ACAT1-associated Late Endosomes Improve NPC

We previously demonstrated that macrophages exhibit endoplasmic reticulum fragmentation under cholesterol-rich conditions, which results in the generation of acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1)-associated late endosomes/lysosomes (ACAT1-LE). ACAT1-LE efficiently esterify free cholesterol in loco, even with abnormal egress of free cholesterol from late endosomes. Because impaired free cholesterol transport from late endosomes results in Niemann-Pick type C disease (NPC), the induction of ACAT1-LE is a potential therapeutic intervention for NPC. To examine the effects of ACAT1-LE induction on intracellular cholesterol metabolism, we incubated bone marrow-derived macrophages possessing NPC phenotype (npc1–/–) with methyl-β-cyclodextrin-cholesterol complex (mβCD-cho), a cholesterol donor. Immunofluorescence confocal microscopy revealed that mβCD-cho treatment of npc1–/– macrophages resulted in significant colocalization of signals from ACAT1 and lysosome-associated membrane protein 2, a late endosome/lysosome marker. npc1–/– macrophages contained significant amounts of free cholesterol with negligible amounts of cholesteryl ester, while wild-type macrophages possessed the same amounts of both cholesterols. mβCD-cho treatment also induced marked restoration of cholesterol esterification activity. mβCD-cho administration in neonate npc1–/– mice improved survival. These results indicate that ACAT1-LE induction in npc1–/– mice corrects impaired intracellular cholesterol metabolism and that restoring cholesterol esterification improves prognosis of npc1–/–. These data suggest that ACAT1-LE induction is a potential alternative therapeutic strategy for NPC

Thoracoscopic esophagectomy was effective in a case of lower esophageal stenosis due to recurrence of achalasia after myotomy 40 years previously

When planning surgery for achalasia, it is important to plan for adequate myotomy and prevention of reflux. However, achalasia may recur if the procedure was inadequate or in patients with a long-term course. The present case is a 68-year-old woman who underwent myotomy of the lower esophageal sphincter 40 years ago, but recently reported difficulty in swallowing. Dilatation of the thoracic esophagus and stenosis of the abdominal esophagus were identified by examination, and the patient was diagnosed with recurrence of achalasia. After percutaneous endoscopic gastrostomy was performed to recover nutritional status, thoracoscopic esophagectomy was carried out. The patient'spost-operative course was uneventful and oral intake was enabled. At the time of writing, there has been no re-recurrence. There is no standard therapy for post-operative recurrence of achalasia. We believe that thoracoscopic esophagectomy for the recurrence of achalasia is a safe and minimally invasive alternative to conventional surgery

Thoracoscopic esophagectomy was effective in a case of lower esophageal stenosis due to recurrence of achalasia after myotomy 40 years previously

When planning surgery for achalasia, it is important to plan for adequate myotomy and prevention of reflux. However, achalasia may recur if the procedure was inadequate or in patients with a long-term course. The present case is a 68-year-old woman who underwent myotomy of the lower esophageal sphincter 40 years ago, but recently reported difficulty in swallowing. Dilatation of the thoracic esophagus and stenosis of the abdominal esophagus were identified by examination, and the patient was diagnosed with recurrence of achalasia. After percutaneous endoscopic gastrostomy was performed to recover nutritional status, thoracoscopic esophagectomy was carried out. The patient'spost-operative course was uneventful and oral intake was enabled. At the time of writing, there has been no re-recurrence. There is no standard therapy for post-operative recurrence of achalasia. We believe that thoracoscopic esophagectomy for the recurrence of achalasia is a safe and minimally invasive alternative to conventional surgery

Vaccination and Infection as Causative Factors in Japanese Patients With Rasmussen Syndrome: Molecular Mimicry and HLA Class I

Rasmussen syndrome is an intractable epilepsy with a putative causal relation with cellular and humoral autoimmunity. Almost half of the patients have some preceding causative factors, with infections found in 38.2%, vaccinations in 5.9% and head trauma in 8.9% of Japanese patients. In a patient with seizure onset after influenza A infections, cross-reaction of the patient's lymphocytes with GluRε2 and influenza vaccine components was demonstrated by lymphocyte stimulation test. Database analyses revealed that influenza A virus hemagglutinin and GluRε2 molecules contain peptides with the patient's HLA class I binding motif (HLA − A*0201). The relative risks of HLA class I genotypes for Rasmussen syndrome are 6.1 (A*2402), 6.4 (A*0201), 6.3 (A*2601) and 11.4 (B*4601). The relative risks of HLA class I-A and B haplotypes are infinity (A*2601+B*5401), 21.1 (A*2402+B*1501), 13.3 (A*2402+B*4801) and 5.1 (A*2402+B*5201). Some alleles and haplotypes of HLA class I may be the risk factors in Japanese patients. Cross-reactivity of cytotoxic T lymphocytes may contribute to the processes leading from infection to the involvement of CNS

Use of fluid-attenuated inversion recovery (FLAIR) pulse sequences for differential diagnosis of hepatic hemangiomas and hepatic cysts

Fluid-attenuated inversion recovery (FLAIR) imaging of hepatic hemangiomas (10 patients, 16 lesions) and hepatic cysts (8 patients, 10 lesions) was performed. All hemangiomas were hypointense on T1-weighted images and hyperintense on T2-weighted images. With Gd-DTPA (0.1 mmol/kg), all hemangiomas were enhanced but not all cysts. It was necessary to perform contrast enhanced imaging to differentiate hepatic hemangiomas from hepatic cysts. However, on FLAIR imaging, hepatic hemangiomas were strongly hyperintense and 9 of the 10 hepatic cysts were isointense. One of the hepatic cysts was slightly hyperintense. FLAIR images were useful in differential diagnosis of hepatic hemangiomas and hepatic cysts without using Gd-DTPA.</p

Cerebral Hemodynamics in Speech-Related Cortical Areas: Articulation Learning Involves the Inferior Frontal Gyrus, Ventral Sensory-Motor Cortex, and Parietal-Temporal Sylvian Area

Although motor training programs have been applied to childhood apraxia of speech (AOS), the neural mechanisms of articulation learning are not well understood. To this aim, we recorded cerebral hemodynamic activity in the left hemisphere of healthy subjects (n = 15) during articulation learning. We used near-infrared spectroscopy (NIRS) while articulated voices were recorded and analyzed using spectrograms. The study consisted of two experimental sessions (modified and control sessions) in which participants were asked to repeat the articulation of the syllables “i-chi-ni” with and without an occlusal splint. This splint was used to increase the vertical dimension of occlusion to mimic conditions of articulation disorder. There were more articulation errors in the modified session, but number of errors were decreased in the final half of the modified session; this suggests that articulation learning took place. The hemodynamic NIRS data revealed significant activation during articulation in the frontal, parietal, and temporal cortices. These areas are involved in phonological processing and articulation planning and execution, and included the following areas: (i) the ventral sensory-motor cortex (vSMC), including the Rolandic operculum, precentral gyrus, and postcentral gyrus, (ii) the dorsal sensory-motor cortex, including the precentral and postcentral gyri, (iii) the opercular part of the inferior frontal gyrus (IFGoperc), (iv) the temporal cortex, including the superior temporal gyrus, and (v) the inferior parietal lobe (IPL), including the supramarginal and angular gyri. The posterior Sylvian fissure at the parietal–temporal boundary (area Spt) was selectively activated in the modified session. Furthermore, hemodynamic activity in the IFGoperc and vSMC was increased in the final half of the modified session compared with its initial half, and negatively correlated with articulation errors during articulation learning in the modified session. The present results suggest an essential role of the frontal regions, including the IFGoperc and vSMC, in articulation learning, with sensory feedback through area Spt and the IPL. The present study provides clues to the underlying pathology and treatment of childhood apraxia of speech

Detection of subependymal veins using high-resolution magnetic resonance venography

High-resolution magnetic resonance venography (HR-MRV) of intracranial subependymal veins using a two-dimensional Fourier-transform time-of-flight technique was performed on normal volunteers and clinical cases of cerebral disease. For the pulse sequence, fast-field-echo sequence was used with the following parameters: TR/TE/ flip angle = 34ms/12ms/50deg., 256 x 256 matrix, 1 mm effective slice thickness, 150mm field of view, and one signal acquisition. Sequential vertical coronal sections were taken against the skull base. The anterior septal vein, the medial atrial vein, the anterior caudate vein and thalamostriate vein were detected in all subjects. In all clinical cases, HR-MRV was equal in diagnostic capability to conventional cerebral angiography.</p

Left atrial extension of metastatic lung tumor via pulmonary vein: report on the first case of Ewing sarcoma

Extension of metastatic lung tumors into the left atrium via pulmonary veins is rare. Here, we report the first case of Ewing sarcoma exhibiting such extension. A 31-year-old man with pulmonary metastasis from Ewing sarcoma presented with a mass in the left lung, extending to the left atrium through the left inferior pulmonary vein. As the patient was considered to be at risk of tumor embolism, the mass was excised surgically

Management of axitinib (AG-013736)-induced fatigue and thyroid dysfunction, and predictive biomarkers of axitinib exposure: results from phase I studies in Japanese patients

Background Axitinib is an oral, potent and selective inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2 and 3. We report on data obtained from 18 Japanese patients with advanced solid tumors in two phase I trials that evaluated the safety, pharmacokinetics and antitumor activity of axitinib and also examined potential biomarkers. Methods Six patients received a single 5-mg dose of axitinib followed by 5 mg twice daily (BID), and an additional six patients received axitinib 5 mg BID only. Another six patients received axitinib at 5-mg, 7-mg and 10-mg single doses followed by 5 mg BID. Results Plasma pharmacokinetics following single doses of axitinib was generally linear. Common treatment-related adverse events were fatigue (83%), anorexia (72%), diarrhea (67%), hand–foot syndrome (67%) and hypertension (61%). Sixteen patients (89%) experienced thyroid-stimulating hormone (TSH) elevation. Grade 3/4 toxicities included hypertension (33%) and fatigue (28%). No grade 3/4 fatigue occurred in patients who started thyroid hormone replacement therapy when TSH was elevated. Thyroglobulin elevation was observed in all patients who continued treatment with axitinib for ≥3 months. Abnormal TSH correlated with exposure to axitinib (r = 0.72). Decrease in soluble (s) VEGFR-2 levels significantly correlated with exposure to axitinib (r = –0.94). Axitinib showed antitumor activity across multiple tumor types. Conclusions Axitinib-related thyroid dysfunction could be due to a direct effect on the thyroid gland. Grade 3/4 fatigue and hypothyroidism appear to be controllable with use of thyroid hormone replacement therapy. sVEGFR-2 and TSH may act as biomarkers of axitinib plasma exposure