Carotid lesions detected by B-mode ultrasonography in Takayasu's arteritis: "macaroni sign" as an indicator of the disease.

Twenty-three patients were studied to evaluate the clinical usefulness of high resolution B-mode ultrasonography in the detection of carotid lesions in patients with Takayasu's arteritis. In each patient the carotid arteries were examined using both B-mode ultrasonography (midfrequency of 7.5 MHz) and contrast angiography. In 19 of 23 patients, B-mode ultrasonography clearly demonstrated the characteristic circumferential arterial wall thickening of either one or both sides of the common carotid arteries as a macaroni-like, diffusely thickened intima-media complex. Conversely, contrast angiography demonstrated carotid lesions in only 13 of 23 patients. These results clearly show that B-mode ultrasonography is quite sensitive and superior in the detection of the characteristic thick intima-media complex of the common carotid artery in patients with Takayasu's arteritis, when compared with contrast angiography that is usually used for the definitive diagnosis of this disease.     

A case of slowly progressive type 1 diabetes mellitus developing myeloperoxidase-specific anti-neutrophil cytoplasmic antibody-associated vasculitis with hypertrophic pachymeningitis manifesting as multiple cranial nerve palsy

We report a 63-year-old man with a 35-year history of slowly progressive type 1 diabetes mellitus (SPIDDM), complicated with myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis presenting alveolar hemorrhage and pachymeningitis. The patient was first diagnosed as having DM at age of 28 years old and deteriorated secretion of insulin and the typical clinical course led us to the diagnosis of SPIDDM. When he was 58 years old, he suffered from fever, headache, and alveolar hemorrhage. He was diagnosed as having MPO-ANCA associated vasculitis based on a high titer of MPO-ANCA and histological findings of lung biopsy. Treatment with steroid pulse therapy, followed by oral prednisolone and oral cyclophosohamide, resulted in clinical improvement. Five years later, he complained of double vision. A gadolinium-enhanced magnetic resonance imaging (MRI) study of the brain showed normal. Two months later, he developed right cranial nerve V~XII palsy. A second MRI study revealed thickening of the right temporal region and cerebellar dura mater, leading us to the diagnosis of hypertrophic pachymeningitis. He responded well to oral prednisolone (50 mg/day) and intravenous cyclophosohamide (500 mg). This is the first case report of SPIDDM complicated with MPO-ANCA-associated vasculitis, manifesting as alveolar hemorrhage and hypertrophic pachymeningitis.     

Lag-phase autophagy in the methylotrophic yeast Pichia pastoris

When microbes sense environmental changes, they often temporarily attenuate cell growth to adapt to the new situations, showing a lag phase. In this study, we report that the methylotrophic yeast, Pichia pastoris , induced autophagy during the lag phase after the cells were shifted from glucose to methanol medium. Through the autophagic process at least two proteins, aminopeptidase I precursor and cytosolic aldehyde dehydrogenase, were found to be transported into the vacuole, which was dependent on PpAtg11 and PpAtg17, respectively. Notably, PpAtg1 and PpAtg17 were required for early exit from the lag phase during the methanol adaptation. In accordance, phosphorylation states of elongation initiation factor 2α indicated reductions of intracellular amino-acid pools in the atg mutant strains. Together, these data demonstrate the importance of amino acid recycling by autophagy during a cell-remodeling process.     

Glycinergic interneurons are functionally integrated into the inspiratory network of mouse medullary slices

Neuronal activity in the respiratory network is functionally dependent on inhibitory synaptic transmission. Using two-photon excitation microscopy, we analyzed the integration of glycinergic neurons in the isolated inspiratory pre-Bötzinger complex-driven network of the rhythmic slice preparation. Inspiratory (96%) and ‘tonic’ expiratory neurons (4%) were identified via an increase or decrease, respectively, of the cytosolic free calcium concentration during the inspiratory-related respiratory burst. Furthermore, in BAC-transgenic mice expressing EGFP under the control of the GlyT2-promoter, 50% of calcium-imaged inspiratory neurons were glycinergic. Inspiratory bursting of glycinergic neurons in the slice was confirmed by whole-cell recording. We also found glycinergic neurons that receive phasic inhibition from other glycinergic neurons. Our calcium imaging data show that glycinergic neurons comprise a large population of inspiratory neurons in the pre-Bötzinger complex-driven network of the rhythmic slice preparation.     

Anaerobic NADH-fumarate reductase system is predominant in the respiratory chain of Echinococcus multilocularis, providing a novel target for the chemotherapy of alveolar echinococcosis

Alveolar echinococcosis, which is due to the massive growth of larval Echinococcus multilocularis, is a life-threatening parasitic zoonosis distributed widely across the northern hemisphere. Commercially available chemotherapeutic compounds have parasitostatic but not parasitocidal effects. Parasitic organisms use various energy metabolic pathways that differ greatly from those of their hosts and therefore could be promising targets for chemotherapy. The aim of this study was to characterize the mitochondrial respiratory chain of E. multilocularis, with the eventual goal of developing novel antiechinococcal compounds. Enzymatic analyses using enriched mitochondrial fractions from E. multilocularis protoscoleces revealed that the mitochondria exhibited NADH-fumarate reductase activity as the predominant enzyme activity, suggesting that the mitochondrial respiratory system of the parasite is highly adapted to anaerobic environments. High-performance liquid chromatography-mass spectrometry revealed that the primary quinone of the parasite mitochondria was rhodoquinone-10, which is commonly used as an electron mediator in anaerobic respiration by the NADH-fumarate reductase system of other eukaryotes. This also suggests that the mitochondria of E. multilocularis protoscoleces possess an anaerobic respiratory chain in which complex II of the parasite functions as a rhodoquinol-fumarate reductase. Furthermore, in vitro treatment assays using respiratory chain inhibitors against the NADH-quinone reductase activity of mitochondrial complex I demonstrated that they had a potent ability to kill protoscoleces. These results suggest that the mitochondrial respiratory chain of the parasite is a promising target for chemotherapy of alveolar echinococcosis.     

Repeat reduction surgery after an initial hepatectomy for patients with colorectal cancer

A hepatectomy is the only treatment offering long-term survival in patients with colorectal liver metastases. However, 70-80% of the patients with a complete resection develop recurrent disease after an initial hepatectomy. Sixty-one patients who underwent metastases from colorectal carcinoma with a curative hepatectomy were entered into this study. Recurrence after hepatectomy was observed in 41 patients (67.2%). We reviewed the outcome of these 41 patients. Repeat reduction surgery was performed on 16 out of 41 patients (39.0%). According to a multivariate analysis, repeat reduction surgery and tumor size were found to be independent prognostic factors for the survival rate (p=0.007, p=0.018). Furthermore, in the group that underwent repeat reduction surgery, the rate of positive lymph nodes was significantly lower in the primary lesions, and the disease-free interval (DFI) was also significantly longer than in the group that did not undergo repeat reduction surgery (p=0.023, p=0.045), respectively. Repeat reduction surgery was found to be the most important prognostic factor. Patients with a longer DFI and with negative lymph node findings at the primary site may therefore be considered to be good candidates for repeat reduction surgery.     

Identification of a compound heterozygous inactivating ABCC8 gene mutation responsible for young‐onset diabetes with exome sequencing

Activating mutations in the ABCC8 gene cause diabetes and inactivating mutations usually cause hyperinsulinemic hypoglycemia in infancy. Patients with hypoglycemia in infancy due to a heterozygous inactivating mutation have been reported to occasionally progress to diabetes later in life. We explored the gene responsible for diabetes in two brothers, who were suspected to have diabetes at 15 and 18 years‐of‐age, respectively, with whole exome sequencing, and identified a compound heterozygous ABCC8 gene mutation (p.Arg168Cys and p.Arg1421Cys). Although their father and mother were heterozygous carriers of the p.Arg168Cys and the p.Arg1421Cys mutation, respectively, neither parent had diabetes. These mutations have been reported to be responsible for hypoglycemia in infancy and function as an inactivating mutation. Our results suggest that the inactivating ABCC8 gene mutation is also important in the etiology of diabetes.