MM2-thalamic-type sporadic Creutzfeldt-Jakob disease with widespread neocortical pathology

We report an autopsy case of MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD) with widespread cerebral neocortical pathology. Initial symptoms were progressive insomnia and mental disturbance. Magnetic resonance imaging revealed no high-signal intensity lesions on diffusion-weighted images and later showed gradually progressive cerebral atrophy. Periodic synchronous discharges and myoclonus were not observed. Upon neuropathologic examination, widespread cerebral neocortical involvement with fine vacuole-type spongiform change was observed. Severe degeneration with almost complete neuronal loss, tissue rarefaction, numerous fat-laden macrophages and hypertrophic astrocytosis of the medial thalamic nucleus was evident. The inferior olivary nucleus showed severe involvement with neuronal loss and hypertrophic astrocytosis. In the cerebellar cortex, moderate depletion of Purkinje neurons was evident, with no spongiform change in the molecular layer and no neuronal loss in the granule cell layer. Immunohistochemistry for prion protein (PrP) revealed widespread synaptic-type deposits with some primitive plaque-type deposits in the cerebral neocortex, basal ganglia and cerebellar cortex. PrP deposition was also observed in the brainstem, particularly the tegmentum, substantia nigra and pontine nucleus, and spinal cord, particularly the posterior horn. In the medial thalamus and inferior olivary nucleus, PrP deposition was sparse. Analysis of the PrP gene showed no mutation but did show methionine homozygosity at polymorphic codon 129. Western blot analysis of protease-resistant PrP indicated the presence of type 2 PrP. We believe that this patient suffered from MM2-thalamic-type sCJD (sporadic fatal insomnia) with widespread cerebral neocortical pathology due to prolonged disease duration. The present case showed different patterns of spongiform degeneration and PrP deposition in the cerebral neocortex than those in previously reported MM2-thalamic-type sCJD cases.     

Withdrawal symptom after discontinuation of transdermal fentanyl at a daily dose of 0.6 mg

Neurophysiologic disorders developed in three patients after discontinuation of transdermal fentanyl (TDF) at a daily dose of 0.6mg (2.5mg per a patch), although direct removal of a 2.5mg patch is permitted by the manufacturer as the formulation has the lowest fentanyl content among all the commercially available patch formulations. These observations indicate that the discontinuation of TDF carries a risk for developing withdrawal symptoms even when using a 2.5mg patch. To avoid such adverse events, we considered the necessity of gradual reduction in the daily fentanyl requirements. For this purpose, we covered part of the application surface of the patch with an insulating tape, and then increased the covered area in a stepwise manner. There were no apparent withdrawal signs during the procedure described above.     

Expression and localization of MUC1, MUC2, MUC5AC and small intestinal mucin antigen in pancreatic tumors

Alterations in the expression of mucin family members play an important role as well as alterations in oncogenes and onco-suppressor genes in carcinogenesis and progression of pancreatic cancer. We analyzed the expression and localization of MUC1, MUC2, MUC5AC and small intestinal mucin antigen (SIMA) in pancreatic tumors. MUC1 expression was observed in almost all samples, whereas MUC2 expression was not. MUC5AC expression was observed in 73.9% of the cancerous regions, 48.7% of the dysplastic regions and 72.0% of the hyperplastic regions but not in the normal pancreatic duct. SIMA expression was observed in 45.7% of cancerous regions, 17.9% of the dysplastic regions and 8.0% of the hyperplastic regions. Furthermore, stromal expression of MUC1, MUC5AC and SIMA was observed in 37.0%, 60.9% and 26.1% of the cancerous regions, respectively. Stromal expression of these mucins was not observed in the hyperplastic regions and normal pancreatic duct and was observed in only two dysplastic regions. The survival of pancreatic cancer patients with stromal expression of MUC1 or SIMA was worse than that of other patients (P=0.04). In conclusion, the localization of mucin expression, especially stromal expression of MUC1 or SIMA, might be a prognostic factor for patients with pancreatic cancer.     

Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer

In gastric cancer, lymph node metastasis is one of the major prognostic factors and forms the basis for surgical removal of local lymph nodes. Recently, several studies have demonstrated that overexpression of lymphangiogenic growth factor VEGF-C or VEGF-D induces tumor lymphangiogenesis and promotes lymphatic metastasis in mouse tumor models. We examined whether these processes could be inhibited in naturally metastatic tumors by blocking of their cognate receptor VEGFR-3 signaling pathway. Using a mouse orthotopic gastric cancer model which has a high frequency of lymph node metastasis, we estimated lymphatic vessels in gastric cancers by immunostaining for VEGFR-3 and other specific lymphatic markers, LYVE-1 and prox-1. Then we systemically administered anti-VEGFR-3 blocking antibodies. This treatment resulted in the inhibition of regional lymph node metastasis and reduction of lymphatic vessel density in the primary tumors. In addition, increased density of LYVE-1-positive lymphatic vessels of primary tumors was closely correlated with lymph node metastasis in human samples of gastric cancer. Antilymphangiogenesis by inhibiting VEGFR-3 signaling could provide a potential strategy for the prevention of lymph node metastasis in gastric cancer.     

Expression profiles of the duplicated matrix metalloproteinase-9 genes suggest their different roles in apoptosis of larval intestinal epithelial cells during Xenopus laevis metamorphosis.

Matrix metalloproteinases (MMPs) play a pivotal role in development and/or pathogenesis through degrading extracellular matrix (ECM) components. We have previously shown that Xenopus MMP-9 gene is duplicated. To assess possible roles of MMP-9 and MMP-9TH in X. laevis intestinal remodeling, we here analyzed their expression profiles by in situ hybridization and show that their expression is transiently up-regulated during thyroid hormone-dependent metamorphosis. Of interest, MMP-9TH mRNA is strictly localized in the connective tissue and most highly expressed just beneath the larval epithelium that begins to undergo apoptosis. On the other hand, cells expressing MMP-9 mRNA become first detectable in the connective tissue and then, after the start of epithelial apoptosis, also in the larval epithelium. These results strongly suggest that MMP-9TH is responsible in the larval epithelial apoptosis through degrading ECM components in the basal lamina, whereas MMP-9 is involved in the removal of dying epithelial cells during amphibian intestinal remodeling.     

Effects of imatinib vary with the types of KIT-mutation in gastrointestinal stromal tumor cell lines

Mutations of proto-oncogene c-kit in gastrointestinal stromal tumors (GISTs) are considered to cause a constitutive activation of KIT responsible for their oncogenesis. Imatinib has therapeutic potential for GISTs because of its inhibitory effect on KIT kinase activity. However, no study has been published concerning the effects of imatinib on GIST cells with various types of KIT mutation. To investigate the effects of imatinib on various c-kit mutations found in GISTs, cell proliferation and apoptosis assays were performed in two GIST cell lines with different KIT mutations. One of the cell lines, GIST-T1, revealed a heterozygous deletion of exon 11 in the c-kit, while the other cell line, GIST882, possessed a homozygous missense mutation of exon 13 in the c-kit gene. Imatinib inhibited proliferation and induced apoptosis in both cell lines. Imatinib potently suppressed proliferation of the GIST882 cell line at the concentration of 1.0 microM, whereas it inhibited the GIST-T1 at 0.1 microM. In two types of activating mutant KIT, imatinib could inhibit the constitutive activation of both types of KIT mutant, although the antiproliferative effect on GIST882 was weaker than on GIST-T1. Western blot analysis revealed that apoptosis related proteins were activated or suppressed by imatinib in both cell lines in the respective manner. Our results suggest that the apoptotic signal trans-duction caused by imatinib in GISTs is susceptible to various types of KIT mutation.     

Anterior spinal artery syndrome after minimally invasive direct coronary artery bypass grafting under general combined epidural anesthesia

A 65-year-old patient with ischemic heart disease and severe diabetes mellitus underwent minimally invasive direct coronary artery bypass grafting under general combined with epidural anesthesia. Paraplegia developed after surgery and the diagnosis of anterior spinal artery syndrome was made based on the patient s neurological condition and magnetic resonance imaging findings. Paraplegia following epidural anesthesia is a rare but recognized complication and this complication should be taken into account, especially in patients at risk, when considering epidural analgesia techniques in the minimally invasive cardiac surgery.     

Visual field loss in patients with normal-tension glaucoma under topical nipradilol or timolol: Subgroup and subfield analyses of the nipradilol-timolol study

Purpose  

To estimate the deterioration rates of visual field loss in Japanese normal-tension glaucoma (NTG) patients under either topical nipradilol or timolol, and to explore intergroup differences in the treatment results.     

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