Polymorphism in senile dementia of the Alzheimer type from a viewpoint of senile plaque formation

The present article describes polymorphism in senile dementia of the Alzheimer type (SDAT) from a view point of senile plaque formation. Senile dementia of the Alzheimer type is a disorder in which cerebral β amyloid deposition progresses with age and, finally, causes dementia. Aging, apolipoprotein E (apoE) ε4 gene and head trauma are risk factors for senile plaque formation. Senile plaques begin to appear in some subjects in their 40s, whereas other subjects over the age of 100 years do not have any senile plaques. The apoE gene and other unknown factors may cause this difference in the age onset of plaque formation. Plaque density reaches a plateau before clinical dementia appears. As a result, some non-demented subjects have considerable amounts of senile plaques and it may take 20–30 years from the beginning of senile plaque formation for the clinical manifestations of dementia to appear. In this subclinical period, areas of plaque formation spread throughout the cortex from association areas to the primary cortex. The pattern of this progression is consistent in SDAT subjects and, therefore, the pattern of plaque distribution is an important factor for the pathological diagnosis of SDAT. The predominant plaque type is also different among subjects: whereas diffuse plaques are predominant in some SDAT subjects, typical plaques and amyloid angiopathy are predominant in others. This polymorphism cannot be explained by the apoE genotype. Further studies are required to understand the relationship between plaque formation and both known and yet unidentified risk factors in order to explain the polymorphism of SDAT.     

Phase I and pharmacokinetic study of edotecarin, a novel topoisomerase I inhibitor, administered once every 3 weeks in patients with solid tumors

Purpose: Edotecarin (J-107088) is a potent indolocarbazole topoisomerase I inhibitor which is structurally distinct from the camptothecins. This study aimed to determine the maximum tolerated dose (MTD), the recommended dose for future Phase II studies and the safety, pharmacokinetic profile, and preliminary antitumor activity of edotecarin in a population of patients with advanced solid tumors. Experimental design: Edotecarin was administered as a single dose by IV infusion over 2 h every 21 days (with 1 week permitted for recovery from toxicities, if needed) in patients with advanced solid tumors. Doses ranged from 8 to 15 mg/m². Pharmacokinetic assessments were performed during and after the first administration. Results: Twenty-four patients received 61 cycles of therapy. Dose-limiting toxicities (infection, febrile neutropenia, constipation, ileus, and prolonged grade 4 granulocytopenia) were observed in 3 of 5 evaluable patients at the 15 mg/m² dose, defining the MTD. The most commonly reported non-hematologic toxicities were anorexia, nausea, malaise, and constipation. Diarrhea was neither frequent nor severe. Neutropenia was the most common hematologic toxicity (grade 3–4 in 21/23 patients during cycle 1). Plasma concentrations of edotecarin rose rapidly following the start of the 2-hour infusion, reaching C _max values of 103±17 ng/ml at the 13 mg/m² dose, and decreased steeply after the end of the infusion. Plasma concentrations declined to approximately 1–2 ng/ml at 26 h post start of infusion, the last PK sampling time point. The mean apparent plasma half-life of the drug was 20 h, which should be considered a preliminary estimate until results from studies with a longer duration of plasma sampling are available. A mean of 1.4–3.6% of the dose was recovered as unchanged drug in the urine over 48 h. Unconfirmed tumor regression ≥50% was observed in 2 patients, 1 with metastatic gastric carcinoma and 1 with esophageal cancer. Conclusions: The MTD of edotecarin administered IV over 2 h every 21 days was 15 mg/m². The recommended dose for Phase II studies with a 3-week schedule (with 1 week permitted for recovery from toxicities, if needed) is 13 mg/m². The observed safety profile and preliminary evidence of antitumor activity warrant further investigation of this drug in solid tumors.Presented at the American Society of Clinical Oncology 2002 Annual Meeting (abstract no. 385).     

Ischemia-reperfusion injury causes oxidative stress and apoptosis of Schwann cell in acute and chronic experimental diabetic neuropathy

Mild ischemia-reperfusion (IR) injury to diabetic peripheral nerve is known to cause severe ischemic fiber degeneration. Little information is available on its effects on Schwann cell (SC). In this study, we evaluated oxidative stress and apoptosis of SC following mild IR, using immunohistochemistry in streptozotocin (STZ)- induced diabetic rats. Twenty-six rats were divided into four groups according to the duration of diabetes: 1- month STZ-induced diabetic group (n=7) and age-matched control group (n=7); 4-month STZ-induced diabetic group (n=6) and age-matched control group (n=6). Using our established IR model of 3 h of ischemia followed by 7 days of reperfusion, sciatic and tibial nerves were harvested and labeled with 8-hydroxydeoxyguanosine (8-OHdG; oxidative stress marker), caspase-3 (apoptotic executor), and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) activity (apoptotic indicator). Marked positive staining with 8-OHdG, caspase-3, and TUNEL were found in diabetic ischemic nerves (right side) following IR in both 1-month and 4-month groups. Only mild positive staining or no staining was seen in the nonischemic side (left side) of diabetic and age-matched control groups. Co-labeling with S-100 confirmed that the cells labeled with 8-OHdG, caspase3, and TUNEL were SC. SC was susceptible to oxidative injury and apoptosis in experimental diabetic neuropathy when subjected to mild IR injury.     

Benefits of off-campus education for students in the health sciences: a text-mining analysis

ABSTRACT: BACKGROUND: In Japan, few community-based approaches have been adopted in health-care professional education, and the appropriate content for such approaches has not been clarified. In establishing community-based education for health-care professionals, clarification of its learning effects is required. A community-based educational program was started in 2009 in the health sciences course at Gunma University, and one of the main elements in this program is conducting classes outside school. The purpose of this study was to investigate using text-analysis methods how the off-campus program affects students. METHODS: In all, 116 self-assessment worksheets submitted by students after participating in the off-campus classes were decomposed into words. The extracted words were carefully selected from the perspective of contained meaning or content. With the selected terms, the relations to each word were analyzed by means of cluster analysis. RESULTS: Cluster analysis was used to select and divide 32 extracted words into four clusters: cluster 1---"actually/direct," "learn/watch/hear," "how," "experience/participation," "local residents," "atmosphere in community-based clinical care settings," "favorable," "communication/conversation," and "study"; cluster 2---"work of staff member" and "role"; cluster 3---"interaction/communication," "understanding," "feel," "significant/important/necessity," and "think"; and cluster 4---"community," "confusing," "enjoyable," "proactive," "knowledge," "academic knowledge," and "class." CONCLUSIONS: The students who participated in the program achieved different types of learning through the off-campus classes. They also had a positive impression of the community-based experience and interaction with the local residents, which is considered a favorable outcome. Off-campus programs could be a useful educational approach for students in health sciences.     

A rare ring-shaped anomaly of the main pancreatic duct accompanying a branch duct IPMN

The patient was a 74-year-old female. Screening computed tomography for examination of the abdomen showed a cystic mass in the pancreatic body. Close investigation using endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography revealed a very rare finding: the main pancreatic duct bifurcated at the pancreatic body, and these two ducts converged at the caudal side. A multilocular cystic mass in the pancreatic body and mucus discharge from the orifice of major papilla were observed. There was no protruded lesion in the main pancreatic duct. No findings suggested apparent malignancy. The patient was diagnosed as having hyperplastic intraductal papillary mucinous neoplasm of branch type showing a ring-shaped pancreatic duct, and was placed under follow-up.     

Teeth contacting habit as a contributing factor to chronic pain in patients with temporomandibular disorders

Many different factors are known to cause and perpetuate the symptoms of temporomandibular disorders (TMD). However, the roles of parafunctional factors have not been clearly elucidated. We found one of these habits in the clinical setting. This parafunctional habit involves daily light touching of the upper and lower teeth, when the mouth is closed. We named this habit Teeth Contacting Habit (TCH). [OBJECTIVES] To investigate the following hypotheses: 1) TCH is associated with perpetuation of chronic pain of TMD patients; 2) TCH is associated with other behavioral factors. [METHODS] Two hundred and twenty-nine TMD outpatients with chronic pain were analyzed with multivariate logistic regression models. [RESULTS] TCH was found in 52.4% of patients. Patients with TCH and pain lasting for more than four months were less likely to experience improvements in pain at the first visit (OR = 1.944, p = 0.043). Other factors associated with TCH were as follows: unilateral chewing (OR = 2.802) and involvement in a precision job (OR = 2.195). [CONCLUSION] TCH can prolong TMD pain and is associated with other behavioral factors.     

Analysis of the loading and hydroxylation steps in lankamycin biosynthesis in Streptomyces rochei

The biosynthetic gene cluster of lankamycin (LM), a 14-member macrolide antibiotic, is encoded on the 210-kb linear plasmid pSLA2-L in Streptomyces rochei 7434AN4. LM contains a 3-hydroxy-2-butyl group at the C-13 position, which is different from an ethyl group in erythromycin. The following two possibilities could be considered for the origin of this starter moiety of LM biosynthesis: (i) an extra module exists in the biosynthetic gene cluster and loads an additional acetate molecule, or (ii) 3-hydroxy-2-butyrate or its equivalent is loaded and incorporated as a starter. The former possibility was eliminated by the complete sequencing of pSLA2-L, which showed no extra module. On the other hand, the latter was confirmed by incorporation of deuterium in [3-(2)H]dl-isoleucine into the C-14 position of LM. The timing of hydroxylation reactions at the C-15 and C-8 positions of LM was studied by constructing disruptants of two P450 hydroxylase genes, lkmF (orf26) and lkmK (orf37). The lkmF disruptant produced 8-deoxylankamycin, while the lkmK disruptant produced both 15-deoxylankamycin and 8,15-dideoxylankamycin. These results clearly showed that LkmF is a C-8 hydroxylase and LkmK is a C-15 hydroxylase in LM biosynthesis and in addition suggested the order of hydroxylation steps; namely, hydroxylation may occur at first at C-15 by LkmK and then at C-8 by LkmF.     

Modification of the functional reach test: analysis of lateral and anterior functional reach in community-dwelling older people

The purpose of this study was to evaluate the validity and reproducibility of the modified lateral functional reach (FR), and to examine the associations between a variety of functional variables and the FR in community-dwelling older people (>65 years of age). A total of 383 aged Japanese participated in this study at the rural district Kahoku, Kochi, Japan, in 2002. The average age of the subjects was 78.6 years. The activity of daily living (ADL) and mental status were measured as outcomes. FR (anterior and lateral) and timed up and go (TUG) were measured as predictors. The test-retest reliability of lateral FR between the first and second measurement was very consistent. Subjects with greater lateral FR had higher basic and instrumental ADL (IADL) scores than did those with shorter lateral FR. However, there was no significant relationship between anterior FR and ADLs. The lateral FR of participants with depression was shorter than in those without depression, while the anterior FR did not correlate with the participants' scores on the geriatric depression scale (GDS). Lateral FR should be considered as a new, alternative means of assessing geriatric social activity and mental status in the elderly.     

Voxel-based diffusion tensor analysis reveals aberrant anterior cingulum integrity in posttraumatic stress disorder due to terrorism

Recent functional neuroimaging work has suggested that interregional functional connectivity between the anterior cingulate cortex (ACC), other limbic, and prefrontal regions may be involved in the pathophysiology of posttraumatic stress disorder (PTSD). However, less attention has been paid to the white matter network. Voxel-based analysis enables an exploration of morphological or functional changes throughout the entire brain. Here we undertook the first application of this technology to diffusion tensor data in patients with PTSD. Participants were 9 victims of the Tokyo subway sarin attack with PTSD and 16 matched victims of the same traumatic event without PTSD. The voxel-based analysis showed a significant fractional anisotropy increase in the left anterior cingulum, subjacent to the left ACC gray matter where we previously found a volume decrement, in PTSD subjects. Moreover, the severity was positively, but not significantly associated with the fractional anisotropy of the left anterior cingulum in the victims with PTSD, using the region of interest defined in the native space with the inverse normalization technique. The present study demonstrated further evidence of abnormalities of both the ACC, a structure that is pivotally involved in attention, emotional regulation, and fear conditioning, and of subjacent white matter in the pathology of PTSD.     

A stress-induced, superoxide-mediated caspase-1 activation pathway causes plasma IL-18 upregulation

Psychological/physical stresses are known to cause relapses of autoimmune and inflammatory diseases. To reveal a mechanism by which noninflammatory stresses affect host defenses, responses to immobilization stress in mice were investigated, focusing on the role of a multifunctional cytokine, interleukin-18 (IL-18). In the adrenal cortex, the stress induced IL-18 precursor proteins (pro-IL-18) via adrenocorticotropic hormone (ACTH) and a superoxide-mediated caspase-1 activation pathway, resulting in conversion of pro-IL-18 to the mature form, which was released into plasma. Inhibitors of caspase-1, reactive oxygen species, and P38 mitogen-activated protein kinase (MAPK) suppressed stress-induced accumulation of plasma IL-18. These inhibitors also blocked stress-induced IL-6 expression. This, together with the observation that IL-6 was not induced in IL-18-deficient mice, showed that IL-6 induction by stress is dependent on IL-18. In stressed organisms, IL-18 may influence pathological and physiological processes. Controlling the caspase-1 activating pathway to suppress IL-18 levels may provide preventative means against stress-related disruption of host defenses.