[Is an oral disintegrating tablets a formulation that is easy to ingest for patients experiencing difficulty with eating and swallowing?].

Oral disintegrating tablets (hereafter, ODT) can be ingested without water. We conducted a videoscopic examination to determine whether they are also useful as internal agents for patients experiencing difficulty with eating and swallowing. Normal tablets and dummy preparations of ODT were orally administered to six patients with neurological diseases who were either diagnosed with or aware of difficulty in eating and swallowing, and observations were conducted using a videoscope. Two subjects were able to ingest both the normal tablet and the dummy preparation without any problem; two subjects were able to ingest the normal tablet without any problem but the dummy preparation remained in their pharynx; and two subjects had both the normal tablet and the dummy preparation remained in the pharynx. There was no feeling of residue in the four cases in which the dummy preparation remained in the pharynx. ODT is not necessarily easy to ingest for patients with neurological diseases who have difficulty eating and swallowing, and it was believed that repeated swallowing or alternate swallowing of a thick liquid is required for ingestion.

[Prolonged apnea/hypopnea during water swallowing in patients with amyotrophic lateral sclerosis].

PURPOSE: Swallowing difficulty is increased along with progression of respiratory disturbance in patients with Amyotrophic Lateral Scalerosis (ALS). To analyze the respiratory patterns during swallowing is important for the management of this disease. In this study, we evaluated apnea/hypopnea during water swallowing and the respiratory cycle at rest and after water swallowing. METHOD: We evaluated respiratory patterns in swallowing in 10 ALS patients (66.0 +/- 7.1 years old), in 10 Myotonic dystrophy (MD) patients (46.5 +/- 12.2 years old), and in 10 healthy volunteers as control subjects (61.7 +/- 10.0 years old). The ALS and MD patients had consulted the Department of Neurology of Toneyama National Hospital or Tokushima National Hospital between April 2002 and July 2006. Respiratory patterns were evaluated by simultaneous recording of cervical swallowing sound in water swallow. A hypersensitive microphone measured cervical sound. A thermister was used for pneumography. The means of four continuous respiratory cycles at rest and after swallow of 3 ml water were used for analysis. Respiration with amplitude of 1/2 or smaller than that of the pneumography at rest was defined as hypopnea, and the apnea/hypopnea duration was evaluated as the respiratory suppression time. STATISTICAL ANALYSIS: All analyses were performed using SPSS 11.0J (SPSS Inc., Chicago, IL). RESULTS: In the ALS group, the respiratory cycle was 3.15 +/- 0.76 sec (2.31-4.39 sec) at rest, while after swallowing, it was 2.78 +/- 0.83 sec (1.77-4.80 sec) (p = 0.1). In the MD group, the respiratory cycle was 2.56 +/- 0.46 sec (1.91-3.67 sec) at rest, while after swallowing, it was 2.94 +/- 0.60 sec (2.03-4.29 sec). In the control group, it was 3.46 +/- 0.57 sec (3.18-4.34 sec) at rest and 3.24 +/- 0.50 sec (2.64-4.04 sec) after swallowing. The apnea/hypopnea duration during water swallow was 14.33 +/- 8.89 sec (2.50-30.68 sec) in the ALS group, 3.66 +/- 1.58 sec (1.78-6.42 sec) in the MD group, and 3.64 +/- 1.00 sec (2.34-5.56 sec) in the control group. The apnea/hypopnea duration in the ALS group was significantly longer than that in MD and control groups (p = 0.005, p = 0.004 by the t-test). The ALS patients with severe respiratory failure or with aspiration in videofuoroscopy showed extended apnea/hypopnea duration. CONCLUSION: Prolonged apnea/hypopnea was observed during water swallowing in ALS patients. We speculate that this prolongation is caused by severe swallowing disturbance and respiratory failure, which increases the risk of aspiration. The respiration of ALS patients should be closely monitored during eating.

[Videofluorographic assessment of swallowing function in patients with Duchenne muscular dystrophy].

OBJECTIVE: To identify the characteristics of swallowing function in patients with Duchenne muscular dystrophy (DMD). METHODS: Swallowing function was evaluated using videofluorography (VF) in a cross-sectional observational study of 102 DMD patients (mean age 21.5 years) who had dysphagia or in whom dysphagia was suspected based on clinical signs. Reduced tongue movement, impaired bolus transport to the pharynx, decreased pharyngeal contraction, bolus delivery into the airway, and bolus residue at the epiglottic vallecula and at the piriform recess were qualitatively evaluated for test swallows of jelly and juice. During VF, the length of time of both the oral and pharyngeal phases of swallowing was measured in 59 patients. RESULTS: Patients started to show oral phase abnormalities in their mid-teens and pharyngeal phase abnormalities such as pharyngeal residue around age 20. Oral phase abnormalities was higher with juice than with jelly. Total oral/pharyngeal transit duration was longer with age, and total duration of hyoid maximum elevation was shorter with age. CONCLUSION: The weak positive correlation of total oral/pharyngeal transit duration and age was presumably due to gradual onset of functional abnormalities associated with deteriorated swallowing muscles starting in the teenage years. Reduced tongue movement and impaired bolus transport to the pharynx was more common in teenage DMD patients because they have limited tongue movements associated with structural abnormalities such as macroglossia and open bite. VF showed that the swallowing difficulties were more severe during the oral phase than in the pharyngeal phase in the teenage patients. The pharyngeal phase disorders such as pharyngeal residue and decreased pharyngeal contraction were seen more often in the patients in their 20s, presumably due to deterioration of swallowing muscles that becomes more apparent in the older age group.

Motor neuron involvement in a patient with long-term corticosteroid administration.

An asthmatic patient with corticosteroid treatment for 45 years presented with slowly progressive limb muscle atrophy. His muscle symptoms were involved in four limbs and tongue, and deep tendon reflexes were exaggerated. Biopsied muscle pathology indicated the presence of neurogenic muscular atrophy in combination with corticosteroid myopathy. Furthermore, 8-hydroxy-deoxyguanosine (8-OH-dG) was prominently increased in mitochondrial and nuclear DNA. An aerobic exercise test demonstrated remarkable serum lactate elevation, which was attenuated by the administration of coenzyme Q10. These findings are consistent with the assumption that long-term corticosteroid administration potentially induces not only myopathy but also motor neuron involvement as in mitochondrial diseases.

Deletion of vitamin D receptor gene in mice results in abnormal skeletal muscle development with deregulated expression of myoregulatory transcription factors.

Although rachitic/osteomalacic myopathy caused by impaired vitamin D actions has long been described, the molecular pathogenesis remains elusive. To determine physiological roles of vitamin D actions through vitamin D receptor (VDR) in skeletal muscle development, we examined skeletal muscle in VDR gene deleted (VDR -/-) mice, an animal model of vitamin D-dependent rickets type II, for morphological changes and expression of myoregulatory transcription factors and myosin heavy chain isoforms. We found that each muscle fiber was small and variable in size in hindlimb skeletal muscle from VDR -/- mice, although overall myocyte differentiation occurred normally. These abnormalities were independent of secondary metabolic changes such as hypocalcemia and hypophosphatemia, and were accompanied by aberrantly high and persistent expression of myf5, myogenin, E2A, and early myosin heavy chain isoforms, which are normally down-regulated at earlier stages. Moreover, treatment of VDR-positive myoblastic cells with 1,25(OH)2D3 in vitro caused down-regulation of these factors. These results suggest that VDR plays a physiological role in skeletal muscle development, participating in temporally strict down-regulation of myoregulatory transcription factors. The present study can form a molecular basis of VDR actions on muscle and should help further establish the physiological roles of VDR in muscle development as well as pharmacological effects of vitamin D on muscle functions.

Mitochondrial damage in patients with long-term corticosteroid therapy: development of oculoskeletal symptoms similar to mitochondrial disease.

Two patients with long-term corticosteroid administration sporadically developed limb muscle wasting followed by ophthalmoplegia, and the skeletal muscle pathology revealed ragged-red fibers (RRFs) with abnormal mitochondria, in addition to the findings of corticosteroid myopathy. The oculoskeletal symptoms of the present cases resemble those of chronic progressive external ophthalmoplegia, a type of mitochondrial disease. The ocular muscles have more RRFs than limb muscles, and large multiple deletions of mitochondrial DNA was detected in ocular and limb muscles of the two patients by PCR but not by Southern blotting. Immunohistochemistry demonstrated that 8-hydroxy-deoxyguanosine (8-OH-dG) and 4-hydroxy-2-nonenal were intensely stained in skeletal muscles of these patients particularly in RRFs. High-performance liquid chromatography with electrochemical detection analysis revealed an increase in 8-OH-dG from mitochondrial DNA. These findings may suggest that long-term corticosteroid administration potentially induces oxidative stress-mediated mitochondrial damage, resulting in the development of the oculoskeletal symptoms in some patients.

Apoptosis-related changes in skeletal muscles of patients with mitochondrial diseases.

Much interest has recently been shown in apoptosis-mediated roles in the pathophysiology of mitochondrial diseases, because mitochondrial defects are implicated in a wide variety of degenerative diseases. We investigated whether apoptotic events occurred in skeletal muscles of patients with mitochondrial diseases, including chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayer syndrome (KSS), and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). In a immunohistochemical study, stainings for 8-hydroxy-deoxyguanosine (8-OH-dG), 4-hydroxy-nonenal (4-HNE), Mn-SOD, Bcl-2, cytochrome c, DNase I and Bcl-x L showed a pronounced granular distribution in the cytochrome c oxidase (COX)-negative ragged-red fibers (RRFs). On the other hand, the signals for Bax, p53, Fas and caspase 3 were not obviously increased in RRFs. In situ labeling of DNA breaks demonstrated preferential signals not only in myonuclei but also in subsarcolemmal regions of RRFs, indicating that mitochondrial as well as myonuclear DNA is fragmented in RRFs. An immunoblotting study demonstrated that cytochrome c was increased in the cytosol of diseased muscles and that DNase I was increased in mitochondria, compared to that of normal muscles. No difference was observed between protein bands at 20 kDa corresponding to caspase 3 in diseased and normal muscles. These findings demonstrate that these mitochondrial diseases harbor unique apoptosis-related changes that differ from caspase 3-dependent apoptosis. It is thought that these changes are induced by superoxide overproduction and cytochrome c release resulting from an inherent mitochondrial defect and that the events are associated with DNase I activation.