RESUMO
Alzheimer's disease (AD) is characterized by the presence of tau protein inclusions and amyloid beta (Aß) plaques in the brain, with Aß peptides generated by cleavage of the amyloid precursor protein (APP) by BACE1 and γ-secretase. We previously described a primary rat neuron assay in which tau inclusions form from endogenous rat tau after seeding cells with insoluble tau isolated from the human AD brain. Here, we used this assay to screen an annotated library of â¼8700 biologically active small molecules for their ability to reduce immuno-stained neuronal tau inclusions. Compounds causing ≥30% inhibition of tau aggregates with <25% loss of DAPI-positive cell nuclei underwent further confirmation testing and assessment of neurotoxicity, and non-neurotoxic hits were subsequently analyzed for inhibitory activity in an orthogonal ELISA that quantified multimeric rat tau species. Of the 173 compounds meeting all criteria, a subset of 55 inhibitors underwent concentration-response testing and 46 elicited a concentration-dependent reduction of neuronal tau inclusions that were distinct from measures of toxicity. Among the confirmed inhibitors of tau pathology were BACE1 inhibitors, several of which, along with γ-secretase inhibitors/modulators, caused a concentration-dependent lowering of neuronal tau inclusions and a reduction of insoluble tau by immunoblotting, although they did not decrease soluble phosphorylated tau species. In conclusion, we have identified a diverse set of small molecules and related targets that reduce neuronal tau inclusions. Notably, these include BACE1 and γ-secretase inhibitors, suggesting that a cleavage product from a shared substrate, such as APP, might affect tau pathology.
Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Neurônios , Proteínas tau , Animais , Humanos , Ratos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Neurônios/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
The hallmark pathological features of Alzheimer's disease (AD) brains are senile plaques, comprising ß-amyloid (Aß) peptides, and neuronal inclusions formed from tau protein. These plaques form 10-20 years before AD symptom onset, whereas robust tau pathology is more closely associated with symptoms and correlates with cognitive status. This temporal sequence of AD pathology development, coupled with repeated clinical failures of Aß-directed drugs, suggests that molecules that reduce tau inclusions have therapeutic potential. Few tau-directed drugs are presently in clinical testing, in part because of the difficulty in identifying molecules that reduce tau inclusions. We describe here two cell-based assays of tau inclusion formation that we employed to screen for compounds that inhibit tau pathology: a HEK293 cell-based tau overexpression assay, and a primary rat cortical neuron assay with physiological tau expression. Screening a collection of â¼3500 pharmaceutical compounds with the HEK293 cell tau aggregation assay, we obtained only a low number of hit compounds. Moreover, these compounds generally failed to inhibit tau inclusion formation in the cortical neuron assay. We then screened the Prestwick library of mostly approved drugs in the cortical neuron assay, leading to the identification of a greater number of tau inclusion inhibitors. These included four dopamine D2 receptor antagonists, with D2 receptors having previously been suggested to regulate tau inclusions in a Caenorhabditis elegans model. These results suggest that neurons, the cells most affected by tau pathology in AD, are very suitable for screening for tau inclusion inhibitors.
Assuntos
Agregados Proteicos/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Antagonistas dos Receptores de Dopamina D2/química , Antagonistas dos Receptores de Dopamina D2/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Células HEK293 , Humanos , Camundongos , Microscopia de Fluorescência , Neurônios/citologia , Neurônios/metabolismo , Ratos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Proteínas tau/antagonistas & inibidores , Proteínas tau/genéticaRESUMO
Filamentous tau aggregates, the hallmark lesions of Alzheimer disease (AD), play key roles in neurodegeneration. Activation of protein degradation systems has been proposed to be a potential strategy for removing pathological tau, but it remains unclear how effectively tau aggregates can be degraded by these systems. By applying our previously established cellular model system of AD-like tau aggregate induction using preformed tau fibrils, we demonstrate that tau aggregates induced in cells with regulated expression of full-length mutant tau can be gradually cleared when soluble tau expression is suppressed. This clearance is at least partially mediated by the autophagy-lysosome pathway, although both the ubiquitin-proteasome system and the autophagy-lysosome pathway are deficient in handling large tau aggregates. Importantly, residual tau aggregates left after the clearance phase leads to a rapid reinstatement of robust tau pathology once soluble tau expression is turned on again. Moreover, we succeeded in generating monoclonal cells persistently carrying tau aggregates without obvious cytotoxicity. Live imaging of GFP-tagged tau aggregates showed that tau inclusions are dynamic structures constantly undergoing "fission" and "fusion," which facilitate stable propagation of tau pathology in dividing cells. These findings provide a greater understanding of cell-to-cell transmission of tau aggregates in dividing cells and possibly neurons.
Assuntos
Proteínas tau/metabolismo , Autofagia , Linhagem Celular , Humanos , Cinética , Lisossomos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Agregados Proteicos , Proteólise , Solubilidade , Tauopatias/tratamento farmacológico , UbiquitinaçãoRESUMO
Compound 5 was selected from our in-house library as a suitable starting point for the rational design of new GSK-3ß inhibitors. MC/FEP calculations of 5 led to the identification of a structural class of new GSK-3ß inhibitors. Compound 18 inhibited GSK-3ß with an IC50 of 0.24 µM and inhibited tau phosphorylation in a cell-based assay. It proved to be a selective inhibitor of GSK-3 against a panel of 17 kinases and showed >10-fold selectivity against CDK2. Calculated physicochemical properties and Volsurf predictions suggested that compound 18 has the potential to diffuse passively across the blood-brain barrier.
Assuntos
Desenho de Fármacos , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Indolizidinas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Succinimidas/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Indolizidinas/síntese química , Indolizidinas/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Succinimidas/síntese química , Succinimidas/químicaRESUMO
Alzheimer disease and several other neurodegenerative disorders are characterized by the accumulation of intraneuronal fibrils comprised of the protein Tau. Tau is normally a soluble protein that stabilizes microtubules, with splice isoforms that contain either three (3-R) or four (4-R) microtubule binding repeats. The formation of Tau fibrils is thought to result in neuronal damage, and inhibitors of Tau fibrillization may hold promise as therapeutic agents. The process of Tau fibrillization can be replicated in vitro, and a number of small molecules have been identified that inhibit Tau fibril formation. However, little is known about how these molecules affect Tau fibrillization. Here, we examined the mechanism by which the previously described aminothieno pyridazine (ATPZ) series of compounds inhibit Tau fibrillization. Active ATPZs were found to promote the oxidation of the two cysteine residues within 4-R Tau by a redox cycling mechanism, resulting in the formation of a disulfide-containing compact monomer that was refractory to fibrillization. Moreover, the ATPZs facilitated intermolecular disulfide formation between 3-R Tau monomers, leading to dimers that were capable of fibrillization. The ATPZs also caused cysteine oxidation in molecules unrelated to Tau. Interestingly, methylene blue, an inhibitor of Tau fibrillization under evaluation in Alzheimer disease clinical trials, caused a similar oxidation of cysteines in Tau and other molecules. These findings reveal that the ATPZs and methylene blue act by a mechanism that may affect their viability as potential therapeutic agents.
Assuntos
Cisteína/química , Azul de Metileno/química , Complexos Multiproteicos/química , Proteínas tau/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Cisteína/metabolismo , Humanos , Complexos Multiproteicos/metabolismo , Oxirredução , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
The current study reports on two sequential studies that developed and provided a pilot evaluation of a Behavioral Activation (BA) training package based on an online, modular, active learning model for community mental health providers. In the first study, training outcomes were assessed with a within-subjects design by measuring trainees' (N = 8) reported implementation of learned BA skills in clinical practice and their satisfaction with the training at pretraining baseline and throughout the training. The results showed that trainees reported increased implementation of BA techniques in actual sessions. Several improvements were made in the second study, including incorporating more active learning strategies to the training protocol and including a role-play Behavioral Activation Skills Assessment (BASA) for an objective rather than self-report measure of trainees' (N = 9) performance before, after, and 6 weeks after training. Results suggested that skill at implementing two of the three core BA techniques (providing the rationale and activity scheduling) increased significantly, and overall performance was maintained at follow-up. Furthermore, trainees reported high satisfaction with the training in both studies.
Assuntos
Terapia Comportamental/educação , Instrução por Computador/métodos , Transtorno Depressivo Maior/terapia , Educação a Distância/métodos , Internet , Aprendizagem Baseada em Problemas/métodos , Adulto , Terapia Comportamental/métodos , Comportamento do Consumidor , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Avaliação de Programas e Projetos de SaúdeRESUMO
Previous studies demonstrated that members of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors exhibit a promising combination of in vitro activity as well as favorable pharmacokinetic properties (i.e., brain-penetration and oral bioavailability). Here we report the synthesis and evaluation of several new analogues. These studies indicate that the thienopyridazine core is essential for inhibition of tau fibrillization in vitro, while the choice of the appropriate scaffold decoration is critical to impart desirable ADME-PK properties. Among the active, brain-penetrant ATPZ inhibitors evaluated, 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide (43) was selected to undergo maximum tolerated dose and one-month tolerability testing in mice. The latter studies revealed that this compound is well-tolerated with no notable side-effects at an oral dose of 50mg/kg/day.
Assuntos
Ciclopropanos/química , Piridazinas/química , Proteínas tau/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Encéfalo/metabolismo , Ciclopropanos/síntese química , Ciclopropanos/farmacocinética , Camundongos , Piridazinas/síntese química , Piridazinas/farmacocinética , Relação Estrutura-Atividade , Proteínas tau/metabolismoRESUMO
Agents capable of preventing the misfolding and sequestration of the microtubule-stabilizing protein tau into insoluble fibrillar aggregates hold considerable promise for the prevention and/or treatment of neurodegenerative tauopathies such as Alzheimer's disease. Because tauopathies are characterized by amyloidosis that is restricted to the central nervous system (CNS), plausible candidate compounds for in vivo evaluation must both prevent tau fibrillization and achieve significant brain levels. Recently, we reported the discovery of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors and now describe a series of new analogues that are both effective inhibitors of tau fibrillization and display significant brain-to-plasma exposure ratios after administration to mice. Further, two of the most promising examples, 15 and 16, were found to reach significant brain exposure levels following oral administration. Taken together, these results suggest that examples from the ATPZ class hold promise as candidates for in vivo efficacy studies in animal models of neurodegenerative tauopathies.
Assuntos
Barreira Hematoencefálica/metabolismo , Piridazinas/farmacocinética , Tauopatias/tratamento farmacológico , Proteínas tau/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Descoberta de Drogas , Camundongos , Multimerização Proteica/efeitos dos fármacos , Tauopatias/prevenção & controleRESUMO
The microtubule-associated protein tau forms insoluble filaments that deposit as neurofibrillary tangles (NFTs) in the brains of those with Alzheimer's disease (AD) and other related neurodegenerative disorders. The presence of both NFTs and amyloid beta (Abeta)-containing senile plaques within the brain is required to confirm the diagnosis of AD. However, the demonstration that familial AD can be caused by mutations that result in increased Abeta production has resulted in AD drug discovery strategies that are largely focused on reducing brain Abeta levels, with substantially less emphasis on tau-directed approaches. This trend may be changing, as there are an increasing number of research programs that are exploring ways to reduce NFTs in AD and related tauopathies. We briefly review recent advances in tau-based drug discovery, with an emphasis on the identification of compounds that inhibit the assembly of tau into multimers and fibrils.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Tauopatias/tratamento farmacológico , Tauopatias/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Descoberta de Drogas , Humanos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Tauopatias/patologiaRESUMO
Inclusions comprised of fibrils of the microtubule- (MT-) associated protein tau are found in the brains of those with Alzheimer's disease (AD) and other neurodegenerative tauopathies. The pathology that is observed in these diseases is believed to result from the formation of toxic tau oligomers or fibrils and/or from the loss of normal tau function due to its sequestration into insoluble deposits. Hence, small molecules that prevent tau oligomerization and/or fibrillization might have therapeutic value. Indeed, examples of such compounds have been published, but nearly all have properties that render them unsuitable as drug candidates. For these reasons, we conducted quantitative high-throughput screening (qHTS) of approximately 292000 compounds to identify drug-like inhibitors of tau assembly. The fibrillization of a truncated tau fragment that contains four MT-binding domains was monitored in an assay that employed complementary thioflavin T fluorescence and fluorescence polarization methods. Previously described classes of inhibitors as well as new scaffolds were identified, including novel aminothienopyridazines (ATPZs). A number of ATPZ analogues were synthesized, and structure-activity relationships were defined. Further characterization of representative ATPZ compounds showed they do not interfere with tau-mediated MT assembly, and they are significantly more effective at preventing the fibrillization of tau than the Abeta(1-42) peptide which forms AD senile plaques. Thus, the ATPZ molecules described here represent a novel class of tau assembly inhibitors that merit further development for testing in animal models of AD-like tau pathology.
Assuntos
Descoberta de Drogas , Piridazinas/química , Proteínas tau/antagonistas & inibidores , Proteínas tau/química , Animais , Humanos , Estrutura Molecular , Conformação Proteica , Multimerização Proteica , Tauopatias/patologia , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Tau is a microtubule-associated protein that promotes microtubule assembly and stability. In Alzheimer's disease and related tauopathies, tau fibrillizes and aggregates into neurofibrillary tangles. Recently, oleocanthal isolated from extra virgin olive oil was found to display non-steroidal anti-inflammatory activity similar to ibuprofen. As our unpublished data indicates an inhibitory effect of oleocanthal on amyloid beta peptide fibrillization, we reasoned that it might inhibit tau fibrillization as well. Herein, we demonstrate that oleocanthal abrogates fibrillization of tau by locking tau into the naturally unfolded state. Using PHF6 consisting of the amino acid residues VQIVYK, a hexapeptide within the third repeat of tau that is essential for fibrillization, we show that oleocanthal forms an adduct with the lysine via initial Schiff base formation. Structure and function studies demonstrate that the two aldehyde groups of oleocanthal are required for the inhibitory activity. These two aldehyde groups show certain specificity when titrated with free lysine and oleocanthal does not significantly affect the normal function of tau. These findings provide a potential scheme for the development of novel therapies for neurodegenerative tauopathies.
Assuntos
Aldeídos/farmacologia , Emaranhados Neurofibrilares/efeitos dos fármacos , Fenóis/farmacologia , Tauopatias/tratamento farmacológico , Proteínas tau/efeitos dos fármacos , Aldeídos/química , Aldeídos/metabolismo , Aldeídos/uso terapêutico , Sequência de Aminoácidos/efeitos dos fármacos , Sequência de Aminoácidos/fisiologia , Aminoácidos/efeitos dos fármacos , Aminoácidos/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Monoterpenos Ciclopentânicos , Encefalite/tratamento farmacológico , Encefalite/metabolismo , Encefalite/fisiopatologia , Humanos , Lisina/metabolismo , Estrutura Molecular , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Neurofibrilas/química , Neurofibrilas/efeitos dos fármacos , Neurofibrilas/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Peptídeos/química , Peptídeos/metabolismo , Fenóis/química , Fenóis/uso terapêutico , Dobramento de Proteína/efeitos dos fármacos , Bases de Schiff/química , Bases de Schiff/metabolismo , Tauopatias/metabolismo , Tauopatias/fisiopatologia , Proteínas tau/química , Proteínas tau/metabolismoRESUMO
Lanthanum (La) is a phosphate binder used in patients on dialysis in the UK. As it has only recently been in use, there are no long-term data about safety of this rare metal in human subjects with renal failure on renal replacement therapy. La has not been previously reported to cause any adverse reactions apart from nausea, sickness, dialysis graft occlusion and abdominal pain. We report here La induced abnormal liver function tests in a male and a female patient of 70 and 44 years old each, on peritoneal dialysis (PD) and haemodialysis (HD) respectively, the first report of such an adverse reaction to this agent.
RESUMO
INTRODUCTION: This study pools data from the UK Intensive Care National Audit and Research Center (ICNARC) Case Mix Programme (CMP) to evaluate the case mix, outcome and activity for 17,326 patients with severe acute kidney injury (AKI) occurring during the first 24 hours of admission to intensive care units (ICU). METHODS: Severe AKI admissions (defined as serum creatinine >/=300 mumol/l and/or urea >/=40 mmol/l during the first 24 hours) were extracted from the ICNARC CMP database of 276,326 admissions to UK ICUs from 1995 to 2004. Subgroups of oliguric and nonoliguric AKI were identified by daily urine output. Data on surgical status, survival and length of stay were also collected. Severity of illness scores and mortality prediction models were compared (UK Acute Physiology and Chronic Health Evaluation [APACHE] II, Stuivenberg Hospital Acute Renal Failure [SHARF] T0, SHARF II0 and the Mehta model). RESULTS: Severe AKI occurred in 17,326 out of 276,731 admissions (6.3%). The source of admission was nonsurgical in 83.7%. Sepsis was present in 47.3% and AKI was nonoliguric in 63.9% of cases. Admission to ICU with severe AKI accounted for 9.3% of all ICU bed-days. Oliguric AKI was associated with longer length of stay for survivors and shorter length of stay for nonsurvivors compared with nonoliguric AKI. Oliguric AKI was associated with significantly greater ICU and hospital mortality (55.8% and 77.3%, respectively) compared with nonoliguric AKI (33.4% and 49.3%, respectively). Surgery during the 1 week before admission or during the first week in the CMP unit was associated with decreased odds of mortality. UK APACHE II and the Mehta scores under-predicted the number of deaths, whereas SHARF T0 and SHARF II0 over-predicted the number of deaths. CONCLUSIONS: Severe AKI accounts for over 9% of all bed-days in adult, general ICUs, representing a considerable drain on resources. Although nonoliguric AKI continues to confer a survival benefit, overall survival from AKI in the ICU and survival to leave hospital remains poor. The use of APACHE II score measured during the first 24 hours of ICU stay performs well as compared with SHARF T0, SHARF II0 and the Mehta score, but it lacks perfect calibration.
Assuntos
Injúria Renal Aguda/mortalidade , Bases de Dados Factuais/tendências , Grupos Diagnósticos Relacionados/tendências , Unidades de Terapia Intensiva/tendências , Admissão do Paciente/tendências , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/terapia , Idoso , Cuidados Críticos/métodos , Cuidados Críticos/tendências , Feminino , Mortalidade Hospitalar , Humanos , Tempo de Internação/tendências , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Taxa de Sobrevida/tendências , Fatores de Tempo , Resultado do TratamentoRESUMO
Sepsis is an important and serious complication in hemodialysis (HD) patients. Here we report on a case of spina bifida with ventriculo-peritoneal (VP) shunt infection who was on HD and underwent at least 5 months of investigations before a source of the infection was found and eventually treated successfully. We believe this to be the first reported case of VP shunt-associated sepsis in a patient on HD.
Assuntos
Falência Renal Crônica/complicações , Infecções Relacionadas à Prótese/etiologia , Diálise Renal , Sepse/etiologia , Disrafismo Espinal/complicações , Derivação Ventriculoperitoneal/efeitos adversos , Adulto , Antibacterianos/uso terapêutico , Humanos , Falência Renal Crônica/terapia , Masculino , Infecções Relacionadas à Prótese/diagnóstico por imagem , Infecções Relacionadas à Prótese/tratamento farmacológico , Sepse/diagnóstico por imagem , Sepse/tratamento farmacológico , Tomografia Computadorizada por Raios XRESUMO
A library of approximately 51,000 compounds was interrogated by high throughput screening (HTS) using a heparin-induced tau fibrillization assay. HTS was conducted with bacterially expressed recombinant tau fragment K18 and the reaction was monitored by thioflavine T fluorescence. Hits meeting criteria set for selection in HTS were further evaluated in a panel of assays designed (a) to confirm the initial results and (b) to identify possible false positives arising from non-specific mechanisms or assay-dependent artifacts. Two 2,3-di(furan-2-yl)-quinoxalines were confirmed as inhibitors of tau fibrillization with IC(50)s in the low micromolar range (l-3 microM). Among false positive hits, members of the pyrimidotriazines, benzofurans, porphyrins, and anthraquinone, inhibited tau fibrillization by generating peroxides via catalytic redox cycles due to the reducing agent dithiothreitol (DTT) in the assay. This study delineates focused strategies for HTS of tau fibrillization inhibitors that are relevant to drug discovery for Alzheimer's disease and related tauopathies.
Assuntos
Furanos/química , Heparina/química , Emaranhados Neurofibrilares/química , Quinoxalinas/química , Proteínas tau/química , Benzotiazóis , Avaliação Pré-Clínica de Medicamentos , Fluorescência , Corantes Fluorescentes , Proteínas Recombinantes/química , Relação Estrutura-Atividade , TiazóisRESUMO
INTRODUCTION: This report describes the case mix, outcome and activity for admissions to intensive care units (ICUs) of patients who require prior chronic renal dialysis for end-stage renal failure (ESRF), and investigates the effect of case mix factors on outcome. METHODS: This was a secondary analysis of a high-quality clinical database, namely the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme Database, which includes 276,731 admissions to 170 adult ICUs across England, Wales and Northern Ireland from 1995 to 2004. RESULTS: During the eight year study period, 1.3% (n = 3,420) of all patients admitted to ICU were receiving chronic renal dialysis before ICU admission. This represents an estimated ICU utilization of six admissions (32 bed-days) per 100 dialysis patient-years. The ESRF group was younger (mean age 57.3 years versus 59.5 years) and more likely to be male (60.2% versus 57.9%) than those without ESRF. Acute Physiology and Chronic Health Evaluation II score and Acute Physiology Score revealed greater severity of illness on admission in patients with ESRF (mean 24.7 versus 16.6 and 17.2 versus 12.6, respectively). Length of stay in ICU was comparable between groups (median 1.9 days versus 1.8 days) and ICU mortality was only slightly elevated in the ESRF group (26.3% versus 20.8%). However, the ESRF group had protracted overall hospital stay (median 25 days versus 17 days), and increased hospital mortality (45.3% versus 31.2%) and ICU readmission (9.0% vs. 4.7%). Multiple logistic regression analysis adjusted for case mix identified the increased hospital mortality to be associated with increasing age, emergency surgery and nonsurgical cases, cardiopulmonary resuscitation before ICU admission and extremes of physiological norms. The adjusted odds ratio for ultimate hospital mortality associated with chronic renal dialysis was 1.24 (95% confidence interval 1.13 to 1.37). CONCLUSION: Patients with ESRF admitted to UK ICUs are more likely to be male and younger, with a medical cause of admission, and to have greater severity of illness than the non-ESRF population. Outcomes on the ICU were comparable between the two groups, but those patients with ESRF had greater readmission rates, prolonged post-ICU hospital stay and increased post-ICU hospital mortality. This study is by far the largest comparative outcome analysis to date in patients with ESRF admitted to the ICU. It may help to inform clinical decision-making and resource requirements for this patient population.
Assuntos
Grupos Diagnósticos Relacionados/estatística & dados numéricos , Unidades de Terapia Intensiva/estatística & dados numéricos , Falência Renal Crônica/terapia , Avaliação de Processos e Resultados em Cuidados de Saúde/estatística & dados numéricos , Diálise Renal/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Inglaterra/epidemiologia , Feminino , Mortalidade Hospitalar , Humanos , Falência Renal Crônica/mortalidade , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Irlanda do Norte/epidemiologia , Razão de Chances , Análise de Regressão , Fatores Sexuais , Taxa de Sobrevida , País de Gales/epidemiologiaRESUMO
Frontotemporal dementia (FTD) is a clinically heterogeneous disorder characterized by alterations in language and/or behavior, often in association with Parkinsonism or motor neuron disease. A familial form of FTD is associated with mutations in the microtubule-associated protein tau (MAPT) gene. We report here on the clinical, neuroimaging, cerebral spinal fluid biomarker, genetic, biochemical and postmortem neuropathological analyses of a case of familial FTD with a Leu266Val MAPT mutation which results in a very early age of onset and a rapid course of disease. This is also the first reported case of any MAPT mutation in an individual of African American ethnicity.
Assuntos
Demência/genética , Leucina/genética , Mutação , Valina/genética , Proteínas tau/genética , Adulto , Negro ou Afro-Americano/etnologia , Proteínas de Ligação a DNA/metabolismo , Demência/metabolismo , Demência/patologia , Demência/fisiopatologia , Saúde da Família , Feminino , Humanos , Imageamento por Ressonância Magnética , Testes Neuropsicológicos , Proteínas do Grupo Polycomb , Fatores de Transcrição/metabolismoRESUMO
We present the clinicopathological features of two siblings from a consanguineous marriage who presented with respiratory hypoventilation and died 10 days and 4 years later, respectively. This disorder showed extensive tau neuropathology, and both had a novel homozygous S352L tau gene mutation. This is the first description of a pathologically proved young-onset tauopathy with apparent recessive inheritance.