Search

The post-vaccination antibody response in patients with immune-mediated neuromuscular diseases under immuno-suppressive therapy has not been sufficiently verified. The Japanese Society of Neurology has stated that coronavirus disease 2019 (COVID-19) vaccination should be given priority in patients with immunotherapy-associated neuromuscular diseases; however, data on antibody production to a novel mRNA vaccine are scarce in these patients. In this study, we aimed to measure residual antibody titers after the second dose and produced antibodies after the third dose of SARS-CoV-2 mRNA vaccine in 25 patients with neuromuscular diseases under immuno-suppressive therapy (disease group). We compared the disease group antibody titers with those of 829 healthy employees in our hospital (control group). The disease group included 17 patients with myasthenia gravis, 4 with multiple sclerosis, 3 with inflammatory muscle disease, and 1 with chronic inflammatory demyelinating polyneuropathies. Seven cases of the disease group showed negative antibody levels (<15.0 s/co) before the third vaccination, and antibody titers in the positive cases ranged from 16.9 to 4,589.0 s/co. Three of the seven antibody-negative cases turned positive after the third vaccination, and all but one of the antibody-positive cases showed a booster effect, with antibody titers after the third dose ranging from 245.1 to 85,374.0 s/co (1.0 to 885.0 times higher than those before vaccination). Although the immune response in the disease group was modest compared to the control group, in which antibody titers after the third vaccination ranged from 67.8 to 150,000 s/co (0.9 to 5,402.1 times higher than those before vaccination), the result indicated that a constant immune response was achieved under immuno-suppressive therapy. Even in the control group, three participants tested negative for residual antibody before the third inoculation, and four of the antibody-positive participants (27.7-24,054.0 s/co) lacked a booster effect after the third vaccination.

An 89-year-old man was admitted because of persistent fever and impaired consciousness. On admission, his consciousness level was E3V3M4 according to the Glasgow Coma Scale. MRI of the brain showed high intensity lesions in the bilateral cingulate gyri. In the cerebrospinal fluid, both cell counts and glucose level were in the normal ranges. He had received antibiotics and intravenous isotonic saline. On the fifth day of hospitalization, blood examination revealed elevation of anti-herpes simplex virus (HSV) immunoglobulin M antibody, and herpes simplex encephalitis (HSE) was diagnosed. Despite treatment with acyclovir, his respiratory function and consciousness level deteriorated rapidly. On the eighth day, he died of respiratory failure. At autopsy, the brain showed multiple softenings of the gray and white matter in the hippocampus, amygdala, and temporal, insular, and cingulate cortices. Some of these lesions were hemorrhagic. Microscopic examination revealed that the lesions were necrotic and associated with perivascular inflammatory cell infiltration in the limbic system, hypothalamus, brainstem tegmentum area, and medulla. Eosinophilic intranuclear inclusions were rarely found in the astrocytes in the medulla. Immunohistochemistry revealed anti-HSV-1 antibody positive neurons in the brainstem tegmentum including reticular formation and the raphe nuclei. HSV-DNA was also detected in the postmortem cerebrospinal fluid. This was a rare case of HSE in which inflammation in the brainstem proved to be the cause of lethal respiratory failure.

A 61-year-old man with squamous cell lung cancer was admitted to our hospital because of consciousness disturbance after treated with pembrolizumab. Cerebrospinal fluid examination revealed increased protein level (209.2 mg/dl) and lymphocytic pleocytosis(79/μl). He was diagnosed as a meningoencephalitis probably caused by an immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs), and was successfully treated with 1,000 mg methylprednisolone intravenously for 3 days twice and the consequent oral 1 mg/kg prednisolone. As ICIs, which activate the immune systems, are becoming important choices of the treatments against malignancies, we should keep the possibility of irAE in mind and, when needed, start the treatment as soon as possible.

We report cerebral embolism in 2 patients with Duchenne muscular dystrophy (DMD) after respiratory tract infection. A 31-year-old man (Case 1) was admitted to the hospital because of an upper respiratory tract infection, then suddenly developed left-sided hemiparesis. Transthoracic echocardiography revealed an intracardiac thrombus in the left ventricle, and, under assumption of cardioembolic stroke, oral anticoagulation was initiated. Case 2 was a 36-year-old man who developed dysphasia after increasing sputum. Based on brain CT scan findings, we confirmed a diagnosis of cerebral infarction. There was no recurrence in either case. Both cases developed cerebral infarction due to embolism after mild upper respiratory tract infections. DMD patients have various risk factors for thrombus and embolus, while physicians should also be aware of possible cerebral infarction and other coagulation disorders irrespective of respiratory and cardiac therapy.

A 35-year-old man showed a convulsive attack with consciousness loss and was suspected of having Brugada syndrome 6 months prior to admission to our hospital. At the initial examination, the patient showed conjugate deviation, followed by left limb convulsions and consciousness loss. He regained consciousness after 1 minute, though cardiac arrest from ventricular fibrillation was noted during an electroencephalography (EEG) examination. Sinus rhythm recovered with defibrillation, though the convulsions persisted and a Status Epilepticus developed. The patient was diagnosed with Brugada syndrome and received implantable cardioverter defibrillator (ICD). After ICD, he has suffered no further convulsive attacks. Brugada syndrome is an inheritable cardiac disease causing sudden death by ventricular fibrillation. It is important to consider both epilepsy and arrhythmia in diagnosis of the seizures.

A 64-year-old man presented with acute onset of generalized seizure and encephalopathy. FLAIR images of brain MRI showed multifocal high-intensity lesions of the white matter. Within few days after the treatment with intravenous methylprednisolone (1,000 mg/day for 3 days), amelioration of clinical symptoms and recovery of MRI findings were observed. Six months after the withdrawal of oral steroid therapy, recurrent lesions were observed at the same locations as initially revealed on admission. Due to the concomitant development of peripheral lymphocytosis, a brain biopsy was performed from a right frontal lesion. Histological findings suggested extensive demyelination accompanied by infiltration of inflammatory lymphocytes and macrophages. In spite of the temporary remission after re-initiation of oral steroid therapy, reduction of oral steroid dosage resulted in new lesion formation apart from the initial locations. Based upon clinical features, MRI findings and histological examination, he was diagnosed with multiphasic disseminated encephalomyelitis (MDEM). Acute disseminated encephalomyelitis (ADEM) is one of common causes of demyelinating disease among children. However, multiphasic form of ADEM is particularly rare in adult patients. Here we reported a rare case of adult-onset MDEM, in which clinical, radiological and histological features were described, and efficacy of steroid therapy was highlighted.

A seventy-year-old man developed color change in his left toes and was treated for frostbite. Eight months later, he developed cognitive impairment and was admitted to our hospital. A remarkable increase of eosinophils was observed in peripheral blood. Brain MRI revealed abnormal lesions in the fornix, corpus callosum, basal ganglia and frontal lobe. Steroid therapy ameliorated his symptom temporarily, but he suddenly developed cardiopulmonary arrest. His autopsy revealed severe pulmonary hemorrhage with alveolar vasculitis and cholesterol crystals in the brain, kidneys, liver, and the other organs. It was possible that cholesterol embolization to multiple organs including the brain induced systemic vasculitis that caused pulmonary hemorrhage and his critical prognosis. Cholesterol embolization should be considered when we see a patient with brain lesions accompanied with eosinophilia.

We report a 24-year-old Japanese man initially suspected to have Becker's muscular dystrophy at the age of 6 years, because of a high level of creatine kinase in serum, though he discontinued visiting the hospital. At the age of 23, he was admitted to the hospital for severe dilated cardiomyopathy, and subsequently diagnosed with limb-girdle muscular dystrophy2M (LGMD2M) based on muscle biopsy and gene analysis. It was recently reported that some patients with fukutinopathy develop LGMD. Most of the cases reported in Japan showed mild skeletal muscle involvement despite serious cardiomyopathy, which may sometimes the initial symptom of the disease. Since muscular dystrophy patients can develop severe cardiac failure, irrespective of the severity of skeletal muscle involvement, regular examinations of cardiopulmonary function are necessary.

We, herein, report two independent cases with hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) inherited in an autosomal dominant fashion. Their common clinical features are slowly progressive proximal dominant muscular atrophy, fasciculations and mild to moderate distal sensory disturbance with areflexia. Nerve conduction study revealed an absence of sensory nerve action potentials, in contrast to almost normal compound muscle action potentials. Gene analysis in both patients elucidated heterozygous mutation (c.854C>T, p.Pro285Leu) in the TFG, which is an identical mutation, already described by Ishiura et al. Okinawa and Shiga are two foci of HMSN-P in Japan. Eventually, one patient is from Okinawa and the other is from a mountain village in Shiga prefecture. When we see a patient who has symptoms suggestive of motor neuron disease with sensory neuropathy, HMSN-P should be considered as a differential diagnosis despite the patient's actual resident place.

We report a 28-year-old male with dysferlinopathy, who has remained asymptomatic for 10 years from a rhabdomyolysis-like episode. He had been in good health since birth, but felt difficulty in walking after a month and a half of manual labor at 18 years old (at the year 2000). Rhabdomyolysis was suspected because of muscle weakness and elevated serum CK of 28,094U/L. He was hospitalized and his muscle weakness improved. He was referred to us, because his serum CK remained around 2,000U/L. Histological analysis of muscle, when anti-dysferlin antibody was unavailable, was not informative but later analysis at the age of 23 using preserved specimen showed loss of dysferlin immunoreactivity. Subsequently, a missense mutation (c.2997G>T) and a deletion (c.3373delG) of the dysferlin gene, both of which are common in Miyoshi myopathy in Japanese, were identified. He continuously showed hyper-CKemia, but no apparent muscle weakness emerged for more than ten years. Reports on asymptomatic dysferlinopathy over such a long duration are rare. This case may suggest that genetic factors, environmental factors such as intensity of work-load, or both, might affect the clinical course of dysferlinopathy. Further follow-up is necessary.

Mechanical ventilation and cardioprotective therapy have significantly improved the prognosis and quality of life of patients with Duchenne muscular dystrophy (DMD). The incidence of congestive heart failure is on declining trend by meticulous care. Meanwhile, elongation of decreased cardiac function can provoke instability in circulation. Recently, we experienced six DMD patients who died from acute renal failure with preserved cardiac function (brain natriuretic peptide: BNP <100 pg/ml, fractional shortening: FS >15% and left ventricular diameter: LVD <50mm). In some patients, hypovolemia induced by low water intake, diarrhea or dose-up of diuretics was thought to be a trigger of renal failure. Since the value of creatinine (Crnn) decreased in amyotrophic patients, we evaluated renal function in 103 patients with DMD using cystatin C (CysC), which is a sensitive renal marker and unaffected by muscle volume. In addition, we assessed β2-microglobulin (b2MG) in 24 patients, because it is also unaffected by muscle volume. The correlation between logarithm of CysC (LogCysC) and logarithm of b2MG was quite high (r=0.954), though that between LogCysC and logarithm of Crnn was not adequate (r=0.623). The average of CysC increased along with age, and more than 30% of patients over 30 years old showed abnormal values. Hemoglobin and logCysC was also negatively associated (r=-0.519), and patients with hemoglobin less than 10 g/dl showed elevated values of CysC. Cardiac indices such as FS (r=-0.250) and logarithm of BNP (r=0.319) showed weak correlations with logCysC, though significant correlation was not detected between LVD and LogCysC. Since renal dysfunction is a common complication in advanced stage of DMD patients, proper managements of water balance and anemia is important. In the medical managements for DMD, we should pay attention to cardiac-renal-anemia association.

Mechanical ventilation (MV) and cardiac protective therapy have improved the prognosis and quality of life of patients with Duchenne muscular dystrophy (DMD). To understand how these therapies have changed prognosis, we performed a cause-of-death analysis in DMD patients. Mean age at death before initiation of MV (January 1977-July 1984) was 18.9±4.1 years. After the introduction of MV, from August 1984 to December 1993 (1(st) term), it was 20.0±4.5 years, from January 1994 to December 2003 (2(nd) term), it was 25.2±4.6 years, and from January 2004 to December 2010 (3(rd) term), it was 31.1±5.4 years. Almost half of all deaths before MV were due to respiratory failure (RF). Because MV was performed by a tracheostomy in the initial stage, some patients were reluctant to use it, and as a result, RF accounted for 43% of deaths in the 1(st) term. Over time, patients started to accept non-invasive ventilation and home mechanical ventilation, which became available in the 1990s. Consequently, no DMD patients have died from RF since 2000. Respiratory physiotherapy and risk management became important tools, because many patients undergo decades of respiratory managements at home. Cardiac treatments for patients with DMD consisted mainly of diuretics and digitalis in the 1(st) term, angiotensin-converting enzyme inhibitors (ACEI) in the 2(nd) term, and a combination of ACEIs and beta blockers in the 3(rd) term. Compared to the 2(nd) term, the ratios of severe cardiac dysfunction (fractional shortening <10%, left ventricle diastolic dimension >75mm, plasma brain natriuretic peptide >1,000pg/ml) were reduced in the 3(rd) term. In the 3(rd) term, 14% of patients died from renal failure nevertheless their cardiac indices remained mildly abnormal or normal. We should pay enough attention for cardio-renal association.

We treated a 25-year-old woman with encephalitis. Following delivery, the patient developed fever, consciousness disturbance, cognitive dysfunction, and progressive motor dysfunction. In addition, mycobacterium tuberculosis was found in the lung, though there was no evidence of such infection in the central nervous system. Cerebrospinal fluid analysis revealed a slight elevation of mononuclear cells with a normal protein level indicating a possible viral infection. We could not find the origin of the infection, though the serum anti-glutamate epsilon2 receptor antibody was positive. Intravenous administration of methylprednisolone (1000 mg/day for 3 days) was temporarily effective for improvement of the clinical signs and symptoms. However, she finally demonstrated rapid deterioration resulting in death. Diffusion-weighted brain magnetic resonance imaging demonstrated abnormal high intensity lesions in the bilateral pulvinar and gray matter, with an abnormal appearance mimicking pulvinar sign.

A 65-year-old woman showed progressive asymmetric sensory ataxic neuropathy (SAN) in upper limbs over 12 years, beginning with the onset of primary biliary cirrhosis (PBC). Nerve conduction study showed that sensory action potential was not evoked in upper limbs. Right superficial radial nerve biopsy showed the density of myelinated fibers was severely decreased with large-fiber predominance. Since Sjögren's syndrome (SjS) and paraneoplastic syndrome were denied, this type of neuropathy seems accompanied with asymptomatic PBC. Corticosteroid administration and intravenous immunoglobulin therapy failed to obtain any beneficial effect. The pathological mechanism is considered ganglionitis, which resembles that found in association with SjS. We should also consider PBC as the cause of SAN.

A 78-year-old man had undergone transurethral resection of bladder tumor (TUR-Bt) 6 times since he was diagnosed as having bladder cancer. Past histology was urothelial carcinoma, pTa, G1-G2. During the follow-up, recurrent bladder cancer was found. Enhanced computed tomography and drip infusion pyelography revealed pelvic cancer with tumor embolus in the inferior vena cava. Therefore, TUR-Bt and total ureteronephrectomy with removal of the thrombus from the vena cava was performed. The histopathological diagnosis was urothelial carcinoma of the bladder and Bellini duct carcinoma of the kidney, but in immunohistostaining surgical specimen of both bladder and kidney showed some similarities. This disease is rare. Several reports indicate an association between Bellini and urothelial carcinoma. We describe the case of the Bellini duct carcinoma of the kidney during the follow-up for bladder cancer with possibility of the association between Bellini and urothelial carcinoma.

Various autoantibodies had been detected in patients with dilated cardiomyopathy (DCM). Among them, anti-beta 1 adrenoreceptor antibody (ARAb) had been proven to act as agonist on beta 1 adrenoreceptor and cause DCM. Cardiomyopathy is also serious problem in progressive muscular dystrophy (PMD). Because cardiac dysfunction is quite variable even in siblings sharing identical mutations, it is highly possible that there are some modifier factors. Thus, we measured ARAb in 93 patients with PMD and 11 patients with DCM to clarify immune function for cardiac impairment of PMD. The titer was abnormally elevated in 30.1% of PMD, 72.7% of DCM and 75.0% (9/12) of PMD patients with symptomatic cardiac failure. ARAb was weakly correlated to fractional shortening, brain natriuretic peptide, noradrenalin and severity of premature ventricular contractions (Lown grade). During the study period, four patients developed cardiac failure and ARAb was increased in all these patients. In DMD, although the patients receiving both beta blocker and angiotensin converting enzyme inhibitor showed worst cardiac function, the titers were rather low compared to patients with angiotensin converting enzyme inhibitor alone. Four of five patients initiating beta blocker showed decrease of ARAb. Autoantibodies for myocardium actually exist in PMD in certain ratio as is the case with DCM. It is highly possible that immune system plays some role in cardiac impairment even in PMD. We should pay enough attention to immune system to elucidate the mechanism of cardiac dysfunction and refine strategy of cardiac treatments.

Intermittent indirect hyperbilirubinemia was occasionally observed in Duchenne muscular dystrophy (DMD) patients. We suspected that hyperbilirubinemia might be caused by hemolysis of fragile erythrocytes due to damaged endothelium, which was reported in DMD. To examine the fragility of erythrocytes, we performed osmotic resistance test in 25 DMD, 12 myotonic dystrophy (DM), 12 amyotrophic lateral sclerosis (ALS) and 24 healthy volunteers (male 15, female 9). Minimum resistance (beginning point of hemolysis) of DMD (0.447 +/- 0.016%) was higher than that of age matched male controls (0.425 +/- 0.018%: p = 0.0008) and that of DM (0.440 +/- 0.015%) was also higher than that of total controls (0.423 +/- 0.016%, p = 0.0077). The number of poikilocytes was increased in DMD (35.45 +/- 41.17 per a high magnitude field), however no obvious correlation was detected between the ratio of poikilocytes and resistances. Total bilirubin showed correlation (p = 0.029) to minimum resistance. These findings suggested that erythrocyte membrane is fragile in DMD. Involvement of endothelial damage could not be proven, because all investigated patients showed normal tissue plasminogen activator inhibitor-1. Although the mechanism of fragile erythrocytes in DMD is still unknown, we should pay attention to interpret bilirubin in DMD, because hemolysis due to erythrocyte fragility may influence the value.

To investigate the effects of creatine monohydrate on muscle performance and cognitive functions in muscular dystrophy patients, we made an open trial. Twenty-nine individuals, including 14 myotonic dystrophy (DM), seven facioscapurohumeral muscular dystrophy (FSHD), two limb-girdle muscular dystrophy and six healthy volunteers, were enrolled in this study and 27 participants completed it. All participants took creatine 20g/day for an initial week and 5g/day for successive eight weeks. Somatotonic measurements, global subjective assessment, muscle performance, cardiopulmonary function, cognitive function, laboratory studies and magnetic resonance spectroscopy (MRS) were evaluated at both pre and post examination. Subjective improvements were reported from twelve individuals. Contrary adverse effects were also complained from ten individuals, although all these problems were not serious. Quantitative muscle power was slightly but significantly increased in the patients and the number of the patients who failed to complete cycle ergometer test was decreased. Phosphocreatine concentrations of left calf muscle were not different between pre and post trial examination. No obvious changes were detected in cardiopulmonary assessment, cognitive function and laboratory date. Creatine has certain expectance for muscular dystrophy patients in motor performance. The effect may be achieved not only by increase of energy buffer, because clinical improvements were observed in our study nevertheless no increase was detected in phosphocreatine concentration. The usage of creatine should be managed under medical monitoring since ideal protocol has not yet been established and adverse effects can not be ignored.

We report a 64-year-old Japanese woman with recurrent ischemic strokes and progressive dementia without any cardiovascular risk factors. Her first stroke was at 45 years old, and she has a family history of ischemic strokes compatible with an autosomal dominant trait. Marked leukoaraiosis and multiple lacunar infarcts were shown on brain MR images, and no atherosclerotic changes were observed in her extra- and intra-cranial arteries by cervical arterial echography and intracranial MR angiography. Excluded other inherited or metabolic diseases causing leukodystrophy by examination of her blood samples, her disease was diagnosed as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and lekoencephalopathy). We demonstrated granular osmiophilic materials (GOM) on the wall of small arteries from a biopsied peripheral nerve tissue specimen and detected a mutation Arg169Cys of Notch 3 gene. Many CADASIL patients have been reported and over 28 kinds of mutations of the Notch 3 were identified in western countries, while few CADASIL patients have been reported in Japanese people. Among them, eleven CADASIL families have been reported and only five mutations (Arg133Cys, Cys174Phe, Arg213Lys, Arg90Cys and Arg141Cys) have been determined so far. The mutation of Notch 3 in our patient was determined as Arg169Cys, and this is the first report on a Japanese patient with CADASIL due to this mutation.

A 73-year-old woman developed myasthenia gravis (MG) with thymoma. She had a very high level of serum antibodies against interferon-alfa (IFN-alpha). We observed the changes to her clinical symptoms and titer of the antibody during therapeutic course. Although she underwent thymectomy, intravenous methylprednisolone therapy, and oral tacrolimus administration, MG symptoms of the patient were not significantly improved and the antibody titer remained at a high level. IFN-alpha is a potent immunomodulating cytokine that regulates MHC class II expression on antigen presenting cells and activities of NK cells, B cells, and helper/suppressor T cells. This case suggests that IFN-alpha related immunological perturbation participates in the pathogenesis of thymoma-associated myasthenia gravis.

We report a facioscapulohumeral muscular dystrophy (FSHD) pedigree having double short (25 kb and 33 kb) BlnI resistant (4 q-like) fragments. Two of three male siblings developed shoulder-girdle weakness and minimum facial involvement from their adolescence. Although the rest (third) brother had non-progressive hemi-palsy in face and upper-extremity and strabismus caused by birth trauma, he had no clinical symptoms of FSHD. Mother presented mild shoulder weakness after cholecystectomy at the age of 50 years, but with no facial involvement and normal serum creatine kinase (CK) level (45 IU/L). On the contrary, father had high CK level (450 IU/L) despite no neurological abnormalities. After EcoRI/BlnI double digestion, two short fragments were detected in the two affected siblings. Then, all family members were examined to determine pathognomonic fragment. Consequently, mother (25 kb and 90 kb) and the third non-affected brother (25 kb and 51 kb) had two 4 q-like fragments, however, three 4 q-like fragments were detected in father (33 kb, 51 kb and 130 kb), proband (25 kb, 33 kb and 130 kb) and affected brother (25 kb, 33 kb and 51 kb). These findings revealed that the 4 q-like 33 kb fragment actually located on 10q26 through inter-chromosomal exchange. Thus the 25 kb fragment inherited from mother was determined as co-segregating with the disease. To ensure genetic diagnosis for FSHD, investigation of family members is surely required.

We report a 73-year-old woman with intravascular malignant lymphomatosis (IML) who showed generalized telangiectasia as well as various neurological symptoms. In July 1998, she developed fever, dizziness, and confusion followed by left hemiparesis, and was admitted to our hospital on August 11, 1998. Laboratory tests indicated a normochromic normocytic anemia, thrombocytopenia, elevated serum lactic dehydrogenase (LDH), C-reactive protein (CRP), and cerebrospinal fluid protein. Magnetic resonance imaging (MRI) of the brain revealed an infarct-like lesion in the left frontal lobe and multiple white matter lesions. After admission, her neurological status deteriorated and lapsed into coma and quadriplegia. At the end of September 1998, generalized telangiectasia appeared, and she was diagnosed as IML on skin biopsy. Although combination chemotherapy failed to improve her neurological symptoms, telangiectasia disappeared in a few days, and the infarct-like lesion on MRI decreased in size. Serum LDH, CRP, and thrombocyte counts were normalized. Autopsy findings revealed perivascular clustering of B cell type lymphoma cells in the left frontal lobe where abnormal signal intensity was found on MRI, as well as the spleen and the bone marrow. This case emphasizes the importance of early diagnosis and treatment in IML.

A 48-year-old man was admitted to our hospital due to multiple cranial neuropathy such as vertigo, hearing loss of the left ear, visual loss of the left eye, left ptosis and total ophthalmoplegia of the left eye. Brain MRI revealed no abnormalities. After 10 days, he suddenly showed hemophagocytic syndrome with high fever, liver dysfunction, jaundice and pancytopenia. In spite of the treatment, he died of multiple organ failure after 26 days. At autopsy, malignant lymphoma cells of T cell origin directly invaded into the liver, spleen, intraperitoneal lymph nodes and other organs. Reports that direct invasion of lymphoma cells could be detected at the cranial nerves in the cavernous sinus are very rare.

Degos' disease is a rare multisystem vasculopathy of unknown etiology. We report a 44-year-old man who presented himself with gait and sensory disturbances mainly due to thoracic transverse myelopathy four years after the appearance of many characteristic umbilicated papules over the trunk and extremities. He did not complain of abdominal pain or discomfort. Laboratory, electrophysiological and imaging studies did not show any characteristic change, except for the increase of protein contents and cell counts in the cerebrospinal fluid. We tried methylprednisolone pulse-dose therapy (1,000 mg/day x 3 days) five times, but this patient's neurological condition worsened stepwise after it, although the appearance of new skin lesion was suppressed. Intravenous infusion of ozagrel sodium and cyclophosphamide (1,000 mg/day) were also ineffective, and this patient died of respiratory failure after showing oculomotor paresis and comatose state. Necropsy revealed Degos' disease-specific vasculopathy in the central nervous system and the gastrointestinal tract, where occlusions of small-sized arteries and veins due to the intimal thickening were evident. The tissue necrosis was macroscopically remarkable in the brainstem and the thoracic spinal cord. The efficacy of steroid therapy for this disease should be investigated more carefully.

The effect of L-carnosine-zinc complex(Car-Zn) on ethanol absorption was investigated after oral administration(adm) to mice. One hour after oral adm of Car-Zn, and 14C-ethanol was given orally or intraperitoneally(i.p.). After passage of time, the blood was drawn from the tail vein, and 14C-radioactivities determined. The Car-Zn showed a dose-dependent inhibition of the appearance of 14C-radioactivities in blood following oral 14C-ethanol loading, while Zn acetate did not induce any alteration as compared with control. Car-Zn pretreatment did not induce any change in the blood 14C-radioactivity when ethanol was given i.p. The 14C-radioactivity and zinc in gastrointestinal tract after oral adm of Car-Zn and 14C-ethanol showed significantly higher levels than those of control for 7 hr. Distribution of 14C-radioactivities in other organs of Car-Zn treated mice were lower than those of control 3 hr after adm, while it was similar or higher than those of control 7 hr after adm. The excretions of 14C-radioactivity through expiration in Car-Zn group was a lower than that of control. Also, the urinary and fecal excretions of 14C-radioactivity were low values at 5.0% and 0.5% of the administered dose 72 hr after adm, respectively. Also, the 14C-radioactivities remaining in the organs did not detect or were very low values. In vitro study, Car-Zn stimulated the metabolism of ethanol to acetaldehyde and acetic acid in 9,000 g supernatant of small intestine. The major route of excretions of 14C-radioactivity may be excreted into the expired air. The results suggest that Car-Zn shows a long-term adhesive and permeable action on gastrointestinal tract in the mouse; as a result, this may inhibited ethanol absorption.

Successful transfer of multiple sclerosis (MS) into severe combined immunodeficient (SCID) mice by intracisternal injection of cerebrospinal fluid (CSF) cells from six of 15 patients at exacerbation has been reported. The relative expression of mRNA for cytokines in demyelinated lesions from SCID-hu-MS by a semiquantitative reverse transcriptase-polymerase chain reaction analysis revealed marked increase in expression of mRNAs for TNF-alpha and IL-6. This result raised the possibility that these cytokines played an important role in the demyelinating process in SCID-hu-MS. To test whether or not an antibody (Ab) to murine TNF-alpha has a preventive effect on transfer of MS into SCID mice, intracisternal injection of CSF cells from two patients at exacerbation together with anti-murine TNF-alpha Ab was performed, and we observed effective prevention of transfer. In addition, we also found an Ab to human CD3 (OKT3) to have a preventive effect. The former result suggests that control of TNF-alpha may be effective in treatment of MS and the latter suggests that MS is a T cell-mediated disease.

Continuous hyperthermic peritoneal perfusion (CHPP) with cisplatin (CDDP) was performed for a 65-year-old female with malignant peritoneal mesothelioma. Ascites disappeared after CHPP, and she has survived 3 years and 3 months after the diagnosis. CHPP might be a useful therapy for malignant peritoneal mesothelioma.

We reported the anesthetic management of a 1-day-old female neonate (2,110 gm) with esophageal atresia combined with double tracheoesophageal fistulae, which is classified as Gross type D. Though Gross type C was suspected preoperatively, the proximal fistula was found coincidentally during the preparation of the upper pouch. Because, for one thing, the origin of the proximal fistula was close to the end of the upper pouch (1cm), and for another, the distance between the both fistulae was short (1cm). As for the proximal fistula, it was 2 mm in diameter, and it was easily sealed with the side of the endotracheal tube. No other respiratory managements were needed except frequent suctionings of copious intratracheal secretions. On the other hand, the distal fistula, 10 mm in diameter, caused hypercapnea due to hypoventilation before gastrostomy. It was so big that it is easily intubated. This type of tracheoesophageal fistula is extraordinarily rare and its proximal fistula is difficult to find before, during, and even after operation. The missing of the proximal fistula often provokes severe respiratory infections and furthermore, sepsis postoperatively. It is concluded that in all the cases of tracheoesophageal fistula, the existence of the proximal fistula should be considered without fail and managed accordingly. To diagnose correctly, the use of preoperative bronchofiberscopy is also recommended.

The purpose of the present report is to reveal the relation between hemodynamic changes and serum catecholamine concentrations during operation of 23 neuroblastoma patients. The patients were aged from 6 months to 7 years (mean 1.2 year), and 20 patients (86%) were under 1 year of age. All the patients were in early stage of tumor development because they were diagnosed as neuroblastoma mainly by mass screening test for VMA and HVA in urine utilizing HPLC. This urinary mass screening test for infants is performed routinely in Japan. Operative manipulation of tumor provoked the significant elevation of blood pressure, and the increasing tendency of heart rate and rectal temperature. The mean concentrations of three kinds of serum catecholamine, epinephrine, norepinephrine and dopamine, were all very high during manipulation of tumor. Especially, the norepinephrine concentration was 90.2 times higher than the preoperative value. The children who showed high blood pressure, over 70% of the control level, showed high urinary VMA and VMA/HVA ratio preoperatively and a high norepinephrine secretion during operation. We conclude that for the anesthetic management of neuroblastoma, it is necessary to control the elevation of blood pressure even in small children, especially in the patients who have showed high values of urinary VMA and VMA/HVA ratio preoperatively.

We reported here a 64-year-old man with a central apnea resulted from unilateral medullary infarction. He was admitted because of cerebellar ataxia, dysarthria and dysphasia of abrupt onset. After the injection of diazepam for alcohol forbidden syndrome, he induced complete apnea and required the endotracheal intubation. At the spontaneous respiration under room air, his arterial blood gas showed hypercapnea without hypoxemia, and he fell into severe hypoventilation when hypnotic drug was injected. Respisomnogram revealed the frequent presence of central apnea both while he was awake and asleep. MRI demonstrated an abnormal high intensity area on T2 weighted image at the right lateral medulla just below the ponto-medullary junction. At autopsy, areas of the infarction were limited within the right lateral medulla, including lateral portion of the medullary reticular formation, the ambigual nucleus, one part of the solitary nuclear complex, the inferior cerebellar peduncle and the spinal trigeminal nucleus. However, the dorsomotor nucleus of vagus was completely free from the infarct lesion. There was no other lesion within central nervous system. Such a distribution seemed the minimal extent of the lesion responsible for central, apnea compared to the previous reports. We suggest that central apnea occurs not infrequently in the cases of Wallenberg's syndrome.

We reported a 15-year-old male patient of subacute sclerosing panencephalitis (SSPE), progressed from stage I to stage IV. On his admission, his clinical state was stage I with disturbance of generalized attention, myoclonus of upper limbs and no focal cortical signs. After rapid progression to stage III in a month, his clinical state became fairly stable and gradually advanced to stage IV. We followed him with serial CT and MR images. On imagings we found initial lesion in left parietoocipital lobe and spread in right parietoocipital lobe, anterior lobe and then brain stem, showing low density on plain CT scans and high intensity of T2 weighed MR images. This initial lesion situated in watershed area was hardly distinguishable from watershed infarction. In addition, we found blood flow decrease in vertebral artery system with SPECT and Doppler flowmetry. These findings suggested vascular pathogenesis of SSPE. We showed the imaging processes of SSPE progression from formation of initial lesion to demyelination and gliosis of total brain.

A 59-year-old demented Japanese man who was proven to have high titer of serum alpha-fetoprotein (AFP) and carcino-embryonic antigen (CEA) was admitted to our hospital. Neurological examinations revealed moderate dementia with deterioration and loss of memory, and decreased deep tendon reflexes in all extremities. Sensory disturbances were not obvious. There were no significant changes in the usual laboratory findings including CSF, except for elevated serum AFP and CEA. Three months after admission, he died of gastric cancer and its metastases in liver and lymph nodes. Post-mortem examination in the central nervous system (CNS) revealed many senile plaques and neurofibrillary tangles throughout the cerebral cortex and hippocampus. There was marked loss of neurons in the hippocampus. All the neuropathological findings in the CNS were consistent with those in Alzheimer disease. In the peripheral nervous system, necrotizing arteritis was found throughout the length of sciatic nerve. Large myelinated fibers seemed to be preferentially degenerated with proximo-distal gradient. Teased fiber preparation revealed de/remyelination and axonal degeneration more frequently at the distal portion. Immunohistologically, the serum IgG of this patient specifically reacted to the endothelial cells of all vessels in control organs, which strongly suggested the autoimmune mechanism for the necrotizing arteritis in this patient. The pathogenetic role of this antibody for necrotizing arteritis, found selectively in the peripheral nervous system, still remained unclear. However, paraneoplastic neuropathy due to necrotizing arteritis is a distinct entity in addition to common form of paraneoplastic subacute sensory neuropathy.

The serum albumin-interaction of suprofen (SPF), a novel anti-inflammatory drug, was compared with those of indomethacin (IM) and ketoprofen (KTP). The binding constants of these drugs were determined with difference absorption spectra based on the binding to bovine serum albumin (BSA). The constants for SPF and IM were nearly equal, and the value for KTP was smaller than those of the other drugs. The magnitude of the inhibitory effect on heat denaturation of BSA reflected the difference in these binding constants. In the presence of these drugs, the tryptophan fluorescence in BSA was quenched (IM, SPF and KTP, in this order). The metachromagy based on the binding of an azodye, HABA, to BSA was potentiated by IM or SPF. Phenylbutazone suppressed the absorption of the metachromagy. SPF displaced only the binding of the fluorescent Site II probe, dansylproline, to human serum albumin (HSA), and both the bindings of dansylproline and dansylamide (Site I probe) to HSA were inhibited by KTP or IM. KTP released bilirubin from BSA and HSA, but SPF and IM did not show any effects on the bilirubin-serum albumin binding. These results all support that there is considerable interaction between SPF and serum albumin and that the mode of the interaction differs from those of KTP and phenylbutazone.

Since many opioid receptor preparations are heterogeneous systems containing multiple types of receptor, characterization of each type of the receptor is influenced by contamination with other types of receptor. Demonstrating kappa receptor proved more difficult owing to the ability of kappa ligands to interact with a number of receptor classes and to the lack of the homogeneous preparation. It has been reported that kappa ligands selectively bind to human placental membrane. To establish homogeneous kappa receptor preparation, the kappa binding to human placenta was characterized. The portion which was predominantly villus tissue was removed from freshly collected placenta, and the P3-membrane fraction was prepared. Kappa opioid agonist, such as 3H-Dynorphin A, 3H-ethylketocyclazocine and 3H-U-69593, bound to the human placental membrane fraction in a manner of single class of binding site (Bmax: approximately 40 fmol.mg-1 protein). In contrast, 3H-dihydromorphine, 3H-DAGO (mu agonist), 3H-DADLE (delta agonist) or 3H-SKF-10047 (sigma agonist) showed no binding activity. The specific binding of 3H-diprenorphine was displaced only by kappa-selective ligand (U-50488H, dynorphin, butorphanol). These results suggest that opioid binding in human placental membrane is specific for kappa opioid.

A study was attempted to establish a screening method for detecting cholelitholytic ingredients from a wide variety of natural substances. Although mice were selected as a suitable pathological model of cholelithiasis to detect a small amount of the ingredients, all the conventional lithogenic diets caused unfavorable influence on the animals. Therefore, as the first step we formulated a new lithogenic diet consisting of butter, cholesterol, cholic acid, etc, which was adequate for mice. Subsequently, the pathological characteristics and persistence of cholelithiasis were examined in the animals; the changes in bile compositions including free and conjugated bile acids, cholesterol and phospholipids were observed before and at the onset of cholelithiasis. Following confirmation of the stone formation, a normal diet was substituted for the lithogenic diet to likewise assess the bile compositions 4 and 6 weeks later. An increasing tendency for deoxycholic acid, disappearance of chenodeoxycholic acid and decrease in ursodeoxycholic acid were seen under the condition of cholelithiasis. In addition, the cholic acid-glycine conjugate which should not exist in the normal state and the increase in free and tauring-conjugated cholic acid were noticed. The biliary cholesterol level in treated mice increased to about 4 times higher than that in untreated mice, while the biliary phospholipids and total bile acids levels increased to only about 1.5 and about 2 times the control levels, respectively. The incidence of stone formation rose sharply at an experimental period between 2 and 3 weeks after starting the lithogenic diet. Gallstones die not disappear even at the 6th week after substituting a normal diet for the lithogenic one. However, the cholic acid-glycine conjugate disappeared, and deoxycholic acid as well as chenodeoxycholic acid and ursodeoxycholic acid tended to recover to the normal levels in the bile.

The anti-allergic effect of Mequitazine (LM-209) which was found to have an anti-histaminic activity was investigated in guinea-pigs. The inhibitory activities of LM-209 on the Schultz-Dale reaction and ileum contraction by some mediators released from the sensitized guinea-pig lung were the same as those of clemastine fumarate (CL) but with 5 times the potency. LM-209 and CL, but these activities were less potent than in the case of disodium cromoglycate. The various anaphylactic reactions mediated by IgG in guinea-pigs were inhibited by LM-209, CL and chlorpheniramine maleate (CPM). The homologous PCA mediated IgE in rats was also inhibited by LM-209, CL and CPM, but the duration of the action with LM-209 was markedly longer. In experimentally-induced asthma, the decrease of respiratory rate and volume was significantly inhibited by LM-209, but was not affected by CL. Thus, LM-209 seems to inhibit the allergic reaction mainly by an antagonistic action on allergic mediators.

PZ-177 was found to have potent analgesic, anti-inflammatory and mild central depressive actions. In the present work, the general pharmacological actions of PZ-177 were tested in order to investigate other significant actions and to determine the side effects. PZ-177 showed no significant pharmacological activities on the respiratory and cardiovascular system, on the renal function, on the autonomic nervous system, on the sugar level and coagulation in blood and on local irritation. Volume and acidity of gastric juice were decreased and turn over was not inhibited in the connective tissure. Thus PZ-177 was considered to have no ulcerogenic action on the gastric mucosa. The compound relaxed the tonus of isolated small intestine, tracheal muscles and uterus and stopped spontaneous movement. Moreover the contraction of those smooth muscles by such spasmogens as acetylcholine, histamine serotonin, BaCl2 and oxytocin was inhibited by PZ-177 and the activity was almost the same with each spasmogen. It was found therefore to have spasmolytic activity and no specific antagonistic action on the chemical mediators. PZ-177 showed also wear relaxant activity on the skeletal muscle. Those actions on the muscles may have a curative effect on inflammation in bronchotracheal and gastrointestinal tracts or on pain with contraction of skeletal muscle. From the above results, it may be considered that PZ-177 is a relatively safe and useful analgesic and anti-inflammatory compound.

It has been already reported that ketoprofen (KP) has a potent anti-inflammatory action comparable to indomethacin, but with oral administration, gastric mucous membrane disturbances occur. In the present work, we administered the Na salt of KP (KP-Na) subcutaneously and found that the anti-inflammatory action was more potent in subacute and chronic inflammations than in the acute one. As an acidic compound, KP-Na had a relatively potent analgesic-antipyretic action and a medical efficacy comparable to the usual non-steroidal anti-inflammatory drugs given orally. The efficacy in case of subcutaneous administration was 2 to 3 times stronger over both acute and chronic inflammations than in case of oral administration. On the other hand, the gastric mucous membrane disturbance was decreased to about 1/3 in case of subcutaneous administration, thus the gastric disturbance could be abated and the medical efficacy can be increased when KP-Na is given subcutaneously. As KP-Na was less irritative at the injection site, the compound could be used clinically for a subcutaneous administration.

Effects of tiemonium iodide (tiemonium, 20 micrograms/kg), mepenzolate bromide (mepenzolate, 20 micrograms/kg), butylscopolamine bromide (butylscopolamine, 50 micrograms/kg) and atropine sulfate (atropine, 10 micrograms/kg) on the colonic motility in dogs were evaluated using a balloon method. The frequency of the wave motion was analyzed by fast Fourier transform, and the power spectra were obtained. The value of the first term of the power spectrum is regarded as an indication of the colonic tonus. Inhibitory effects of tiemonium on both the normal proximal colonic motility and the accelerating motility induced by neostigmine metylsulfate (neostigmine, 50 micrograms/kg) were equal to those of butylscopolamine. In the case of distal colonic motility, tiemonium showed potent mepenzolate-like inhibition. When the drugs were injected into the veins after administration of PGF2 alpha (10 micrograms/kg), all of the drugs depressed the colonic constriction induced by PGF2 alpha. The colonic motility was not restored by the administration of tiemonium or mepenzolate before the injection of PGF2 alpha, but such an effect was not observed in the case of butylscopolamine and atropine. It is suggested that tiemonium shows an extensive inhibition on the colonic motility in the mode of mepenzolate-like action and by some additional mechanism.