Metabolic myopathies

Six glycogen storage diseases (resulting from deficiencies of acid maltase, phosphorylase, phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase) and one mitochondrial myopathy (cytochrome c oxidase deficiency) are reviewed to illustrate: 1) clinical heterogeneity, 2) biochemical heterogeneity, 3) evidence for tissue-specific and developmentally controlled isozymes, and 4) molecular genetic studies.     

Nonfunctional parathyroid carcinoma

A 65-year-old female patient was admitted to our hospital presenting with a superior mediastinal big mass that was elastic, hard, and painless. Laboratory data including serum calcium level and thyroid and parathyroid hormonal functions revealed no abnormalities. Further examination consisting of computed tomography, magnetic resonance imaging, and ultrasonography demonstrated that it was a solid tumor extending into the superior mediastinum. Technetium (Tc-99) sestamibi scan revealed a hypofunctioning focus in that area. The preoperative diagnosis was a thyroid tumor or a metastatic lymph node. Parathyroid carcinoma was suspected on intraoperative frozen pathological examination. The tumor was successfully removed with left thyroid lobectomy, and neck node dissection was performed. Macroscopically, it appeared as a dark reddish solid tumor, and the cut surface presented opalescence. Immunohistology confirmed that there was proliferation of tumor cells with positive chromogranin A staining. Thus, the tumor was diagnosed as parathyroid carcinoma histopathologically despite a lack of clinical evidence for hyperparathyroidism. This patient has been followed with no evidence of recurrence, a normal serum calcium 4 years after surgery, and postoperative radiotherapy. This report describes a case of nonfunctional parathyroid carcinoma with a massive mass that technetium (Tc-99) sestamibi scan failed to detect, and we showed negative immunostaining for parathyroid hormone (PTH) (N).     

Ambulatory blood pressure variability and brachial-ankle pulse wave velocity in untreated hypertensive patients

Blood pressure (BP) variability is estimated as the standard deviation of 24-h ambulatory BP. The present study was performed to determine the effect of the mean 24-h ambulatory BP values and standard deviations on arterial wall stiffness assessed by brachial-ankle pulse wave velocity (baPWV). Brachial-ankle pulse wave velocity, carotid intima-media thickness (IMT), urinary albumin excretion (UAE) and 24-h ambulatory BP were measured before the start of antihypertensive therapy in 203 newly diagnosed hypertensive patients (53.3+/-0.7 years old; clinic systolic/diastolic BP: 154+/-1/98+/-1 mm Hg), and univariate and multivariate regression analyses of these clinical and biological parameters were performed. Univariate regression analyses revealed a significant association between mean baPWV values and the standard deviations of ambulatory systolic/diastolic BP. Mean ambulatory systolic/diastolic BP values were also associated with UAE, and the standard deviations of ambulatory systolic BP were associated with maximum carotid IMT. Quintile analyses showed that patients with a mean 24-h ambulatory mean BP value and standard deviation below 110 and 20 mm Hg, respectively, had the lowest baPWV. Moreover, the multivariate regression analyses confirmed a significant correlation between baPWV and the standard deviation of 24-h ambulatory systolic BP. In conclusion, untreated hypertensive patients with a higher 24-h ambulatory systolic BP variability had stiffer arterial walls. Ambulatory systolic BP variability may be involved in stiffening of the arteries of hypertensive patients.     

A vaccine prepared from a non-pathogenic H5N1 avian influenza virus strain confers protective immunity against highly pathogenic avian influenza virus infection in cynomolgus macaques

In order to prepare for the emergence of pandemic influenza viruses, we have established an influenza virus library that contains non-pathogenic influenza A virus strains with 135 combinations of 15 hemagglutinin and 9 neuraminidase subtypes. In this study, we developed a vaccine against H5N1 highly pathogenic avian influenza (HPAI) virus infection in humans using a virus strain selected from the library. We examined its immunogenic potency using cynomolgus macaques as a primate model. Virus antigen-specific antibodies were elicited by intranasal or subcutaneous administration of inactivated whole virus particle vaccines. After challenge with an H5N1 HPAI virus isolate obtained from a Vietnamese patient, the virus was detected only on next day following inoculation in the nasal and/or tracheal swabs of vaccinated macaques that were asymptomatic. On the other hand, the viruses were isolated from nasal and tracheal swabs from non-vaccinated macaques until day 5 and day 7 after inoculation of the H5N1 HPAI virus, respectively. Although six non-vaccinated macaques developed a high body temperature, and two of them lost their appetite after HPAI virus infection, they recovered by the end of the 12-day observation period and did not show the severe symptoms that have been reported in human H5N1 virus infection cases. This demonstrates that the vaccine prepared with the non-pathogenic H5N1 virus from our influenza virus library conferred protective immunity against H5N1 HPAI virus infection to macaques.     

Contribution of nonproteolytically activated prorenin in glomeruli to hypertensive renal damage

Prorenin is activated without proteolysis by binding of prorenin receptor to the pentameric "handle region" (HR) of prorenin prosegment. It was hypothesized that such activation occurs in the kidneys of hypertensive rats and causes tissue renin-angiotensin system (RAS) activation and end-organ damage. Because the HR's binding to its binding protein made the adjacent tetrameric "gate region" (GR) accessible to its specific antibody, immunohistochemistry of the GR was performed to test the hypothesis. Methods also were devised specifically to inhibit the nonproteolytic activation by the decapeptide corresponding to the HR as a decoy. Immunohistochemistry of the GR demonstrated that the majority of nonproteolytically activated prorenin is present in podocytes of the kidneys from stroke-prone spontaneously hypertensive rats, in which activation of renal tissue RAS, proteinuria, and glomerulosclerosis occurred. Continuous subcutaneous administration of the HR decoy peptide completely inhibited both nonproteolytic activation of tissue prorenin and activation of tissue RAS without affecting circulating RAS or arterial pressure and significantly attenuated the development and progression of proteinuria and glomerulosclerosis. These studies clearly demonstrated that nonproteolytic activation of prorenin in glomeruli is critically involved in renal tissue RAS activation, leading to renal damage in hypertensive animals.     

Aspirin use and risk of biliary tract cancer: a population-based study in Shanghai, China.

The association of gallbladder and bile duct cancers with gallstones, cholecystitis, and cholangitis suggest that chronic inflammation contributes to the carcinogenic process. However, the effect of nonsteroidal anti-inflammatory drugs, such as aspirin, on biliary tract cancer has not been well studied. In a population-based case-control study conducted in Shanghai, China, we examined the relationship between aspirin use and the risk of biliary disease. A total of 627 patients with biliary tract cancer, including cancers of the gallbladder (n = 368), extrahepatic bile duct (n = 191), and ampulla of Vater (n = 68); 1,037 patients with biliary stones; and 958 healthy adults were included in the study. Self-reported data on aspirin use was collected from study participants by in-person interview. The prevalence of aspirin use was low, with 5.7% of the population controls being regular users. After controlling for age, sex, education, and biliary stone status, aspirin use was associated with a reduced risk of gallbladder cancer [odds ratio (OR), 0.37; 95% confidence interval (CI), 0.17-0.88]. An inverse relationship was also observed for frequency and duration of use and with younger age when starting use. In addition, there was a nonsignificant reduction in the risk of bile duct (OR, 0.48; 95% CI, 0.19-1.19) and ampullary cancers (OR, 0.22; 95% CI, 0.03-1.65) associated with aspirin use, whereas no clear association was seen with biliary stones (OR, 0.92; 95% CI, 0.59-1.44). Further studies of biliary tract cancer in other populations are needed to confirm these results and to elucidate the mechanisms that underlie the reduced risk associated with use of aspirin and possibly other nonsteroidal anti-inflammatory drugs.     

Japanese cedar pollen in house dust]

Caring for oneself against Japanese cedar pollinosis is important as well as receiving medical-care. Although the importance of avoiding pollen is described in the guideline for nasal allergy medical treatment, however, there is no information for effective dust cleaning for the home. This study examined how many cedar pollens were included in indoor dust in order to obtain basic data whether dust removal for cedar pollen is available for pollinosis suffers. As a result, the study found that there were many Japanese cedar pollens in indoor dust even before the pollen season. Cedar pollen increased with the increasing number of airborne pollen. The highest number of pollen found in one week was approximately 450 pollens in a square meter of a living room floor. The study concluded that cleaning is one of the best way to remove Japanese cedar pollens found in indoor dust.     

Increased number of mitochondria in capillaries distributed in stroke‐like lesions of two patients with MELAS

We investigated two autopsy cases of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS) using immunohistochemical staining with an anti‐mitochondrial antibody against translocase of the outer membrane 20 (TOMM20). In case 1, the patient was a 42‐year‐old man with a disease duration of 53 days, and in case 2, the patient was a 62‐year‐old woman with a disease duration of 27 months. In both the cases autopsy revealed moderate atrophy of the cerebrum and cerebellum and multifocal necrotizing lesions, irrespective of the vascular territory. Case 1 showed multiple areas with total necrosis in the cortex, accompanied by increases in number of protoplasmic astrocytes and acidophilic neurons as well as axonal swelling, suggestive of acute or subacute stage stroke‐like lesions (SLLs). In case 2, most of the SLLs displayed laminar spongy change in a rarefied cortex, and were considered to be at the chronic stage. In both the cases, capillary proliferation was noted within the SLLs, particularly in the acute phase. Endothelial cells of proliferating capillaries were strongly positive for TOMM20. In the cortex outside the SLLs, microvessels displayed only a fine granular immunoreactivity, as is seen in the controls. Although smooth muscle cells and endothelial cells in pial arteries and arterioles were also strongly positive for TOMM20, the territories of the affected pial arteries and arterioles did not correlate with the distribution of the SLLs. Although MELAS is characterized by recurrent stroke‐like episodes (SLEs), the pathogenetic relationship between SLEs and mitochondrial angiopathy remains unknown. An aberrant increase of mitochondria in the capillary endothelial cells of SLLs may disturb endothelial function, thus playing a role in the formation or development of SLLs.     

Comparative study on the inhibitory effects of antioxidant vitamins and radon on carbon tetrachloride-induced hepatopathy

We have previously reported that radon inhalation activates anti-oxidative functions and inhibits carbon tetrachloride (CCl₄)-induced hepatopathy. It has also been reported that antioxidant vitamins can inhibit CCl₄-induced hepatopathy. In the current study, we examined the comparative efficacy of treatment with radon, ascorbic acid and α-tocopherol on CCl₄-induced hepatopathy. Mice were subjected to intraperitoneal injection of CCl₄ after inhaling approximately 1000 or 2000 Bq/m³ radon for 24 h, or immediately after intraperitoneal injection of ascorbic acid (100, 300, or 500 mg/kg bodyweight) or α-tocopherol (100, 300, or 500 mg/kg bodyweight). We estimated the inhibitory effects on CCl₄-induced hepatopathy based on hepatic function-associated parameters, oxidative damage-associated parameters and histological changes. The results revealed that the therapeutic effects of radon inhalation were almost equivalent to treatment with ascorbic acid at a dose of 500 mg/kg or α-tocopherol at a dose of 300 mg/kg. The activities of superoxide dismutase, catalase, and glutathione peroxidase in the liver were significantly higher in mice exposed to radon than in mice treated with CCl₄ alone. These findings suggest that radon inhalation has an anti-oxidative effect against CCl₄-induced hepatopathy similar to the anti-oxidative effects of ascorbic acid or α-tocopherol due to the induction of anti-oxidative functions.