Lysosomal glycogen storage disease without acid maltase deficiency

Lysosomal glycogen storage disease without acid maltase deficiency is characterized by the triad of clinical manifestations (hypertrophic cardiomyopathy), mental retardation, and mild myopathy), morphologic findings (glycogen storage, glycogenosomes, and autophagic vacuoles), and normal glycolytic enzyme activities. Though most of the patients suffering from the triad were males, family studies often revealed female patients with only cardiomyopathy. So far 27 cases have been reported. The cardiac involvement is progressive and fatal and as severe in females as in males. Many patients of both sexes die in their youth, unexpectedly, because of cardiac failure. The specific biochemical defect causing this disease remains unknown. From abnormal lectin staining patterns on the membrane and preclinical morphologic changes in biopsied skeletal muscle, membranous abnormality is suspected in this disease.     

Respiratory muscles and ventilatory failure: 1993 perspective

Some conditions that predispose to ventilatory failure increase the work of breathing (chronic obstructive pulmonary disease [COPD], obesity, kyphoscoliosis), whereas others cause severe respiratory muscle weakness. Specific reasons for muscle weakness include critical illness (electrolyte imbalance, acidemia, shock, sepsis), chronic illness (poor nutrition, cachexia), and neuromuscular diseases. Inspiratory muscle weakness from mechanical disadvantage to the diaphragm is characteristic of asthma and COPD. The increased work of breathing combined with muscle weakness increases the pressure needed to inspire a breath and decreases maximal inspiratory pressure. When this pressure exceeds 0.4, dyspnea and inspiratory muscle fatigue ensue. One way to lower this pressure and avert fatigue is to lower the tidal volume. Ventilatory drive is high, not low, in ventilatory failure. Concomitant shortening of inspiration and breath duration cause the small tidal volume and increased respiratory rate. Gas exchange is compromised by ventilation/perfusion imbalance, and the ratio of dead space to tidal volume is also increased by rapid, shallow breathing. Reduction in tidal volume minimizes dyspnea, but the small tidal volume is inadequate for gas exchange. Acute treatment of respiratory muscle failure involves respiratory muscle rest through mechanical ventilation and removal of noxious influences (infection, metabolic disarray), whereas chronic treatment involves rebuilding the contractile apparatus by nutritional repletion and training.     

Adenovirus-mediated transfer of human acid maltase gene reduces glycogen accumulation in skeletal muscle of Japanese quail with acid maltase deficiency

Acid maltase deficiency (AMD) causes a lysosomal glycogenosis inherited as an autosomal recessive trait. The infantile type of AMD (Pompe disease) leads to early death due to severe dysfunction of cardiac and respiratory muscles and no effective therapy is available. Replication-defective adenovirus vectors offer a promising tool for in vivo gene delivery and gene therapy. We constructed a recombinant adenovirus containing the human acid maltase (AM) cDNA downstream of the CAG promoter, composed of modified chicken beta-actin promoter and CMV IE enhancer (AxCANAM). Japanese quail with AMD was used for this study as an animal model for human AMD. When cultured fibroblasts from AMD quail were infected with AxCANAM, AM activity in the cells increased in proportion to the multiplicity of infection (MOI). When AxCANAM (4.5 x 10(8) PFU) was injected into unilateral superficial pectoral muscle of AMD quail, PAS staining showed that glycogenosomes disappeared and stainability of acid phosphatase was reduced in the injected area as compared with the contralateral muscle of the same birds. Biochemically, AM activity increased and glycogen content decreased in the injected muscle. Western blot analysis showed that AMD quail muscle injected with AxCANAM expressed human AM protein processed to active forms. These results suggest that the human AM cDNA transferred by an adenovirus vector was sufficiently expressed, leading to a marked reduction of the glycogen accumulation in the skeletal muscle of AMD quail.     

Peripheral and respiratory muscles in chronic heart failure

It is well-established that in patients with congestive heart failure (CHF), exercise is limited by fatigue and shortness of breath. The poor correlation between the fatigue and indices of central haemodynamic function might indicate that peripheral muscle alterations contribute to impaired exercise capacity. Intrinsic abnormalities of the skeletal muscles have been suggested as a possible explanation. Since the shortness of breath correlates poorly with changes in lung function, changes in the respiratory muscles have been investigated. Studies have demonstrated diaphragmatic myopathy and atrophy similar, in part, to the changes in peripheral skeletal muscles. In CHF, type I (slow twitch) fibre atrophy is seen in respiratory as well as in peripheral muscles. The mechanism of these alterations remains to be elucidated. Studies into the mechanism of muscle dysfunction in congestive heart failure are relevant to the prospect of treatment of the changes in peripheral and respiratory muscles.     

Selenium deficiency associated with cardiac dysfunction in three patients with chronic respiratory failure

We encountered three patients with chronic respiratory failure who had heart failure of cardiac arrhythmias and low levels of serum selenium. All three had tracheostomies and had received long-term parenteral nutrition that had not included selenium. All three also had refractory cardiac dysfunction, which was manifested in edema, heart failure, and various tachycardias. We suspected that selenium deficiency had caused their cardiac dysfunction. Serum selenium concentrations were found to be much lower than normal in all three, so 100 micrograms/day of selenium was administered in addition to their tube feedings. Cardiac function improved after replacement of selenium. These cases show the need for preventing selenium deficiency in patients with chronic respiratory failure during long-term administration of parenteral nutrition.     

Detection of free radicals in blood by electron spin resonance in a model of respiratory failure in the rat

Previous work has suggested that a free radical mechanism is involved in some types of muscle fatigue and that there can be free radicals released extracellularly. Because muscle fatigue may be an important factor in respiratory failure, the authors tested the hypothesis that increased concentrations of free radicals could be detected in the blood of animals undergoing severe resistive loading to respiratory failure. An ex vivo spin trapping technique with alpha-phenyl-N-tert-butylnitrone (PBN) was used to investigate the possible formation of free radicals in systemic blood samples by electron spin resonance (ESR) spectrometry. After 2.5-3 h of severe inspiratory resistive loading with 70% supplemental inspired oxygen, free radical levels in the form of PBN-adducts were found to rise significantly over the control group breathing room air and the control group breathing 70% oxygen (p < 0.05, N = 8). There were no significant differences between control groups breathing room air and control groups breathing 70% oxygen. This study presents direct evidence that free radicals are produced ex vivo and that they can be detected in the systemic circulation due to excessive resistive loading of the respiratory muscles.     

Effect of global inspiratory muscle fatigue on ventilatory and respiratory muscle responses to CO2

We evaluated the effect of global inspiratory muscle fatigue on ventilation and respiratory muscle control during CO2 rebreathing in normal subjects. Fatigue was induced by breathing against a high inspiratory resistance until exhaustion. CO2 response curves were measured before and after fatigue. During CO2 rebreathing, global fatigue caused a decreased tidal volume (VT) and an increased breathing frequency but did not change minute ventilation, duty cycle, or mean inspiratory flow. Both esophageal and transdiaphragmatic pressure swings were significantly reduced after global fatigue, suggesting decreased contribution of both rib cage muscles and diaphragm to breathing. End-expiratory transpulmonary pressure for a given CO2 was lower after fatigue, indicating an additional decrease in end-expiratory lung volume due to expiratory muscle recruitment, which leads to a greater initial portion of inspiration being passive. This, combined with the reduction in VT, decreased the fraction of VT attributable to inspiratory muscle contribution; therefore the inspiratory muscle elastic work and power per breath were significantly reduced. We conclude that respiratory control mechanisms are plastic and that the respiratory centers alter their output in a manner appropriate to the contractile state of the respiratory muscles to conserve the ventilatory response to CO2.     

Allergic granulomatous angiitis associated with cerebral infarction, myo-pericarditis and acute respiratory failure due to eosinophilic pneumonia

We encountered a 23-year-old woman with allergic granulomatous angiitis (AGA) associated with cerebral infarction, myo-pericarditis, and acute respiratory failure due to extended eosinophilic pneumonia. She underwent emergency treatment at our hospital because of right hemiparesis and impaired consciousness. AGA was suspected because the patient had a history of bronchial asthma accompanied by pulmonary infiltrations with eosinophilia, and presented with diffuse pulmonary infiltrates, pericardial effusion, diffuse hypokinesis of myocardium, cerebral infarction and marked peripheral eosinophlia. Pulmonary eosinophilia was confirmed by examination of broncho-alveolar lavage fluid. Myocardial tissue biopsy specimens revealed fibrous granulation indicative of myocarditis. The patient responded well to corticosteroid therapy.     

Apoptosis of undifferentiated progenitors and granule cell precursors in the postnatal human cerebellar cortex correlates with expression of BCL-2, ICE, and CPP32 proteins

This article reviews the literature of noninvasive positive pressure ventilation (NPPV) in patients with acute respiratory failure. The article divides acute respiratory failure into the categories of primary ventilation failure and oxygenation failure, and examines various diagnostic groups within these categories. Although the use of NPPV for patients with acute respiratory failure of other etiologies requires further study, the authors conclude that there is sufficient evidence to support the use of NPPV in acute, severe exacerbations of chronic obstructive pulmonary disease.     

Respiratory failure sometimes is due to a cardiac cause

In two women aged 65 and 49 years and a man aged 64 years, severe respiratory failure developed and a pulmonary disease was suspected. They also had a minor systolic murmur. At further investigation no pulmonary cause for the disease could be established. Pulmonary artery catheterization revealed increased pulmonary artery and wedge pressures and transthoracic and transoesophageal echocardiography revealed mitral valve insufficiency. Two patients had valve surgery, the third received medication. Respiratory failure is a common problem in an intensive care unit. If this condition is caused by mitral valve insufficiency the clinical picture is not always that of acute left ventricular failure with hydrostatic pulmonary oedema due to backward failure. In patients with respiratory failure due to mitral valve pathology initial diagnostic problems may be overcome by combining the findings of pulmonary artery catheterization and transthoracic and transoesophageal echocardiography.     

Enteral absorption of insulin in rats from mucoadhesive chitosan-coated liposomes

Whole muscle contractile characteristics and fatigue resistance were studied in male patients with chronic heart failure (n = 6) and in healthy control subjects (n = 6). Maximum voluntary isometric strength in the major muscle groups of leg (plantar flexors and knee extensors) and arm (elbow extensors and elbow flexors), was found to be similar for both groups of subjects. However, a faster isometric twitch time course was observed in the plantar flexor and knee extensor muscles of heart failure chronic patients. The poor resistance to fatigue in the knee extensors of chronic heart failure patients was confirmed in the present study, but using twitch interpolation this was shown not to be due to poor activation. The plantar flexors of chronic heart failure patients also showed a tendency to be less resistant to fatigue, even when the muscle was activated by direct electrical stimulation. The present study shows that independent of muscle strength, patients with chronic heart failure may possess muscles that are faster to contract and less resistant to fatigue. However, it seems this increased fatigability is not due to poor muscle activation.     

Relationship between chronic hypercapnia and inspiratory-muscle weakness in myotonic dystrophy

We studied 134 patients with Steinert's myotonic dystrophy (MD) in order to determine the prevalence of chronic hypercapnia, the level of muscle weakness and forced expiratory volume at which hypercapnic respiratory failure is likely to occur, and how clinical assessment might help predict hypercapnic respiratory failure. Subjects were divided into five classes with a muscular disability rating scale (MDRS): 0 = no clinical impairment (n = 9), I = minimal signs of impairment (n = 11), II = distal weakness (n = 41), III = moderate proximal weakness (n = 62), and IV = nonambulatory (n = 11). The prevalence of hypercapnia (PaCO2 > or = 43 mm Hg) was found to be 0%, 27%, 29%, 45% and 55% for MDRS 0 to 4, respectively (p = 0.03). A multiple regression analysis limited to clinical data showed that daytime hypersomnolence was a significant cofactor with the MDRS (p = 0.01) in predicting PaCO2 (r = 0.40). Among respiratory parameters, FVC, respiratory muscle strength (RMS), and maximal inspiratory pressure against occluded airways (PImax) were found to be predictors of nearly equal strength, explaining 16%, 15%, and 14% of the PaCO2 variance, respectively. In multiple regression analysis, sex, daytime sleepiness, and the expected/observed FVC ratio for a given RMS were found to be significant cofactors with PImax in predicting PaCO2 (r = 0.51). It is concluded that respiratory insufficiency should be suspected in MD patients with proximal weakness or daytime sleepiness. The likelihood of hypercapnia also increases with volume restriction and respiratory muscle weakness. Our study suggests that the combination of inspiratory muscle weakness and loading plays a predominant role in the pathogenesis of chronic alveolar hypoventilation in MD patients. The occurrence of daytime hypersomnolence suggests that other factors, such as low central ventilatory drive or sleep apnea, might play an additional role.     

Critical illness myopathy unrelated to corticosteroids or neuromuscular blocking agents

Acute myopathy occurs in critically ill patients, receiving neuromuscular blocking agents or corticosteroids during intensive care hospitalisation. We report three patients with acute quadriplegic myopathy, two of whom were not exposed to corticosteroids or neuromuscular blocking agents. The first of these latter two patients had a history of generalised anoxia with coma related to surgery, complicated by multiple organ failure and sepsis. The second patient, suffering from acute leukaemia, developed sepsis and acute respiratory distress syndrome with the need for mechanical ventilation in the intensive care unit. Electrophysiological studies and muscle biopsy findings were consistent with the diagnosis of critical illness myopathy with loss of myosin filaments. Selective loss of myosin was confirmed by biochemical analysis of muscle. These findings demonstrate that acute myopathy with loss of myosin filaments may occur in patients with severe systemic illness without exposure to corticosteroids or neuromuscular blocking agents.     

Dissipation of heat during polymerization of acrylics used for external skeletal fixator connecting bars

BACKGROUND: To determine the functional changes in the extraocular muscles in patients with thyroid-associated ophthalmopathy (TAO). PATIENTS AND METHODS: Horizontal saccades with an amplitude of 20 degrees were carried out over a period of 2 min. Eight patients with acute TAO and five patients with chronic TAO were compared with ten age-matched healthy individuals. Ocular movements were recorded using the "Ober 2" system based on infrared technology. For evaluation of fatigue effects, the parameters of the first five and the last five saccades were analysed. RESULTS: A significant difference of four and five, respectively, out of nine tested saccadic variables including maximum velocity (Vmax) was found both before and after fatigue. In comparison to normal subjects, patients with chronic TAO revealed mildly increased reduction of Vmax after fatigue. Results in patients with acute TAO were related to the action of the most severely affected muscle. On active contraction of the medial rectus muscle (adducting saccades), Vmax was not significantly decreased after fatigue. On passive elongation of the medial rectus muscle (abducting saccades), however, Vmax was initially markedly decreased and increased significantly after fatigue. CONCLUSIONS: Functional changes of extraocular muscles in patients with TAO can be demonstrated by saccadic analysis. The inverse change in velocity after fatigue in acute disease indicates an improvement of muscle elasticity during exertion and strongly supports the concept that early impairment of bulbar motility in active TAO results from contracture of myofilaments. Thus, analysis of the fatigue effect may help to differentiate between acute and chronic disease.     

Fatal neonatal liver failure and mitochondrial cytopathy (oxidative phosphorylation deficiency): a light and electron microscopic study of the liver

Mitochondrial cytopathies are multisystemic disorders of extremely variable expression due to a deficiency in oxidative phosphorylation. Cases have recently been reported in which fatal liver failure with neonatal onset was the major clinical and biochemical syndrome. In this series we reviewed the liver histology of 10 such patients who died in the first weeks of life (from 3 days to 6 mo). In six cases the diagnosis was confirmed by study of the mitochondrial respiratory chain in the muscle, liver or both; in the other four, appropriate tests were not available for diagnosis but symptoms were identical and all other diagnoses were ruled out. In all 10 cases we noted significant steatosis, mostly microvesicular; widespread hepatocytic, canalicular and bile duct cholestasis with bile thrombi and cholangiolar proliferation; and different degrees of hepatosiderosis and glycogen depletion. Fibrosis took varying forms: perisinusoidal, periportal with the formation of septa, even precirrhosis. In the two cases of infants who died, one at 5 and one 6 mo, micronodular cirrhosis was also present. Mitochondria, either densely or loosely packed, were abnormal-pleiomorphic with few or no cristae and a granular fluffy matrix. Dense, large granules were seen in two cases. The association of neonatal liver failure and hyperlactacidemia should lead to immediate examination of the respiratory chain. The expression of this mitochondrial cytopathy can be lethal, associated with severe liver damage due to the deficiency in oxidative phosphorylation.     

Acute hormone responses to heavy resistance lower and upper extremity exercise in young versus old men

In the final stage of amyotrophic lateral sclerosis (ALS) the majority of patients develop chronic respiratory failure due to respiratory muscle weakness. The interaction between the patient with ALS and the physician should be characterized by continuous communication, especially with respect to the prospect of ventilatory failure and for support. The patient and his family must be informed thoroughly about the natural history and the prognosis of ALS, depending on the individual disease process. Already in the early stage of the disease coping strategies should be discussed so that imminent respiratory emergencies can be handled. If ALS patients are not informed about the acute respiratory insufficiency they run the risk of having to be intubated and mechanically ventilated over a long term. If dyspnea and hypersecretion dominate the final stage of ALS, the therapeutic strategy consists of the administration of morphine, insufflation of oxygen and bronchoscopic suction. Mechanical ventilation should only be initiated in the exceptional case. However, if dyspnea occurs in the early stage of the disease, when there is no bulbar paralysis and peripheral muscle function is intact, then noninvasive mechanical ventilation via mask may improve the quality of life substantially. Nevertheless, invasive mechanical ventilation via a tracheostomy should be avoided.     

Structure of Sesbania mosaic virus at 4.7 A resolution and partial sequence of the coat protein

Serum IgG subclasses and Serum IgA were studied in 43 infants with acute bronchiolitis and 20 healthy infants. IgG subclasses were determined by a capture ELISA and IgA was quantified by turbidimetry. IgG1 concentrations were significantly lower in infants with bronchiolitis than in normal infants. The other IgG subclasses and IgA did not differ between the groups. The subgroups of infants with bronchiolitis who had previously suffered from otitis media or bronchitis, had significantly lower IgG2 than the other infants with bronchiolitis. The same was found for infants with bronchiolitis who had suffered from three or more lower respiratory tract infections. In infants who had suffered from upper or lower respiratory infections before the acute bronchiolitis, IgA was significantly higher than in infants without previous respiratory infections. Ten infants with bronchiolitis (23%) had IgG1 deficiency, that is values below the lower reference limit calculated in a population of healthy Norwegian infants. No healthy infants had any IgG1 deficiency. No infant with bronchiolitis had IgG2 or IgG3 deficiency. The low IgG1 values found in infants with acute bronchiolitis, may be one cause for infants to be more susceptible to RS virus infections.     

A case of Satoyoshi syndrome with symptoms resembling neuroleptic malignant syndrome]

Satoyoshi syndrome is a rare neurological disorder of unknown etiology characterized by progressive muscle spasms, alopecia, diarrhea and skeletal abnormalities. We here describe a 25-year-old man who developed symptoms similar to neuroleptic malignant syndrome (NMS). He began to have the clinical characteristics of Satoyoshi syndrome at the age of 12 years. He was admitted to hospitals many times with painful muscle spasms and pyrexia in the early stage of the disease. He received steroid pulse therapy and oral prednisone at the age of 19, the extent and frequency of the spells being reduced thereafter. He was admitted to our hospital due to recurrence of his usual muscle spasms. He was treated with midazolam intravenously to relieve severe muscle ache, pain in the left shoulder, and insomnia. About 90 minutes later, he became comatose, with the following manifestations: hyperthermia, low blood pressure, tachycardia, profuse perspiration, acute respiratory failure, and ensuing cardiac arrest. He developed rhabdomyolysis, acute renal failure, hepatic damage, and diffuse intravascular coagulation. Serum creatine kinase level was elevated to 306,910 IU. He died of multiple organ failure 13 days after admission. His symptoms resembled NMS and malignant hyperthermia (MH). None of patients with Satoyoshi syndrome accompanied by NMS or MH have been reported. It remains to be clarified whether midazolam administration induces NMS in Satoyoshi syndrome. Nevertheless, careful attention should be paid when one administers midazolam to patients with this syndrome.     

Long-term persistence of hemopoietic chimerism following sex-mismatched bone marrow transplantation

Wegener's granulomatosis is a distinct clinicopathologic entity characterized by granulomatous vasculitis of the upper and lower respiratory tract and glomerulonephritis. This disease can present as a clinical picture which resembles sepsis and adult respiratory distress syndrome (ARDS). Wegener's disease requires immunosuppression which can have detrimental consequences when used in sepsis. The following case report illustrates the diagnostic difficulties encountered by intensive care physicians treating severe pulmonary failure and multiple organ dysfunction in Wegener's granulomatosis appearing as ARDS with sepsis. CASE REPORT: A 19-year-old female patient had developed acute respiratory and renal failure after a prolonged period (many months) of antibiotic resistant otitis, sinusitis and mastoiditis. The patient had required intubation at another hospital and there was a history of tension pneumothorax and cardiopulmonary resuscitation during mechanical ventilation. Emergency extracorporeal membrane oxygenation (ECMO) for acute hypercapnic and hypoxic respiratory failure was instituted and the patient was transported to our institution while on ECMO. The patient was treated empirically for suspected pulmonary and systemic infection and received hydrocortisone (0.18 mg/kg/h) as part of a protocol-driven treatment of septic shock in addition to antibiotic and antimycotic regime. The use of ECMO was required for 10 and mechanical ventilation for another 50 days after admission. After successful extubation, central nervous system dysfunction became evident with a somnolent and generally unresponsive patient. When the hydrocortisone dose was gradually tapered, the clinical status of the patient further deteriorated, pulmonary gas exchange worsened and she developed renal failure with proteinura and hematuria. A renal biopsy was performed demonstrating vasculitis and focal segmental glomerulonephritis, a systemic granulomatous vasculitis was suspected; the serum was tested for anti-proteinase 3 antibodies (PR3-ANCA) and turned out to be positive (17.5 U/ml; normal range < 7 U/ml). The morphologic findings from renal biopsy, the positive test for antiproteinase 3 antibodies and the pulmonary-renal involvement with evidence of multisystem disease established the diagnosis of Wegener's granulomatosis. Immunosuppressive therapy with cyclophosphamide and prednisolone was instituted resulting in rapid improvement with recovery of pulmonary, renal and central nervous system function within two weeks. The use of ECMO in this patient served as a life-saving immediate measure usefull to "buy time" until a definite diagnosis could be established. ARDS represents an uniform pulmonary reaction to a large number of different noxious stimuli and disease entities. This case demonstrates that intensive care physicians caring for critically ill patients with ARDS should include even rare causes of pulmonary injury into their differential diagnosis.