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INTRODUCTION: Non-motor fluctuations (NMF) in Parkinson's disease (PD) remain poorly recognized but have a high impact on patients' quality of life. The lack of assessment tools limits our understanding of NMF, compromising appropriate management. Our objective was to validate a hetero-questionnaire for NMF in PD patients at different stages of the disease: without treatment, without motor fluctuations, with motor fluctuations. METHODS: We included patients in 15 centers in France. Our questionnaire, NMF-Park, resulted from previous studies, allowing us to identify the more pertinent NMF for evaluation. Patients reported the presence (yes or no) of 22 selected NMF, and their link with dopaminergic medications. The assessment was repeated at one and two years to study the progression of NMF. We performed a metrological validation of our questionnaire. RESULTS: We included 255 patients (42 without treatment, 88 without motor fluctuations and 125 with motor fluctuations). After metrological validation, three dimensions of NMF were found: dysautonomic; cognitive; psychiatric. The sensory/pain dimension described in the literature was not statistically confirmed by our study. DISCUSSION: Our questionnaire was validated according to clinimetric standards, for different stages of PD. It was clinically coherent with three homogeneous dimensions. It highlighted a link between fatigue, visual accommodation disorder, and cognitive fluctuations; and the integration of sensory/pain fluctuations as part of dysautonomic fluctuations. It focused exclusively on NMF, which is interesting considering the described differences between non-motor and motor fluctuations. CONCLUSION: Our study validated a hetero-questionnaire of diagnosis for NMF for different stages of PD.
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Doença de Parkinson , Disautonomias Primárias , Humanos , Dor , Doença de Parkinson/terapia , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Poor impulse control is a common feature in patients with Parkinson's disease (PD). However, before testing whether patients with PD and controls differ in impulsivity, one must assess whether impulsivity measures are invariant across groups. Consequently, we examined (a) the measurement and structural invariance of a scale assessing changes in four dimensions of impulsivity (urgency, lack of premeditation, lack of perseverance and sensation seeking) among patients with PD and controls; and (b) whether the four impulsivity traits relate differentially to risky decisions by patients. METHOD: Close relatives of 78 patients with idiopathic PD and 96 control participants were given the short Urgency-Premeditation-Perseverance-Sensation seeking Impulsive Behaviour Scale (UPPS), which assesses changes in four dimensions of impulsivity. Participants also completed the Game of Dice Task (GDT), a laboratory measure of risk taking. RESULTS: Multigroup confirmatory factor analyses supported measurement invariance across groups, whereas structural invariance was not confirmed. Patients with PD showed greater variability and higher impulsivity than controls. Furthermore, patients with impulse control disorders (ICDs) demonstrated even greater levels of sensation seeking than patients without ICDs. Finally, lower premeditation and greater perseverance were significantly associated with greater risk taking in patients with PD, and higher agonist dopaminergic doses with less risky choices on the GDT. CONCLUSIONS: The questionnaire appears to function comparably across patients and controls. Thus, group comparisons on the questionnaire can be considered valid. Mean differences between groups on the dimensions of impulsivity may reflect executive impairments and/or abnormal reward processing in patients with PD, which may lead to risky behaviours.
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Comportamento Impulsivo/fisiologia , Doença de Parkinson/fisiopatologia , Comportamento Problema , Escalas de Graduação Psiquiátrica/normas , Psicometria/instrumentação , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Rhythmic auditory cues can immediately improve gait in Parkinson's disease. However, this effect varies considerably across patients. The factors associated with this individual variability are not known to date. Patients' rhythmic abilities and musicality (e.g., perceptual and singing abilities, emotional response to music, and musical training) may foster a positive response to rhythmic cues. To examine this hypothesis, we measured gait at baseline and with rhythmic cues in 39 non-demented patients with Parkinson's disease and 39 matched healthy controls. Cognition, rhythmic abilities and general musicality were assessed. A response to cueing was qualified as positive when the stimulation led to a clinically meaningful increase in gait speed. We observed that patients with positive response to cueing (n = 17) were more musically trained, aligned more often their steps to the rhythmic cues while walking, and showed better music perception as well as poorer cognitive flexibility than patients with non-positive response (n = 22). Gait performance with rhythmic cues worsened in six patients. We concluded that rhythmic and musical skills, which can be modulated by musical training, may increase beneficial effects of rhythmic auditory cueing in Parkinson's disease. Screening patients in terms of musical/rhythmic abilities and musical training may allow teasing apart patients who are likely to benefit from cueing from those who may worsen their performance due to the stimulation.
RESUMO
INTRODUCTION: Rhythmic auditory cueing improves certain gait symptoms of Parkinson's disease (PD). Cues are typically stimuli or beats with a fixed inter-beat interval. We show that isochronous cueing has an unwanted side-effect in that it exacerbates one of the motor symptoms characteristic of advanced PD. Whereas the parameters of the stride cycle of healthy walkers and early patients possess a persistent correlation in time, or long-range correlation (LRC), isochronous cueing renders stride-to-stride variability random. Random stride cycle variability is also associated with reduced gait stability and lack of flexibility. METHOD: To investigate how to prevent patients from acquiring a random stride cycle pattern, we tested rhythmic cueing which mimics the properties of variability found in healthy gait (biological variability). PD patients (n=19) and age-matched healthy participants (n=19) walked with three rhythmic cueing stimuli: isochronous, with random variability, and with biological variability (LRC). Synchronization was not instructed. RESULTS: The persistent correlation in gait was preserved only with stimuli with biological variability, equally for patients and controls (p's<0.05). In contrast, cueing with isochronous or randomly varying inter-stimulus/beat intervals removed the LRC in the stride cycle. Notably, the individual's tendency to synchronize steps with beats determined the amount of negative effects of isochronous and random cues (p's<0.05) but not the positive effect of biological variability. CONCLUSION: Stimulus variability and patients' propensity to synchronize play a critical role in fostering healthier gait dynamics during cueing. The beneficial effects of biological variability provide useful guidelines for improving existing cueing treatments.
Assuntos
Estimulação Acústica , Sinais (Psicologia) , Marcha , Doença de Parkinson/fisiopatologia , Caminhada , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PeriodicidadeRESUMO
The complementation group F of Xeroderma pigmentosum (XP-F) is rare in the Caucasian population, and usually devoid of neurological symptoms. We report two cases, both Caucasian, who exhibited progressive cerebellar ataxia, chorea, a mild subcortical frontal cognitive impairment, and in one case severe polyneuropathy. Brain MRI demonstrated cerebellar (2/2) and cortical (1/2) atrophy. Both patients had only mild sunburn sensitivity and no skin cancer. Mini-exome sequencing approach revealed in ERCC4, two heterozygous mutations, one of which was never described (c.580-584+1delCCAAGG, exon 3), in the first case, and an already reported homozygous mutation, in the second case. These cases emphasize that XP-F is a rare cause of recessive cerebellar ataxia and can in some cases clinically mimic Huntington's disease due to chorea and executive impairment. The association of ataxia, chorea, and sun hypersensitivity are major guidance for the diagnosis, which should not be missed, in order to prevent skin neoplastic complications.
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Ataxia Cerebelar/etiologia , Coreia/etiologia , Xeroderma Pigmentoso/complicações , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/genética , Ataxia Cerebelar/fisiopatologia , Coreia/diagnóstico por imagem , Coreia/genética , Coreia/fisiopatologia , Proteínas de Ligação a DNA/genética , Diagnóstico Diferencial , Feminino , Humanos , Masculino , População Branca/genética , Xeroderma Pigmentoso/diagnóstico por imagem , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/fisiopatologiaRESUMO
BACKGROUND AND PURPOSE: Patients with vascular parkinsonism have higher cognitive decline and more basal ganglia lesions. We aimed to evaluate the relationship of cognitive impairment with functional connectivity between the basal ganglia and cingulate cortex in vascular parkinsonism. MATERIALS AND METHODS: Thirty patients (8 with vascular parkinsonism and 22 with Parkinson disease) and 23 controls were enrolled. The Mattis Dementia Rating Scale and the Stroop Task were used to assess cognitive decline. MR imaging examinations included T1-MPRAGE, FLAIR, and resting-state fMRI sequences. MPRAGE was segmented to obtain basal ganglia and cingulate cortex volumes. FLAIR was segmented to obtain white matter hyperintensity lesion volume. Resting-state fMRI sequences were used to compare basal ganglia functional connectivity with the cingulate cortex between patients and controls. RESULTS: Patients with vascular parkinsonism exhibited impaired attention, resistance to interference, and inhibitory control and an increased number of errors on the Stroop Task. They also had higher caudate nucleus and white matter hyperintensity lesion volumes, which were positively correlated (ρ = 0.75, P < .0001). Caudate nucleus functional connectivity with the perigenual anterior cingulate cortex was increased in patients with vascular parkinsonism compared with controls and patients with Parkinson disease, and it was positively correlated with the caudate nucleus volume (ρ = 0.44, P = .016). Caudate nucleus functional connectivity with the posterior cingulate cortex was decreased in patients with vascular parkinsonism compared with controls and negatively correlated with the number of errors on the Stroop test (ρ = -0.51, P = .0003). CONCLUSIONS: In patients with vascular parkinsonism, cognitive decline could be related to changes of caudate nucleus functional connectivity with the cingulate cortex at resting-state, which may be induced by ischemia-related remodelling.
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Gânglios da Base/fisiopatologia , Encéfalo/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Vias Neurais/fisiopatologia , Doença de Parkinson Secundária/fisiopatologia , Gânglios da Base/patologia , Encéfalo/patologia , Disfunção Cognitiva/etiologia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Vias Neurais/patologia , Doença de Parkinson Secundária/complicações , Doença de Parkinson Secundária/patologiaAssuntos
Síndrome de Creutzfeldt-Jakob/complicações , Delusões/etiologia , Idoso , Encéfalo/patologia , Encéfalo/fisiopatologia , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/patologia , Delusões/diagnóstico , Eletroencefalografia , Evolução Fatal , Feminino , Fluoxetina/uso terapêutico , Mãos , Humanos , Imageamento por Ressonância Magnética , Mioclonia/etiologia , Reflexo/fisiologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
Drug-induced adverse effects are one of the main avoidable causes of hospitalization in older people. Numerous lists of potentially inappropriate medications for older people have been published, as national and international guidelines for appropriate prescribing in numerous diseases and for different age categories. The present review describes the general rules for an appropriate prescribing in older people and summarizes, for the main conditions encountered in older people, medications that are too often under-prescribed, the precautions of use of the main drugs that induce adverse effects, and drugs for which the benefit to risk ratio is unfavourable in older people. All these data are assembled in educational tables designed to be printed in a practical pocket format and used in daily practice by prescribers, whether physicians, surgeons or pharmacists.
Assuntos
Idoso , Prescrições de Medicamentos , Padrões de Prática Médica , Fatores Etários , Idoso de 80 Anos ou mais , Prescrições de Medicamentos/normas , Prescrições de Medicamentos/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Humanos , Prescrição Inadequada/prevenção & controle , Prescrição Inadequada/estatística & dados numéricos , Erros de Medicação/prevenção & controle , Erros de Medicação/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricosRESUMO
OBJECTIVES: To compare the expression of endogenous retroviruses in MS patients and controls. MATERIAL AND METHODS: Peripheral blood mononuclear cells were obtained from 22 MS patients, a corresponding number of matched healthy donors and five patients with other central nervous system disease. Also brain specimens from MS patients and controls were obtained. Transcripts of various endogenous retroviruses in these samples were detected by RNA-PCR. RESULTS: Several endogenous retroviral sequences were transcribed in peripheral blood mononuclear cells and brain tissue from MS patients as well as controls. A composite transcript of an endogenous retrovirus and a zinc finger sequence was more frequently found in healthy donors than in MS patients. CONCLUSION: Some endogenous retroviruses are normally transcribed in white blood cells and brain tissue. The significance of those findings, which concerned the composite transcripts of the zinc finger sequence and its associated endogenous retrovirus is uncertain.
Assuntos
Esclerose Múltipla/virologia , Retroviridae/genética , Adulto , Encéfalo/virologia , Feminino , Regulação Viral da Expressão Gênica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/virologia , Reação em Cadeia da Polimerase , Infecções por Retroviridae/virologia , Transcrição Gênica/genética , Dedos de Zinco/genéticaRESUMO
In investigating a possible link between a novel retroviral agent (provisionally called MSRV), recently characterised in multiple sclerosis (MS), and the neuropathology of MS, it was found that there was a significant correlation between gliotoxicity and reverse transcriptase activity in monocyte/macrophage culture supernatants (MMCS) unique to MS patients. MMCS from healthy controls and patients with other neurological diseases did not display either gliotoxicity or reverse transcriptase activity. The observed gliotoxic effect was an initial, intermediate filament network disorganization and subsequent cell death which was specific to astrocytes and oligodendrocytes. The reverse transcriptase activity and MSRV-specific RNA were observed during the first 2 weeks of culture in MMCS from patients with active MS. The further elucidation of the molecular form(s) of this gliotoxic factor and its original source may be crucial in elucidating important etiopathogenic mechanisms in MS.
Assuntos
Macrófagos/patologia , Monócitos/patologia , Esclerose Múltipla/sangue , Esclerose Múltipla/virologia , Neurotoxinas/isolamento & purificação , RNA Viral/isolamento & purificação , DNA Polimerase Dirigida por RNA/isolamento & purificação , Retroviridae/isolamento & purificação , Animais , Astrócitos/citologia , Astrócitos/patologia , Linhagem Celular Transformada , Células Cultivadas , Córtex Cerebral/citologia , Meios de Cultura , Feto , Humanos , Macrófagos/citologia , Macrófagos/virologia , Monócitos/citologia , Monócitos/virologia , Neurotoxinas/toxicidade , Oligodendroglia/citologia , Oligodendroglia/patologia , Proteínas/isolamento & purificação , Proteínas/toxicidade , Ratos , Ratos Wistar , Retroviridae/enzimologia , Retroviridae/genéticaRESUMO
Various mitochondrial DNA abnormalities have been described in patients with encephalomyopathies. We performed Southern blot analysis of skeletal muscle mitochondrial DNA in nine adult patients with clinical features and ragged red fibres suggesting mitochondrial dysfunction. Two patients with encephalomyopathy and two with the MERRF syndrome (myoclonus epilepsy with ragged red fibres) had the normal PvuII restriction pattern of muscle mitochondrial DNA. In contrast, mitochondrial DNA deletion was observed in two of six patients with ophthalmoplegia. One suffered from typical Kearns-Sayre syndrome and the other from isolated external ophthalmoplegia. None of these patients had affected relatives. The detection of mitochondrial DNA deletion in external ophthalmoplegia and their site and size support previously reported data.
Assuntos
Encefalopatias/genética , DNA Mitocondrial/análise , Epilepsias Mioclônicas/genética , Mitocôndrias Musculares/química , Southern Blotting , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Oftalmoplegia/genética , SíndromeRESUMO
Neural tissue from human fetuses is currently used for intracerebral transplantation to treat patients with Parkinson's disease. The development of the human fetal tissue following grafting has been considered mostly, up to now, from the neuronal point of view in xenografts. Very little is known, in contrast, about nonneuronal, glial, or vascular cells in the grafts. Comparison of the data gathered on the development of grafted human neurons with those obtained in comparable studies using rat transplants has demonstrated species-specific features. We have therefore undertaken a series of studies dealing with nonneuronal cells in human-to-rat transplants to reveal other possible species-specificity of the human tissue. This study has, accordingly, been devoted to the immunohistochemical analysis of microglia of host and donor origins in a human to rat xenograft paradigm allowing clear distinction of the origin of the cells. Human neural tissue was transplanted as a cell suspension into the thalamus of adult rats. Amoeboid human microglia were observed in 1-, 2-, and 3-month-old transplants, but their density, already relatively low at the first stage, decreased further over time. Ramified human microglia were only occasional. In sharp contrast, host rat microglia rapidly invaded the transplant in the absence of any sign of necrosis. The rat cells exhibited first an amoeboid morphology but progressed at the later stages toward a more mature, ramified morphology. These results indicate that donor microglia are quite few in number at first and, at least, do not proliferate actively after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Transplante de Tecido Fetal/fisiologia , Microglia/fisiologia , Medula Espinal/transplante , Quimeras de Transplante/fisiologia , Transplante Heterólogo/fisiologia , Animais , Agonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Antígenos HLA/imunologia , Humanos , Imuno-Histoquímica , Terapia de Imunossupressão , Ácido Caínico/toxicidade , Contagem de Leucócitos , Complexo Principal de Histocompatibilidade/imunologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Pseudotumoral presentation of Neuro-Behçet's disease has been described before. The diagnosis may be difficult obtain in patients without mucosal, cutaneous, and ocular signs. We report the observation of a young patient suffering from a right hemiparesis with computed-tomographic (CT) features suggestive of a thalamocapsular expanding lesion. Histologic study of brain biopsy tissue ruled out a tumor but did not show any specific diagnosis. The patient improved with steroid therapy.
Assuntos
Síndrome de Behçet/diagnóstico , Encefalopatias/diagnóstico , Adulto , Síndrome de Behçet/complicações , Biópsia , Encefalopatias/complicações , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/diagnóstico , Diagnóstico Diferencial , Humanos , Masculino , Técnicas EstereotáxicasRESUMO
Five patients with idiopathic PD were followed by neuropsychological tests after brain fetal neuronal transplantation. The following tests were used in order to assess memory as well as visuospatial and frontal functions: MMSE, Mattis Scale, Wisconsin Card Sorting Test, Stroop task, word fluency tasks, 15-objects test, WAIS-R (Digit span, Arithmetic, Block design, Pictures completion, Pictures arrangement), learning of 15 words of Rey, WMS-R (Logical memory) and Visual memory of L. Israël. The same tests were performed before, then one year following the transplantation. Pooled data did not show any significant difference between pre and post-operative tests. Individual results varied among patients: 2 remained unchanged, 1 had a pathological deterioration which increased after one year, 1 had some frontal symptoms whereas the last patient improved. Our data confirm that this surgical procedure do not induce permanent neuropsychological deficits, but do not indicate at the present time any clear effect of dopamine reinnervation on cognitive functions.
Assuntos
Neurônios/transplante , Testes Neuropsicológicos , Doença de Parkinson/cirurgia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/psicologia , Período Pós-Operatório , Fatores de TempoRESUMO
The central nervous system was examined in 135 adult AIDS patients who died between August 1982 and December 1990. Twenty two brains showed non-diagnostic changes including microglial nodules, discrete myelin pallor with reactive astrocytosis, mineralization of blood vessels and granular ependymitis. In 105 brains with specific changes, toxoplasmosis was the most frequent finding (55 cases) manifested by multifocal necrotic lesions or diffuse pseudo-encephalitic process. Other opportunists included cytomegalovirus (21 case), progressive multifocal leukoencephalopathy (1 cases), cryptococcosis (6 cases), mycobacterium avium intracellulaire (2 cases), varicella-zoster virus (2 cases), aspergillosis (1 case) and multiple bacterial microabscesses (1 case). Multinucleated giant cells were found in 52 cases. In 40 cases, they were widely disseminated throughout the brain and in 39 cases, they were associated with diffuse or multifocal white matter changes. Fifteen cases had a cerebral lymphoma, 9 hepatic encephalopathy, 1 centropontine myelinolysis and 1 focal pontine leukoencephalopathy. Three cases had a cerebral haemorrhage due to disseminated intravascular coagulation, antithrombin therapy and amyloid angiopathy. Spinal changes in 13 cases included vacuolar myelopathy (7 cases), HIV myelitis (1 case) and ganglio-radiculitis (1 cases), cytomegalovirus myelo-radiculitis (1 case) secondary spread from a lymphoma (1 case) and spinal infarcts due to disseminated intravascular coagulation (1 case). These lesions were frequently atypical and various combinations of all these pathologies were encountered in the same brain, sometimes in the same area and occasionally in the same cell. Chronological variations in the incidence of some complications could be related to changes in treatment.
Assuntos
Síndrome da Imunodeficiência Adquirida/patologia , Doenças do Sistema Nervoso Central/patologia , Síndrome da Imunodeficiência Adquirida/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças do Sistema Nervoso Central/etiologia , Encefalite/patologia , Feminino , Gânglios Espinais/patologia , Humanos , Inflamação/patologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas/patologia , Estudos Retrospectivos , Viroses/patologiaRESUMO
A variety of the central nervous system lesions may cause a diffuse encephalopathy in AIDS patients. Apart from viral encephalitides already described in part one, metabolic encephalopathies are a classical cause of diffuse brain dysfunction and are frequent at the terminal stage of the disease. Atypical forms of some infectious, vascular or tumoural processes which usually determine focal lesions, may cause diffuse encephalopathies. These forms are not exceptional in AIDS. The association in the same patient of lesions due to different agents is the rule. Whereas most of the neurological complications of AIDS occur late in the course of the disease, symptomatic, usually transient encephalopathies have been described in the early stages of HIV infection in rare cases. The authors conclude by proposing a management plan, since therapeutic advances have raised some hopes of improvement and even regression of some of these disorders in a few cases, so that physicians do not systematically give up when an AIDS patient presents with a diffuse encephalopathy.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Síndrome da Imunodeficiência Adquirida/complicações , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Micoses/diagnóstico , Neurossífilis/diagnóstico , Tuberculose Meníngea/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/complicações , Adulto , Fatores Etários , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/etiologia , Transtornos Cerebrovasculares/diagnóstico , Transtornos Cerebrovasculares/etiologia , Humanos , Leucoencefalopatia Multifocal Progressiva/etiologia , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/etiologia , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/etiologia , Micoses/complicações , Neurossífilis/complicações , Toxoplasmose Cerebral/complicações , Toxoplasmose Cerebral/diagnóstico , Tuberculose Meníngea/complicaçõesRESUMO
The diagnostic approach of focal central nervous system lesions in AIDS patients is now well established. In contrast, it is extremely difficult to determine the cause of diffuse encephalopathies, occurring frequently at the terminal stage of AIDS. Imaging is usually non specific and laboratory investigations are seldom contributive. In most cases, the aetiological diagnosis is provided by post mortem examination. In this first part of the study the authors deal with viral encephalitides which represent a classical and frequent cause of diffuse encephalopathy in AIDS. HIV encephalitis usually causes a progressive brain disease resulting in severe dementia; imaging may show diffuse leucoencephalopathy and/or cortico-subcortical atrophy. CMV encephalitis is often asymptomatic, discovered at autopsy; however, this diagnosis should be considered in patients with an encephalopathy of rapid onset, discrete signs of meningitis, symptoms of myelo-radiculitis, or a systemic CMV infection. Varicella-zoster virus encephalitis is not uncommon and may occur in the absence of characteristic rash. Infections by herpes simplex and measles viruses are exceptional.
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Complexo AIDS Demência/diagnóstico , Síndrome da Imunodeficiência Adquirida/complicações , Varicela/diagnóstico , Infecções por Citomegalovirus/diagnóstico , Encefalite/diagnóstico , Complexo AIDS Demência/líquido cefalorraquidiano , Complexo AIDS Demência/etiologia , Infecções Oportunistas Relacionadas com a AIDS/líquido cefalorraquidiano , Infecções Oportunistas Relacionadas com a AIDS/complicações , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Adulto , Varicela/complicações , Infecções por Citomegalovirus/líquido cefalorraquidiano , Infecções por Citomegalovirus/complicações , Encefalite/líquido cefalorraquidiano , Encefalite/complicações , Encefalite/microbiologia , Herpes Zoster/complicações , Herpes Zoster/diagnóstico , HumanosRESUMO
The synthesis of one of the most potent dual inhibitors of the anti-apoptotic proteins Bcl-xL and Mcl-1 is reported. This analogue of a natural sesquiterpenoid dimer meiogynin A was elaborated by a convergent asymmetric synthesis with 36% yield in ten steps.
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Reação de Cicloadição/métodos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Sesquiterpenos/síntese química , Proteína bcl-X/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Sesquiterpenos/farmacologia , Proteína bcl-X/antagonistas & inibidoresRESUMO
A tetravalent dengue vaccine based on four live, attenuated, chimeric viruses (CYD1-4), constructed by replacing the genes coding for premembrane (prM) and envelope (E) proteins of the yellow fever (YF)-17D vaccine strain with those of the four serotypes of dengue virus, is in clinical phase III evaluation. We assessed the vaccine's genetic stability by fully sequencing each vaccine virus throughout the development and manufacturing process. The four viruses displayed complete genetic stability, with no change from premaster seed lots to bulk lots. When pursuing the virus growth beyond bulk lots, a few genetic variations were observed. Usually both the initial nucleotide and the new one persisted, and mutations appeared after a relatively high number of virus duplication cycles (65-200, depending on position). Variations were concentrated in the prM-E and non-structural (NS)4B regions. PrM-E variations had no impact on lysis-plaque size or neurovirulence in mice. None of the variations located in the YF-17D-derived genes corresponded with reversion to the wild-type Yellow Fever sequence. Variations in NS4B likely reflect virus adaptation to Vero cells growth. A low to undetectable viremia has been reported previously [1-3] in vaccinated non-human and human primates. Combined with the data reported here about the genetic stability of the vaccine strains, the probability of in vivo emergence of mutant viruses appears very low.