 Inhibidora de la Diferenciación , Neoplasias/patologíaAsunto(s)
Antiparkinsonianos/análisis , Levodopa/análisis , Leche Humana/química , Adulto , Antiparkinsonianos/sangre , Carbidopa/uso terapéutico , Combinación de Medicamentos , Femenino , Humanos , Lactancia/fisiología , Levodopa/sangre , Levodopa/uso terapéutico , Concentración Osmolar , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismoRESUMEN
The objective of this study was to examine the experience of spouses caregiving for their spouse with Parkinson's disease (PD) and to determine whether their experiences differed by stage of disease. By using a cross-sectional design and mail questionnaire data from 380 spouse caregivers across 23 sites of the Parkinson Study Group, key caregiver variables were examined by stage of PD. Three categories of variables--caregiver role strain (10 measures), caregiver situation (four measures), and caregiver characteristics (four measures)--were analyzed by using t tests with Bonferroni correction. Specific types and amounts of role strain accumulated as the disease progressed, and they differed significantly between stages (p < 0.05). In the caregiving situation, the mean number of caregiving tasks tripled by stage 4/5. Negative changes in lifestyle plus decreases in predictability in caregivers' lives increased significantly in late-stage disease (p < 0.05). Caregiver characteristics of physical health and preparedness did not significantly differ across stages of disease. Depression was significantly higher by stage 4/5. Mutuality, the positive quality of the relationship as perceived by the caregiving spouse, declined beginning at stage 2. Caregiver strain is experienced across all stages of PD and accumulates significantly as the disease progresses. This study defines types and amounts of strain by stage of disease, which will be helpful in designing formal intervention trials to provide more effective help for spouse caregivers.
Asunto(s)
Cuidadores/psicología , Salud de la Familia , Enfermedad de Parkinson/psicología , Anciano , Análisis de Varianza , Estudios Transversales , Depresión/etiología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Muestreo , Índice de Severidad de la EnfermedadRESUMEN
UNLABELLED: Brain metastases are a common and devastating complication in patients with malignant melanoma. Therapeutic options for these patients are limited, and the prognosis is usually poor. OBJECT: A retrospective review of 6953 patients with melanoma treated at a single institution was undertaken to identify demographic factors associated with the development of clinically significant brain metastases in 702 of these patients and to determine the factors influencing the prognosis of this population to permit more informed recommendations regarding surgical therapy. METHODS: Factors found to be associated with the development of brain metastases included male gender, primary lesions located on mucosal surfaces or on the skin of the trunk or head and neck, thick or ulcerated primary lesions, and histological findings of acral lentiginous or nodular lesions. The overall median survival time of all patients with brain metastases was 113.2 days, and these metastases contributed to the death of 94.5% of the patients in this group. Patients with primary lesions located in the head or neck region had a significantly shorter survival time relative to other patients with brain metastases, whereas patients with a single brain metastasis, patients without lung or multiple other visceral metastases, and patients whose initial presentation with melanoma included a brain metastasis had a significantly better prognosis. The small group of patients who survived for more than 3 years was characterized by the presence of a surgically treated, single brain metastasis in the absence of other visceral metastatic disease. CONCLUSIONS: Although most patients with brain metastases resulting from melanoma have a dismal prognosis, some who are likely to survive for longer periods can be identified. In these patients surgical resection can significantly prolong meaningful survival. The decision to recommend surgery should be based primarily on the resectability of the brain metastases and on the status and number of other organs with metastatic lesions.