Chronic paleocerebellar stimulation for the treatment of neuromuscular disorders. Four case report.

4 patients suffering severe neuromuscular diseases were subjected to a subtentorial implantation of electrodes over the anterior cerebellar lobe surface. Chronic stimulation was applied for 90 min to 7 h daily, with a rate of 20--180 Hz, 6--10 V and a schedule of 15 min "on", 15 min "off". Some improvement was observed in 3 patients treated with high frequency stimulation. 1 patient suffered seizures after three months of chronic stimulation. In 2 cases, posterior fossa explorations were necessary for revision of the stimulation apparatus and marked meningeal proliferation surrounding the electrodes was observed. Light and electron microscopic examination of the biopsies showed loss of Purkinje cells and gliofibrillar reaction. Effectiveness and side effects of chronic stimulation of the cerebellum are discussed.     

Glycobiology of neuromuscular disorders

There has been a recent explosion in the identification of neuromuscular diseases caused by mutations in genes that affect carbohydrate metabolism or protein glycosylation. A number of these findings relate to defects in the glycosylation of alpha dystroglycan. Alpha dystroglycan is an essential component of the dystrophin-glycoprotein complex, and aberrant glycosylation of alpha dystroglycan is associated with multiple forms of muscular dystrophy in mice and humans. We review the evidence that defects in dystroglycan glycosylation cause muscular dystrophy. In addition, we review evidence that glycobiology is important in other disorders that affect muscle, including hereditary inclusion body myopathy type II and congenital disorders of glycosylation. Finally, we discuss the long-term potential of glycotherapies for muscle disorders.     

Active oxygen in neuromuscular disorders

Although muscle and nerve are reasonably well protected against active oxygen and related free radicals, environmental or inherited malfunctions can overpower their defences. Active oxygen is involved in many neuropathies and myopathies. In every case the damage is caused by agents which exert effects disproportionately greater than the quantites encountered, through a variety of amplification mechanisms. We can categorize these amplification mechanisms as follows: (a) non-replacement of targets (e.g. loss of genetic information, ataxia telangectasia being an hereditary ataxia in which an oxygen mediated chromosomal instability is apparent), (b) non-removal of unwanted materials (e.g. lipofuscin accumulation in brain and heart), (c) redox cycling, usually involving catalysis by trace-metal ions (e.g. some forms of Parkinsonism), (d) non-redox catalysis (e.g. toxicity in cardiac muscle or brain due to vanadium or aluminium respectively), (e) modification of ion transport (e.g. calcium ionophore or acrylamide induce histopathological changes in muscle, similar in some respects to those seen in Duchenne muscular dystrophy), (f) compromised defences (e.g. muscle and nerve become particularly susceptible to free radical damage after loss of the protective actions of vitamin E), and (g) amplification by inflammatory and immune responses (e.g. multiple sclerosis, reperfusion injury to brain and heart, and traumatic injury to nervous tissue). Unfortunately, a variety of therapeutic agents which might be expected to protect against almost every conceivable form of oxygen mediated damage have proved clinically ineffective in most of these disorders. The reasons for this will be explored with an emphasis on common features, differences, mechanisms, and potential therapeutic approaches.     

AMPK is mitochondrial medicine for neuromuscular disorders

Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), and spinal muscular atrophy (SMA) are the most prevalent neuromuscular disorders (NMDs) in children and adults. Central to a healthy neuromuscular system are the processes that govern mitochondrial turnover and dynamics, which are regulated by AMP-activated protein kinase (AMPK). Here, we survey mitochondrial stresses that are common between, as well as unique to, DMD, DM1, and SMA, and which may serve as potential therapeutic targets to mitigate neuromuscular disease. We also highlight recent advances that leverage a mutation-agnostic strategy featuring physiological or pharmacological AMPK activation to enhance mitochondrial health in these conditions, as well as identify outstanding questions and opportunities for future pursuit.     

Telethonin protein expression in neuromuscular disorders

Telethonin is a 19-kDa sarcomeric protein, localized to the Z-disc of skeletal and cardiac muscles. Mutations in the telethonin gene cause limb-girdle muscular dystrophy type 2G (LGMD2G).We investigated the sarcomeric integrity of muscle fibers in LGMD2G patients, through double immunofluorescence analysis for telethonin with three sarcomeric proteins: titin, alpha-actinin-2, and myotilin and observed the typical cross striation pattern, suggesting that the Z-line of the sarcomere is apparently preserved, despite the absence of telethonin. Ultrastructural analysis confirmed the integrity of the sarcomeric architecture. The possible interaction of telethonin with other proteins responsible for several forms of neuromuscular disorders was also analyzed. Telethonin was clearly present in the rods in nemaline myopathy (NM) muscle fibers, confirming its localization to the Z-line of the sarcomere. Muscle from patients with absent telethonin showed normal expression for the proteins dystrophin, sarcoglycans, dysferlin, and calpain-3. Additionally, telethonin showed normal localization in muscle biopsies from patients with LGMD2A, LGMD2B, sarcoglycanopathies, and Duchenne muscular dystrophy (DMD). Therefore, the primary deficiency of calpain-3, dysferlin, sarcoglycans, and dystrophin do not seem to alter telethonin expression.     

Respiratory load compensation in neuromuscular disorders

First-breath ventilatory responses to graded elastic (delta E) and resistive (delta R) loads from 10 people with spinal muscular atrophy (SMA), 15 people with Duchenne muscular dystrophy (DMD), and 80 able-bodied people were compared. The SMA and DMD groups produced equal tidal volume, respiratory frequency, inspiratory duration (TI), expiratory duration, mean inspiratory airflow, and duty cycle responses to both delta E and delta R. Thus SMA (primarily a motoneuron disorder) and DMD (primarily a muscle disorder) have the same net effect on loaded breathing responses. The SMA and DMD groups failed to duplicate the normal group's short expirations during delta E, long inspirations during delta R, and thus, extended duty cycles during both delta E and delta R. The deficit in load compensation therefore was due to impaired regulation of respiratory timing (reflecting neural mechanisms) but not airflow defense (reflecting mechanical and neural mechanisms). One-fifth of the normal but none of the SMA or DMD subjects actively generated an "optimal" TI response (defined theoretically as TI greater than 160% control during large delta R and TI less than 75% control during large delta E). This lack of optimal responses, which is the same abnormality exhibited by quadriplegic people, suggests that SMA and DMD also impair human ability to discriminate between large delta R and delta E. These findings support the hypothesis that neuromuscular disorders can lead to disturbances in respiratory perception.     

Muscle contractility in chronic disorders of neuromuscular transmission

Muscle contractility of the thumb was studied in 24 normal subjects, 84 patients with myasthenia and 4 patients with hypothyrosis in response to supramaximal stimulation, on the basis of the time of contraction and semi-relaxation, staircase phenomena, and posttetanic potentiation. During hormonal therapy, the patients with myasthenia and those with hypothyrosis treated by substitution therapy manifested the normalization of the staircase and posttetanic potentiation, reduction of the contraction force and twitch time during single contraction. The comparison of the changes seen in the contraction force, staircase and posttetanic potentiation during examination of the patients over time suggested that the muscle has a regulatory system that determines the force and twitch time of muscle contraction.     

Double discharges of motor units in neuromuscular disorders.

Repetitive discharges (RDs) are observed in electromyograms recorded from healthy as well as diseased muscles. We have evaluated the prevalence of RDs in some neuromuscular diseases and analysed the time parameters of recordings displaying RDs as well as shapes of the potentials. In our clinical material, RDs have been observed exclusively in lower motor neuron lesions, never in healthy or in myopathic muscles. The prevalence index of RDs in amyotrophic lateral sclerosis (0.06) was found to be different from that in chronic spinal muscle atrophy (0.004). The types of double potential shape have been categorised. The relationships between the amplitude of the second component and the interspike duration and that between the interspike duration and the jitter were calculated. The amplitude of the second component diminished and jitter of the components increased with the shortening of the interval between components. The authors suggest that in lower motor neuron lesions, the RDs of the motorunit (MU) may be one of the first signs of the MU's dysfunction.     

Molecular targets for autoimmune and genetic disorders of neuromuscular transmission.

The neuromuscular junction is the target of a variety of autoimmune, neurotoxic and genetic disorders, most of which result in muscle weakness. Most of the diseases, and many neurotoxins, target the ion channels that are essential for neuromuscular transmission. Myasthenia gravis is an acquired autoimmune disease caused in the majority of patients by antibodies to the acetylcholine receptor, a ligand-gated ion channel. The antibodies lead to loss of acetylcholine receptor, reduced efficiency of neuromuscular transmission and muscle weakness and fatigue. Placental transfer of these antibodies in women with myasthenia can cause fetal or neonatal weakness and occasionally severe deformities. Lambert Eaton myasthenic syndrome and acquired neuromyotonia are caused by antibodies to voltage-gated calcium or potassium channels, respectively. In the rare acquired neuromyotonia, reduced repolarization of the nerve terminal leads to spontaneous and repetitive muscle activity. In each of these disorders, the antibodies are detected by immunoprecipitation of the relevant ion channel labelled with radioactive neurotoxins. Genetic disorders of neuromuscular transmission are due mainly to mutations in the genes for the acetylcholine receptor. These conditions show recessive or dominant inheritance and result in either loss of receptors or altered kinetics of acetylcholine receptor channel properties. Study of these conditions has greatly increased our understanding of synaptic function and of disease aetiology.     

Instrumentation for distraction by limited surgery in scoliosis treatment

A principle for secondary instrumental spinal distraction by a rod appliance of the Knodt and Harrington types is described. The principle entails the rotation of the screw rod by wire traction. The wire is, in a secondary procedure, unwound from a wire barrel mounted onto the screw rod in the primary operative procedure. The study describes the devices employed, modified according to the wire traction—instrument distraction principle Previous results from intra-vital studies of the Harrington instrumentation have been reported from experiments performed². Thus, a final distraction force of 18 kp effected for correction of a scoliosis curvature, was taken as a value of distraction prior to secondary instrumental distraction by wire traction. In the extra vital study, the wire traction was adjusted to surmount a compressive force of 20 kpby means of a Bessmann weight scale. Wire traction created a distraction force of 39.5 kp, and a metric distraction, from the position resulting from 20 kp distraction to that resulting from 39.5 kp distraction, of 2.8 mm, which was considered to affect the prevalling scoliosis geometry to a considerable and sufficient extent.     

Exercise-based cardiac rehabilitation in patients with chronic heart failure: a Dutch practice guideline

Rationale

To improve the quality of exercise-based cardiac rehabilitation (CR) in patients with chronic heart failure (CHF) a practice guideline from the Dutch Royal Society for Physiotherapy (KNGF) has been developed.

Guideline development

A systematic literature search was performed to formulate conclusions on the efficacy of exercise-based intervention during all CR phases in patients with CHF. Evidence was graded (1–4) according the Dutch evidence-based guideline development criteria.

Clinical and research recommendations

Recommendations for exercise-based CR were formulated covering the following topics: mobilisation and treatment of pulmonary symptoms (if necessary) during the clinical phase, aerobic exercise, strength training (inspiratory muscle training and peripheral muscle training) and relaxation therapy during the outpatient CR phase, and adoption and monitoring training after outpatient CR.

Applicability and implementation issues

This guideline provides the physiotherapist with an evidence-based instrument to assist in clinical decision-making regarding patients with CHF. The implementation of the guideline in clinical practice needs further evaluation.

Conclusion

This guideline outlines best practice standards for physiotherapists concerning exercise-based CR in CHF patients. Research is needed on strategies to improve monitoring and follow-up of the maintenance of a physical active lifestyle after supervised CR.     

Three-color flowcytometric analysis of mature and immature hematological malignancies. A guideline of the Dutch Foundation for Immunophenotyping of Hematological Malignancies (SIHON)

Multiparameter flowcytometry offers an insight into differentiation pathways, maturation stages and abnormal features of cell (sub)populations thus helping to establish and classify hematological malignancies. The Dutch Foundation for Immunophenotyping of Hematological Malignancies (SIHON) has formulated a guideline for a rapid screening followed by confirmation and classification in a standardized way. For this aim seven carefully composed monoclonal antibody combinations are elucidated for screening the test sample in a first phase. In this phase a relative frequency distribution of the cells will be established and a decision will be made about abnormal cells present, as well as their mature or immature state and the cell lineage they belong to. In a second phase, panels with cell lineage dependent monoclonal antibody combinations may be used to confirm and classify the abnormal cell population indicated in phase 1, as well as to establish the presence or absence of an abberant immunophenotype.     

A mechanism for gene-environment interaction in the etiology of congenital scoliosis

Congenital scoliosis, a lateral curvature of the spine caused by vertebral defects, occurs in approximately 1 in 1,000 live births. Here we demonstrate that haploinsufficiency of Notch signaling pathway genes in humans can cause this congenital abnormality. We also show that in a mouse model, the combination of this genetic risk factor with an environmental condition (short-term gestational hypoxia) significantly increases the penetrance and severity of vertebral defects. We demonstrate that hypoxia disrupts FGF signaling, leading to a temporary failure of embryonic somitogenesis. Our results potentially provide a mechanism for the genesis of a host of common sporadic congenital abnormalities through gene-environment interaction.