Therapeutic effect of camostat mesilate on Duchenne muscular dystrophy in mdx mice

Duchenne muscular dystrophy is known to be caused by a defective gene of dystrophin, a 427-kDa cytoskeletal protein, but the effective therapeutic drug is presently unavailable. We previously reported that a trypsin-like protease designated as dystrypsin is markedly activated in the muscle microsomal fraction immediately before onset of the clinical signs in mdx mice, a dystrophin-deficient hereditary animal model for human Duchenne muscular dystrophy. In order to examine the possible participation of dystrypsin in the occurrence of the disease, we investigated the therapeutic effects of dystrypsin inhibitors on the occurrence and progress of muscular dystrophy. Here, we show that camostat mesilate, a low-molecular-weight inhibitor of trypsin-like proteases, including dystrypsin, is a candidate drug for Duchenne muscular dystrophy.     

Cerebral oxygenation monitor during head-up and -down tilt using near-infrared spatially resolved spectroscopy

Reflectance near-infrared spectroscopy (NIRS) has become a suitable and easily manageable method to monitor cerebral oxygenation changes in presyncopal and syncopal symptoms caused by postural changing or standing. A new clinical tissue oxygenation monitor has been recently developed which measures absolute tissue haemoglobin saturation (Tissue Oxygenation Index, TOI) utilizing spatially resolved spectroscopy (SRS). The present study examined the effects of postural changes on cerebral oxygenation as reflected in SRS-NIRS findings. Cerebral oxyhaemoglobin (O2Hb), deoxyhaemoglobin (HHb), and the TOI were recorded from both sides of the forehead in five healthy male subjects (age range, 28-40 years) during 90 degrees head-up tilt (HUT) and -6 degrees head-down tilt (HDT). Three series of measurements were carried out on separate days. O2Hb was decreased during HUT. TOI was significantly lower in HUT than in the supine position (SUP). There was no significant change in TOI during HDT. A significant session effect was observed in the left forehead TOI during SUP, but not in the right. SRS-NIRS measurements confirmed sub-clinical alterations of cortical oxygenation during HUT. NIRS data from the left side of the forehead, which may vary with cognitive or emotional activation, were more variable than those from the right side.     

A case of mitochondrial myopathy with external ophthalmoplegia and ataxic neuropathy]

We report a 70-year-old woman with bilateral optic atrophy, external ophthalmoplegia, bilateral blepharoptosis, and sensory ataxic neuropathy. She had a visual disturbance since childhood. She had dysarthria and gait disturbance at 28 years old. She had bilateral blepharoptosis, marked gait disturbance and dysphagia at 50. On neurological examination, external ophthalmoplegia, bilateral blepharoptosis, mild weakness and muscular atrophy of promixal muscles, hyporeflexia, positive Romberg sign, glove and stocking type sensory disturbance including hypesthesia, hypalgesia, and bathyhypesthesia were found. She did not show pigmented retinopathy, cognitive dysfunctions, hearing loss, cerebellar ataxia, Hoffman reflex nor Babinski sign. She did not show increased lactic acid nor pyruvic acid in the cerebrospinal fluid but mild increase of pyruvic acid (1.0 mg/dl) in her serum. The conduction velocity and amplitude of CMAP of tibial nerve was 37.4 m/sec and 2.9 mV, respectively. The SNAP of ulner and sural nerve were not evoked. Brain MRI showed no pathological findings. Muscle biopsy from the biceps muscle showed many ragged-red fibers (5.3%) and some fibers with decreased or absent COX activity. Sural nerve biopsy showed a marked loss of large myelinated fibers with thin myelinated fibers, and onion-bulb formation. The clinical findings of our patient is similar to that of SANDO (the triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis), however, large mtDNA deletion reported by Fadic in patients with SANDO was not found in our patient. It might be possible that her mtDNA deletion is small or point mutation is existed.     

Superior immunogenicity of a freeze-dried, cell culture-derived Japanese encephalitis vaccine (inactivated)

Japanese encephalitis is an infectious disease caused by the Japanese encephalitis virus, which is widespread throughout Asia. The worldwide incidence is 50,000 cases per year. There is no specific treatment available, but inactivated mouse brain-derived vaccine was used from the 1950s to prevent infection. However, quality control of mouse brain-derived vaccines is difficult, and therefore a new freeze-dried, cell culture-derived Japanese encephalitis vaccine (inactivated) (JEBIK V; development code: BK-VJE) was developed. In this paper, we report an analysis of neutralizing antibody titers in vaccinated subjects enrolled in clinical study of BK-VJE at various doses, and study of BK-VJE with the mouse brain-derived vaccine as a control. The results show that BK-VJE has superior immunogenicity compared to mouse brain-derived vaccine.     

Partial characterization of a uteroglobin-like protein in the human uterus and its temporal relationship to prostaglandin levels in this organ

During the past decade several corticosteroid-dependent, low mol wt proteins with phospholipase-A2 (PLA2) inhibitory activity have been described. This family of proteins is collectively known as lipocortins. Blastokinin or uteroglobin (utg), a progesterone-induced protein, first discovered in the pregnant rabbit uterus, is also a potent PLA2 inhibitor, but genetically distinct from lipocortins. Although utg has been found in rabbits, its presence in humans has not been well established. Here, we present biochemical, immunological, and immunohistological evidence for the detection of a utg-like protein in the human uterus. Since inhibition of PLA2 may modulate tissue eicosanoid levels and since rabbit utg has been reported to be a potent PLA2 inhibitor, we also studied the temporal relationship between utg and tissue prostaglandin E2 and F2 alpha levels in estrogen- and progesterone-dominated endometrial tissue. We found an inverse temporal relationship between utg-like protein and eicosanoid levels in this organ. Since some eicosanoids (e.g. prostaglandins, leukotrienes, etc.) are known to be involved in smooth muscle contractility and inflammatory processes, our findings may help to understand the pathogenesis of some human disorders in which abnormal eicosanoid production occurs.     

Gastric gastrointestinal stromal tumor smaller than 20 mm with liver metastasis

There have been no reports of gastric gastrointestinal stromal tumors (GISTs) <20 mm with distant metastasis. We report a case of a 15-mm gastric GIST with liver metastasis 1 year after surgical resection of the primary lesion. A 35-year-old man underwent routine esophagogastroduodenoscopy in July 2009. A submucosal tumor (SMT) <20 mm was incidentally detected at the posterior wall of the gastric body. Endoscopic ultrasound (EUS) indicated that it was a gastrointestinal mesenchymal tumor, including GIST, leiomyoma or schwannoma. He did not accept regular follow-up for this gastric SMT, therefore local laparoscopic excision was carried out in October 2009. The final pathological diagnosis after surgery was GIST, 15 mm in size, and a mitotic rate of 7/50 high-power fields, which did not indicate a high metastatic risk. The patient was followed up regularly without adjuvant chemotherapy. At 1 year after surgery, a space-occupying lesion ~15 mm was detected in the left lobe of the liver by abdominal ultrasound, where no mass lesion had been observed before surgery. To make a definite diagnosis of the hepatic mass lesion, EUS-guided fine-needle aspiration was performed, which demonstrated a metastatic liver tumor from a gastric GIST. Although this was a rare case, we should keep in mind that gastric GISTs do have a chance of malignant behavior, even if <20 mm.     

Plasma Endotoxin and Serum Cytokine Levels in Patients With Alcoholic Hepatitis: Relation to Severity of Liver Disturbance

Background: Endotoxin plays an important role in the initiation and aggravation of alcoholic liver disease. In this study, we evaluated plasma endotoxin levels and serum concentrations of cytokines and lipopolysaccharide binding protein (LBP) during the acute and recovery phase of patients with alcoholic hepatitis; we also explored the prognostic factors associated with a fatal outcome. Methods: Fourteen patients, consisting of eight patients with alcoholic hepatitis (AH), five cirrhotics with superimposed AH (LC+AH), and one patient with severe alcoholic hepatitis (SAH), were studied. Among these, two with LC+AH died of hepatic failure. Results: Plasma endotoxin levels in the acute phase were higher in patients with AH (184.4 ± 159.4 pg/ml) and LC+AH (206.9 ± 174.9 pg/ml) than in healthy subjects (10.4 ± 5.5 pg/ml, p < 0.001). In particular, in one patient with SAH and one of two nonsurvivors, plasma endotoxin levels were markedly high relative to the other cases. In most survivors, plasma endotoxin levels decreased in the recovery phase, whereas they further increased at the terminal stage in one of two nonsurvivors. Serum interleukin (IL)-6 and IL-8 levels in the acute phase were significantly higher in patients with AH and LC+AH as compared with healthy subjects. These levels were especially high in nonsurvivors and in one patient with SAH. IL-10 increased in two nonsurvivors, one patient with SAH, and one with LC+AH. In the recovery phase, these cytokine levels in survivors tended to decrease, but in nonsurvivors, IL-6 remained high, and IL-8 and IL-10 further increased. Tumor necrosis factor-α levels were below the detection limit throughout the course in all patients. Serum lipopolysaccharide binding protein (LBP) generally was elevated in the acute phase and decreased in the recovery phase in all survivors, but in one of the nonsurvivors, LBP was elevated markedly at the terminal stage. In the acute phase, plasma endotoxin levels were correlated positively with white blood cell counts, neutrophil counts, and serum IL-8. IL-8 was correlated positively with neutrophil counts and negatively with serum Cholinesterase, hepaplastin test, and serum albumin levels. IL-6 was correlated positively with white blood cell and neutrophil counts, C-reactive protein, and serum total bilirubin and negatively with hepaplastin test and serum total protein levels. Serum LBP was correlated positively with white blood cell and neutrophil counts. Conclusions: Endotoxemia and related elevation of IL-8 may play an important role in the activation and migration of neutrophils in patients with alcoholic hepatitis. Marked elevation of inflammatory cytokines, IL-6 and IL-8, are related to severity and poor prognosis of alcoholic hepatitis. Serum LBP may serve as an index of inflammatory reaction in alcoholics.     

A 25-year prospective study of visual acuity in the Japan Air Self Defense Force personnel.

BACKGROUND: In the Japan Air Self Defense Force (JASDF), new vision standards for student pilots allow lower uncorrected monocular acuity (from 1.0 to 0.8). In flight environments, where the use of corrective lenses may present problems, the risk of decreasing visual acuity in pilots who should wear corrective lenses must be defined. METHODS: We conducted a 25-yr prospective study of visual acuity with regard to distance vision in 752 JASDF nonaviation personnel followed from ages 20 to 45. The test subjects were divided into four groups according to their right monocular visual acuity at entry: > or =1.0, between 0.9 and 0.7, between 0.6 and 0.2, and <0.2. RESULTS: At entry, 94.1% of all subjects had visual acuity > or =0.7. The proportion of subjects who required corrective lenses for distance increased with age from 15.8% to 37.1%. After 25-yr, 30.2% of subjects with visual acuity > or =1.0 at entry and 62.7% of subjects with visual acuity between 0.9 and 0.7 at entry required corrective lenses. CONCLUSIONS: Over 25 yr, the population with the best eyesight at age 20 had a lower increase in the need for corrective lenses than the population with visual acuity between 0.9 and 0.7 at age 20. These results suggest an increased risk of visual acuity loss in pilots over time as a result of the lower vision standards for student pilots in the JASDF.