Neuromyelitis optica preceded by hyperCKemia episode.

BACKGROUND: Neuromyelitis optica (NMO) is a disease of the CNS characterized by severe optic neuritis and longitudinally extended transverse myelitis. Recent studies suggest that anti-aquaporin-4 (AQP4) antibodies, NMO-specific biomarkers, are pathogenic and target AQP4-expressing astrocytes in NMO, although an additional event (T-cell response or infection) should occur for anti-AQP4 antibodies and complements to pass through the blood-brain barrier and cause the CNS lesions. AQP4 is the major water channel in the CNS, but it is also expressed in fast-twitch skeletal muscle fibers. However, muscle diseases have not been described in NMO. METHODS: We retrospectively examined the serologic database of 733 cases of NMO with anti-AQP4 antibody at the Department of Neurology, Tohoku University School of Medicine. The serum samples were sent to our laboratory for testing anti-AQP4 antibody from around the country during the period from 2006 to 2009. RESULTS: We found 3 anti-AQP4 antibody-positive female patients (7, 34, and 67 years old) with NMO who had episodes of prominent hyperCKemia (12,520, 19,415, and 59,660 IU/L) with general fatigue some weeks before the onset of optic neuritis. HyperCKemia was transient without any treatment in all patients, but recurred once in one of them. CONCLUSIONS: These cases suggest that hyperCKemia may be involved in the pathogenesis of neuromyelitis optica (NMO) in a fraction of patients. The causes of transient hyperCKemia are unknown. Further studies are needed to know the frequency of hyperCKemia in NMO and clarify its pathogenic role.

The expression of dystrophin and alpha1-syntrophin during skeletal muscle regeneration.

The expression of dystrophin and alpha1-syntrophin in rat tibialis anterior muscles were evaluated during a cycle of regeneration after myonecrosis induced by the injection of cardiotoxin. Immunohistochemical studies were performed in cryosections of muscles on days 1, 3, 5, 7, 10, 14, 21 and 28 after injection of cardiotoxin. Western blot analysis was also examined in muscle on days 1, 3, 5, 7, 10, 14, 21 and 28. In immunohistochemical studies, dystrophin was stained weakly at the sarcolemma of some regenerating muscle fibers on day 3, and by day 10 it was stained strongly on almost all regenerating muscle fibers. Alpha1-syntrophin was stained weakly at the sarcolemma of some regenerating fibers on day 5, and by day 14 it was detected on all regenerating muscle fibers. In Western blot analysis, dystrophin (DYS1) and alpha1-syntrophin (alpha1S) were completely absent on day 1. Re-expression of DYS1 and alpha1S was visible by day 5 and accelerated thereafter. The Western blots of DYS1 and alpha1S were densitometrically analyzed on each day. The protein levels on each day were converted to the percentage of the protein level on day 28, which was taken as 100%. From the sequential line based on these data, the following results were obtained on the chronological course of DYS1 and alpha1S. DYS1: 25% of the protein level on day 28 was reached by 3.5 days, 50% was reached by 5.3 days, and 90% was reached by 6.9 days. Alpha1S: 25% of the protein level on day 28 was reached by 4.6 days, 50% was reached by 6.0 days, and 90% was reached by 12.5 days. In this study, DYS1 regenerated earlier than alpha1S at the sarcolemma of regenerating muscle fibers.

Identification of the hexon region of an adenovirus involved in a new outbreak of keratoconjunctivitis.

We tested 15 adenovirus (Ad)-positive patients involved in a case of nosocomial spread of keratoconjunctivitis. A neutralization test, PCR-restriction fragment length polymorphism analysis, and sequencing of the hypervariable regions of the hexons were performed in order to identify the type of Ad involved. The serotype of the Ad was not identical to any published Ad sequence by either method.

alpha1-syntrophin gene disruption results in the absence of neuronal-type nitric-oxide synthase at the sarcolemma but does not induce muscle degeneration.

alpha1-Syntrophin is a member of the family of dystrophin-associated proteins and is strongly expressed in the sarcolemma and the neuromuscular junctions. All three syntrophin isoforms have a PDZ domain that appears to participate in protein-protein interactions at the plasma membrane. alpha1-Syntrophin has additionally been shown to associate with neuronal nitric-oxide synthase (nNOS) through PDZ domains in vitro. These observations suggest that alpha1-syntrophin may work as a modular adaptor protein that can link nNOS or other signaling enzyme to the sarcolemmal dystrophin complex. In the sarcolemma, nNOS regulates the homeostasis of reactive free radical species and may contribute to the oxidative damage to muscle protein in muscle disease such as Duchenne muscular dystrophy. In this study, we generated alpha1-syntrophin knock-out mice to clarify the interaction between alpha1-syntrophin and nNOS in the skeletal muscle. We observed that nNOS, normally expressed in the sarcolemma, was largely absent from the sarcolemma, but considerably remained in the cytosol of the knock-out mice. Even though the distribution of nNOS was altered, the knock-out mice displayed no gross histological changes in the skeletal muscle. We also discovered that muscle contractile properties have not been influenced in the knock-out mice.

Targeted disruption of exon 52 in the mouse dystrophin gene induced muscle degeneration similar to that observed in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a degenerative disorder of the skeletal muscle in human and is caused by mutations in the dystrophin gene. The mdx mouse is a spontaneous mutant and an animal model for DMD. It has a point mutation in exon 23 of the dystrophin gene that eliminates the expression of dystrophin. However, this mutation does not disrupt the expression of four other shorter isoforms that are also expressed from the dystrophin gene through differential promoter usage. We generated another mutant mouse by gene targeting. Exon 52 of the dystrophin gene was disrupted, because the deletion of this exon is known to result in the DMD phenotype in human. In this mouse (mdx52), Dp140 and Dp260, shorter dystrophin isoforms, were absent in addition to dystrophin. The skeletal muscles were hypertrophic and the histology exhibited variations in the fiber size with a necrotic and regenerating process. This mouse is thus considered to represent another model for DMD.

Dp260 disrupted mice revealed prolonged implicit time of the b-wave in ERG and loss of accumulation of beta-dystroglycan in the outer plexiform layer of the retina.

Dp260 is a C-terminal isoform of dystrophin and is expressed specifically in the retina. Abnormal electroretinograms (ERG) in some Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients are likely linked to a disruption of Dp260. To clarify the importance of Dp260 in the retina, we examined dystrophin exon 52 knock-out mice, whose expression of Dp260 is impaired. We also confirmed the localization of Dp260 in the outer plexiform layer (OPL) of the retina. Disruption of Dp260 causes a change in the localization of beta-dystroglycan, which is normally found in the OPL of the retina. This suggests a requirement for Dp260 for normal formation of the dystrophin-dystroglycan complex in the retina. Dp71, also expressed in the retina, was, however, not detected in the OPL. The difference in localization of Dp260 and Dp71 implies that the two isoforms have different functions. The dystrophin exon 52 knock-out mice had a prolonged implicit time of the b-wave in ERG, although no significant change was observed in amplitude. These ERG findings differed from those of DMD and BMD patients, especially with regard to amplitude of the b-wave, but make it clear that Dp260 is required for normal electrophysiology.

[A case of primary mucinous adenocarcinoma of jejunum].

A 73-year old woman consulted our hospital for consciousness disorder and was hospitalized under a diagnosis of cerebral infarction. On admission, retention of a large volume of ascites was noted. There were also marked increases in tumor markers. Serum CEA, CA19-9 and CA125 levels were 871.9 ng/ml, 1048.2U/ml, and 444.7U/ml, respectively. Cytological examination of the ascites showed class V. Abdominal CT showed a mass measuring 4 cm in diameter and dilatation of the small intestinal tract. During detailed examination, she developed ileus. Fluoroscopy through the lung tube suggested a small intestinal tumor. Laparotomy was performed to relieve ileus. In the abdominal cavity, the greater omentum formed a mass due to dissemination. Tumor was found in the jejunum approximately 60 cm from Treitz's ligament toward the anal side. Omentectomy and partial jejunectomy were performed. Macroscopic findings showed tumor protruding from the mucosal surface. Histological diagnosis was mucinous adenocarcinoma. Primary small intestinal cancer is very rare. In particular, only one case of mucinous adenocarcinoma of the small intestine was reported in Japan. We reported the second case in Japan with a review of the literature.

Elevation of serum phospholipase A2 in patients at an intensive care unit.

To evaluate the organ specificity of pancreatic phospholipase A2 (PLA2) and the diagnostic value of the elevation of serum PLA2 levels in patients with serious diseases not involving the pancreas, we studied the organ distribution of PLA2 in autopsy specimens and serum level of PLA2 in patients who required admission to an intensive care unit (ICU). PLA2 was measured by a specific radioimmunoassay (RIA), using monoclonal antibody against human pancreatic PLA2. Organ distribution of PLA2 revealed that the pancreas showed a much higher content of pancreatic PLA2 immunoreactivity than any other organ. An abnormally high value of serum PLA2 was observed in 18 of 30 patients (60%) at ICU. Both serum PLA2 and pancreatic isoamylase were elevated in 11 patients (37%). Of 11 patients with hyperphospholipasemia and hyperamylasemia, serum creatinine was elevated in five patients and blood urea nitrogen in nine patients. Serum PLA2 levels did not always rise comparably to serum creatinine and blood urea nitrogen levels. Serum PLA2 values showed the best correlation with serum lactate dehydrogenase levels among routine blood-chemistry tests. The elevation of serum PLA2 was ascribable to renal dysfunction or ischemic pancreatic damage secondary to circulatory collapse with multiple organ failure.

[Continuous arterial infusion chemotherapy in cancer cases followed as outpatients].

Continuous arterial infusion chemotherapy is associated with a significantly greater tumor response rate, though patients must be hospitalized for a long time. This paper describes techniques and our experience with arterial continuous infusion chemotherapy for outpatients using implantable port and ambulatory pump. Eleven patients (liver metastasis of colorectal cancer, hepatocellular carcinoma and local recurrence of rectal cancer) were treated with continuous arterial infusion chemotherapy at our outpatient clinic. The chemotherapy infusions were carried out repeatedly for 5.7 months on average (10-2 months) with 5-FU or CDDP. Total periods of infusions were 64.8 days on the average (136-24 days). The infusion dose and frequency of drug refilling were limited by pump quality. A major complication occurred only in one patient who developed arterial thrombosis. Minor complications were mainly gastrointestinal symptoms (nausea, vomiting) and abdominal pain, which were easily corrected with drugs. The tumor responses were as follows: PR 1 case, MR 1 case, NC 7 cases and PD 2 cases. Home arterial continuous infusion chemotherapy reduced the hospitalized period and helped patients return to work. Therefore it may well contribute to improve the quality of life of cancer patients.

A case of double pylorus accompanied by adrenal adenoma.

We report here a case of double pylorus diagnosed endoscopically in a patient with adrenal adenoma. A 44-yr-old man was found to have double pylorus during examinations for recurrent epigastric pain and obesity. We think that the formation of double pylorus in this case resulted from recurrent peptic ulcer which, in turn, probably was induced by the hypersecretion of endogenous corticosteroids accompanying adrenal adenoma.

[Blood and tumor levels of tegafur, 5-fluorouracil, and uracil].

The blood and tissue concentrations of tegafur (TGF), 5-fluorouracil (5-FU) and uracil were tested by administering 6 capsules of UFT (600 mg as tegafur (TGF)) per day to 21 patients awaiting operation for stomach cancer. At the same time, comparative tests were performed by dividing the patients into two groups, giving UFT before meals in one group and in another after meals. Both 5-FU and uracil levels tend to reach to the maximum blood concentration after one hour, while showing similar variations with time lapse. Furthermore, a significantly positive relationship was observed between 5-FU and uracil in the rate of changes of blood concentration during six hours after administration of UFT. The 5-FU concentration within tumor tissue was 10 times higher than that within the blood and 2 times higher than that within normal tissue. A similar tendency was observed with uracil, which was of value in the clinical determination of the effect of uracil in inhibiting decomposition of 5-FU. With regard to the comparative test between the groups of pre- and post-meal UFT administration, the concentration of tegafur (TGF) and 5-FU in tumor tissue tended to be higher in the pre-meal group which indicates a need for further study of the phenomenon.

The sign of Leser-Trélat associated with carcinoma of the stomach.

The sign of Leser-Trélat, which refers to the sudden appearance and rapid increase in size and number of seborrheic keratosis associated with a visceral malignant tumor, is very uncommon. This case concerns a 54-yr-old woman presenting with Leser-Trélat's sign associated with advanced gastric cancer. Seborrheic keratosis faded after resection of the tumor, but returned when the cancer recurred. At that time, 24-h urinary excretion of epidermal growth factor determined by radioreceptor assay was slightly elevated. Epidermal growth factor may play a part in the development of Leser-Trélat's sign.

Macroautoradiographic and densitometric studies of [14C]dimethadione in rats: accumulation of the compound in the pancreas.

Whole-body autoradiographic and densitometric distribution studies were performed on rats to investigate the accumulation of [14C]dimethadione (DMO) in the pancreas. [14C]DMO was intravenously administered at a dose of 167 microCi/0.5 mg/kg. Animals were sacrificed 1, 15, 30, 60 and 180 min after administration of the radioactive compound. The compound was found to rapidly distribute in all body tissues. The distribution pattern of the compound in the pancreas was spotty or linear due to the presence of the radioactive compound in blood of intrapancreatic vessels and in pancreatic ducts at higher levels than parenchyma. The radioactivity of pancreatic ducts became more evident with time, indicating the gradual accumulation of the compound in the ducts. These findings provide morphological evidence that DMO is accumulated in the pancreas and possibly eliminated from pancreatic juice. Densitometry revealed that the levels of radioactive compound in the pancreas were virtually as high as those in the liver and kidney.

Dissolution of pancreatic stones by oral trimethadione in a dog experimental model.

Experiments were conducted to develop a dissolution therapy for human pancreatic calculi in a dog experimental model of pancreatic calculi surgically prepared. On plain x-ray films of the abdomen, pancreatic calculi appeared in 19 of 39 dogs within 12 mo after operation. The antiepileptic agent trimethadione was given orally to 13 dogs at a dose of 1.0-1.5 g daily. Pancreatic calculi disappeared in 13 of 15 observations. The scanning electron microscopy, the elemental analysis, and the powder x-ray diffractometry of pancreatic calculi in this model revealed that the calculi closely resembled human pancreatic calculi, consisting mainly of a calcite of calcium carbonate. There was no histologic finding suggesting drug toxicity in the liver, the kidney, and the blood. Pancreatic calculi in 6 control dogs without the treatment neither disappeared nor diminished spontaneously. The oral treatment with trimethadione may have potential for dissolving human pancreatic calculi.

Hyperamylasemia in patients at an intensive care unit.

We have evaluated the prevalence of hyperamylasemia in various acute disorders that required admission to an intensive care unit. Hyperamylasemia was found in 27 of 53 patients (51%). The source of hyperamylasemia was determined by isoamylase analysis with an inhibition method using an inhibitor specific to salivary type isoamylase. Increased pancreatic type isoamylase with a high P/S ratio was found in six patients with disorders related to the pancreas and elevated salivary type isoamylase with a low P/S ratio in 17 with various extrapancreatic diseases of heart, lung, trauma, or in the postoperative state. We found a simultaneous rise in pancreatic and salivary type isoamylases with normal P/S ratio in four patients with renal failure. Our experience suggests that isoamylase analysis by an inhibition method can be done rapidly and inexpensively. Knowing whether hyperamylasemia is pancreatic or nonpancreatic in origin should help to exclude unnecessary evaluation and treatment.

Chemical studies of pancreatic nonopaque concretions and protein plug.

Chemical studies were performed on all or part of four X-ray translucent (nonopaque) concretions and one protein plug to investigate a possible relationship between these substances, and to find the similarities and differences between these materials and pancreatic stone protein. Through elemental analysis, infrared absorption spectrometry, quantitative analysis of protein, and amino acid analysis, nonopaque concretions and protein plug were found to consist mainly of protein. One nonopaque concretion contained a very small amount of crystalline which differed greatly from calcite type calcium carbonate as observed in pancreatic calcified stones. The pattern of amino acid composition was very similar between the concentrations and the protein plug: rich in acidic amino acids, but poor in basic and aromatic residues. The aspartic acid content was the highest among detected amino acids. Comparison of amino acid composition between the nonopaque concretions which we analyzed and the pancreatic stone protein reported from Sarles' laboratory suggested that the concretions seem to contain some stone protein.

Clinical value of routine isoamylase analysis of hyperamylasemia.

To study incidence and cause of hyperamylasemia in various diseases, serum amylase was determined in 1371 consecutive patients and subsequent isoamylase analysis was carried out in 91 hyperamylasemic sera. Hyperamylasemia was observed in various diseases: acute pancreatitis (5/5), chronic pancreatitis (0/3), mumps (3/3), cerebrovascular diseases (2/39), respiratory diseases (6/69), heart diseases (5/89), liver diseases (16/101), cholelithiasis (0/13), diabetes mellitus (2/66), peptic ulcer (0/46), other digestive diseases (0/33), malignant tumor (9/249), renal failure (21/25), intraabdominal surgery (9/35), extraabdominal surgery (2/20), trauma (1/23), and miscellaneous (10/552). Salivary type hyperamylasemia due to dominant increase of salivary type isoamylase occurred in over half of the hyperamylasemic patients. Knowledge of hyperamylasemia in various diseases and routine isoamylase analysis of hyperamylasemic sera would enhance diagnostic accuracy and exclude unnecessary treatment of pancreatitis solely because of the presence of hyperamylasemia.