Sometimes they come back: New and old spinal muscular atrophy adults in the era of nusinersen.

BACKGROUND AND PURPOSE: Following the commercial availability of nusinersen, there have been a number of new referrals of adults with spinal muscular atrophy (SMA) not regularly followed in tertiary-care centers or enrolled in any disease registry. METHODS: We compared demographics and disease characteristics, including assessment of motor and respiratory function, in regularly followed patients and newcomers subdivided according to the SMA type. RESULTS: The cohort included 166 adult patients (mean age: 37.09 years): one type I, 65 type II, 99 type III, and one type IV. Of these 166, there were 67 newcomers. There was no significant difference between newcomers and regularly followed patients in relation to age and disease duration. The Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module scores were higher in the regularly followed patients compared to newcomers in the whole cohort and in both SMA II and II. A difference was also found on ventilatory status (p = 0.013) and Cobb's angle >50° (p = 0.039) between the two subgroups. No difference was found in scoliosis surgery prevalence (p > 0.05). CONCLUSIONS: Our results showed differences between the two subgroups, even if less marked in the type III patients. In the type II patients, there was a higher proportion of newcomers who were in the severe end of the spectrum. Of the newcomers, only approximately a third initiated treatment, as opposed to the 51% in the regularly followed patients. The identification of patients who were not part of the registries will help to redefine the overall prevalence of SMA and the occurrence of different phenotypes.

Clinical and neuroimaging features of the m.10197G>A mtDNA mutation: New case reports and expansion of the phenotype variability.

Complex I (CI) is the largest component of the mitochondrial respiratory chain (MRC) and it is made up of 7 mitochondrial DNA (mtDNA)-encoded and at least 38 nuclear DNA-encoded subunits. Isolated CI deficiency is the most common single enzyme deficiency in the heterogeneous group of MRC disorders and it is a relatively common etiology of Leigh-like syndrome (LS). With a few exceptions, descriptions of the clinical spectrum of specific mutations in CI are scarce. We here present three unrelated Italian children who harbored the homoplasmic m.10197G>A mutation in MT-ND3 associated with reduced enzyme activity of CI in muscle. Compared with the spectrum of phenotypes seen in 13 previously described families with the same mutation, these children showed some novel clinical features. Two of the boys presented with subacute onset of dystonia, which showed a remitting-relapsing clinical course in one of them. The third boy presented acute symptoms consisting of speech impairment, progressive left-sided hemiparesis, and also vertebral and arterial malformations. In all the children, molecular studies identified a similar mutation load in tissues, and neuroimaging findings were consistent with the features seen in LS. Functional investigations in cultured skin fibroblasts suggested low ATP production in homoplasmic cells. Our results confirm that the m.10197G>A mutation is relevant to these patients' clinical and biochemical phenotypes, which thus expand the array of phenotypes associated with this variant.

Expanding the histopathological spectrum of CFL2-related myopathies.

Congenital myopathies (CMs) caused by mutation in cofilin-2 gene (CFL2) show phenotypic heterogeneity ranging from early-onset and rapid progressive forms to milder myopathy. Muscle histology is also heterogeneous showing rods and/or myofibrillar changes. Here, we report on three new cases, from two unrelated families, of severe CM related to novel homozygous or compound heterozygous loss-of-function mutations in CFL2. Peculiar histopathological changes showed nemaline bodies and thin filaments accumulations together to myofibrillar changes, which were evocative of the muscle findings observed in Cfl2-/- knockout mouse model.

MYH7-related myopathies: clinical, histopathological and imaging findings in a cohort of Italian patients.

BACKGROUND: Myosin heavy chain 7 (MYH7)-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions. RESULTS: As a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7. Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps. CONCLUSION: This work adds to the genotype-phenotype correlation of MYH7-relatedmyopathies confirming the complexity of the disorder.

Chronic inflammatory demyelinating polyneuropathy of childhood: clinical and neuroradiological findings.

INTRODUCTION: This study aims to report on serial magnetic resonance imaging (MRI) studies and clinical features in a cohort of children with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Clinical, neuroradiological, and statistical investigations performed on nine children with CIDP were retrospectively reviewed. Pathological nerve root enhancement was categorized according to severity, extension, and morphology. A MRI score was thus obtained, and correlations with the clinical picture and disease course were explored. RESULTS: Intrathecal nerve root enhancement (NRE) of varying degrees was seen in a high percentage of patients. There was no significant correlation between the total MRI score at the first MRI study and either severity or course of the disease. However, we found a significant difference (p = 0.002) in NRE of patients with improving CIDP with respect to those with stable or progressing disease at the time of follow-up MRI. CONCLUSION: Contrast-enhanced MRI plays a pivotal role in children with CIDP, both for the initial diagnosis as well as a biomarker of clinical evolution, and should be performed in all children with suspected CIDP both at initial presentation and during follow-up. Further multicenter studies on larger cohorts are awaited to determine the ideal timing for follow-up MRI.

Noninvasive ventilation with positive airway pressure in paediatric intensive care.

AIM: The aim of the present study is to retrospectively evaluate the effectiveness of noninvasive pressure ventilation in the 24-bed Pediatric Intensive Care Unit (PICU) of the G. Gaslini Institute during a 24-month period. METHODS: A retrospective analysis of the characteristics (pH, CO2, SpO2, respiratory rate, oxygen requirement) of patients treated with noninvasive mechanical ventilation for different acute pathologies has been performed. RESULTS: Twenty patients (mean age 7.4+/-0.28 years) with acute respiratory failure due to different pathologies were treated with noninvasive mechanical ventilation. They were divided into 2 groups: the hypoxic group, suffering from pulmonary diseases, and the hypercapnic group, presenting a failure of the mechanical strength or increased dead space. Modalities of ventilation were pressure assisted/controlled or pressure support, delivered through nasal or facial masks. Fifteen out of 20 patients presented a marked improvement of oxygenation and ventilation. Mean times of treatment were 69 and 200 h in the hypoxic and hypercapnic groups, respectively. Five patients required intubation. Two patients presented reversible skin lesions over the nasal bridge. CONCLUSIONS: Noninvasive ventilation can be used in PICU. Major advantages regard immunocompromised children and patients with exacerbations from chronic respiratory diseases, whereas the exact role of noninvasive positive pressure ventilation in patients affected by acute respiratory distress syndrome is still controversial.

Expanding the clinical spectrum of POMT1 phenotype.

Mutations in POMT1 have been identified in Walker-Warburg syndrome and in patients with limb-girdle muscular dystrophy and mental retardation (LGMD2K). The authors report new POMT1 mutations in three unrelated children with severe motor impairment, leg hypertrophy, and mental retardation but without brain and ocular malformations. These patients are similar to LGMD2K but have earlier onset and more severe motor disability. The current findings expand the spectrum of POMT1-associated phenotypes.

[The auditory system in sleep]. / El sistema auditivo en el ciclo sueño-vigilia.

INTRODUCTION: The sensory information that the central nervous system receives represents an enormous amount of data coming from the outer world and from the body itself. This constitutes a set of influences that affects the general brain developing as well as on the sleep-waking organization. DEVELOPMENT: We have proposed changes in the auditory information processing throughout the sleep-wakefulness cycle may be at least partially evidenced by single neurons extracellular recordings. We introduce the concept that the neural network organization during sleep vs that of wakefulness is different and can be modulated by sensory signals, and vice versa, the sensory input may be influenced by the central nervous system asleep or awake. During sleep the evoked firing of auditory units increases, decreases or remains similar to that observed during quiet wakefulness. There has been no auditory unit yet that stopped firing as the guinea pig enters sleep. Approximately half of the cortical neurons studied did not change firing rate when passing into sleep while others increased or decreased. Thus, the system is continuously aware of the environment. CONCLUSIONS: We postulate that those neurons that changed their evoked firing during sleep, increasing or decreasing, are part of active sleep processes. Thus, the continuous sensory information input to the brain during sleep may serve to 'sculpt', modulate, the brain by activity-dependent mechanisms of neural development as has been postulated for wakefulness.

El sistema auditivo en el ciclo sueño-vigilia / The auditory system in sleep

Introducción. El ingreso sensorial que recibe el sistema nervioso central representa un enorme espectro de información proveniente tanto del mundo exterior como del propio cuerpo. Esto constituye un conjunto de influencias sobre el desarrollo del cerebro que incluye, en el caso particular que nos ocupa, la organización del ciclo vigilia-sueño. Desarrollo. Hemos propuesto que el cambio en el procesamiento de información sensorial en el ciclo vigilia-sueño puede evidenciarse parcialmente a través del registro extracelular de la actividad unitaria neuronal y que algunas de estas neuronas pueden formar parte de procesos activos en relación con la generación y/o mantenimiento del sueño. La organización de redes neuronales en vigilia es diferente de la encontrada durante el sueño y ambas están moduladas por la información sensorial. Durante el sueño, las neuronas auditivas presentan una actividad provocada en incremento, en decremento o bien mantienen las mismas características que en vigilia tranquila. Esto se demostró a distintos niveles de la vía; se incluyeron las neuronas corticales y la mitad de las neuronas estudiadas presentaron cambios en la configuración de descarga. No se ha hallado neurona auditiva alguna que detuviera su actividad cuando el animal dormía. Conclusiones. El sistema auditivo está en contacto permanente con el ambiente a través de aquellas neuronas que mantienen su actividad, en tanto que las que aumentan o disminuyen se postulan, además, como participantes activas de los procesos del sueño. El continuo ingreso de información sensorial durante el sueño estaría al servicio de 'esculpir', modular, el cerebro a través de un mecanismo actividad-dependiente como se ha propuesto para la vigilia (AU)

Introduction. The sensory information that the central nervous system receives represents an enormous amount of data coming from the outer world and from the body itself. This constitutes a set of influences that affects the general brain developing as well as on the sleep-waking organization. Development. We have proposed changes in the auditory information processing throughout the sleep-wakefulness cycle may be at least partially evidenced by single neurons extracellular recordings. We introduce the concept that the neural network organization during sleep vs that of wakefulness is different and can be modulated by sensory signals, and vice versa, the sensory input may be influenced by the central nervous system asleep or awake. During sleep the evoked firing of auditory units increases, decreases or remains similar to that observed during quiet wakefulness. There has been no auditory unit yet that stopped firing as the guinea pig enters sleep. Approximately half of the cortical neurons studied did not change firing rate when passing into sleep while others increased or decreased. Thus, the system is continuously aware of the environment. Conclusions. We postulate that those neurons that changed their evoked firing during sleep, increasing or decreasing, are part of active sleep processes. Thus, the continuous sensory information input to the brain during sleep may serve to ‘sculpt’, modulate, the brain by activity-dependent mechanisms of neural development as has been postulated for wakefulness (AU)

[Sensory processing could be temporally organized by ultradian brain rhythms]. / El procesamiento sensorial podría estar organizado en el tiempo por ritmos cerebrales ultradianos.

INTRODUCTION: Neuronal activity of sensory systems depends on input from the environment, the body and the brain itself. Various rhythms have been shown to affect sensory processing, such as the waking-sleep cycle and hippocampal theta waves, our aim in this revision. The hippocampus, known as a structure involved in learning and memory processing, has the theta rhythm (4-10 Hz), present in all behavioural states. This rhythm has been temporally related to automatic, reflex and voluntary movements, both during wakefulness and sleep, and in the autonomic control of the heart rate. On the other hand theta rhythm has been considered as a novelty detector expressing different level of attention, selecting the information and protecting from interference. DEVELOPMENT AND CONCLUSIONS: Our research is based on the hypothesis that sensory processing needs a timer to be processed and stored, and hippocampal theta rhythm could contribute to the temporal organization of these events. We have demonstrated that auditory and visual unitary discharges in guinea pigs show phase-locking to the hippocampal theta rhythm. This temporal correlation appears during both spontaneous and specific sensory stimulation evoked discharges. Neuronal discharges fluctuate between phase-locked and uncorrelated firing modes relative to the theta rhythm. This changing state depends on known and unknown situations. We have provoked, changing the visual stimuli, a power theta rhythm increment and the phase-locking between this rhythm and the lateral geniculate neurone discharge during wakefulness. In slow wave sleep results were different demonstrating that the ways of the inputs processing have changed.

El procesamiento sensorial podría estar organizado en el tiempo por ritmos cerebrales ultradianos / Sensory processing could be temporally organized by ultradian brain rhythms

Introducción. La actividad neuronal de sistemas sensoriales depende de múltiples factores provenientes del ambiente, el cuerpo y el propio cerebro. Varios son los ritmos que afectan al procesamiento sensorial, como el ciclo vigilia-sueño y ritmos ultradianos como el ritmo theta ( θ) del hipocampo, que nos ocupa en el presente trabajo. El hipocampo, estructura reconocidamente involucrada en los procesos de aprendizaje y memoria, posee un ritmo característico, el ritmo θ(4-10 Hz), presente en todos los estados del comportamiento. Este ritmo ha sido relacionado temporalmente con movimientos voluntarios, automáticos y reflejos, tanto durante la vigilia como en el sueño, así como con el control autonómico de la frecuencia cardíaca. Por otra parte, se ha considerado como un detector de novedad, el cual expresa distintos niveles de atención, selecciona las señales de interés y protege de la interferencia. Desarrollo y conclusiones. Nuestra investigación se basa en la hipótesis de que los procesamientos sensoriales necesitan de una organización temporal, una secuenciación de la información que debe procesarse y almacenarse, y que el ritmo θdel hipocampo podría contribuir con dicha función. Hemos demostrado que las descargas unitarias tanto de neuronas auditivas como visuales en cobayas presentan correlación temporal con el ritmo θhipocámpico (phaselocking). Esta relación temporal aparece tanto en las descargas espontáneas como en las provocadas por los estímulos específicos para cada modalidad sensorial. Las descargas neuronales fluctúan entre la situación de correlación y no correlación de fase con el ritmo θ. Este estado cambiante depende de distintas situaciones, conocidas y desconocidas. Podemos provocar, cambiando los estímulos visuales, un aumento en la potencia del ritmo θy la aparición de correlación temporal entre este ritmo y las descargas de más del 50% de las neuronas del núcleo geniculado lateral durante la vigilia. Durante el sueño lento los resultados son diversos: se demuestra que las vías de procesamiento de la información son diferentes

Introduction. Neuronal activity of sensory systems depends on input from the environment, the body and the brain itself. Various rhythms have been shown to affect sensory processing, such as the waking-sleep cycle and hippocampal theta waves, our aim in this revision. The hippocampus, known as a structure involved in learning and memory processing, has the theta ( θ) rhythm (4-10 Hz), present in all behavioural states. This rhythm has been temporally related to automatic, reflex and voluntary movements, both during wakefulness and sleep, and in the autonomic control of the heart rate. On the other hand θ rhythm has been considered as a novelty detector expressing different level of attention, selecting the information and protecting from interference. Development and conclusions. Our research is based on the hypothesis that sensory processing needs a timer to be processed and stored, and hippocampal θrhythm could contribute to the temporal organization of these events. We have demonstrated that auditory and visual unitary discharges in guinea pigs show phase-locking to the hippocampal θrhythm. This temporal correlation appears during both spontaneous and specific sensory stimulation evoked discharges. Neuronal discharges fluctuate between phase-locked and uncorrelated firing modes relative to the θ rhythm. This changing state depends on known and unknown situations. We have provoked, changing the visual stimuli, a power θrhythm increment and the phase-locking between this rhythm and the lateral geniculate neurone discharge during wakefulness. In slow wave sleep results were different demonstrating that the ways of the inputs processing have changed

Clinical and molecular findings in patients with giant axonal neuropathy (GAN).

Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder of early onset, clinically characterized by a progressive involvement of both peripheral and CNS. The diagnosis is based on the presence of characteristic giant axons, filled with neurofilaments, on nerve biopsy. Recently, the defective protein, gigaxonin, has been identified and different pathogenic mutations in the gigaxonin gene have been reported as the underlying genetic defect. Gigaxonin, a member of the BTB/kelch superfamily proteins, seems to play a crucial role in the cross talk between the intermediate filaments and the membrane network. The authors report clinical and molecular findings in five Italian patients with GAN. This study shows the allelic heterogeneity of GAN and expands the spectrum of mutations in the GAN gene. The frequent occurrence of private mutations stresses the importance of a complete gene analysis.

[Clinical data that are essential for the primary care clinical records: an experience of evaluation and improvement]. / Datos clínicos esenciales de la historia clínica de atención primaria: una experiencia de evaluación y mejora.

OBJECTIVES: To evaluate and improve the presence of essential clinical data in the clinical records of a primary care management area (PCMA) by means of an intervention programme. DESIGN: Intervention study without a control, using evaluation and improvement-of-quality methods. We chose 4 criteria from the minimum technical standards: personal history (PH), family background (FB), allergies to medicines (AM) and list of problems (LP). We evaluated overall compliance and compliance per primary care team (PCT) through batch quality acceptance of samples (LQAS), designed an intervention to improve the situation, and then re-evaluated. SETTING: PCMA of Murcia (45 PCTs). Participants. 42 PCTs (3 were excluded because they had poor coverage in their records). INTERVENTIONS: These lasted 12 months (October 1999-October 2000) and involved the following: graphic report per PCT; session with the PCT; discussion on results and strategies in the Area Management Council; and inclusion of an explicit objective, with incentives, in the management contracts. MAIN MEASUREMENTS AND RESULTS: Significant improvement of the four criteria of the PCMA (improvements: FB, 48.1%; PH, 51.1%; AM, 55.4%; LP, 50.9%). LQAS analysis: we rejected 24 batches (14.3%) at the 1st evaluation and 15 (9.0%) at the second, with FB being the criterion most rejected in both instances. Defects appeared in 14 PCT (33.3%; 3 PCT accounted for 41.7%) at the 1st evaluation, and 7 PCT at the re-evaluation (16.7%; 2 reaching 46.7%). CONCLUSIONS: The presence of essential clinical data in clinical records has improved. LQAS proved to be a rapid and simple method for evaluating, improving and monitoring quality in primary care.

El ritmo Theta del hipocampo: ¿Un organizador temporal de la información sensorial y autonómica en la vigilia y el sueño? / Hippocampal Theta rhythm: is it a temporal organizer of sensory and autonomic information during wakefulness and sleep?

El ritmo theta (0) del hipocampo, presente en todos los estados del comportamiento, ha sido relacionado temporalmente con movimientos voluntarios, automáticos y reflejos, tanto durante la vigilia como en el sueño. Nuestra investigación se basa en la hipótesis de que los procesamientos sensoriales necesitan de un ordenamiento, una organización temporal de la información a ser procesada y almacenada, y que el ritmo del hipocampo podría contribuir a dicho ordenamiento temporal. Hemos demostrado que las descargas unitarias de neuronas auditivas y visuales en cobayas presentan correlación temporal con el ritmo hipocámpico (phase-locking). Esta relación temporal aparece tanto en las descargas espontáneas como en las provocadas por los estímulos específicos para cada modalidad sensorial. Las descargas neuronales fluctúan entre la situación de correlación y no correlación de fase con el ritmo . Este estado cambiante depende de distintas situaciones, conocidas y desconocidas. Entre las conocidas son destacables el cambio de estado comportamental (vigilia, sueño lento, sueño paradójico), cambios en las características del estímulo y cambios atencionales. Hemos encontrado, además, una importante correlación temporal entre el ritmo y la frecuencia cardíaca, fundamentalmente durante el sueño paradójico, situación en que los sistemas de control vegetativos se encuentran en su mínima expresión (AU)

Datos clínicos esenciales de la historia clínica de atención primaria: una experiencia de evaluación y mejora / Clinical data that are essential for the primary care clinical records: an experience of evaluation and improvement

Objetivo. Evaluar y mejorar la presencia de datos clínicos esenciales en la historia clínica de una gerencia de atención primaria (GAP), mediante un programa de intervención. Diseño. Estudio de intervención no controlado, siguiendo la metodología de evaluación y mejora de la calidad. Seleccionamos 4 criterios usando las Normas Técnicas Mínimas: antecedentes personales (AP), antecedentes familiares (AF), alergias medicamentosas (AM) y lista de problemas (LP). Evaluamos su cumplimiento global y por equipo de atención primaria (EAP); mediante aceptación de muestras por lotes (LQAS), diseñamos una intervención para mejorar y revaluamos. Emplazamiento. GAP de Murcia (45 EAP).Participantes. Cuarenta y dos EAP (excluidos tres por baja cobertura en historias).Intervenciones. Durante 12 meses (octubre 1999 a octubre 2000): informe gráfico por EAP; sesión en los EAP; debate de resultados y estrategias de mejora en el Consejo de Gestión de Área, e inclusión de un objetivo explícito e incentivado en los contratos de gestión. Mediciones y resultados principales. Mejora significativa de los 4 criterios en la GAP (mejoras relativas: AF, 48,1 per cent; AP, 51,1 per cent; AM, 55,4 per cent; LP, 50,9 per cent). Análisis LQAS: rechazamos 24 lotes (14,3 per cent) en la primera evaluación y 15 (9,0 per cent) en la segunda, siendo en ambas AF el más rechazado. Aparecieron defectos en 14 EAP (33,3 per cent; tres EAP acaparan el 41,7 per cent) en la primera evaluación y en 7 EAP al revaluar (16,7 per cent, reuniendo dos el 46,7 per cent).Conclusión. Ha mejorado la presencia de datos clínicos esenciales en la historia clínica. LQAS demostró ser un método rápido y sencillo para la evaluación, mejora y monitorización de la calidad en atención primaria (AU)

Auditory deprivation modifies biological rhythms in the golden hamster.

To assess to what extent auditory sensory deprivation affects biological rhythmicity, sleep/wakefulness cycle and 24 h rhythm in locomotor activity were examined in golden hamsters after bilateral cochlear lesion. An increase in total sleep time as well as a decrease in wakefulness (W) were associated to an augmented number of W episodes, as well as of slow wave sleep (SWS) and paradoxical sleep (PS) episodes in deaf hamsters. The number of episodes of the three behavioural states and the percent duration of W and SWS increased significantly during the light phase of daily photoperiod only. Lower amplitudes of locomotor activity rhythm and a different phase angle as far as light off were found in deaf hamsters kept either under light-dark photoperiod or in constant darkness. Period of locomotor activity remained unchanged after cochlear lesions. The results indicate that auditory deprivation disturbs photic synchronization of rhythms with little effect on the clock timing mechanism itself.

Reciprocal actions between sensory signals and sleep.

To the best of our knowledge, there is no simple way to induce neural networks to shift from waking mode into sleeping mode. Our best guess is that a whole group of neurons would be involved and that the process would develop in a period of time and a sequence which are mostly unknown. The quasi-total sensory deprivation elicits a new behavioral state called somnolence. Auditory stimulation as well as total auditory deprivation alter sleep architecture. Auditory units exhibiting firing shifts on passing to sleep (augmenting or diminishing) are postulated to be locked to sleep-related networks. Those ( approximately 50%) that did not change during sleep are postulated to continue informing the brain as in wakefulness. A rhythmic functional plasticity of involved networks is postulated. A number of auditory and visual cells have demonstrated a firing phase locking to the hippocampal theta rhythm. This phase locking occurs both during wakefulness and sleep phases. The theta rhythm may act as an organizer of sensory information in visual and auditory systems, in all behavioral states adding a temporal dimension to the sensory processing. Sensory information from the environment and body continuously modulates the central nervous system activity, over which sleep phenomenology must develop. It also produces a basal tonus during wakefulness and sleep, determining changes in the networks that contribute to sleep development and maintenance and, eventually, it also leads to sleep interruption.

Transgenic overexpression of caveolin-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype.

It recently was reported that Duchenne muscular dystrophy (DMD) patients and mdx mice have elevated levels of caveolin-3 expression in their skeletal muscle. However, it remains unknown whether increased caveolin-3 levels in DMD patients contribute to the pathogenesis of DMD. Here, using a genetic approach, we test this hypothesis directly by overexpressing wild-type caveolin-3 as a transgene in mice. Analysis of skeletal muscle tissue from caveolin-3- overexpressing transgenic mice reveals: (i) a dramatic increase in the number of sarcolemmal muscle cell caveolae; (ii) a preponderance of hypertrophic, necrotic, and immature/regenerating skeletal muscle fibers with characteristic central nuclei; and (iii) down-regulation of dystrophin and beta-dystroglycan protein expression. In addition, these mice show elevated serum creatine kinase levels, consistent with the myo-necrosis observed morphologically. The Duchenne-like phenotype of caveolin-3 transgenic mice will provide an important mouse model for understanding the pathogenesis of DMD in humans.