Impact of the catechol-O-methyltransferase Val158Met polymorphism on the pharmacokinetics of L-dopa and its metabolite 3-O-methyldopa in combination with entacapone.

In the pharmacotherapy of patients with Parkinson's disease (PD), entacapone reduces the peripheral metabolism of L-dopa to 3-O-methyldopa (3-OMD), thereby prolonging the half-life (t1/2) of L-dopa and increasing the area under the concentration curve (AUC). The effect of entacapone on the pharmacokinetics of L-dopa differs between patients with high-activity (H/H) and low-activity (L/L) catechol-O-methyltransferase (COMT) Val158Met polymorphisms, but the effects are unclear in heterozygous (H/L) patients. 3-OMD has a detrimental effect and results in a poor response to L-dopa treatment in patients with PD; however, the influence of this polymorphism on the production of 3-OMD remains unknown. Therefore, the present study aimed to clarify the effect of the COMT Val158Met polymorphism on the concentrations of L-dopa and 3-OMD in the presence of entacapone. We performed an open-label, single-period, single-sequence crossover study at two sites in Japan. The study included 54 Japanese patients with PD, who underwent an acute L-dopa administration test with and without 100 mg entacapone on two different days. Entacapone increased L-dopa AUC0-infinity by 1.59 ± 0.26-fold in the H/H group, which was significantly higher than that in the H/L (1.41 ± 0.36-fold) and L/L (1.28 ± 0.21-fold) groups (p < 0.05). The concurrent administration of L-dopa with entacapone suppressed the increase in 3-OMD levels compared with L-dopa alone in all genotypes. Our results suggest that the COMT Val158Met polymorphism may be an informative biomarker for individualized dose adjustment of COMT inhibitors in the treatment of PD.

A case of malignant insulinoma: successful control of glycemic fluctuation by replacing octreotide injections with octreotide LAR injections.

A 73-year-old woman with malignant insulinoma was treated with 100 µg/day octreotide for unresected insulinoma and liver metastases. The daily administration of the drug induced hyperglycemia after dinner in addition to existing fasting hypoglycemia possibly because this drug suppressed both insulin and glucagon secretion and its blood concentration was unstable. After replacing a daily injection of octreotide with a monthly injection of octreotide long-acting repeatable (LAR), blood glucose levels stabilized within the normal range. The findings of the present study showed that octreotide LAR could be useful for the long-term treatment of unresectable insulinomas.

NOTCH2NLC mutation-positive neuronal intranuclear inclusion disease with retinal dystrophy: A case report and literature review.

INTRODUCTION: Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that produces a broad spectrum of clinical conditions such as dementia, upper motor neuron involvement, extrapyramidal symptoms, and neuropathy. Some studies have reported ophthalmological conditions associated with the disease; however, the details of these conditions remain unclear. PATIENT CONCERNS: We report a 63-year-old Japanese female with cognitive decline, blurred vision, photophobia, and color blindness at 52 years of age who was diagnosed with cone dystrophy. She also had anxiety, insomnia, depression, delusions, hallucinations, a wide-based gait with short steps, and urinary incontinence. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Magnetic resonance imaging revealed diffuse cerebral white matter changes and subcortical hyperintensity on diffusion-weighted imaging. Skin biopsy showed p62-positive intranuclear inclusions in sweat glands. NOTCH2NLC gene analysis revealed abnormal GGC expansion; therefore, NIID was diagnosed. CONCLUSION: NOTCH2NLC mutation-positive NIID may be associated with retinal dystrophy. Brain magnetic resonance imaging and skin biopsy are helpful diagnostic clues, and gene analysis is crucial for accurate diagnosis and appropriate management.

Tenascin-C is expressed in abdominal aortic aneurysm tissue with an active degradation process.

Abdominal aortic aneurysm (AAA) is a common disease caused by segmental weakening of the aortic walls and progressive aortic dilation leading to the eventual rupture of the aorta. Currently no biomarkers have been established to indicate the disease status of AAA. Tenascin-C (TN-C) is a matricellular protein that is synthesized under pathological conditions. In the current study, we related TN-C expression to the clinical course and the histopathology of AAA to investigate whether the pattern of TN-C expression could indicate the status of AAA. We found that TN-C and matrix metalloproteinase (MMP)-9 were highly expressed in human AAA. In individual human AAA TN-C deposition associated with the tissue destruction, overlapped mainly with the smooth muscle actin-positive cells, and showed a pattern distinct from macrophages and MMP-9. In the mouse model of AAA high TN-C expression was associated with rapid expansion of the AAA diameter. Histological analysis revealed that TN-C was produced mainly by vascular smooth muscle cells and was deposited in the medial layer of the aorta during tissue inflammation and excessive destructive activities. Our findings suggest that TN-C may be a useful biomarker for indicating the pathological status of smooth muscle cells and interstitial cells in AAA.

Cell Proliferation PET Imaging with 4DST PET/CT in Colorectal Adenocarcinoma and Adenoma.

An age of 70-year-old man was incidentally found two focal high 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) uptake in the descending colon and in the sigmoid colon. We observed the feature of these two areas in the preplanned 4'-[methyl-11C]-thiothymidine (4DST) positron emission tomography (PET)/computed Tomography (CT)providing cell proliferation imaging. A mass forming high 4DST uptake in the descending colon and focal moderate 4DST uptake in the sigmoid colon was confirmed, and that were proven pathologically as adenocarcinoma and moderate to severe type tubular adenoma, respectively. This is the first report to present that colorectal adenoma can be visualized by proliferation PET imaging and the degree of uptake may enable discrimination of colorectal adenoma from adenocarcinoma, based on pathological considerations.

Cybernic treatment with wearable cyborg Hybrid Assistive Limb (HAL) improves ambulatory function in patients with slowly progressive rare neuromuscular diseases: a multicentre, randomised, controlled crossover trial for efficacy and safety (NCY-3001).

BACKGROUND: Rare neuromuscular diseases such as spinal muscular atrophy, spinal bulbar muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, distal myopathy, sporadic inclusion body myositis, congenital myopathy, and amyotrophic lateral sclerosis lead to incurable amyotrophy and consequent loss of ambulation. Thus far, no therapeutic approaches have been successful in recovering the ambulatory ability. Thus, the aim of this trial was to evaluate the efficacy and safety of cybernic treatment with a wearable cyborg Hybrid Assistive Limb (HAL, Lower Limb Type) in improving the ambulatory function in those patients. RESULTS: We conducted an open-label, randomised, controlled crossover trial to test HAL at nine hospitals between March 6, 2013 and August 8, 2014. Eligible patients were older than 18 years and had a diagnosis of neuromuscular disease as specified above. They were unable to walk for 10 m independently and had neither respiratory failure nor rapid deterioration in gait. The primary endpoint was the distance passed during a two-minute walk test (2MWT). The secondary endpoints were walking speed, cadence, and step length during the 10-m walk test (10MWT), muscle strength by manual muscle testing (MMT), and a series of functional measures. Adverse events and failures/problems/errors with HAL were also evaluated. Thirty patients were randomly assigned to groups A or B, with each group of 15 receiving both treatments in a crossover design. The efficacy of a 40-min walking program performed nine times was compared between HAL plus a hoist and a hoist only. The final analysis included 13 and 11 patients in groups A and B, respectively. Cybernic treatment with HAL resulted in a 10.066% significantly improved distance in 2MWT (95% confidence interval, 0.667-19.464; p = 0.0369) compared with the hoist only treatment. Among the secondary endpoints, the total scores of MMT and cadence at 10MWT were the only ones that showed significant improvement. The only adverse effects were slight to mild myalgia, back pain, and contact skin troubles, which were easily remedied. CONCLUSIONS: HAL is a new treatment device for walking exercise, proven to be more effective than the conventional method in patients with incurable neuromuscular diseases. TRIAL REGISTRATION: JMACTR, JMA-IIA00156.

[Two cases of cancer in the reconstructed gastric tube after resection of esophageal cancer -An analysis of 7 cases in our hospital-].

We review 7 cases of cancer in the reconstructed gastric tube after resection for esophageal cancer in our hospital. From this experience, we report 2 cases which were resected curatively by endoscopic or open surgery. Case 1, a 61-year-old man received a subtotal esophagectomy reconstructed by a gastric tube, retromediastinally. 85 months after operation, cancer in the gastric tube was detected endoscopically, and partial resection was performed. Case 2, a 75-year-old man received subtotal esophagectomy reconstructed by a gastric tube via a retro-mediastinal route. After 104 months, early cancer in the gastric tube was diagnosed and we performed endoscopic mucosal dissection (ESD). Long-term follow-up by regular endoscopy is necessary in patients after esophageal surgery to screen for cancer in the reconstructed gastric tube.

Successful treatment tailored to each splanchnic arterial lesion due to segmental arterial mediolysis (SAM): report of a case.

Segmental arterial mediolysis (SAM) is a rare condition characterized by splanchnic arterial catastrophe caused by mediolysis. We report a 59-year-old man with a ruptured splenic arterial aneurysm who was successfully treated by coil embolization. He underwent additional resection of large gastroepiploic and residual splenic aneurysms. Pathological examination showed mediolysis and tearing, compatible with SAM. Furthermore, he developed acute dissection of the superior mesenteric artery (SMA) one and a half years later, demonstrated by computed tomography. This report demonstrates that SAM is characterized by multiple lesions of the splanchnic arteries at different times, and requires treatment suited to the lesions, including careful long-term observation.

Comparison of the number of spermatogonia and Sertoli cells in fetal and neonatal testes autopsied between 1958-1964 and 1989-1998 in Tokyo.

Background: Studies in several countries have reported a decline in human sperm quality similar to that observed in wild animals. To quantify whether the number of sperm in humans has decreased and whether humans are affected by similar environmental influences, we compared the number of spermatogonia and Sertoli cells in human fetal and neonatal testes autopsied at two institutions in Tokyo between 1958-1964 (term A) and 1989-1998 (term B), with special attention to chronological changes during gestation. Methods: We used an immunohistochemical method with antibody against neuron-specific enolase to determine the percentage of seminiferous tubules containing spermatogonia in the formalin-fixed tissue samples, and a morphometrical method using a dissector to count the number of spermatogonia. Results: There were no significant statistical differences between the two time periods in the regression parameters compared for the number of spermatogonia and Sertoli cells, nor was there a remarkable difference in the estimated number of Leydig cells. Conclusion: The results indicate that even if there has been a deterioration in human semen quality, it is not necessarily caused by endocrine disruption of fetal testicular development. (Reprod Med Biol 2006; 5: 65-70).

Histological difference between pulsed wave laser and continuous wave laser in endovenous laser ablation.

BACKGROUND: Endovenous laser ablation to saphenous veins has been popular as a minimally invasive treatment for chronic venous insufficiency. However, adverse effects after endovenous laser ablation using continuous wave laser still remain. Pulsed wave with enough short pulse duration and sufficiently long thermal relaxation time may avoid the excess energy delivery, which leads to the perforation of the vein wall. METHOD: (1) Free radiation: Laser is radiated in blood for 10 s. (2) Endovenous laser ablation: Veins were filled with blood and placed in saline. Endovenous laser ablations were performed. RESULTS: (1) There were clots on the fiber tips with continuous wave laser while no clots with pulsed wave laser. (2) In 980-nm continuous wave, four of 15 specimens had ulcers and 11 of 15 had perforation. In 1470-nm continuous wave with 120 J/cm of linear endovenous energy density, two of three presented ulcers and one of three showed perforation. In 1470-nm continuous wave with 60 J/cm of linear endovenous energy density, two of four had ulcers and two of four had perforation. In 1320-nm pulsed wave, there were neither ulcers nor perforation in the specimens. CONCLUSIONS: While endovenous laser ablation using continuous wave results in perforation in many cases, pulsed wave does not lead to perforation.

[A case of myasthenia gravis following sarcoidosis and rheumatoid arthritis].

We report an elderly woman with sarcoidosis and rheumatoid arthritis who subsequently developed myasthenia gravis. She was given a diagnose of rheumatoid arthritis at the age of 65 years and sarcoidosis, proved by multiple lymphadenopathy with noncaseating granuloma at the age of 67. Prednisolone, methotrexate, and etanercept had been administrated for rheumatoid arthritis. She consulted our hospital because of bilateral ptosis with diurnal fluctuation at the age of 72. Myasthenia gravis was confirmed by an elevated serum anti-acetylcholine receptor antibody titer (1,100 nmol/l, normal <0.2) and a positive edrophonium test. A chest CT showed a small granular structure in the anterior mediastinum, suggesting thymic hyperplasia. This is the first reported case of myasthenia gravis complicated by sarcoidosis and rheumatoid arthritis. Administration of etanercept may be involved in the onset of myasthenia gravis.

Depression of local cell-mediated immunity and histological characteristics of disseminated AIDS-related Mycobacterium avium infection after the initiation of antiretroviral therapy.

OBJECTIVE: The aim of the present study was to examine the immunohistological characteristics of disseminated Mycobacterium avium infection after the initiation of antiretroviral therapy (ART) for acquired immunodeficiency syndrome (AIDS). METHODS: We histologically investigated five autopsied AIDS patients with systemic M. avium infection. RESULTS: The inflammatory cell composition in the affected tissues was assessed using immunohistochemistry. The celiac lymph nodes and intestinal canal were the most commonly involved organs in the AIDS cases. The most common histological feature was unstructured aggregation of histiocytes. Immunohistochemistry revealed depression of CD4(+), CD8(+) and CD57(+) cells in the gut lamina propria and mesenteric lymph nodes. CONCLUSION: These findings suggest that local cell-mediated immunity is depressed in affected tissues and that the primary histological feature is poor organization of granulomas in mycobacterial lesions, despite the administration of adequate ART.

Impact of decreased estimated glomerular filtration rate on Japanese acute stroke and its subtype.

OBJECTIVE: Patients with chronic kidney disease (CKD) are at a high risk for cardiovascular diseases including stroke. However, the characteristics of the stroke subtypes in patients with CKD remain to be determined. METHODS: We investigated the associations between stroke subtypes and estimated glomerular filtration rate (eGFR), and traditional risk factors in 451 (males, 239; mean age, 71.1 y) acute stroke patients at our hospital between 2006 and 2010. RESULTS: The stroke subtype was cardiogenic cerebral embolism in 129 (29%), cerebral hemorrhage in 104 (23%), unclassified cerebral infarction in 65 (14%), lacunar infarction in 65 (14%), subarachnoid hemorrhage in 41 (9%), atherothrombosis in 30 (7%), and transient ischemic attacks in 17 (4%). Among the 451 patients, 134 (30%) had CKD with eGFR <60 mL/min/1.73 m2. Compared with a group without CKD, mean age (75.9 vs. 69.0 years, p<0.05), the prevalence of atrial fibrillation (AF) (44% vs. 21%, p<0.01) and a history of cardiovascular disease (37% vs. 19%, p<0.01) were significantly higher in that with CKD. A comparison of stroke subtypes revealed a significantly higher incidence of cardiogenic cerebral embolism (36% vs. 26%, p<0.05) in the group with, than without CKD. CONCLUSION: We showed the prevalence of CKD in about 30% of acute stroke patients, and those patients were older, had a significantly higher prevalence of AF and a higher rate of cardiogenic cerebral embolism compared with patients without CKD. Thus, strict control of blood pressure and management of AF should be important to prevent stroke among patients with CKD.

Severely fluctuating blood glucose levels associated with a somatostatin-producing ovarian neuroendocrine tumor.

CONTEXT: Somatostatin-producing tumors are a rare type of neuroendocrine tumor. Their effects on blood glucose levels have been variously reported, and detailed reports have been scarce. OBJECTIVE: The aim of this study was to identify the reasons for the extraordinary blood glucose fluctuations in a case with no previous history of diabetes. PATIENTS AND METHODS: A 68-yr-old nondiabetic woman with an ovarian tumor was suffering from hyper- and hypoglycemia. Based on the results of an oral glucose tolerance test and continuous glucose monitoring, we speculated that the fluctuating blood glucose level was accompanied not only by a low insulin level but also by low counter-regulatory hormones levels, and that those broad hormonal suppressions were caused by a high somatostatin level produced in the ovarian tumor. We performed an oophorectomy and assessed the pathology of the tumor and changes in the blood glucose profile as well as hormonal levels postoperatively. RESULTS: The blood glucose level was completely normalized after the oophorectomy. Insulin secretion was also normalized. Histological examination showed that the tumor comprised a mature cystic teratoma and a stromal carcinoid. Immunohistochemically, the stromal carcinoid component was positive for somatostatin. The somatostatin level was 8505 pmol/liter preoperatively, which dropped down to 71.5 pmol/liter postoperatively. We found two previous reports of somatostatin-producing ovarian neuroendocrine tumors. Somatostatin levels among cases of ovarian origin were much higher than those among cases of gastrointestinal origins, and cases of ovarian origin all experienced blood glucose fluctuations. CONCLUSION: Extremely high somatostatin levels and blood glucose fluctuations may be characteristics of somatostatin-producing ovarian neuroendocrine tumors.

4'-[Methyl-11C]-thiothymidine PET/CT for proliferation imaging in non-small cell lung cancer.

UNLABELLED: A new tracer, 4'-[methyl-(11)C]-thiothymidine ((11)C-4DST), has been developed as an in vivo cell proliferation marker based on the DNA incorporation method. This study evaluated the potential of (11)C-4DST PET/CT for imaging proliferation in non-small cell lung cancer (NSCLC), compared with (18)F-FDG PET/CT. METHODS: Eighteen patients with lung lesions were examined by PET/CT using (11)C-4DST and (18)F-FDG. We constructed decay-corrected time-activity curves of 9 major regions as the mean standardized uptake value. We then compared the maximum standardized uptake value (SUVmax) of lung tumors on both (11)C-4DST and (18)F-FDG PET/CT with the Ki-67 index of cellular proliferation and with CD31-positive vessels as a marker of angiogenesis in surgical pathology. RESULTS: NSCLC was pathologically confirmed in 19 lesions of 18 patients. Physiologic accumulation of (11)C-4DST was high in liver, kidney, and bone marrow and low in aorta, brain, lung, and myocardium. Biodistribution of (11)C-4DST was almost stable by 20 min after injection of (11)C-4DST. Mean (11)C-4DST SUVmax for lung cancer was 2.9 ± 1.0 (range, 1.5-4.7), significantly different from mean (18)F-FDG SUVmax, which was 6.2 ± 4.5 (range, 0.9-17.3; P < 0.001). The correlation coefficient between SUVmax and Ki-67 index was higher with (11)C-4DST (r = 0.82) than with (18)F-FDG (r = 0.71). The correlation coefficient between SUVmax and CD31 was low with both (11)C-4DST (r = 0.21) and (18)F-FDG (r = 0.21), showing no significant difference between the tracers. CONCLUSION: A higher correlation with proliferation of lung tumors was seen for (11)C-4DST than for (18)F-FDG. (11)C-4DST PET/CT may allow noninvasive imaging of DNA synthesis in NSCLC.

A patient with diabetes and breast cancer in whom virilization was caused by a testosterone-producing mature cystic teratoma containing a Brenner tumor.

A 74-year-old woman with impaired glucose tolerance exhibited virilization. An examination of various hormone levels showed normal pituitary hormone and adrenal hormone levels. However, the patient's blood testosterone level was remarkably high and was suspected of having caused the virilization. An abdominal computed tomography revealed a multilocular cystoma in the left ovary with the features of a mature cystic teratoma. In addition, a chest computed tomography revealed the presence of a mass in the left breast that was subsequently diagnosed as breast cancer based on the results of a biopsy. After the simultaneous surgical resection of the ovarian and breast tumors, her blood testosterone level decreased. The mature cystic teratoma containing a Brenner tumor was considered to be responsible for the high testosterone level because of the presence of androgenic enzymes. This case is extremely rare, but the case was accurately diagnosed through a comprehensive analysis.

Immunohistochemical findings in the pancreatic islets of a patient with transfusional iron overload and diabetes: case report.

Excessive iron storage sometimes causes diabetes in patients with hemochromatosis, a disease caused by iron overloading. We performed an immunohistochemical analysis to study an autopsy case of aplastic anemia and diabetic hemochromatosis caused by frequent blood transfusions, and extensive hemosiderin deposition was observed in the liver and pancreas. The pancreatic islets of the patient and a control subject were stained to detect glucagon, insulin, and proinsulin. Significantly lower levels of immunoreactivity with both insulin antibodies and proinsulin antibodies, but not with glucagon antibodies, was observed in the islet cells in the patient's tissue than in the islet cells of the control. Hemosiderin deposition in the islets is known to be exclusively distributed in the ß-cells, thus, selective iron-induced damage to the ß-cells may have affected insulin synthesis and secretion and led to glucose intolerance in the patient.

Diagnostic usefulness of 18F-FDG PET/CT in the differentiation of pulmonary artery sarcoma and pulmonary embolism.

OBJECTIVE: The purpose of this study was to evaluate the usefulness of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in differentiating pulmonary artery sarcoma from pulmonary embolism. MATERIALS AND METHODS: We evaluated three patients with pulmonary artery sarcoma and 10 patients with proximal pulmonary embolism (6 men and 7 women, ranging in age from 35 to 94 years). All the patients had evidence of perfusion defects in their proximal pulmonary arteries on contrast-enhanced computed tomography (CT) scans performed prior to PET/CT. The maximum standardized uptake value (SUV(max)) of FDG uptake in all the lesions was measured using PET/CT. The location of lesions, background uptake or thrombi in the legs were evaluated in both groups as basic characteristics. RESULTS: The mean SUV(max) of the pulmonary artery sarcomas (7.63 +/- 2.21, n = 3) and the pulmonary embolisms (2.31 +/- 0.41, n = 10) were significantly different (P < 0.05). The mean times between the initial contrast-enhanced CT scan and PET/CT scan were similar in both groups (P = 0.7804). The differences in the locations in lesions between the three groups (right, left and bilateral) or background uptakes were not significant. CONCLUSION: FDG PET/CT could distinguish pulmonary artery sarcoma from pulmonary embolism based on the SUV(max) value.