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1.
BMJ Ment Health ; 26(1)2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37541700

RESUMEN

BACKGROUND: The components of care delivered by Early Intervention in Psychosis (EIP) services vary, but the impact on patient experience is unknown. OBJECTIVE: To investigate associations between components of care provided by EIP services in England and patient-reported outcomes. METHODS: 2374 patients from EIP services in England were surveyed during the National Clinical Audit of Psychosis. Participants were asked about the care they received, and completed the 'Patient Global Impressions' Scale (rating whether their mental health had improved), and 'Friends and Family Test' (rating whether they would recommend their service). Information about service structure was obtained from service providers. We analysed associations between outcomes and components of care using multilevel regression. FINDINGS: The majority of participants were likely to recommend the treatment they had received (89.8%), and felt that their mental health had improved (89.0%). Participants from services where care coordinators had larger case loads were less likely to recommend their care. Participants were more likely to recommend their care if they had been offered cognitive behavioural therapy for psychosis, family therapy or targeted interventions for carers. Participants were more likely to report that their mental health had improved if they had been offered cognitive behavioural therapy for psychosis or targeted interventions for carers. CONCLUSIONS: Specific components of EIP care were associated with improved patient reported outcomes. Psychosocial interventions and carer support may be particularly important in optimising outcomes for patients. CLINICAL IMPLICATIONS: These findings emphasise the need for small case load sizes and comprehensive packages of treatment in EIP services.


Asunto(s)
Terapia Cognitivo-Conductual , Servicios de Salud Mental , Trastornos Psicóticos , Humanos , Estudios Transversales , Trastornos Psicóticos/diagnóstico , Salud Mental
2.
Reactions (Basel) ; 3(1): 59-69, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35072056

RESUMEN

Synthetic access to poly(indazolyl)methanes has limited their study despite their structural similarity to the highly investigated chelating poly(pyrazolyl)methanes and their potentially important indazole moiety. Herein is presented a high yielding, one-pot synthesis for the 3d-metal catalyzed formation of bis(1H-indazol-1-yl)methane from 1H-indazole utilizing dimethylsulfoxide as the methylene source. Complete characterization of bis(1H-indazol-1-yl)methane is given with 1H and 13C NMR, UV/Vis, FTIR, high resolution mass spectrometry and for the first time, single crystal X-ray diffraction. This simple, inexpensive pathway to yield exclusively bis(1H-indazol-1-yl)methane provides synthetic access to further investigate the coordination and potential applications of the family of bis(indazolyl)methanes.

3.
Neurology ; 95(16): e2246-e2258, 2020 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-32913023

RESUMEN

OBJECTIVE: To test the hypothesis that there is shared regional or global functional connectivity dysfunction in a large cohort of patients with isolated focal dystonia affecting different body regions compared to control participants. In this case-control study, we obtained resting-state MRI scans (three or four 7.3-minute runs) with eyes closed in participants with focal dystonia (cranial [17], cervical [13], laryngeal [18], or limb [10]) and age- and sex-matched controls. METHODS: Rigorous preprocessing for all analyses was performed to minimize effect of head motion during scan acquisition (dystonia n = 58, control n = 47 analyzed). We assessed regional functional connectivity by computing a seed-correlation map between putamen, pallidum, and sensorimotor cortex and all brain voxels. We assessed significant group differences on a cluster-wise basis. In a separate analysis, we applied 300 seed regions across the cortex, cerebellum, basal ganglia, and thalamus to comprehensively sample the whole brain. We obtained participant whole-brain correlation matrices by computing the correlation between seed average time courses for each seed pair. Weighted object-oriented data analysis assessed group-level whole-brain differences. RESULTS: Participants with focal dystonia had decreased functional connectivity at the regional level, within the striatum and between lateral primary sensorimotor cortex and ventral intraparietal area, whereas whole-brain correlation matrices did not differ between focal dystonia and control groups. Rigorous quality control measures eliminated spurious large-scale functional connectivity differences between groups. CONCLUSION: Regional functional connectivity differences, not global network level dysfunction, contributes to common pathophysiologic mechanisms in isolated focal dystonia. Rigorous quality control eliminated spurious large-scale network differences between patients with focal dystonia and control participants.


Asunto(s)
Encéfalo/fisiopatología , Trastornos Distónicos/fisiopatología , Adulto , Anciano , Mapeo Encefálico , Estudios de Casos y Controles , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Vías Nerviosas/fisiopatología
4.
Bioinorg Chem Appl ; 2018: 4560757, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30254666

RESUMEN

Numerous therapies for the treatment of cancer have been explored with increasing evidence that the use of metal-containing compounds could prove advantageous as anticancer therapeutics. Previous works on Ru(III) complexes suggest that structurally similar Co(III) complexes may provide good alternative, low-cost, effective prodrugs. Herein, a new complex, trans-[Co(imidazole)4Cl2]Cl (2), has been synthesized in high yields utilizing ligand exchange under refluxing conditions. The structure of 2 has been characterized by elemental analysis, 1H and 13C·NMR, ESI-MS, CV, and UV-Vis. The ability of 2 to become reduced in the presence of ascorbic acid was probed demonstrating the likely reduction of the Co(III) metal center to Co(II). In addition, preliminary cell line testing on 2 shows a lack of cytotoxicity.

5.
Mov Disord ; 33(3): 449-458, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29460980

RESUMEN

BACKGROUND: Focal embouchure dystonia impairs orofacial motor control in wind musicians and causes professional disability. A paucity of quantitative measures or rating scales impedes the objective assessment of treatment efficacy. OBJECTIVES: We quantified specific features of focal embouchure dystonia using acoustic measures and developed a metric to assess severity across multiple domains of symptomatic impairment. METHODS: We recruited 9 brass musicians with and 6 without embouchure dystonia. The following 4 domains of symptomatic dysfunction in focal embouchure dystonia were identified: pitch inaccuracy, sound instability and tremor, sound breaks, and timing variability. Musicians performed sustained tones and sequences, and then acoustic variables within each domain were quantified. A composite brass acoustic severity score composed of these variables was validated against clinical global impressions of severity. RESULTS: Musicians with dystonia performed worse in acoustic domains of pitch inaccuracy (median: dystonia = 100%, control = 62%), instability (median shimmer: dystonia = 3%, control = 2%), and breaks (median: dystonia = 0.34%, control = 0.05%). Tremor in embouchure dystonia was 5 to 8 Hz, intermittent, and variable in amplitude. Rhythmic variability did not differ between groups. Participants with embouchure dystonia had different patterns of impairment across variables. Composite severity scores strongly predicted clinical global impression of severity (R2 = 0.95). CONCLUSIONS: Acoustic variables distinguish musicians with embouchure dystonia from controls and reflect different types of symptomatic impairments. Our composite acoustic severity score predicts severity of clinical global impression for musicians with different patterns of symptomatic impairment and may provide a foundation for developing a clinical rating scale. © 2018 International Parkinson and Movement Disorder Society.


Asunto(s)
Percepción Auditiva/fisiología , Trastornos Distónicos/fisiopatología , Músculos Faciales/fisiopatología , Música , Desempeño Psicomotor/fisiología , Acústica , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Profesionales , Estadísticas no Paramétricas , Factores de Tiempo , Temblor/fisiopatología , Adulto Joven
6.
J Bone Miner Res ; 26(6): 1283-94, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21308771

RESUMEN

Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Ninety percent of patients who present with metastatic and 30% to 40% of patients with nonmetastatic disease experience relapse, creating an urgent need for novel therapeutic strategies. The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are important for mitosis, motility, and cell survival. Upregulation of Met/HGF signaling via receptor overexpression, amplification, or mutation drives the proliferation, invasiveness, and metastasis of a variety of cancer cells, including OS, prompting the development of Met/HGF inhibitors. OS cells depend on Met overexpression because introduction of dominant-negative Met inhibits in vivo tumorigenicity. Despite the importance of Met/HGF signaling in the development and maintenance of OS, the potential efficacy of pharmacologic Met inhibition in OS has been addressed only in in vitro studies. PF-2341066 is an orally bioavailable, selective ATP-competitive Met inhibitor that showed promising results recently in a phase I clinical trial in non-small cell lung cancer (NSCLC) patients. We tested the ability of PF-2341066 to inhibit malignant properties of osteosarcoma cells in vitro and orthotopic xenograft growth in vivo. In vitro, PF-2341066 inhibited osteosarcoma behavior associated with primary tumor growth (eg, proliferation and survival) as well as metastasis (eg, invasion and clonogenicity). In nude mice treated with PF-2341066 via oral gavage, the growth and associated osteolysis and extracortical bone matrix formation of osteosarcoma xenografts were inhibited by PF-2341066. PF-2341066 may represent an effective new systemic therapy for localized and potentially disseminated osteosarcoma.


Asunto(s)
Matriz Ósea/metabolismo , Osteólisis/patología , Osteosarcoma/patología , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Piridinas/administración & dosificación , Piridinas/farmacocinética , Ensayos Antitumor por Modelo de Xenoinjerto , Administración Oral , Animales , Apoptosis/efectos de los fármacos , Disponibilidad Biológica , Matriz Ósea/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Clonales , Crizotinib , Humanos , Ratones , Ratones Desnudos , Invasividad Neoplásica , Osteogénesis/efectos de los fármacos , Osteólisis/complicaciones , Osteosarcoma/complicaciones , Fosforilación/efectos de los fármacos , Piperidinas/farmacología , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirazoles , Piridinas/farmacología , Transducción de Señal/efectos de los fármacos
7.
J Int Neuropsychol Soc ; 16(1): 157-68, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19849883

RESUMEN

The primary aims of this study were to examine post-injury cognitive development in young children with traumatic brain injury (TBI) and to investigate the role of the proximal family environment in predicting cognitive outcomes. Age at injury was 3-6 years, and TBI was classified as severe (n = 23), moderate (n = 21), and complicated mild (n = 43). A comparison group of children who sustained orthopedic injuries (OI, n = 117) was also recruited. Child cognitive assessments were administered at a post-acute baseline evaluation and repeated at 6, 12, and 18 months post-injury. Assessment of the family environment consisted of baseline measures of learning support and stimulation in the home and of parenting characteristics observed during videotaped parent-child interactions. Relative to the OI group, children with severe TBI group had generalized cognitive deficiencies and those with less severe TBI had weaknesses in visual memory and executive function. Although deficits persisted or emerged across follow-up, more optimal family environments were associated with higher scores for all injury groups. The findings confirm other reports of poor recovery of cognitive skills following early childhood TBI and suggest environmental influences on outcomes.


Asunto(s)
Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/psicología , Desarrollo Infantil/fisiología , Trastornos del Conocimiento/etiología , Procesos Mentales/fisiología , Factores de Edad , Lesiones Encefálicas/clasificación , Niño , Preescolar , Familia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Pruebas Neuropsicológicas
8.
Inorg Chem ; 48(10): 4411-20, 2009 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-19351133

RESUMEN

A 1997 Nature paper (Nature 1997, 388, 353-355) and subsequent 1998 J. Am. Chem. Soc. paper (J. Am. Chem. Soc. 1998, 120, 11969-11976) reported that a putative Ru(2)-substituted polyoxoanion, "[WZnRu(2)(III)(H(2)O)(OH)(ZnW(9)O(34))(2)](11-)", (1), is an all inorganic dioxygenase able to incorporate one O(2) into two adamantane CH bonds to yield 2 equiv of 1-adamantanol as the primary product. In a subsequent 2005 Inorg. Chem. publication (Inorg. Chem. 2005, 44, 4175-4188), strong evidence was provided that the putative dioxygenase chemistry is, instead, the result of classic autoxidation catalysis. That research raised the question of whether the reported Ru(2) precatalyst, 1, was pure or even if it contained two Ru atoms, since Ru is known to be difficult to substitute into polyoxoanion structures (Nomiya, K.; Torii, H.; Nomura, K.; Sato, Y. J. Chem. Soc. Dalton Trans. 2001, 1506-1521). After our research group had contact with three other groups who also had difficulties reproducing the reported synthesis and composition of 1, we decided to re-examine 1 in some detail. Herein we provide evidence that the claimed 1 actually appears to be the parent polyoxoanion [WZn(3)(H(2)O)(2)(ZnW(9)O(34))(2)](12-) with small amounts of Ru (

Asunto(s)
Dioxigenasas/química , Rutenio/química , Compuestos de Tungsteno/química , Catálisis , Estructura Molecular
9.
Inorg Chem ; 48(8): 3496-8, 2009 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-19317407

RESUMEN

Transition-metal complexes containing redox-active quinoid ligands are of interest because of their catalytic capabilities in multielectron, substrate-activation reactions such as dioxygenase catalysis using O(2). The new catecholate complex V(V)(3,6-DBSQ)(3,6-DBCat)(2) (where 3,6-DBSQ = 3,6-di-tert-butylsemiquinone and 3,6-DBCat = 3,6-di-tert-butylcatecholate) was synthesized by combining VO(acac)(2) with 1 equiv of 3,6-DBBQ (where 3,6-DBBQ = 3,6-di-tert-butylbenzoquinone) and 2 equiv of H(2)(3,6-DBCat) in dry methanol under an inert atmosphere. The resultant complex was characterized by single-crystal X-ray diffraction, elemental analysis, near-IR, UV/vis, and electron paramagnetic resonance (EPR) spectroscopy. The crystallography as well as the near-IR and EPR studies suggest that the radical spin is localized on the 3,6-DBSQ ligand at room temperature, making V(V)(3,6-DBSQ)(3,6-DBCat)(2) a type 1 mixed-valence complex. Initial dioxygenase catalysis studies reveal that V(V)(3,6-DBSQ)(3,6-DBCat)(2) is a good dioxygenase precatalyst for the substrate H(2)(3,6-DBCat) with O(2) in ca. 600 total turnovers to >93% intra- and extradiol products with only 1-2% of the undesired benzoquinone autoxidation product.


Asunto(s)
Catecoles/química , Dioxigenasas/metabolismo , Compuestos Organometálicos/química , Compuestos Organometálicos/síntesis química , Quinonas/química , Vanadio/química , Catálisis , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular
10.
Biochim Biophys Acta ; 1794(3): 375-97, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19071235

RESUMEN

Protein aggregation is an important phenomenon that alternatively is part of the normal functioning of nature or, central to this review, has negative consequences via its hypothesized central role in neurodegenerative diseases. A key to controlling protein aggregation is understanding the mechanism(s) of protein aggregation. Kinetic studies, data curve-fitting, and analysis are, in turn, keys to rigorous mechanistic studies. The main goal of this review is to analyze and report on the primary literature contributions to protein aggregation kinetics, mechanism, and curve-fitting. Following a brief introduction, the multiple different physical methods that have been employed to follow protein aggregation are presented and briefly discussed. Next, key information on the starting proteins and especially the products, and any detectable intermediates, involved in protein aggregation are presented. This is followed by tabulation (in the Supporting information) and discussion (in the main text), of the many approaches in the literature striving to determine the kinetics and mechanism of protein aggregation. It is found that these approaches can be broadly divided into three categories: (i) kinetic and thermodynamic, (ii) empirical, and (iii) other approaches. The first two approaches are the main focus of the present contribution, their goal being curve-fitting the available kinetic data and obtaining quantitative rate constants characterizing the nucleation, growth, and any other parts of the overall aggregation process. The large literature of protein aggregation is distilled down to five classes of postulated mechanisms: i) the subsequent monomer addition mechanism, ii) the reversible association mechanism, iii) prion aggregation mechanisms, iv) an "Ockham's razor"/minimalistic model first presented in 1997 and known as the Finke-Watzky 2-step model, and v) quantitative structure activity relationship models. These five classes of mechanisms are reviewed in detail in historical order; where possible corresponding kinetic equations, and fits to aggregation data via the proposed mechanisms, are analyzed and discussed. The five classes of mechanisms are then analyzed and discussed in terms of their similarities and differences to one another. Also included is a brief discussion of selected empirical approaches used to investigate protein aggregation. Three problem areas in the protein aggregation kinetic and mechanistic studies area are identified, and a Summary and Conclusions section is provided en route to moving the field forward towards the still unachieved goal of unequivocal elucidation of the mechanism(s) of protein aggregation.


Asunto(s)
Proteínas/química , Actinas/química , Amiloide/química , Hemoglobina Falciforme/química , Humanos , Cinética , Microtúbulos/química , Modelos Químicos , Polímeros/química , Conformación Proteica , Pliegue de Proteína , Estructura Cuaternaria de Proteína , Termodinámica
11.
Biophys Chem ; 140(1-3): 9-15, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19101068

RESUMEN

The aggregation of proteins is believed to be intimately connected to many neurodegenerative disorders. We recently reported an "Ockham's razor"/minimalistic approach to analyze the kinetic data of protein aggregation using the Finke-Watzky (F-W) 2-step model of nucleation (A-->B, rate constant k(1)) and autocatalytic growth (A+B-->2B, rate constant k(2)). With that kinetic model we have analyzed 41 representative protein aggregation data sets in two recent publications, including amyloid beta, alpha-synuclein, polyglutamine, and prion proteins (Morris, A. M., et al. (2008) Biochemistry 47, 2413-2427; Watzky, M. A., et al. (2008) Biochemistry 47, 10790-10800). Herein we use the F-W model to reanalyze protein aggregation kinetic data obtained under the experimental conditions of variable temperature or pH 2.0 to 8.5. We provide the average nucleation (k(1)) and growth (k(2)) rate constants and correlations with variable temperature or varying pH for the protein alpha-synuclein. From the variable temperature data, activation parameters DeltaG(double dagger), DeltaH(double dagger), and DeltaS(double dagger) are provided for nucleation and growth, and those values are compared to the available parameters reported in the previous literature determined using an empirical method. Our activation parameters suggest that nucleation and growth are energetically similar for alpha-synuclein aggregation (DeltaG(double dagger)(nucleation)=23(3) kcal/mol; DeltaG(double dagger)(growth)=22(1) kcal/mol at 37 degrees C). From the variable pH data, the F-W analyses show a maximal k(1) value at pH approximately 3, as well as minimal k(1) near the isoelectric point (pI) of alpha-synuclein. Since solubility and net charge are minimized at the pI, either or both of these factors may be important in determining the kinetics of the nucleation step. On the other hand, the k(2) values increase with decreasing pH (i.e., do not appear to have a minimum or maximum near the pI) which, when combined with the k(1) vs. pH (and pI) data, suggest that solubility and charge are less important factors for growth, and that charge is important in the k(1), nucleation step of alpha-synuclein. The chemically well-defined nucleation (k(1)) rate constants obtained from the F-W analysis are, as expected, different than the 1/lag-time empirical constants previously obtained. However, k(2)x[A](0) (where k(2) is the rate constant for autocatalytic growth and [A](0) is the initial protein concentration) is related to the empirical constant, k(app) obtained previously. Overall, the average nucleation and average growth rate constants for alpha-synuclein aggregation as a function of pH and variable temperature have been quantitated. Those values support the previously suggested formation of a partially folded intermediate that promotes aggregation under high temperature or acidic conditions.


Asunto(s)
alfa-Sinucleína/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Cinética , Modelos Biológicos , Pliegue de Proteína , Temperatura , Termodinámica , alfa-Sinucleína/química
12.
Biochemistry ; 47(40): 10790-800, 2008 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-18785757

RESUMEN

Recently, we reported 14 amyloid protein aggregation kinetic data sets that were fit using the "Ockham's razor"/minimalistic Finke-Watzky (F-W) two-step model of slow nucleation (A --> B, rate constant k 1) and fast autocatalytic growth (A + B --> 2B, rate constant k 2), yielding quantitative (average) rate constants for nucleation ( k 1) and growth ( k 2), where A is the monomeric protein and B is the polymeric protein [Morris, A. M., et al. (2008) Biochemistry 47, 2413-2427]. Herein, we apply the F-W model to 27 representative prion aggregation kinetic data sets obtained from the literature. Each prion data set was successfully fit with the F-W model, including three different yeast prion proteins (Sup35p, Ure2p, and Rnq1p) as well as mouse and human prions. These fits yield the first quantitative rate constants for the steps of nucleation and growth in prion aggregation. Examination of a Sup35p system shows that the same rate constants are obtained for nucleation and for growth within experimental error, regardless of which of six physical methods was used, a unique set of important control experiments in the protein aggregation literature. Also provided herein are analyses of several factors influencing the aggregation of prions such as glutamine/asparagine rich regions and the number of oligopeptide repeats in the prion domain. Where possible, verification or refutation of previous correlations to glutamine/asparagine regions, or the number of repeat sequences, in literature aggregation kinetics is given in light of the quantitative rate constants obtained herein for nucleation and growth during prion aggregation. The F-W model is then contrasted to four literature mechanisms that address the molecular picture of prion transmission and propagation. Key limitations of the F-W model are listed to prevent overinterpretation of the data being analyzed, limitations that derive ultimately from the model's simplicity. Finally, possible avenues of future research are suggested.


Asunto(s)
Amiloide/química , Proteínas Fúngicas/química , Modelos Químicos , Priones/química , Amiloide/genética , Amiloide/metabolismo , Animales , Catálisis , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Humanos , Cinética , Enfermedades Neurodegenerativas/metabolismo , Priones/genética , Priones/metabolismo
13.
Biochemistry ; 47(8): 2413-27, 2008 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-18247636

RESUMEN

The aggregation of proteins has been hypothesized to be an underlying cause of many neurological disorders including Alzheimer's, Parkinson's, and Huntington's diseases; protein aggregation is also important to normal life function in cases such as G to F-actin, glutamate dehydrogenase, and tubulin and flagella formation. For this reason, the underlying mechanism of protein aggregation, and accompanying kinetic models for protein nucleation and growth (growth also being called elongation, polymerization, or fibrillation in the literature), have been investigated for more than 50 years. As a way to concisely present the key prior literature in the protein aggregation area, Table 1 in the main text summarizes 23 papers by 10 groups of authors that provide 5 basic classes of mechanisms for protein aggregation over the period from 1959 to 2007. However, and despite this major prior effort, still lacking are both (i) anything approaching a consensus mechanism (or mechanisms), and (ii) a generally useful, and thus widely used, simplest/"Ockham's razor" kinetic model and associated equations that can be routinely employed to analyze a broader range of protein aggregation kinetic data. Herein we demonstrate that the 1997 Finke-Watzky (F-W) 2-step mechanism of slow continuous nucleation, A --> B (rate constant k1), followed by typically fast, autocatalytic surface growth, A + B --> 2B (rate constant k2), is able to quantitatively account for the kinetic curves from all 14 representative data sets of neurological protein aggregation found by a literature search (the prion literature was largely excluded for the purposes of this study in order provide some limit to the resultant literature that was covered). The F-W model is able to deconvolute the desired nucleation, k1, and growth, k2, rate constants from those 14 data sets obtained by four different physical methods, for three different proteins, and in nine different labs. The fits are generally good, and in many cases excellent, with R2 values >or=0.98 in all cases. As such, this contribution is the current record of the widest set of protein aggregation data best fit by what is also the simplest model offered to date. Also provided is the mathematical connection between the 1997 F-W 2-step mechanism and the 2000 3-step mechanism proposed by Saitô and co-workers. In particular, the kinetic equation for Saitô's 3-step mechanism is shown to be mathematically identical to the earlier, 1997 2-step F-W mechanism under the 3 simplifying assumptions Saitô and co-workers used to derive their kinetic equation. A list of the 3 main caveats/limitations of the F-W kinetic model is provided, followed by the main conclusions from this study as well as some needed future experiments.


Asunto(s)
Amiloide/metabolismo , Modelos Teóricos , Enfermedades Neurodegenerativas/metabolismo , Amiloide/química , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Catálisis , Precipitación Química , Cristalización , Interpretación Estadística de Datos , Humanos , Cinética , Enfermedades Neurodegenerativas/etiología , Péptidos/química , Péptidos/metabolismo , Propiedades de Superficie , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo
14.
J Autism Dev Disord ; 38(3): 440-8, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17619131

RESUMEN

Behavior checklists are often utilized to screen for Autism Spectrum Disorders (ASDs) when comprehensive evaluations are unfeasible. The usefulness of two behavioral checklists, the Gilliam Autism Rating Scale (GARS) and Child Behavior Checklist (CBCL), in identifying ASDs was investigated among 109 children with Autism, 32 children with ASD, and 51 Non-Spectrum children based on Autism Diagnostic Observation Schedule-Generic classifications. The GARS did not distinguish children with ASDs from those without. The Withdrawn and Pervasive Developmental Problems subscales of the CBCL were higher among children with Autism than among Non-Spectrum children. These CBCL subscales also had better sensitivity and specificity in identifying children with Autism than the GARS. Results suggest that the CBCL is a useful behavioral checklist for screening ASDs.


Asunto(s)
Trastorno Autístico/epidemiología , Trastornos de la Conducta Infantil/epidemiología , Padres , Pruebas Psicológicas , Niño , Trastornos de la Conducta Infantil/diagnóstico , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Índice de Severidad de la Enfermedad
15.
Inorg Chem ; 45(15): 5804-11, 2006 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-16841985

RESUMEN

The reactions of Cd2+ and Zn2+ with the pyridine-arm isoindoline ligand 4'-MeLH = 1,3-bis[2-(4-methylpyridyl)imino]isoindoline produced the series of octahedrally coordinated complexes M(4'-MeL)2, [M(4'-MeLH)2]2+, and [M(4'-MeL)(4'-MeLH)]+. The complexes M(4'-MeL)2 resulted from reactions of the respective metal perchlorates with deprotonated ligand, whereas the complexes [M(4'-MeLH)2](ClO4)2 resulted from reactions with ligand in the absence of added base. The mixed-ligand complexes [M(4'-MeL)(4'-MeLH)]+ were generated in solution by reactions of equimolar quantities of M(4'-MeL)2 and [M(4'-MeLH)2]2+. Whereas [Cd(4'-MeL)(4'-MeLH)]+ is stable in solution, [Zn(4'-MeL)(4'-MeLH)]+ converts to and establishes equilibrium with the tetrahedrally coordinated, trinuclear complex [Zn3(4'-MeL)4]2+. The complexes Cd(4'-MeL)2 (1), Zn(4'-MeL)2 (2), and [Cd(4'-MeL)(4'-MeLH)]ClO4 (5) were characterized by single-crystal X-ray diffraction, with the latter complex being shown to contain 4'-MeLH coordinated as a protonated iminium zwitterionic ligand. The [M(4'-MeLH)2]2+ and [M(4'-MeL)(4'-MeLH)]+ complexes are tautomeric in solution because of the shuttling of the iminium protons between imine N atoms. The rate of prototropic tautomerism in [Cd(4'-MeLH)2]+ was followed by 1H NMR spectroscopy. Over the temperature range 276-312 K, a linear Eyring plot with the activation parameters DeltaG++ = 16.0 +/- 0.1 kcal/mol, DeltaH++ = 2.9 +/- 0.1 kcal/mol, and DeltaS++ = -44.0 +/- 0.3 cal/mol.K was obtained.


Asunto(s)
Cadmio/química , Zinc/química , Cristalografía por Rayos X , Entropía , Ligandos , Espectroscopía de Resonancia Magnética , Metales/química , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Percloratos/química , Termodinámica , Difracción de Rayos X
16.
Inorg Chem ; 44(18): 6476-81, 2005 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-16124830

RESUMEN

The sterically crowded isoindoline pincer ligand, 6'-MeLH, prepared by condensation of 4-methyl-2-aminopyridine and phthalonitrile, exhibits very different reaction chemistry with Cd2+, Zn2+, and Pd2+. Three different ligand coordination modes are reported, each dependent upon choice of metal ion. This isoindoline binds to Cd2+ as a charge-neutral, zwitterionic, bidentate ligand using imine and pyridine nitrogen atoms to form the eight-coordinate fluxional complex, Cd(6'-MeLH)2(NO3)2. In the presence of Zn2+, however, loss of a pyridine arm occurs through solvolysis and tetrahedrally coordinated complexes are formed with coordination of pyrrole and pyridine nitrogen atoms. Reaction with Pd2+ produces the highly distorted, square planar complex Pd(6'-MeL)Cl in which a deprotonated isoindoline anion coordinates as a tridentate pyridinium NNC pincer ligand.


Asunto(s)
Cadmio/química , Paladio/química , Zinc/química , Ligandos , Modelos Químicos , Modelos Moleculares , Estructura Molecular
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