Enhanced spontaneous and aflatoxin-induced liver tumorigenesis in xeroderma pigmentosum group A gene-deficient mice

Xeroderma pigmentosum (XP) is an autosomal recessive hereditary disease featuring defective nucleotide excision repair (NER). XP patients are highly sensitive to sunlight and develop skin cancer at an early age. While the fact that XP patients have a large increase in mortality from skin cancers has been extensively documented, the relation between XP and internal tumors has received little attention. We therefore analyzed development of spontaneous and aflatoxin B(1) (AFB(1))-induced liver tumors in XPA-deficient congenic mice, originally created by repeated back-crosses with inbred C3H/HeN mice. Spontaneous liver tumors were assessed at the age of 16 months in two separate experiments using F5 and F10 lines. The incidence of and average number of spontaneous tumors per mouse were significantly higher in XPA-/- than in XPA+/+ and +/- mice. Similarly, F10 XPA-/- mice receiving i.p. injection of 0.6 or 1.5 mg/kg b.w. AFB(1) at 7 days of age demonstrated more liver tumors than their heterozygous or homozygous positive counterparts when examined at month 11. These results demonstrate that XPA-deficient mice have increased susceptibility to both spontaneous liver tumor development and AFB(1)-induced hepatocarcinogenesis.     

Prognostic Value of Loss of Heterozygosity around three Candidate Tumor Suppressor Genes on Chromosome 10q in Astrocytomas

We thoroughly examined loss of heterozygosity (LOH) around three candidate tumor suppressor genes on chromosome 10q to determine whether LOH of each tumor suppressor gene is associated with the previously defined clinical prognostic indices. We also examined whether LOH can help predict prognostic variables in astrocytomas.We selected samples from 40 astrocytomas (grades 2–4), performed Ki-67 immunostaining, and counted positive cells. Using DNA from aliquots of tumor blocks and leukocytes, we investigated LOH around the PTEN, NEURL, and DMBT1 genes (10q23.3–26.1) with the silver staining procedure. We then statistically evaluated the relationship among histological features, regional LOH on chromosome 10q, and survival. The mean survival period for patients with LOH around PTEN was 7.2 months after surgery, while that for patients without LOH around PTEN was 21.4 months. Thus, LOH around PTEN was closely associated with a reduced overall survival (p = 0.0020) but LOH at NEURL or DMBT1 was not (p > 0.05).The combined features of an increase in histological grading and Ki-67-positive cells and the presence of LOH around PTEN significantly correlated with poor prognosis. These factors may be useful predictors of survival, and LOH analysis of tumor suppressor genes on chromosome 10q can contribute greatly to the treatment of patients with astrocytoma.     

Expression of dystroglycan and the laminin-alpha 2 chain in the rat peripheral nerve during development

In Schwann cells, the transmembrane glycoprotein beta-dystroglycan comprises the dystroglycan complex, together with the extracellular glycoprotein alpha-dystroglycan, which binds laminin-2 (alpha 2/beta 1/gamma 1), a major component of the Schwann cell basal lamina. To provide clues to the biological functions of the interaction of the dystroglycan complex with laminin-2 in peripheral nerves, we investigated the expression of beta-dystroglycan and the laminin-alpha 2 chain in rat sciatic nerve during development by immunoblot, immunofluorescence, and immunoelectron microscopic studies. The expression of beta-dystroglycan and the laminin-alpha 2 chain in the rat sciatic nerve was low and not confined to the Schwann cell outer membrane from embryonic day 18 to birth, when there was only an immature basal lamina assembly and no compact myelin formation by Schwann cells. However, the expression of these proteins increased markedly and became clearly localized to the Schwann cell outer membrane between birth and postnatal day 7, when both basal lamina assembly and compact myelin formation by Schwann cells progressed rapidly. From postnatal day 7 to adult, there was no remarkable change in the expression of these proteins. Our results support the hypothesis that the dystroglycan complex functions as an adhesion apparatus, binding the Schwann cell outer membrane with the basal lamina, and suggest that the dystroglycan complex plays a role in Schwann cell myelination through its interaction with laminin-2.     

Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene

The authors present three novel missense mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, the causative gene for hereditary inclusion body myopathy, in Japanese patients with distal myopathy with rimmed vacuoles. Seven out of nine patients had homozygous V572L mutation, one was a compound heterozygote with C303V and V572L mutations, and the remaining patient bore homozygous A631V mutation.     

Colocalization of CA19-9 and KL-6 to epithelial cells in dilated bronchioles in a patient with idiopathic pulmonary fibrosis complicated by diffuse alveolar damage

A 73-year-old woman with idiopathic pulmonary fibrosis (IPF) had an elevated serum CA19-9 level, but not KL-6. Her condition worsened and she subsequently died and this was associated with a rise in the serum KL-6 level. At autopsy, the lung showed a honeycomb appearance macroscopically and, microscopically, hyaline membrane formation was seen. Immunohistochemical staining revealed partial colocalization of KL-6 and CA19-9 to dilated bronchiolar cells. These features suggest that the mechanisms that cause the synthesis and release of CA19-9 and KL-6 from damaged lung tissue in IPF are likely to differ from those in diffuse alveolar damage. In addition, serum KL-6 levels may reflect the severity of disease more sensitively than CA19-9 levels.     

Palinopsia and perilesional hyperperfusion following subcortical hemorrhage

We report a patient who exhibited transient palinopsia and visual hallucinations. Disturbances initially included an auditory component and increasingly were localized to the left visual field. These events occurred during recovery from a right subcortical hematoma with left homonymous hemianopia. Single-photon emission computed tomography (SPECT) demonstrated extensive perilesional hyperperfusion involving parts of the right parietal, temporal, and occipital cortex. Perilesional hyperperfusion disappeared as the visual abnormalities diminished. We believe that excitatory neuronal activation in perilesional cortex during recovery contributed importantly to the transient abnormal perceptions.     

Role of endothelium in hyperemia during cortical spreading depression (CSD) in the rat

The purpose of this study was to examine whether endothelium-mediated dilation is responsible for the cortical hyperemia that occurs during cortical spreading depression (CSD) in rats using three different approaches. The first approach taken was the acute pharmacological inhibition of the predominant endothelium-centered dilator systems, using indomethacin, a cyclooxygenase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, and miconazole, a cytochrome P-450 epoxygenase inhibitor. The second approach used was the acute general pharmacological impairment of endothelial function by the intravascular administration of phorbol 12, 13-dibutyrate (PDBu). The third approach taken was the chronic impairment of endothelium-dependent dilator responses by diet in insulin resistant (IR) rats. Cerebral blood flow (CBF) was measured using laser Doppler flowmetry. CSD was elicited by the topical application of potassium chloride. Pharmacological inhibition of endothelium-dependent dilator factors did not affect CSD. For example, with 20 mg/kg L-NAME, CBF peak of the first series of CSDs was 377 +/- 67% of baseline CBF. After drug administration, CBF peaks of the second and the third series of CSDs were 451 +/- 67% and 390 +/- 69% (n=5, P=n.s.), respectively. Control and IR animals and those treated with indomethacin, miconazole and PDBu showed similar results. We also calculated the area under the CBF curve to fully represent the extent of hyperemia during CSD. However, there were no significant differences in the CBF area with any treatment compared to control animals. Thus, our results provide strong evidence that endothelium-mediated mechanisms have minimal effects on the CSD-associated hyperemia.     

Serum cytokine level during continuous venovenous hemofiltration in toxic shock-like syndrome due to group G beta Streptococcus bacteremia in a patient with idiopathic thrombocytopenic purpura

We report a case of toxic shock-like syndrome due to a rare infection of group G Streptococcus bacteremia in a patient with idiopathic thrombocytopenic purpura and its successful treatment with continuous venovenous hemofiltration (CVVH). As the result of sepsis treatment with CVVH, in addition to administration of vasopressors and antibiotics, serum levels of interleukin-1beta, interleukin-10 and tumor necrosis factor-a fell and shock was controlled.     

Effects of omeprazole and famotidine on fibroblast growth factor-2 during artificial gastric ulcer healing in humans

BACKGROUND AND AIMS: Endoscopic mucosal resection is a widely accepted technique for the treatment of early gastric cancers, while large ulcers induced by the treatment should be treated promptly. This study aimed to compare the effects of omeprazole and famotidine on ulcer healing and fibroblast growth factor-2 levels in gastric ulcers induced by endoscopic mucosal resection. METHODS: Sixteen patients indicated for endoscopic mucosal resection were enrolled. They were treated by using either omeprazole (n = 8) or famotidine (n = 8) after endoscopic mucosal resection. Endoscopy was performed on days 4, 7 and 28 during each treatment period. Levels of fibroblast growth factor-2 in biopsy specimens were measured by using an enzyme-linked immunosorbent assay at the time of and after endoscopic mucosal resection. Histological variables were also assessed. RESULTS: Ulcer healing rates under endoscopy were not different between the two treatment groups. In both groups, levels of fibroblast growth factor-2 slightly increased on day 4, but the values were not different at any time point. There were no differences in histological variables on days 4 and 7, but fibromuscular hyperplasia was significantly greater in the omeprazole group than in the famotidine group on day 28 (P < 0.05). CONCLUSIONS: Omeprazole and famotidine have an equivalent value for the treatment of ulcers induced by endoscopic mucosal resection. While omeprazole had a more potent effect on fibromuscular hyperplasia than did famotidine, such a difference does not seem to be explained by fibroblast growth factor-2.     

Changes in repolarization properties with long-term cardiac memory modify dispersion of repolarization in patients with Wolff-Parkinson-White syndrome

INTRODUCTION: Transient T wave changes after cessation of preexcitation have been attributed to cardiac memory. However, there have been no reports on the effects of long-term cardiac memory on repolarization dispersion before and after catheter ablation in patients with Wolff-Parkinson-White (WPW) syndrome. METHODS AND RESULTS: We investigated 47 patients with an accessory pathway (AP; 24 manifest left-sided, 14 manifest right-sided, and 9 concealed left-sided). Repolarization dispersion was analyzed by two methods, recovery time (RT) dispersion and newly proposed T wave width (WT), from 87-lead body surface maps before, 1 day after, and 7 days after catheter ablation. RT dispersion and WT were significantly correlated before, 1 day after, and 7 days after catheter ablation (r = 0.78). In patients with preexcitation, RT dispersion and WT increased significantly (P < 0.05) 1 day after catheter ablation (178 +/- 32 msec and 172 +/- 30 msec) compared with those before (154 +/- 24 msec and 156 +/- 18 msec) and 7 days after catheter ablation (147 +/- 19 msec and 156 +/- 16 msec), respectively. However, there were no significant changes in RT dispersion and WT before and after catheter ablation in concealed WPW syndrome. CONCLUSION: The findings suggest that the abrupt changes in activation sequence increase repolarization dispersion in the presence of previous cardiac memory, and that the dispersion decreases days or weeks after alteration of activation sequence by catheter ablation, with development of new cardiac memory in patients with manifest WPW syndrome.