The aspartate-257 of presenilin 1 is indispensable for mouse development and production of beta-amyloid peptides through beta-catenin-independent mechanisms

To differentiate multiple activities of presenilin 1 (PS1), we generated transgenic mice expressing two human PS1 alleles: one with the aspartate to alanine mutation at residue 257 (hPS1D257A) that impairs the proteolytic activity of PS1, and the other deleting amino acids 340-371 of the hydrophilic loop sequence (hPS1Deltacat) essential for beta-catenin interaction. We show here that although hPS1Deltacat is fully competent in rescuing the PS1-null lethal phenotype, hPS1D257A does not exhibit developmental activity. hPS1D257A also leads to the concurrent loss of the proteolytic processing of Notch and beta-amyloid precursor protein (APP) and the generation of beta-amyloid peptides (Abeta). Further, by measuring the levels of endogenous Abeta(X-40) and Abeta(X-42) in primary neuronal cultures, we confirmed the concept that PS1 is indispensable for the production of secreted Abeta.     

Selective COX-2 inhibitor regulates the MAP kinase signaling pathway in human osteoarthritic chondrocytes after induction of nitric oxide

The purpose of this study was to examine the effect of cyclooxygenase-2 (COX-2) inhibitors on the mitogen-activated protein (MAP) kinase signaling pathway and synthesis of glucosaminoglycan after nitric oxide (NO) induction in articular human chondrocytes. After NO induction, the cells were divided into three groups that were treated with either ethanol (control); a selective COX-2 inhibitor (Celecoxib), or no additive, and evaluated. There were no differences in the effect of the selective COX-2 inhibitor on mitochondrial membrane potential or Annexin V levels. However, Celecoxib significantly decreased prostaglandin E2 (PGE2) production. Celecoxib also decreased the phosphorylation state of p38 and p44/42 of MAP kinase. The ratio of chondroitin-6 sulfate (C6S)/C4S was increased in response to the exposure to Celecoxib. Celecoxib did not affect apoptosis, but decreased the activation of MAP kinase in osteoarthritic chondrocytes after NO induction. NO-induced OA chondrocytes were associated with the p38 and the p44/42 MAPK signaling pathways, in a pathway that is distinct from PGE2-mediated apoptosis.     

A 40-year-old gossypiboma (foreign body granuloma) mimicking a malignant femoral surface tumor

The patient was a 61-year-old man who developed gossypiboma of the left thigh and femur resulting in the imaging appearances of a malignant surface tumor. He had a past history of surgery on the left femur for open fracture 40 years previously. Radiographs and CT showed a soft tissue mass with osteolysis and periosteal thickening of the left femur. On MRI, the mass showed heterogeneous signal intensity with contrast enhancement at the periphery, suggesting a malignancy. ^99mTc-HMDP bone scintigraphy showed a faint ring-like uptake, but thallium -201 scintigraphy did not show any uptake in the tumor. An extensive intralesional excision was performed. Postoperative histopathological examination showed a fibrous foreign body with reactive changes. There were neither viable cells nor atypical giant cells around the foreign body. No malignant change was evident. Based on surgical and histopathological examinations, the tumor was finally diagnosed as gossypiboma related to a retained surgical sponge.The patient was treated by Dr. Kenshi Sakayama at Ehime University Hospital, Ehime, Japan     

Topography of the human corpus callosum using diffusion tensor tractography

OBJECTIVE: To evaluate the crossing fiber trajectory through the corpus callosum using distortion-corrected diffusion tensor tractography in the human brain. METHODS: After correcting distortion associated with large-diffusion gradients, T2-weighted echo planar images (EPIs) acquired from 10 right-handed healthy men were coregistered into T2-weighted fast spin echo images using linear through sixth-order nonlinear, 3-dimensional, polynomial warping functions. The optimal transformation parameters were also applied to the distortion-corrected diffusion-weighted EPIs. Diffusion tensor tractography through the corpus callosum was reconstructed, employing the "1 or 2 regions of interest" method. RESULTS: Compared with the lines through the genu, those through the rostrum ran more inferiorly and seemed to enter the orbital gyrus. Those lines entering posterior temporal white matter (tapetum) crossed through the ventral portion of the splenium and were clearly distinguished from lines that reached parieto-occipital white matter (forceps major). CONCLUSION: Diffusion tensor tractography is a feasible noninvasive tool to evaluate commissural fiber trajectory.     

Simple visualization of the corticospinal pathway using tractography: one-ROI and two-ROI methods

Diffusion tensor imaging (DTI), a magnetic resonance (MR) technique to analyze diffusion anisotropy of the brain, is able to demonstrate subtle white matter anatomy. Tractography is expected to be a unique, non-invasive tool to provide more pertinent insights into brain structure and orientation not accessible by conventional MRI. In this report, preliminary experiences of visualization of the corticospinal tract using tractography are described. DTI of the brain was performed in 5 normal volunteers using single-shot echo-planar imaging, then tractography was generated by our original software. We determined that the two-region-of-interest (ROI) method is superior to the one-ROI method.     

MR imaging of ischemic penumbra

Cerebral ischemic stroke is one of the most fatal diseases despite current advances in medical science. Recent demonstration of efficacy using intravenous and intra-arterial thrombolysis demands therapeutic intervention tailored to the physiologic state of the individual tissue and stratification of patients according to the potential risks for therapies. In such an era, the role of the neuroimaging becomes increasingly important to evaluate the extent and location of tissues at risk of infarction (ischemic penumbra), to distinguish it from unsalvageable infarcted tissues or doomed hemorrhagic parenchyma. In this review, we present briefly the current role and limitation of computed tomography and conventional magnetic resonance imaging (MRI). We also present the possible applications of advanced MR techniques, such as diffusion and perfusion imaging, concentrating on the delineation or detection of ischemic penumbra.     

Definitive intraoperative radiotherapy for musculoskeletal sarcomas and malignant lymphoma in combination with surgical excision

Background. The purpose was to estimate retrospectively the outcome of patients with musculoskeletal sarcoma or malignant lymphoma treated with intraoperative radiotherapy (IORT).Methods. Between 1988 and 1999, definitive IORT in combination with surgical excision was performed in 24 patients with musculoskeletal sarcoma (malignant fibrous histiocytoma, 10; osteosarcoma, 6; liposarcoma, 2; chondrosarcoma, 1; synovial sarcoma, 1; Ewing's sarcoma, 1; angiosarcoma, 1; epithelioid sarcoma, 1; malignant schwannoma, 1) and 3 patients with malignant lymphoma. The tumor was excised by marginal margin excision, intralesional margin excision, or wide margin excision; 15–45Gy electrons was then delivered to the affected sites.Results. In the 8 patients without distant metastases at the first visit, 4 patients are alive 6.5–11.5 years after IORT, and 4 patients died <4.5 years after IORT. The incidence of local recurrence was 13%. In the 19 patients with distant metastases at the first visit, 3 patients are alive 2.5–6.7 years after IORT, and 16 patients died 0.2–5.7 years after IORT. The incidence of local recurrence was 45%. Complications after IORT were found in 5 patients: neuropathy, 1 patient; skin necrosis, 1 patient; myelopathy, 1 patient; enteritis ileus, 1 patient; and edema, 1 patient.Conclusion. IORT with a radiation dose of 15–45Gy in combination with surgical excision appeared to be useful for local control and to be more effective in patients without distant metastases at the first visit than in patients with distant metastases.     

Ultrastructural evidence of early non-fibrillar Aβ42 in the capillary basement membrane of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type

The C-terminal profile and ultrastructure of small and presumably early capillary amyloid β protein (Aβ) deposits were investigated in four patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type. The C terminus of the 40 (Aβ40) or the 42 (Aβ42) amino acid form of Aβ was gold labeled in serial, ultrathin sections on glass slides for reflection contrast microscopy and on grids for electron microscopy. In all studied subjects, reflection contrast microscopy revealed capillaries with focal Aβ42 immunolabeling in the absence of Aβ40 labeling. In the adjacent electron microscopic section, Aβ42 labeling was confined to the capillary basement membrane. The majority of Aβ42⁺40^– deposits showed no amyloid fibrils. Aβ42⁺40^– deposits were sometimes observed in an unremarkable basement membrane but usually showed increased electron density and reticular structures. A small subset of Aβ42⁺40^– deposits with basement membrane changes showed few amyloid fibrils. Aβ42⁺40⁺ capillary deposits always showed definite fibrils and were larger than Aβ42⁺40^– capillary deposits. The present findings suggest that in capillaries the accumulation and subsequent polymerization of Aβ42, possibly in conjunction with basement membrane changes, precedes the definite fibril formation with Aβ40. Received: 9 June 1999 / Accepted: 9 September 1999     

Voxel-based analyses of gray/white matter volume and diffusion tensor data in major depression

The purpose of this study is to use voxel-based analysis to simultaneously elucidate regional changes in gray/white matter volume, mean diffusivity (MD), and fractional anisotropy (FA) in patients with unipolar major depressive disorder. We studied 21 right-handed patients and 42 age- and gender-matched right-handed normal subjects. Local areas showing significant gray matter volume reduction in depressive patients compared with controls were observed in the right parahippocampal gyrus, hippocampus, bilateral middle frontal gyri, bilateral anterior cingulate cortices, left parietal and occipital lobes, and right superior temporal gyrus. Local areas showing an increase of MD in depressive patients were observed in the bilateral parahippocampal gyri, hippocampus, pons, cerebellum, left frontal and temporal lobes, and right frontal lobe. There was no significant difference between the two groups for FA and white matter volume in the entire brain. Although there was no local area where brain volume and MD were significantly correlated with disease severity, FA tended to correlate negatively with total days depressed in the right anterior cingulate and the left frontal white matter. These results suggest that the frontolimbic neural circuit might play an important role in the neuropathology of patients with major depressive disorder.