RESUMEN
RATIONALE: In protein studies that employ tandem mass spectrometry the manipulation of protonated peptide fragmentation through exclusive dissociation pathways may be preferred in some applications over the comprehensive amide backbone fragmentation that is typically observed. In this study, we characterized the selective cleavage of the side-chain Cζ-Nε bond of peptides with ortho-hydroxybenzyl-aminated lysine residues. METHODS: Internal lysyl residues of representative peptides were derivatized via reductive amination with ortho-hydroxybenzaldehyde. The modified peptides were analyzed using collision-induced dissociation (CID) on an Orbitrap tandem mass spectrometer. Theoretical calculations using computational methods (density functional theory) were performed to investigate the potential dissociation mechanisms for the Cζ-Nε bond of the derivatized lysyl residue resulting in the formation of the observed product ions. RESULTS: Tandem mass spectra of the derivatized peptide ions exhibit product peaks corresponding to selective cleavage of the side-chain Cζ-Nε bond that links the derivative to lysine. The ortho-hydroxybenzyl derivative is released either as a neutral moiety [C7H6O1] or as a carbocation [C7H7O1](+) through competing pathways (retro-Michael versus Carbocation Elimination (CCE), respectively). The calculated transition state activation barriers indicate that the retro-Michael pathway is kinetically favored over CCE and both are favored over amide cleavage. CONCLUSIONS: The application of ortho-hydroxybenzyl amination is a promising peptide derivatization scheme for promoting selective dissociation pathways in the tandem mass spectrometry of protonated peptides. This can be implemented in the rational development of peptide reactive reagents for applications that may benefit from selective fragmentation paths (including crosslinking or MRM reagents).
Asunto(s)
Benzaldehídos/química , Lisina/química , Fragmentos de Péptidos/química , Espectrometría de Masas en Tándem/métodos , Lisina/análisis , Lisina/metabolismo , Modelos Moleculares , Oxidación-Reducción , Fragmentos de Péptidos/análisis , Fragmentos de Péptidos/metabolismo , Tripsina/química , Tripsina/metabolismoRESUMEN
Motivated by the need for chemical strategies designed to tune peptide fragmentation to selective cleavage reactions, benzyl ring substituent influence on the relative formation of carbocation elimination (CCE) products from peptides with benzylamine-derivatized lysyl residues has been examined using collision-induced dissociation (CID) tandem mass spectrometry. Unsubstituted benzylamine-derivatized peptides yield a mixture of products derived from amide backbone cleavage and CCE. The latter involves side-chain cleavage of the derivatized lysyl residue to form a benzylic carbocation [C(7)H(7)](+) and an intact peptide product ion [(MH(n))(n+) - (C(7)H(7))(+)]((n-1)+). The CCE pathway is contingent upon protonation of the secondary ε-amino group (N(ε)) of the derivatized lysyl residue. Using the Hammett methodology to evaluate the electronic contributions of benzyl ring substituents on chemical reactivity, a direct correlation was observed between changes in the CCE product ion intensity ratios (relative to backbone fragmentation) and the Hammett substituent constants, σ, of the corresponding substituents. There was no correlation between the substituent-influenced gas-phase proton affinity of N(ε) and the relative ratios of CCE product ions. However, a strong correlation was observed between the π orbital interaction energies (ΔE(int)) of the eliminated benzylic carbocation and the logarithm of the relative ratios, indicating the predominant factor in the CCE pathway is the substituent effect on the level of hyperconjugation and resonance stability of the eliminated benzylic carbocation. This work effectively demonstrates the applicability of σ (and ΔE(int)) as substituent selection parameters for the design of benzyl-based peptide-reactive reagents which tune CCE product formation as desired for specific applications.
Asunto(s)
Bencilaminas/química , Lisina/química , Fragmentos de Péptidos/química , Protones , Espectrometría de Masas en Tándem , Gases/química , Espectrometría de Masas en Tándem/métodosRESUMEN
The segrosome is the nucleoprotein complex that mediates accurate plasmid segregation. In addition to its multifunctional role in segrosome assembly, the ParG protein of multiresistance plasmid TP228 is a transcriptional repressor of the parFG partition genes. ParG is a homodimeric DNA binding protein, with C-terminal regions that interlock into a ribbon-helix-helix fold. Antiparallel beta-strands in this fold are presumed to insert into the O(F) operator major groove to exert transcriptional control as established for other ribbon-helix-helix factors. The O(F) locus comprises eight degenerate tetramer boxes arranged in a combination of direct and inverted orientation. Each tetramer motif likely recruits one ParG dimer, implying that the fully bound operator is cooperatively coated by up to eight dimers. O(F) was subdivided experimentally into four overlapping 20-bp sites (A to D), each of which comprises two tetramer boxes separated by AT-rich spacers. Extensive interaction studies demonstrated that sites A to D individually are bound with different affinities by ParG (C > A approximately B >> D). Moreover, comprehensive scanning mutagenesis revealed the contribution of each position in the site core and flanking sequences to ParG binding. Natural variations in the tetramer box motifs and in the interbox spacers, as well as in flanking sequences, each influence ParG binding. The O(F) operator apparently has evolved with sites that bind ParG dissimilarly to produce a nucleoprotein complex fine-tuned for optimal interaction with the transcription machinery. The association of other ribbon-helix-helix proteins with complex recognition sites similarly may be modulated by natural sequence variations between subsites.
Asunto(s)
ADN Bacteriano/genética , Proteínas de Escherichia coli/metabolismo , Escherichia coli/genética , Plásmidos/genética , Proteínas Represoras/metabolismo , 1-Acilglicerol-3-Fosfato O-Aciltransferasa/genética , Secuencia de Bases , Sitios de Unión , ADN Bacteriano/química , Escherichia coli/química , Escherichia coli/citología , Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Datos de Secuencia Molecular , Mutación , Regiones Operadoras Genéticas , Unión Proteica , Proteínas Represoras/química , Proteínas Represoras/genética , Alineación de SecuenciaRESUMEN
YefM-YoeB is among the most prevalent and well-characterized toxin-antitoxin complexes. YoeB toxin is an endoribonuclease whose activity is inhibited by YefM antitoxin. The regions 5' of yefM-yoeB in diverse bacteria possess conserved sequence motifs that mediate transcriptional autorepression. The yefM-yoeB operator site arrangement is exemplified in Escherichia coli: a pair of palindromes with core hexamer motifs and a center-to-center distance of 12 bp overlap the yefM-yoeB promoter. YefM is an autorepressor that initially recognizes a long palindrome containing the core hexamer, followed by binding to a short repeat. YoeB corepressor greatly enhances the YefM-operator interaction. Scanning mutagenesis demonstrated that the short repeat is crucial for correct interaction of YefM-YoeB with the operator site in vivo and in vitro. Moreover, altering the relative positions of the two palindromes on the DNA helix abrogated YefM-YoeB cooperative interactions with the repeats: complex binding to the long repeat was maintained but was perturbed to the short repeat. Although YefM lacks a canonical DNA binding motif, dual conserved arginine residues embedded in a basic patch of the protein are crucial for operator recognition. Deciphering the molecular basis of toxin-antitoxin transcriptional control will provide key insights into toxin-antitoxin activation and function.
Asunto(s)
Toxinas Bacterianas/metabolismo , Proteínas de Escherichia coli/metabolismo , Transcripción Genética/genética , Toxinas Bacterianas/química , Toxinas Bacterianas/genética , Secuencia de Bases , Sitios de Unión , Dicroismo Circular , Huella de ADN , ADN Bacteriano/genética , ADN Bacteriano/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Datos de Secuencia Molecular , Mutación , Unión Proteica , Estructura Secundaria de Proteína , Resonancia por Plasmón de SuperficieRESUMEN
Cognitive impairment is amongst the main symptoms affecting multiple sclerosis (MS) and should be comprehensively and accurately assessed. To study the added value of a computerized neuropsychological battery enabling the measurement of response times in the cognitive domains, 58 randomly selected MS patients and 71 age-, gender- and education-matched healthy subjects were evaluated. Construct and discriminant validity were assessed for the standard Neuropsychological Screening Battery for Multiple Sclerosis (NSBMS) and the Mindstreams Computerized Cognitive Battery (MCCB). The MCCB demonstrated good construct validity in comparison with the NSBMS in memory (P < 0.001), executive function (P < 0.001), attention (P < 0.05) and information processing (P < 0.05) domains. In addition, it showed high discriminant validity most prominently for executive function, attention and motor skills (P < 0.001). Response times measured by the computerized battery were longer in all cognitive domains and varied with cognitive load, demonstrating that response time deficits in MS are associated with particular task demands. We conclude that in MS prolonged response times on a range of cognitive tasks signify abnormal conduction within demyelinative tracts.
Asunto(s)
Cognición/fisiología , Esclerosis Múltiple/fisiopatología , Desempeño Psicomotor/fisiología , Tiempo de Reacción/fisiología , Adulto , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/fisiopatología , Trastornos del Conocimiento/psicología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/psicología , Pruebas NeuropsicológicasRESUMEN
The adhesion of the pathogen Neisseria meningitidis to host cell surface proteoglycan, mediated by the integral outer membrane proteins OpcA and Opa, plays an important part in the processes of colonization and invasion by the bacterium. The precise specificities of the OpcA and Opa proteins are, however, unknown. Here we use a fluorescence-based binding assay to show that both proteins bind to mono- and disaccharides with high affinity. Binding of saccharides caused a quench in the intrinsic fluorescence emission of both proteins, and mutation of selected Tyr residues within the external loop regions caused a substantial decrease in fluorescence. We suggest that the intrinsic fluorescence arises from resonance energy transfer from Tyr to Trp residues in the beta-barrel portion of the structure. OpcA bound sialic acid with a Kd of 0.31 microM and was shown to be specific for pyranose saccharides. The binding specificities of two different Opa proteins were compared; unlike OpcA, neither protein bound to monosaccharides, but both bound to maltose, lactose, and sialic acid-containing oligosaccharides, with Kd values in the micromolar range. OpaB had a 10-fold higher affinity for sialic acid-containing ligands than OpaD as a result of the mutation Y165V, which was shown to restore this specificity to OpaD. Finally, the OpcA- and Opa-dependent adhesion of meningococci to epithelial cells was shown to be partially inhibited by exogenously added sialic acid and maltose. The results show that OpcA and the Opa proteins can be thought of as outer membrane lectins and that simple saccharides can modulate their recognition of complex proteoglycan receptors.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/metabolismo , Metabolismo de los Hidratos de Carbono , Células Epiteliales/metabolismo , Neisseria meningitidis/metabolismo , Proteínas de la Membrana Bacteriana Externa/química , Proteínas de la Membrana Bacteriana Externa/genética , Línea Celular , Conjuntiva/metabolismo , Conjuntiva/microbiología , Células Epiteliales/microbiología , Transferencia Resonante de Energía de Fluorescencia , Humanos , Maltosa/química , Maltosa/metabolismo , Mutación , Ácido N-Acetilneuramínico/química , Ácido N-Acetilneuramínico/metabolismo , Neisseria meningitidis/genética , Estructura Terciaria de ProteínaRESUMEN
OBJECTIVE: To test the effect of different forearm postures on tremor characteristics. We hypothesized that changes in tremor characteristics in relation to posture can subclassify essential tremor (ET) patients. METHODS: Fourteen ET patients were tested while seated and holding a full cup in three well-defined arm postures: 15 cm above the armrest, elbow at 90 degrees flexion and when the cup was near the mouth. Hand movements were recorded using a triaxial accelerometer. Concomitantly, we recorded surface electromyogram (EMG) signals from the wrist extensor muscles. Hand acceleration and the primary tremor frequency from the power spectrum were calculated for each posture in two independent trials. The coherence at the primary tremor frequency between the EMG and the accelerometry signals was calculated. RESULTS: ET patients could be classified into two groups: ET-1 (nine patients) had position-dependent peak frequencies while ET-2 (five patients) had position-independent peak frequencies. The latter group had significantly higher coherencies between EMG and accelerometry of tremor and insignificantly higher tremor amplitudes compared with ET-1. In both groups tremor amplitude increased when the hand was near the mouth. CONCLUSION: The results suggest that ET patients can be classified based on the position dependence of frequency and other physiologic properties.
Asunto(s)
Temblor Esencial/clasificación , Temblor Esencial/diagnóstico , Aceleración , Adulto , Anciano , Anciano de 80 o más Años , Electromiografía , Temblor Esencial/fisiopatología , Retroalimentación , Mano , Humanos , Persona de Mediana Edad , Actividad Motora , PosturaRESUMEN
BACKGROUND: Dysrhythmia is one of the features frequently associated with the motor disturbance in Parkinson's disease (PD). The mechanism responsible for this phenomenon is not known. OBJECTIVES: To assess the rhythmic movements of the hand in PD patients in general and in parkinsonian subtypes. METHODS: Fifty-one PD patients (32 males) with mean age 66.3 +/- 9.1 years (6.6 years of symptoms) and 36 healthy controls (age 64.9 +/- 13.2, range 40-85) were studied. Subjects were asked to tap with their dominant or less affected arm on a digitized switch board at their most comfortable pace (16 s), fastest tapping speed (12 s), and at different frequencies provided by a metronome. The mean rhythm and the tap-to-tap variation were compared. Performance of the PD patients and control subjects were compared, as there were different subtypes of PD patients. Patients were subclassified into: tremor predominant (TP) (14 patients), freezing predominant (FP) (11 patients), akinetic-rigid (AR) (12 patients) and an unclassified group (UC) (14 patients). Results. There was no significance difference between patients and controls in the self-chosen, most comfortable tapping rate or in the tap-to-tap variation of the self-paced task. PD patients tapped at a significantly slower rate than controls when asked to tap at their fastest rate (4.39 +/- 1.32 vs. 5.14 +/- 1.31 Hz; p < 0.01). This difference was the result of an especially slow performance of the TP and AR subgroups (3.85+/-1.20 and 3.88+/-1.46, respectively; p < 0.01 compared to the control group). TP was the only subgroup to show an increased tap-to-tap variation at their fastest tapping rate compared to the control group (0.070 +/- 0.057 vs. 0.029 +/- 0.025 s, respectively, p < 0.05). The TP subgroup also showed hastening when they followed an externally given rhythm of 2.5 Hz and they tapped at 2.73 +/- 0.36 Hz p < 0.05). CONCLUSIONS: Externally driven and self-paced tapping are preserved in patients with PD, when examined at their best 'on' state. The tremor predominant subgroup seems to have specific pacing disturbances.
Asunto(s)
Mano/fisiología , Movimiento/fisiología , Enfermedad de Parkinson/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/clasificación , Factores de TiempoRESUMEN
BACKGROUND: Freezing of gait (FOG) is a common and very disabling parkinsonian symptom, which is poorly understood and responds unsatisfactorily to medical treatment. We recently reported a unique patient with Parkinson's disease (PD) who had significant alleviation of FOG shortly after she was injected with botulinum toxin type A (BTX-A) for foot dystonia (Giladi et al. 1997). OBJECTIVE: To assess the effect of BTX-A injections into the calf muscles of parkinsonian patients on FOG. METHOD: BTX-A was injected in an open fashion into the calf muscles of 10 parkinsonian patients (age 55-75 years) with FOG as a predominant symptom. Response of FOG was assessed subjectively by the patient from worsening (-1) to marked improvement (+3). One patient was injected in a single blind fashion with saline or BTX-A after he had an initial good response. RESULTS: Seven patients reported different rates of improvement of FOG severity in 15 out of 17 therapeutic sessions. Four patients (40%) reported marked improvement (+3) of FOG in 5 sessions. Two patients reported no effect in two sessions. The mean duration of improvement was 6 weeks (range 1-12 weeks) with definite deterioration afterwards. The patient who was injected in a single blind fashion did not respond to saline injections but improved significantly with BTX-A treatment. CONCLUSIONS: We observed a clear temporal relationship between BTX-A injections into the calf muscles of parkinsonian patients and improvement of FOG. A double blind placebo controlled prospective study is needed before any conclusions can be drawn about the role of BTX-A injection in FOG.
Asunto(s)
Antidiscinéticos/farmacología , Toxinas Botulínicas/farmacología , Trastornos Neurológicos de la Marcha/tratamiento farmacológico , Músculo Esquelético/efectos de los fármacos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antidiscinéticos/administración & dosificación , Toxinas Botulínicas/administración & dosificación , Progresión de la Enfermedad , Femenino , Trastornos Neurológicos de la Marcha/etiología , Humanos , Inyecciones Intramusculares , Pierna , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiología , Método Simple Ciego , Factores de Tiempo , Resultado del TratamientoRESUMEN
Nigrostriatal dopaminergic function and cerebral energy metabolism were measured with PET in two brothers with early-onset parkinsonism caused by mutation of the parkin gene. Energy metabolism did not differ, but the nigrostriatal dopaminergic pattern was clearly different than that of sporadic PD. Thus parkinsonism in these two patients was shown to be pathophysiologically different than PD.
Asunto(s)
Cuerpo Estriado/diagnóstico por imagen , Ligasas/genética , Mutación/genética , Trastornos Parkinsonianos/genética , Sustancia Negra/diagnóstico por imagen , Ubiquitina-Proteína Ligasas , Edad de Inicio , Encéfalo/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Trastornos Parkinsonianos/diagnóstico por imagen , Tomografía Computarizada de EmisiónRESUMEN
We have examined the linkage between patterns of activity in several hindlimb motor pools and the modulation of oligosynaptic cutaneous reflex pathways during fictive locomotion in decerebrate unanesthetized cats to assess the notion that such linkages can shed light on the structure of the central pattern generator (CPG) for locomotion. We have concentrated attention on the cutaneous reflex pathways that project to the flexor digitorum longus (FDL) motor pool because of that muscle's unique variable behavior during normal and fictive locomotion in the cat. Differential locomotor control of last-order excitatory interneurons in pathways from low-threshold cutaneous afferents in the superficial peroneal and medial plantar afferents to FDL motoneurons is fully documented for the first time. The qualitative patterns of differential control are shown to remain the same whether the FDL muscle is active in early flexion, as usually found, or during the extension phase of fictive locomotion, which is less common during fictive stepping. The patterns of motor pool activity and of reflex pathway modulation indicate that the flexion phase of fictive locomotion has distinct early versus late components. Observations during "normal" and unusual patterns of fictive stepping suggest that some aspects of locomotor pattern formation can be separated from rhythm generation, implying that these two CPG functions may be embodied, at least in part, in distinct neural organizations. The results are discussed in relation to a provisional circuit diagram that could explain the experimental findings.
Asunto(s)
Marcha/fisiología , Interneuronas/fisiología , Neuronas Motoras/fisiología , Médula Espinal/citología , Médula Espinal/fisiología , Animales , Gatos , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Locomoción/fisiología , Neuronas Aferentes/fisiología , Reflejo/fisiologíaRESUMEN
Recent evidence points to involvement of central nervous system oscillators in Parkinson's disease (PD) rest tremor. It remains unknown whether one or multiple oscillators cause tremor in multiple limbs. Based on the prediction that multiple oscillators would cause low coherence even with similar average frequency, we studied 22 PD patients using accelerometers on multiple limbs. Records were digitized and spectral analysis was performed. Peak frequencies in the arms, legs, and chin were similar, indicating that biomechanical factors did not determine the frequency. Coherence between different axes of individual accelerometers and between different segments of the same limb was high. However, coherence between tremor in different limbs was low. There was no consistent pattern across patients of ipsi- vs. contralateral predominance of coherence. These data suggest that tremor in PD is generated by multiple oscillatory circuits, which operate on similar frequencies.
Asunto(s)
Relojes Biológicos/fisiología , Encéfalo/fisiopatología , Sincronización Cortical , Extremidades/fisiopatología , Vías Nerviosas/fisiopatología , Enfermedad de Parkinson/fisiopatología , Temblor/fisiopatología , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Mentón/inervación , Mentón/fisiopatología , Extremidades/inervación , Femenino , Lateralidad Funcional/fisiología , Humanos , Masculino , Persona de Mediana Edad , Vías Nerviosas/patología , Enfermedad de Parkinson/patología , Temblor/patologíaRESUMEN
BACKGROUND: Freezing of Gait (FOG) is one of the most disturbing and least understood symptom in advanced stage of Parkinson's disease (PD). The contribution of the underlying pathological process and the antiparkinsonian treatment to the development of FOG are controversial. OBJECTIVE: To study the relationships between clinical features of PD and therapeutic modalities in patients with advanced PD and FOG. METHODS: Consecutive patients with 5 years or more of PD symptoms (n = 172) (99 men) with mean age at symptoms onset of 58.3 +/- 13.2 years and mean symptoms duration of 11.8 +/- 5.6 years were studied. Clinical data were collected during the last office visit through physical examination, detailed history, review of patients' charts, and other documents. A patient was considered as "freezer" if he/she reported recent experience that the legs got stuck to the ground while trying to walk. The presence of dyskinesia, early morning dystonia or significant postural reflex abnormalities were assessed through history and neurological examination. Duration of treatment with antiparkinsonian drugs was calculated from history charts. Chi square and t test were used to compare the patients with and without FOG. Logistic regression was used for the comparison of association between the presence of FOG (dependent variable) disease duration and disease stage (explanatory variables) and duration of treatment with anti-parkinsonian drugs. RESULTS: The study population consisted of 45 patients at Hoehn and Yahr (H&Y) stage 2.5 (26%), 104 patients at stage 3 (60.5%), and 23 patients at H&Y stages 4-5 (13.5%). Ninety one patients (53%) reported FOG at the time of the study. Severity of the disease expressed by H&Y stage at "off" was a significant contributing factor for FOG with a significant trend (z = 4.38, p < 0.0001), as was longer duration of levodopa treatment, and confirmed by FOG using the multivariate logistic regression (p = 0.01 and p = 0.004, respectively). Using a univariate model, longer duration of treatment with dopamine agonists contribute to the appearance of FOG (p = 0.07) while longer duration of amantadine treatment decreased the appearance of FOG (p = 0.09). There was a significant association between FOG and the presence of dyskinesia (p < 0.002), early morning foot dystonia (p < 0.003) and significant postural instability (p < 0.0005). CONCLUSION: FOG is a common symptom in advanced PD. It is mainly related to disease progression and levodopa treatment.
Asunto(s)
Antiparkinsonianos/efectos adversos , Trastornos Neurológicos de la Marcha/fisiopatología , Levodopa/efectos adversos , Enfermedad de Parkinson/fisiopatología , Adulto , Edad de Inicio , Amantadina/efectos adversos , Antiparkinsonianos/administración & dosificación , Progresión de la Enfermedad , Agonistas de Dopamina/farmacología , Femenino , Congelación , Trastornos Neurológicos de la Marcha/inducido químicamente , Humanos , Levodopa/administración & dosificación , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Prevalencia , Análisis de Regresión , Estudios Retrospectivos , Selegilina/efectos adversosRESUMEN
OBJECTIVE: To report a unique hereditary, juvenile onset, craniocervical predominant, generalized dystonia and parkinsonism affecting four members of one family. FAMILY DESCRIPTION: A father and three of his four daughters presented to us over the past 30 years with a similar picture of generalized dystonia, starting in the craniocervical region in the second or third decade of life. They later developed moderate parkinsonism, mainly manifesting bradykinesia, rigidity and abnormal postural reflexes. Biochemical and genetic tests excluded Wilson's disease, Huntington's disease and Oppenheim's dystonia. CONCLUSION: This is a new type of familial dystonia-parkinsonism where the craniocervical dystonic symptoms are most prominent in the early stages while parkinsonism becomes the predominant problem later in life. A search for the genetic mutation in this family is underway.
Asunto(s)
Trastornos Distónicos/genética , Enfermedad de Parkinson/genética , Adolescente , Adulto , Edad de Inicio , Comorbilidad , Trastornos Distónicos/epidemiología , Resultado Fatal , Femenino , Humanos , Discapacidad Intelectual/epidemiología , Masculino , Enfermedad de Parkinson/epidemiología , LinajeRESUMEN
Clinical distinction of multiple system atrophy (MSA) from Parkinson's disease (PD) is often difficult. Several recent reports indicate that objective classification may be accomplished using electromyographic (EMG) testing of the anal or urethral sphincters, but some authors have found that these tests are not reliable for this purpose. We studied 13 patients with PD and 10 with probable MSA, as diagnosed by consensus of four movement disorders specialists, according to accepted clinical criteria. Anal sphincter EMG was performed blind to the clinical diagnosis. We found no significant differences in the mean duration of motor unit potentials (MUPs), mean MUP amplitude, or prevalence of polyphasic potentials, satellite potentials, very long duration MUPs, or spontaneous activity between the two groups. Thus, anal sphincter EMG does not differentiate between PD and MSA.
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Canal Anal/fisiopatología , Atrofia de Múltiples Sistemas/diagnóstico , Atrofia de Múltiples Sistemas/fisiopatología , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/fisiopatología , Anciano , Diagnóstico Diferencial , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: To study the relationships between clinical features of Parkinson's disease (PD) and the development of dementia, depression or psychosis in patients with long-standing disease. BACKGROUND: The natural history of dementia and depression in PD, and its relation to psychosis in long standing PD, are unclear. METHOD: 172 consecutive patients (99 men and 73 women, mean age at symptoms onset 58.3 +/- 13.2 years) with 5 years or more of PD (mean symptom duration of 11.8 +/- 5.6 years) were studied. Clinical data were collected during the last office visit through physical examination, detailed history, review of patient charts and outside documents. Dementia and depression were diagnosed according to DSM-IV criteria, while psychosis was diagnosed if hallucinations or delusions were present. Chi-square and t tests were used to compare the patient characteristics among those with vs. those without mental complications of the disease at different disease stages. Logistic regression was used for the comparison of associations between the presence of dementia or depression (dependent variable) and age at onset of PD, duration of PD and disease staging (explanatory variables). RESULTS: The study population consisted of 45 patients at Hoehn & Yahr (H&Y) stage < or = 2.5 (26%), 104 patients at stage 3 (60.5%) and 23 patients at H&Y stage 4-5 (13.5%). Sixty one patients (36%) had dementia, 55 patients had depression (33%) and 50 patients (27%) had psychosis. Dementia and depression were significantly associated with disease severity as reflected in the H&Y scale (P = 0.0003, Z = 3.59; P = 0.006, Z = 3.22, respectively). These associations were significant also for the older age of PD onset (> or = 59 years n = 89) subgroup (p = 0.001, Z = 3.2 for dementia and p = 0.02, Z = 2.9 for depression), but not for younger onset cases (< 59 years n = 83). Dementia was significantly associated with older age of PD onset (beta = 0.04, p = 0.009) while depression was inversely associated with age of PD onset (beta = -0.04, p = 0.02). The presence of dementia was also significantly associated with depression (beta = 1.49, p = 0.0006). Dementia and depression were found to be independent explanatory variables for the development of psychosis (logistic regression, odds ratio (OR) = 26.0, p < 0.0001; OR = 10.2, p < 0.0001, respectively). In patients with younger age of PD onset, depression more than dementia was strongly correlated with the appearance of psychosis. CONCLUSION: Dementia in PD was related to older age of symptoms onset and old age. Depression was associated with dementia or early age of PD onset. Depression seemed to contribute to the appearance of psychosis even more than dementia, especially in patients with younger age of symptoms onset.
Asunto(s)
Demencia/epidemiología , Depresión/epidemiología , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/psicología , Trastornos Psicóticos/epidemiología , Distribución por Edad , Edad de Inicio , Anciano , Antiparkinsonianos/administración & dosificación , Progresión de la Enfermedad , Femenino , Humanos , Levodopa/administración & dosificación , Modelos Lineales , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Prevalencia , Factores de RiesgoRESUMEN
We identified 70 Creutzfeldt-Jakob disease patients with the previously described E200K mutation in the prion protein gene. The purpose of this study was to define the clinical features of E200K homozygous patients (n = 5), compared with heterozygotes. We found a statistically significant younger age at disease onset for the homozygous patients, although the average age at onset in this group was still in midlife. Disease features were not statistically different in the two groups. Possible explanations are discussed.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/genética , Homocigoto , Mutación/genética , Priones/genética , Adulto , Anciano , Síndrome de Creutzfeldt-Jakob/fisiopatología , Síndrome de Creutzfeldt-Jakob/psicología , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Locomotor modulation of disynaptic EPSPs from the mesencephalic locomotor region in cat motoneurons. J. Neurophysiol. 80: 3284-3296, 1998. When low-frequency tetanization of the mesencephalic locomotor region (MLR) produce fictive locomotion in unanesthetized, decerebrate cats, each MLR stimulus produces a distinctive cord dorsum potential (CDP) and oligosynaptic excitatory postsynaptic potentials (EPSPs) in many lumbosacral motoneurons. The average segmental latency from the initial CDP wave [mean delay from stimulus: 4.3 +/- 0.9 (SD) ms] to the onset of detectable MLR EPSPs was 1.6 +/- 0.4 ms, suggesting a disynaptic segmental connection. In gastrocnemius/soleus, flexor hallucis longus, flexor digitorum longus, tibialis anterior, and posterior biceps-semitendinosus motoneurons (35/38 cells), MLR EPSPs either appeared or were enhanced during the phase of fictive stepping in which the target motoneurons were depolarized and the motor pool was active (the phase), with parallel changes between EPSP amplitudes and membrane depolarization. In contrast, MLR stimulation produced small (1/10) or no EPSPs in extensor digitorum longus (EDL) motoneurons, with no phase enhancement (4/10) or oligosynaptic inhibitory postsynaptic potentials during the phase (5/10). Eight of 10 flexor digitorum longus (FDL) cells exhibited membrane depolarization in the early flexion phase of fictive stepping, and five of these showed parallel enhancement of disynaptic MLR EPSPs during early flexion. Three cases were studied when the FDL motor pool exhibited exclusively extensor phase firing. In these cases, the disynaptic MLR EPSPs were enhanced only during the extensor phase, accompanied by membrane depolarizations. We conclude that the last-order interneurons that produce disynaptic MLR EPSPs may well participate in producing the depolarizing locomotor drive potentials (LDPs) found in hindlimb motoneurons during fictive locomotion. However, the absence of linkage between MLR EPSP enhancement and LDP depolarizations in EDL motoneurons suggests that other types of excitatory interneurons also must be involved at least in some motor pools. We compared these patterns with the modulation of disynaptic EPSPs produced in FDL cells by stimulation of the medial longitudinal fasciculus (MLF). In all seven FDL motoneurons tested, disynaptic MLF EPSPs appeared only during the extension phase, regardless of when the FDL motoneurons were active. The fact that the modulation patterns of MLR and MLF disynaptic EPSPs is different in FDL motoneurons indicates that the two pathways do not converge on common last-order interneurons to that motor pool.
Asunto(s)
Potenciales Postsinápticos Excitadores/fisiología , Locomoción/fisiología , Mesencéfalo/fisiología , Neuronas Motoras/fisiología , Sinapsis/fisiología , Animales , Gatos , Estimulación Eléctrica , Electrofisiología , Femenino , Miembro Posterior/inervación , Miembro Posterior/fisiología , Mesencéfalo/citologíaRESUMEN
We have compared state-dependent transmission through oligosynaptic (minimally disynaptic) reflex pathways from low-threshold cutaneous and muscle afferents to some flexor and extensor lumbosacral motoneurons during fictive locomotion and scratching in decerebrate unanesthetized cats. As reported in earlier work, oligosynaptic cutaneous excitatory postsynaptic potentials (EPSPs) in flexor digitorum longus (FDL) and inhibitory postsynaptic potentials (IPSPs) in extensor digitorum (EDL) longus motoneurons were enhanced markedly during the early flexion phase of fictive locomotion. We show in this paper that, in contrast, these cutaneous reflex pathways were depressed markedly during all phases of fictive scratching. On the other hand, disynaptic EPSPs produced by homonymous and synergist group I muscle afferents in flexor (tibialis anterior and EDL) motoneurons were present and strongly modulated during both fictive locomotion and scratching. During both actions, these disynaptic group I EPSPs appeared or exhibited the largest amplitude when the motoneuron membrane potential was most depolarized and the parent motor pool was active. There was an interesting exception to the simple pattern of coincident group I EPSP enhancement and motoneuron depolarization. During locomotion, disynaptic group I EPSPs in both FDL and flexor hallucis longus (FHL) motoneurons cells were facilitated during the extension phase, although FDL motoneurons were relatively hyperpolarized whereas FHL cells were depolarized. The reverse situation was found during fictive scratching; group I EPSPs were facilitated in both FDL and FHL cells during the flexion phase when FDL motoneurons were depolarized and FHL cells were relatively hyperpolarized. These observations suggest that the disynaptic EPSPs in these two motor nuclei are produced by common interneurons. Reciprocal disynaptic inhibitory pathways from group Ia muscle afferents to antagonist motoneurons were also active and subject to phase-dependent modulation during both fictive locomotion and scratching. In all but one cell tested, reciprocal disynaptic group Ia IPSPs were largest during those phases in which the motoneuron membrane potential was relatively hyperpolarized and the parent motor pool was inactive. Oligosynaptic PSPs in motoneurons produced by stimulation of the mesencephalic locomotor region (MLR) were modulated strongly during fictive locomotion but were suppressed powerfully throughout fictive scratching. Large cord dorsum potentials generated by MLR stimuli also were suppressed markedly during fictive scratching. These results allow certain inferences about the organization of interneurons in the pathways examined. They also suggest that the central pattern generators that produce fictive locomotion and scratching are organized differently.
Asunto(s)
Vías Aferentes/fisiología , Actividad Motora/fisiología , Neuronas Motoras/fisiología , Músculo Esquelético/inervación , Nervios Periféricos/fisiología , Estimulación Física , Reflejo/fisiología , Piel/inervación , Médula Espinal/fisiología , Sinapsis/fisiología , Animales , Gatos , Estado de Descerebración , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores , Femenino , Locomoción/fisiología , Potenciales de la Membrana , Modelos Neurológicos , Nervio Peroneo/fisiología , Tiempo de ReacciónRESUMEN
Impaired glycinergic inhibition causes human hyperekplexia, and may be involved in the pathogenesis of movement disorders associated with uremia, spinal cord lesions, DDT poisoning, and tetanus. Three autosomal recessive mutant mouse strains with single-gene mutations affecting either the alpha 1 (spasmodic and oscillator) or beta (spastic) subunits of the glycine receptor were studied. Serial videotaped examinations assessed the severity of hyperkinetic features. Homozygote oscillator mice appeared normal until postnatal day (P) 11-14, when decreased exploratory movements, spastic gait, stimulus-induced myoclonic bouts, rigidity, and tremor were noticeable. All symptoms gradually worsened until death by P21-P23. In contrast, spastic and spasmodic mice were most severely affected by the 3rd-5th week of life and had a lessening of symptom severity in adulthood. Within each mutant strain, there was marked interanimal variation of severity of the other motor abnormalities, possibly because of stochastic variability in developmental processes. These mutants represent good animal models for elucidation of molecular and cellular issues regarding the glycine receptor and for the study of pathogenetic mechanisms of movement disorders.