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The etiology of central diabetes insipidus (DI) is classified into (1) idiopathic, (2) familial, and (3) secondary. Of these, familial central diabetes insipidus shows an autosomal dominant inheritance. We herein report a case in which this disease was diagnosed based on a family history of nocturnal enuresis. A 40-year-old man had had symptoms of polydipsia, polyuria and nocturia since childhood and found that his daughter had the same symptoms. Despite reaching nine years old, his daughter's nocturnal enuresis still had not improved, resulting in her consulting a pediatrician. She was suspected of having familial neurohypophyseal diabetes insipidus (FNDI) based on her family history and was referred along with her father for a detailed examination and treatment. A hypertonic saline load test (HSLT) to evaluate the arginine vasopressin (AVP) reaction was performed in both the proband and his daughter. The results showed no increase in AVP levels in response to high plasma osmolality. The water deprivation test (WDT) revealed he was suffering from partial DI. Based on the above findings and considering the possibility of familial central diabetes insipidus, we performed a gene mutation analysis of AVP-neurophysin II (NPII). Both the father and daughter had an exon 2 abnormality in this gene (c232_234delGAG; pGlu78del), and this gene mutation is known to cause NPII protein abnormality, abolishing the function of AVP as a carrier protein. This case was considered to have provided an opportunity to understand the role of an NPII gene abnormality in familial central diabetes insipidus.

Hashimoto’s encephalopathy with serum anti-NH2-terminal of α-enolase (NAE) antibodies occasionally displays clinical symptoms such as cerebellar ataxia and parkinsonism. We studied the frequency of anti-NAE antibodies in patients with Parkinson-plus syndrome. We examined the positive rates of anti-NAE antibodies in 47 patients with multiple system atrophy (MSA), 29 patients with Parkinson’s disease (PD), eight patients with corticobasal syndrome (CBS), and 18 patients with progressive supranuclear palsy (PSP) using conventional immunoblot analysis. Positive anti-NAE antibody rates of 31.9%, 10.3%, 50.0%, and 11.1% were reported in the MSA, PD, CBS, and PSP patients, respectively. The duration from onset to a wheelchair-bound state in seropositive MSA patients tended to be shorter than that in seronegative MSA patients. Anti-NAE antibodies are detected in some patients clinically diagnosed with MSA and CBS. Although its pathophysiological significance remains uncertain, serum anti-NAE antibodies might represent a prognostic marker in the clinical course of MSA.

A 66-year-old woman presented with upper abdominal pain and weakness in the limbs. She had bilateral uveitis and gastric ulcers. A neurological examination revealed tetraparesis and sensory disturbance in the right arm. A cerebrospinal fluid (CSF) examination showed polymorphonuclear pleocytosis with elevated pro-inflammatory cytokine levels. Magnetic resonance imaging showed brain lesions and a long spinal cord lesion. She was initially diagnosed with neuro-Behcet's disease and was treated with corticosteroids, resulting in no improvement. A gastric mucosa biopsy indicated T-cell lymphoma colocalizing with neutrophils. The cytokine-mediated neutrophilic inflammation probably caused characteristic CSF and histopathological features. It is noteworthy that T-cell lymphoma may present with CSF neutrophilic inflammation.

Myelin oligodendrocyte glycoprotein (MOG)-IgG detected by the cell-based assay is associated with demyelinating diseases of the central nervous system, such as optic neuritis, myelitis, and acute disseminated encephalomyelitis, but rarely with peripheral neuropathy. Here, we describe the case of a 32-year-old MOG-IgG+ woman who developed central and peripheral demyelinating lesions. In contrast to previous similar cases, she uniquely presented with repeated subsequent relapses in the peripheral nerve, mimicking chronic inflammatory demyelinating polyneuropathy. Possible pathogenic implications of MOG-IgG in combined central and peripheral nervous system diseases are considered.

Central nervous system intravascular lymphoma sometimes includes multiple lesions mimicking cerebral infarction. Herein, we report our experience with a case of intravascular large B-cell lymphoma (IVLBCL) with multiple hemorrhages. A 53-year-old woman was admitted to our hospital with clonic convulsions of the left upper limb. Brain MRI revealed a large number of high-intensity areas on FLAIR and low-intensity areas on susceptibility-weighted imaging (SWI). Chest CT showed bilateral multiple high-density lesions in the lungs. Biopsy of pulmonary lesions revealed no abnormal cells. Levetiracetam was administered to prevent the seizures that were assumed to occur due to the cerebral cortex lesions; however, convulsive seizure recurred with a depressed level of consciousness. On a repeat brain MRI examination, severe, multiple new lesions were shown to have developed bilaterally in the cerebral cortex and white matter, exhibiting spotty low intensities on SWI. Biopsy of a new cerebral lesion was carried out and the lesion was pathologically diagnosed as IVLBCL with hemorrhages. IVLBCL should be noted as one of the differential diagnoses not only in case with multiple infarct lesions, but also in case with multiple hemorrhages.

Early neurosyphilis commonly appears in basilar meninges, and its meningeal inflammation can spread to neighboring cranial nerves, resulting in some cranial nerve palsies. Herein, we report a case of a 51-year-old man who presented with right peripheral facial nerve palsy. His symptoms completely disappeared with prednisolone monotherapy without antibiotics use and were not exacerbated during clinical treatment. However, 2 months after remission of seventh cranial neuropathy, fifth and eighth cranial neuropathies appeared on the right side. Serologic tests for syphilis were revealed to be abnormal. Finally, the patient was diagnosed with early neurosyphilis with multiple cranial palsies. His neurological symptoms were markedly improved by combined penicillin-corticosteroid treatment. Systemic corticosteroids could be effective as adjunctive therapy to ameliorate neurological sequelae in early neurosyphilis.

Development of paradoxical cerebral embolism requires both unstable venous thrombosis and right-to-left shunt (RLS). Gastrointestinal endoscopy (GE) has the potential to affect intrathoracic and abdominal venous thrombi and to enhance RLS because the procedure alters intrathoracic and abdominal pressure. We describe a patient with Crohn's disease who developed paradoxical cerebral embolism after GE. Both an unstable venous thrombus in the superior vena cava and RLS through patent foramen ovale were thought to be responsible for the stroke. Considering that patients with digestive system diseases undergo GE as a routine examination or therapy, screenings for hypercoagulable state and intrathoracic and abdominal thrombi are important to prevent thromboembolism related to GE.

Background In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity. Methods We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to

STUDY DESIGN.: Case report. OBJECTIVE.: To present a rare case of extramedullary-intradural hemangioblastoma in the thoracic spine and to review the literature on this condition. SUMMARY OF BACKGROUND DATA.: Spinal hemangioblastoma is rare, and moreover, there is seldom purely extramedullary-intradural hemangioblastoma of the spinal cord and there are few reports on histopathological features of spinal hemangioblastoma. METHODS.: A 65-year-old Japanese woman presented with gait disturbance and numbness below the trunk that had gradually worsened, and finally she was unable to walk by herself. Physiologic and neurologic examinations at admission revealed severe transverse neurologic defects, with no sign of von Hippel-Lindau's disease. Radiologic methods showed an extramedullary-intradural mass at Th4-5. A diagnosis of extramedullary-intradural spinal tumor was done, total tumorectomy was performed with recapped laminoplasty. RESULTS.: The patient's neurologic condition gradually improved after the operation. The immunohistopathological findings revealed the diagnosis of hemangioblastoma. CONCLUSION.: A rare case of extramedullary-intradural spinal hemangioblastoma was reported. The immunohistopathological findings were helpful for making a final diagnosis.

Reddish skin covering the entire body (erythroderma) was observed in a preliminary one-week oral toxicity study of a type of proton pump inhibitor in Beagle dogs. Histologically, full-thickness epidermal necrosis accompanied by apoptosis, evidenced by an immunohistochemical positive reaction to cleaved caspase-3, and detachment of the epidermis were observed in the skin. In the epidermis and upper dermis, a slight infiltration of mononuclear cells was seen, which was predominantly positive for MAC387 (macrophages) and partly positive for CD3 (T lymphocytes). These findings have some similarities to drug-induced severe skin reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) and may represent incipient changes of such lesions. The skin lesions observed in these dogs are being considered as a potential animal model of cutaneous drug reactions.

Recent studies have suggested that basic leucine zipper transcription factor MafA has a crucial role in pancreatic β-cell-specific insulin gene transcription. Thus, we investigated whether MafA overexpression in the intestine induces insulin production in small-intestinal epithelial cells in vivo. Recombinant adenovirus containing MafA gene (Ad-MafA) was prepared and administered orally to streptozocin-treated diabetic rats. Insulin gene expression was observed in the intestine by RT-PCR analysis, and then insulin protein was detected by immunohistochemical analysis after Ad-MafA administration. Furthermore, MafA overexpression in the intestine increased plasma insulin levels and ameliorated hyperglycemia. These results indicate that MafA overexpression in the intestine induces intestinal epithelial cells newly to produce and release insulin.

We have reported the association of variations in the activating protein-2beta (AP-2beta) transcription factor gene with type 2 diabetes. This gene was preferentially expressed in 3T3-L1 adipocytes in a differentiation stage-dependent manner, and preliminary experiments showed that subjects with the disease-susceptible allele showed stronger expression in adipose tissue than those without the susceptible allele. Thus, we overexpressed the AP-2beta gene in 3T3-L1 adipocytes to clarify whether AP-2beta might play a crucial role in the pathogenesis of type 2 diabetes through dysregulation of adipocyte function. In cells overexpressing AP-2beta, cells increased in size by accumulation of triglycerides accompanied by enhanced glucose uptake. On the contrary, suppression of AP-2beta expression by small interfering RNA inhibited glucose uptake. Enhancement of glucose uptake by AP-2beta overexpression was attenuated by inhibitors of phospholipase C (PLC) and atypical protein kinase Czeta/lambda (PKCzeta/lambda), but not by a phosphatidylinositol 3-kinase (PI3-K) inhibitor. Consistently, we found activation of PLC and atypical PKC, but not PI3-K, by AP-2beta expression. Furthermore, overexpression of PLCgamma enhanced glucose uptake, and this activation was inhibited by an atypical PKC inhibitor, suggesting that the enhanced glucose uptake may be mediated through PLC and atypical PKCzeta/lambda, but not PI3-K. Moreover, we observed the increased tyrosine phosphorylation of Grb2-associated binder-1 (Gab1) and its association with PLCgamma, indicating that Gab1 may be involved in AP-2beta-induced PLCgamma activation. Finally, AP-2beta overexpression was found to relate to the impaired insulin signaling. We propose that AP-2beta is a candidate gene for producing adipocyte hypertrophy and may relate to the abnormal characteristics of adipocytes observed in obesity.

膵腺房細胞癌の発生頻度は膵外分泌腫瘍の約1%とまれな腫瘍で, 特に皮下結節脂肪壊死を伴った報告例は本邦で過去2例のみである. 症例は75歳の男性で, 主訴は食欲低下で, 左上腹部には10cm大の弾性硬な腫瘤を認め, 両下腿に皮下結節を認めた. 血液生化学検査ではリパーゼ, エラスターゼIで高値を認め, CEA, CA19-9は基準値範囲内であった. 腹部CTで左上腹部に充実成分と液体成分の混在する巨大な腫瘍を認めた. 膵原発の腫瘍を疑い, 膵尾部切除術を行った. 病理組織検査の結果, 膵腺房細胞癌と診断された. 術前高値を示したリパーゼ, エラスターゼIは正常値となり下腿の皮下結節も消失した. 術後, 4年経過した現在, 再発の兆候なく経過観察中である.

症例は60歳の女性で, 右上腹部痛と嘔吐を主訴に入院となった. 腹部超音波検査, CTで胆嚢内に不整形の腫瘍を認め, 深達度ssの胆嚢癌の診断で胆管, 肝床切除, D2リンパ節郭清を伴う胆嚢摘出術を行った. 病理組織学的には, 腺癌と紡錘形細胞肉腫からなり, 一部で軟骨肉腫への分化を認める胆嚢癌肉腫と診断した. 免疫組織学的検索では, 肉腫領域では上皮性マーカー陰性かつ間葉性マーカー陽性で, 真の癌肉腫と診断した. 胆嚢の癌肉腫は比較的まれな疾患で長期生存報告例は少ない. 今回, 我々は術後4年6か月経過し, 再発の兆候を認めていない症例を経験したので報告する.

胃癌肉腫はまれな疾患であり, なかでも肉腫成分が特定の非上皮系細胞への分化を認める胃原発真性癌肉腫の報告は少ない. 症例は74歳の男性で, 心窩部痛と食思不振を主訴に当院を受診した. 胃内視鏡による生検にて軟骨肉腫への分化を伴う胃原発癌肉腫と診断した. 肝外側区域, 横隔膜に直接浸潤しており浸潤部を合併切除し, 胃全摘術を施行した. 病理学的検索では原発巣において低分化から中分化な腺癌, 軟骨肉腫像の混在と小細胞癌様細胞, 紡錐形細胞など多彩な形態の細胞増殖を認めたのに対し転移リンパ節では腺癌像のみ認めた. 患者は術後5か月目に多発肝転移を生じ死亡, 剖検が施行された. 多発肝転移巣では原発巣同様の病理像を認め肉腫成分の肝転移のポテンシャルが示唆された. 胃原発真性癌肉腫の報告は自験例を含めても10例に満たないことより症例の蓄積が必要と考え報告した.

Pancreatic duodenal homeobox-1 (Pdx1) is a transcription factor, and its phosphorylation is thought to be essential for activation of insulin gene expression. This phosphorylation is related to a concomitant shift in molecular mass from 31 to 46 kDa. However, we found that Pdx1 was modified by SUMO-1 (small ubiquitin-related modifier 1) in β-TC-6 and COS-7 cells, which were transfected with Pdx1 cDNA. This modification contributed to the increase in molecular mass of Pdx1 from 31 to 46 kDa. Additionally, sumoylated Pdx1 localized in the nucleus. The reduction of SUMO-1 protein by use of RNA interference (SUMO-iRNAs) resulted in a significant decrease in Pdx1 protein in the nucleus. A 34-kDa form of Pdx1 was detected by the cells exposed to SUMO-iRNAs in the presence of lactacystin, a proteasome inhibitor. Furthermore, the reduced nuclear sumoylated Pdx1 content was associated with significant lower transcriptional activity of the insulin gene. These findings indicate that SUMO-1 modification is associated with both the localization and stability of Pdx1 as well as its effect on insulin gene activation.

症例は59歳,女性.左上腹部腫瘤と食欲不振を主訴に当院受診.既往歴として48歳時に左胸水に対し他院入院加療.腹部CT検査では左上腹部に小児頭大の不整形な充実性腫瘍が認められ,全身麻酔下に開腹したところ左横隔膜下・胃前面に小児頭大・表面不整・易出血性・淡黄白色の腫瘍が認められた.腫瘍は左横隔膜に強固に浸潤し多数の腹膜播種を伴い,術中迅速病理診断で胸腺腫と判明したため,腫瘍および腹膜播種を可及的に摘出するに留めた.術後胸部X線を再検討したところ左上縦隔に腫瘍像が認められた.胸部CT検査で前縦隔に横隔膜へと続く腫瘍像が認められ,浸潤性胸腺腫が横隔膜へ直接浸潤し腹腔内進展・腹膜播種したものと考えられた.化学療法を行い残存腫瘍は縮小傾向にあり,術後9カ月生存中である.

We have implemented a randomized controlled dietary intervention in patients polypectomized for tumors of the colorectum to elucidate potential beneficial effects of n-3 polyunsaturated fatty acids (PUFAs) on the development of colorectal tumors. Those individuals in the experimental group were advised not only to decrease their consumption of fats/oils as a whole and foods supplying n-6 PUFAs but also to increase intake of foods and supplements containing n-3 PUFAs, while those in the comparison group were cautioned to reduce intake of fats/oils as a whole. Patients' compliance/adherence was monitored with a semi-quantitative food frequency questionnaire and by assessment of fatty acid concentrations in plasma, membranes of red blood cells and sigmoid colon samples. As for endpoints to assess tumor suppressive effects of n-3 PUFAs, the number/multiplicity, sizes and incidence rates of colorectal tumors were compared between the experimental and comparison groups after 12 and 24 months of the dietary intervention. On the specified assumption, the number of pairs needed for achieving statistical significance was calculated to be approximately 60-80. A randomized controlled trial is under way to secure enough patients, sustain compliance/adherence and minimize dropouts.

Since the time of the surgical pioneers in the field, Traverso and Longmire, 1 pylorus-preserving pancreaticoduodenectomy (PPPD) has been considered a good alternative to the Whipple procedure 2 for the resection of malignant or benign disease in the pancreaticoduodenal region. However, delayed gastric emptying (DGE) has been reported as a frequent complication of PPPD, with an incidence of 19% to 70% (average 30%). 3–9 This complication is not life-threatening, but it results in a prolonged length of stay and contributes to increased medical costs. The pathogenesis of DGE after PPPD remains unclear, but several factors have been suggested. 10–13 Some European and American surgeons do not blame pylorus preservation but rather their own pancreatic anasto-motic technique. 5–7 In our series, we found DGE in about 10% of our patients without pancreatic leakage, and the gastric output was inversely related to pancreatic juice output. We hypothesized that residual pancreatic fibrosis secondary to chronic pancreatic duct obstruction would lead to DGE. To investigate this possibility, we studied the pathologic findings of surgical specimens of resected pancreas, measured gastric output and pancreatic juice output, and determined time until a solid diet was tolerated.

原発性小腸癌は消化管悪性腫瘍の中で稀な疾患であり,臨床症状や理学的所見に乏しく,内視鏡検査や生検も施行しにくいため,術前診断することが極めて困難である.また一般に腹部超音波検査は,腸管ガスが存在するため消化管病変を描出することが困難である.今回われわれは,腹部超音波検査を契機に回腸癌と術前診断された症例を経験したので若干の文献的考察を加え報告する. 症例は69歳,女性.慢性C型肝炎で前医通院中に腹部超音波検査で回腸末端の壁肥厚と周囲リンパ節腫大を指摘され,精査目的で当科紹介となった.小腸造影検査や内視鏡検査の結果,回腸癌と術前診断され,結腸右半切除術を施行した.

The effects of vasoactive intestinal polypeptide (VIP) and nitric oxide (NO) on the motor activity of the rat proximal colon were examined in an ex vivo model of vascularly perfused rat proximal colon. VIP reduced motor activity and this inhibitory effect was not altered by either atropine, hexamethonium, tetrodotoxin (TTX) nor TTX plus acetylcholine (ACh), but was completely antagonized by NO synthase inhibitor N(G)-nitro-L-arginine (L-NA) and by VIP receptor antagonist, VIP(10-28). These results suggest that VIP may exert a direct inhibitory effect on the motor activity of the rat proximal colon via a VIP receptor located on the smooth muscle and this effect is mediated by NO but not by cholinergic pathways. Atropine and hexamethonium reduced but ACh stimulated motor activity and the effect of ACh was not changed by TTX, suggesting that the cholinergic pathway may exert a direct stimulatory effect on motor activity. Single injection of TTX, VIP(10-28) or L-NA induced a marked increase in motor activity, suggesting that the motor activity of rat proximal colon is tonically suppressed by VIP and NO generating pathways, and elimination of inhibitory neurotransmission by TTX may induce an abnormal increase of the motor activity. The interaction between VIP and NO in regulation of motor activity was further examined by a measurement of NO release from vascularly perfused rat proximal colon. Results showed that NO release was significantly increased during infusion of VIP and this response was reversed by L-NA. These results suggest that VIP generating neurons may inhibit colonic motility by stimulating endogenous NO production in either smooth muscle cells or nerve terminals.

Apolipoprotein (apo)A-I alone or as a component of high density lipoprotein particles has antiatherogenic properties. The age-dependent decline in abundance of this protein may underlie the higher risk for developing occlu- sive coronary artery disease (CAD) in older individuals. Si- milar to humans, expression of rat apoA-I also declines with age. Results in rats showed that levels of serum apoA-I pro- tein, hepatic mRNA, and transcription of the gene were de- creased to 39%, 18%, and 38%, respectively, in 180-day-old animals compared to those of newborn rats. These findings suggest that a nuclear mechanism(s) may account for the decline in apoA-I expression. Accordingly, we examined he- patic nuclear binding activity to four specific cis -acting ele- ments of the rat apoA-I promoter. There were age-dependent changes of binding activity to two proximal sites, B and C, but not to the more distal elements, IRCE and A. Decreased B-site binding activity correlated with lower mRNA levels encoding the activator, HNF-3 b . The age-dependent change in the pattern of binding to site C was due to a switch from the activator, HNF-4, to the repressor, ARP-1. In summary, the age-related decline in apoA-I expression may arise from a reduction in the activity of both cis-acting elements, B and C. —Nakamura, T., A. Fox-Robichaud, R. Kikkawa, A. Kashi- wagi, H. Kojima, M. Fujimiya, and N. C. W. Wong. Tran- scription factors and age-related decline in apolipoprotein A-I expression. J. Lipid Res. 1999. 40: 1709-1718.

症例は58歳男性.左前耳部の腫脹に気付き受診した.頭部CTにて左側頭骨から発生し周囲組織に浸潤した結節性病変を認め, 悪性腫瘍が疑われた.穿刺吸引細胞診では, 小型類円形細胞と多核巨細胞が混在して認められ, 一部にアルシアンブルー陽性の軟骨基質が証明され, 軟骨芽細胞腫を疑った.腫瘍細胞の核も特徴的で, 不整な陥凹, コーヒー豆様の切れ込み, 核内偽封入体がみられ, これらを確認することが鑑別診断に重要と考えられた.病理組織学的にも同様な所見がみられた.軟骨芽細胞腫は比較的まれな良性骨腫瘍で側頭骨に発生するのは珍しく, また浸潤を示した本症例は非常にまれである.

A case of primary T cell of the small intestine with perforated peritonitis is reported. A 26-year-old man who had 2-month lasting poor appetite, high fever of unknown origine, and abdominal pain lost his body weight by 6kg, and the abdominal pain spreaded entire the abdomen one day before adomission. The patient was admitted to the hospital with a suspicion of peritonitis. Plain abdominal X-ray films and computed tomography revealed remarkable ascites and free air. Emergency laparotomy was performed under a diagnosis of perforative peritonitis. Two sites of perforations associated with ulceration were present in the small intestine approximetely 15cm and 80cm from the ligament of Treiz. Partial resections of the small intestine were performed. A histological diagnosis of diffuse lymphoma, mixed-sized, T cell type was confirmed from the positive findings immunochemical stain with UCHL1. The patient was discharged from the hospital 36days after operation. A total of 15 cases of primary T cell lymphoma of the small intestine including our case have been reported in the Japanese literature.

We analyzed loss of heterozygosity (LOH) and microsatellite instability (MI) in 108 cases of sporadic breast cancers using 22 microsatellite markers on 12 chromosomes. LOH was frequently seen in 1p (13%), 6p (18%), 8p (11%), 11p (18%), 13q (21%), 16q (31%), 17p (44%) and 17q (29%). Individual patients were scored according to the degree of LOH at the above eight chromosomal markers. Patients with no LOH were scored as 1, patients with one to three LOH were scored as 2, and patients with four or more LOH were scored as 3. A high LOH score correlated with a high histological grade (p = 0.019) and a poor prognosis (p = 0.0035). Eleven (10.2%) of 108 patients with breast cancer showed MI, with 6 cases showing MI at a single locus and 5 at multiple loci. Of the 11 Mi-positive patients only one had lymph node involvement (p = 0.015), none had histological grade 3 disease, and Mi-positive patients tended to have a better prognosis than Mi-negative ones. These data suggest that MI may be an early event in mammary tumorigenesis, and that LOH occurs at a later stage. The LOH score may be a useful prognostic marker of operable breast cancer.

Dimaprit, a selective histamine H2 receptor agonist, was examined in experimental models of endotoxin shock and hepatitis in mice. Injection of lipopolysaccharide (8 mg/kg i.v.) into Balb/c mice resulted in an elevation of plasma tumor necrosis factor-alpha (TNF-alpha), reaching the maximal level at 1 h post-lipopolysaccharide (1147 U/ml). Oral administration of dimaprit 200 mg/kg, 1 h prior to lipopolysaccharide challenge, inhibited the increase in plasma TNF-alpha by 71% and also the survival rate was increased to 62.5% from 8.3% in the disease control. In a mouse hepatitis model, simultaneous injection of galactosamine (700 mg/kg i.v.) and lipopolysaccharide (3 micrograms/kg i.v.) into Balb/c mice caused an increase in plasma TNF-alpha, peaking at 1 h, followed by an elevation of L-alanine aminotransferase (E.C.2.6.1.2) activity at 4 h onward. Oral administration of dimaprit 200 mg/kg, 1 h prior to galactosamine and lipopolysaccharide, reduced the increase in plasma TNF-alpha by 99% and L-alanine aminotransferase by 82%. In vitro, dimaprit dose dependently inhibited the production of TNF-alpha in mouse peritoneal macrophages and human peripheral blood monocytes stimulated with lipopolysaccharide with IC50 values of 1 microM. The decrease in TNF-alpha production by dimaprit was reversed by cimetidine, a histamine H2 receptor antagonist. Dimaprit dose dependently suppressed TNF-alpha mRNA in human peripheral blood monocytes. These results suggest that activation of the histamine H2 receptor downregulates the production of TNF-alpha, and that histamine may be an important regulator in pathological conditions in which TNF-alpha plays an important role.

We studied the timing of microsatellite instability (referred to as replication error; RER) presentation during human breast carcinogenesis using tissue microdissected from both in situ and invasive breast cancers of Japanese women. We analyzed 100 breast cancer specimens for RER at nine genomic loci on seven chromosomes. Eight of the 100 cases (8%) were RER-positive at one or more chromosomal loci. Additionally; we obtained genomic DNA from two of four RER-positive patients with an intraductal component, both of which showed microsatellite instability in in situ foci. This finding indicates that microsatellite instability may be an early event during human breast carcinogenesis.

A 62-year-old male presented with glioblastoma multiforme in the left frontal lobe manifesting as motor aphasia, subsequent to a malignant lymphoma in the right orbit. He underwent subtotal removal of the right orbital mass presenting as right exophthalmos which was shown by histological examination to be non-Hodgkin's lymphoma. He received 30 Gy Lineac irradiation to the right orbit. His post-operative course was satisfactory. Magnetic resonance (MR) imaging with gadolinium-diethylenetriaminepenta-acetic acid (Gd-DTPA) 7 months later demonstrated a small spotty enhanced lesion in the left frontal lobe. He developed motor aphasia 1 year after irradiation. MR imaging disclosed an enhanced mass in the left frontal lobe, which was totally removed. Histological examination revealed glioblastoma multiforme. Patients with malignant lymphoma may develop a subsequent second malignant tumor. MR imaging with Gd-DTPA is quite useful for early detection of a second brain tumor.

To study exogenous sterol metabolism during the suppression or stimulation of cholesterol biosynthesis induced by treatments for hyperlipidemia, we determined plasma plant sterol concentrations before and after administration of an HMG-CoA reductase inhibitor, pravastatin, and compared these with changes in these plasma sterol levels by the bile-sequestrating resin, cholestyramine. The effects of the drugs were also studied in a sitosterolemic patient who has had increased plasma levels of plant sterols. Plasma cholesterol levels determined by the HPLC method were decreased significantly after administration of pravastatin. Plasma plant sterol (sitosterol and campesterol) as well as cholestanol concentrations were also significantly reduced. Cholestyramine administration decreased plasma levels of cholesterol, but did not change those of plant sterols in the hypercholesterolemic subjects. Pravastatin had little effect in a sitosterolemic patient on plasma levels of sterols, where cholestyramine decreased the plasma levels of both cholesterol and cholestanol. These results indicate that treatment with the HMG-CoA reductase inhibitor decreases plasma plant sterol concentrations, and suggest that the increased plasma plant sterol levels in sitosterolemia might not be due to the decreased cholesterol biosynthesis in vivo.

Ten cases of thyroid carcinoma with squamous metaplasia were divided into two groups according to the prognosis. The average age of 5 cases with good prognosis was 54.8. Because of negative or slight, if any, invasion to surrounding tissue, successive curative resection was done in all of those cases. All of them were papillary carcinoma with squamous metaplasia. Five cases with poor prognosis had the average age of 65. Complete resection was impossible for all of those cases due to severe invasion to various tissues. Histological evidence of undifferentiated carcinoma was revealed more or less in those 5 cases. Therefore the presence of squamous metaplasia does not influence on the prognosis of the patients. The comment in the WHO classification that the term “squamous cell carcinoma” should be reserved for tumours composed entirely of cells showing so-called intercellular bridge and/or forming keratin, and should not be used for a squamous component with papillary carcinoma of undifferentiated carcinoma has been reaffirmed.

A case of adenocarcinoma of Meckel's diverticulum is reported. A 62-year-old female was admitted to the hospital because of abdominal pain, nausea and vomiting. X-ray film of the small intestine showed an abdominal radiopaque retention like a diverticulum. CT showed a solid intrapelvic tumor. The patient was suspected as having a tumor derived from intestinal diverticulum. On the 4th day of hospital course, emergency operation was performed for perforated peritonitis. At laparotomy, Meckel's diverticulum was found 70cm orally from the Bauhin's valve on the antimesenteric border. An egg-sized tumor was found at the apex of the diverticulum, and there was a perforation in the middle of the diverticulum. No macroscopic metastasis was found. Partial resection of the ileum including the Meckel's diverticulum was performed. Pathological examination of the resected tumor revealed various morphology consisting of well and poorly differentiated adenocarcinoma. There existed ectopic gastric mucosa in the diverticulum, from where the tumor might arise. Nine months after the operation, she died of recurrence. This paper also presents a review of 14 domestic reports of adenocarcinoma of Meckel's diverticulum.

To investigate the hepatic ketone body metabolism in NIDDM, we studied the ketone body production rates in hepatocytes from newly developed non-obese NIDDM model rats. NIDDM model rats were prepared by intraperitoneal injection of streptozotocin at 2 or 5 days of age (STZ2, STZ5 respectively). After 10-15 weeks, ketone body production rates in hepatocytes isolated from these rats were compared with those from control rats as well as ketotic rats made by intravenous injection of streptozotocin into adult rats. Basal ketone body production rates from 0.3 mM [U-14C] palmitate in hepatocytes from control, STZ 2, STZ 5 and ketotic rats were 11.7 +/- 0.98, 14.9 +/- 0.72, 16.0 +/- 0.45, 22.8 +/- 2.32 nmole.palmitate/mg.prot/hr, respectively. These rates were stimulated by 1 microgram/ml of glucagon in control, STZ 2 and STZ 5 rats (14.1 +/- 0.99, 18.6 +/- 1.36, 18.7 +/- 0.69 nmole.palmitate/mg.prot/hr, respectively), but not in ketotic rats (22.8 +/- 2.07 nmole.palmitate/mg.prot/hr). The similar effects were observed by 1 microgram/ml of epinephrine. The basal ketone body production rates were negatively correlated to both hepatic glycogen contents and plasma IRI levels. Considering these parameters together, the extent of metabolic derangement in STZ 2 and STZ 5 rats was between that in control and ketotic rats. These results indicate that the derangements of hepatic ketone body production are related to the severity of insulin deficiency and suggest that the enhanced hepatic ketogenesis contributes in part to the elevated plasma ketone body levels in non-obese NIDDM.

The antitumor effects of recombinant human tumor necrosis factor-alpha (rTNF-alpha) and 5-fluorouracil (5-FU) in combination treatment were examined on Meth A fibrosarcoma implanted intradermally in mice. Growth of the tumor was inhibited when rTNF-alpha was given i.v. on day 7 or 11 after implantation, but the effect was countered when 5-FU was additionally given i.p. once a day on days 1-4 after implantation. Conversely, 5-FU given on days 5-8 after implantation augmented the antitumor effects of rTNF-alpha. Injection of carbon particles showed that fine capillaries did not develop in the tumors of mice treated with 5-FU on days 1-4 after implantation, but that a delicate network of capillaries developed in the tumors of both the mice treated with 5-FU on days 5-8 after implantation and the controls given saline. The results show that the timing of 5-FU treatment is important when attempting to enhance the antitumor effects of rTNF-alpha, and suggest that these effects are directly associated with newly formed fine capillaries in the tumor.

We evaluated whether hyperinsulinaemia stimulates the expression of transcription factor CCAAT/enhancer binding protein (C/EBP)-beta and C/EBP-delta and leads to the induction of the chemokine (C-C motif) ligand 2 gene (Ccl2, also known as MCP-1) expression in aortas.Hyperinsulinaemia was induced by feeding rats a high-fructose diet. CCL2 production was analysed by ELISA. The expression of Ccl2, Cebpb and Cebpd mRNAs was investigated by quantitative RT-PCR. The binding of C/EBP-beta to Ccl2 was assessed by chromatin immunoprecipitation (ChIP) assay.Insulin at a concentration of 10 nmol/l significantly stimulated the expression of Cebpb, Cebpd and Ccl2 mRNAs, depending on activation of phosphatidylinositol 3-kinase (PI3K) in cultured vascular smooth muscle cells. The knock-down of C/EBP-beta with siRNA abolished the insulin-induced Ccl2 mRNA expression. In the aortas from fructose-fed rats, the levels of phosphorylation of Akt/protein kinase B, a downstream effector of PI3K, were also increased. The expression of Cebpb, Cebpd and Ccl2 mRNAs in the aortas from fructose-fed rats were significantly elevated, by 330, 300 and 300%, respectively, compared with those of control-fed rats. The induction Ccl2 mRNA expression in the aortas was significantly correlated with the expression of Cebpb and Cebpd mRNAs in the aortas. Furthermore, the ChIP assay showed elevated binding of C/EBP-beta to the 5' upstream region of Ccl2 in the aortas from fructose-fed rats.These findings clearly indicate the role of C/EBPs in the mechanism of upregulation of CCL2, an inflammation-related protein, observed in the hyperinsulinaemic state, which may initiate the process of atherosclerosis.

To clarify the effect of dietary lipid hydroperoxide (LPO) on development of glucose intolerance, we fed Sprague–Dawley rats on a diet containing elevated LPO level for 10 weeks and measured both insulin sensitivity and insulin secretion. The contents of LPO in both plasma and skeletal muscle in the LPO-fed rats were significantly higher than those in the controls. Both insulin resistance evaluated by steady-state blood glucose (SSBG) methods and impaired insulin secretion evaluated by oral glucose tolerance test (OGTT) were found in the LPO-fed rats as compared with control rats. Furthermore, the levels of insulin receptor substrate (IRS)-1 protein in the skeletal muscle were significantly lower in the LPO-fed rats. Those impairments were not reversed in LPO-fed rats with supernormal levels of plasma vitamin E following vitamin E supplementation for 5 weeks. Moreover, the immunohistochemical study revealed that NF-κB-p50 protein was found in the nucleus of pancreatic β-cells of the LPO-fed rats, whereas it was not observed in the nucleus of the islets in the control rats. These findings indicate that NF-κB is activated in response to oxidative stress in pancreatic islet cells in LPO-fed rats. In conclusion, our studies reveal that diet high in LPO by vitamin E deficiency accelerates glucose intolerance through impairments of both sensitivity and secretion of insulin.

Immature rat intestinal stem cells (IEC-6) given the ability to express the transcription factor, pancreatic duodenal homeobox 1 (Pdx-1), yielded YK cells. Although these cells produced multiple enteroendocrine hormones, they did not produce insulin. Exposure of YK cells to 2 nmol/l betacellulin yielded BYK cells that showed the presence of insulin expression in cytoplasm and that secreted insulin into culture media. By examining the mechanism of differentiation in BYK cells, we found that another transcription factor, islet factor 1 (Isl-1) was newly expressed with the disappearance of Pax-6 expression in those cells after exposure to betacellulin. These results indicated that combined expression of Pdx-1 and Isl-1 in IEC-6 cells was required for the production of insulin. In fact, overexpression of both Pdx-1 and Isl-1 in IEC-6 cells (Isl-YK-12, -14, and -15 cells) gave them the ability to express insulin without exposure to betacellulin. Furthermore, implantation of the Isl-YK-14 cells into diabetic rats reduced the animals’ plasma glucose levels; glucose levels dropped from 19.4 to 16.9 mmol/l 1 day after the injection of cells. As expected, the plasma insulin concentrations were 2.7 times higher in the diabetic rats injected with Isl-YK-14 cells compared to in controls. In summary, our results indicated that immature intestinal stem cells can differentiate into insulin-producing cells given the ability to express the transcription factors Pdx-1 and Isl-1.

To elucidate molecular mechanisms of high fructose-induced metabolic derangements and the influence of peroxisome proliferator-activated receptor-α (PPARα) activation on them, we examined the expression of sterol regulatory element binding protein-1 (SREBP-1) and PPARα as well as its nuclear activation and target gene expressions in the liver of high fructose-fed rats with or without treatment of fenofibrate. After 8-wk feeding of a diet high in fructose, the mRNA contents of PPARα protein and its activity and gene expressions of fatty acid oxidation enzymes were reduced. In contrast, the gene expressions of SREBP-1 and lipogenic enzymes in the liver were increased by high fructose feeding. Similar high fructose effects were also found in isolated hepatocytes exposed to 20 mM fructose in the media. The treatment of fenofibrate (30 mg · kg−1· day−1) significantly improved high fructose-induced metabolic derangements such as insulin resistance, hypertension, hyperlipidemia, and fat accumulation in the liver. Consistently, the decreased PPARα protein content, its activity, and its target gene expressions found in high fructose-fed rats were all improved by fenofibrate treatment. Furthermore, we also found that the copy number of mitochondrial DNA, the expressions of mitochondrial transcription factor A, ATPase-6 subunit, and uncoupling protein-3 were increased by fenofibrate treatment. These findings suggest that the metabolic syndrome in high fructose-fed rats is reversed by fenofibrate treatment, which is associated with the induction of enzyme expression related to β-oxidation and the enhancement of mitochondrial gene expression.

Few previous studies have discussed the changes in serotonin receptor activity in the small intestine of diabetic animals. Therefore, we examined serotonin content in duodenal tissue and dose-dependent effects of serotonin agonists and antagonists on the motor activity of ex vivo vascularly perfused duodenum of streptozotocin (STZ)-diabetic rats. Serotonin content was significantly increased in enterochromaffin cells but not altered in serotonin-containing neurons in STZ-diabetic rats. Motor activity assessed by frequency, amplitude, and percent motility index per 10 min of pressure waves was reduced in the duodenum of diabetic rats, and this reduction was reversed by insulin treatment. Serotonin dose dependently increased the motor activity in control rat duodenum but only a higher concentration of serotonin increased the motor activity in diabetic rats. The 5-hydroxytryptamine (5-HT) receptor subtype 4 (5-HT4) antagonist SB-204070 dose dependently reduced motor activity in both control and diabetic rats, whereas the 5-HT3receptor antagonist azasetron, even at a higher concentration, failed to affect motor activity in diabetic rat duodenum but dose dependently reduced motor activity in control rat duodenum. These results suggest that 5-HT3receptor activity was impaired but 5-HT4receptor activity was intact in STZ-diabetic rat duodenum. Such an impairment of 5-HT3receptor activity may induce the motility disturbance in the small intestine of diabetes mellitus.

The mechanisms regulating the release of serotonin into the portal circulation as well as into the gastric lumen were studied in the isolated vascularly and luminally perfused rat stomach. Immunohistochemical study of the rat stomach showed that serotonin-containing enterochromaffin (EC) cells were densely packed in the antral mucosa, sparsely scattered in the corpus, and not found in the fundus. Such morphological findings suggest that serotonin detected in this study may have originated from antral EC cells. Luminal acidification stimulated the vascular release of serotonin but did not affect the luminal release of serotonin. The basal release of serotonin into the vasculature was 10 times higher than that into the gastric lumen at intragastric pH 2. The vascular release of serotonin is regulated by stimulation from cholinergic nicotinic mechanisms, whereas inhibitory neurotransmitters such as vasoactive intestinal peptide and NO are probably not involved. Somatostatin and peptide YY originating from endocrine cells may exert direct inhibitory effects, possibly via somatostatin and peptide YY receptors on the EC cells, and a cholinergic muscarinic mechanism may exert indirect effects on the vascular release of serotonin via the muscarinic receptor on the endocrine cells.

We studied a 60-yr-old female with a brain tumor who showed severe symptoms of hypoglycemia (plasma glucose, 2.2 mmol/L) and hyperinsulinemia (1.28 nmol/L) after radiotherapy. The cystic brain tumor contained proinsulin and insulin at concentrations of 13.6 and 1.22 nmol/L, respectively. Immunohistochemical studies showed the tumor cells were ectodermal in origin but not endodermal, based on three diagnostic features of neuroectodermal tumors 1) pseudorosette formation noted under light microscopy, 2) finding of a small number of dense core neurosecretory granules on electron microscopy, and 3) positive immunostaining for both neuronal specific enolase and protein gene product 9.5. These cells also expressed the transcription factor, neurogenin-3, NeuroD/β2, and islet factor I, which are believed to be transcription factors in neuroectoderm as well as in pancreatic islet cells, but not pancreatic-duodenal homeobox 1, Pax4, or Nkx2.2. In addition, they did not express glucagon, somatostatin, or glucagon-like peptide-1. Our results show the presence of proinsulin in an ectoderm cell brain tumor that does not express the homeobox gene, pancreatic-duodenal homeobox 1, but expresses other transcription factors, i.e. neurogenin3, NeuroD/β2, and islet factor-1, which are related to insulin gene expression in the brain tumor.

Background and Objective E-cadherin, a calcium-dependent transmembrane glycoprotein, is an adhesion molecule. We studied clinical significance of E-cadherin expression in thyroid neoplasms. Methods We immunohistochemically studied E-cadherin expression in 60 normal tissue specimens of thyroid tissues and in 82 follicular adenomas, 53 papillary carcinomas, 4 follicular carcinomas, 2 medullary carcinomas, and 5 anaplastic carcinomas of the thyroid. Results In papillary carcinoma, E-cadherin expression was preserved significantly less often than in follicular adenoma or normal thyroid tissue (P

We present a woman with consecutively occurring multiple fibroadenomas of thebreast distinguished from phyllodes tumor by clonality analysis of stromal tissue. Fifty-three masses developed in her right breast in an 11.5 year period since first onset. A clonality analysis, performed by polymerase chain reaction (PCR), focused on the Hpa II site within exon 1 of the androgen receptor (AR) gene. Estrogen receptor (ER) alpha immunohistochemistry was performed with a specific polyclonal antibody against the hormone binding domain of the protein. Since all of the nodules were polyclonal in stromal tissues, they were hyperplastic rather than true neoplasms such as phyllodes tumors. The co-existence of abundant adenosisfoci and numerous sub-clinical small nodules in the adjacent breast tissue alsosuggested proliferative stimuli throughout the breast. ER alpha protein was expressed only in the nuclei of epithelial cells. The possible influence of ER positive epithelial cells on stromal cell growth is discussed.

To investigate the alterations of genetic instabilities in carcinogenesis of the breast, we analyzed the allelotypic profile of 65 ductal carcinomas in situ (DCIS), compared with that of 207 invasive ductal carcinomas (IDC) of the breast. These studies were performed by means of examining microsatellite-length polymorphisms at seven loci (AluVpa, ESR, D11S988, D13S267, D16S398, D17S1159, and D17S855) from microdissected paraffin sections. Allelic loss or imbalance, considered a loss of heterozygosity (LOH), tended to be more frequently seen in IDC than in DCIS. In particular, the frequency of LOH at the 17p locus was significantly higher in IDC than in DCIS (42 vs. 23%, P=0.022). LOH in DCIS was most frequently seen at D16S398 (26%). LOH frequency at D16S398 in low- and intermediate-grade DCIS was higher than that in high-grade DCIS, while LOH frequencies at D11S988 and D17S1159 in low- and intermediate-grade DCIS was lower than those in high-grade DCIS. LOH frequency at D11S988 in non-comedo type DCIS was lower than that in comedo type DCIS. Furthermore, the frequency of microsatellite instability (MSI) at only one locus in DCIS (28%) was statistically higher than that in IDC (6%) (P

We report a case of carcinoma in solitary rectal ulcer syndrome. The diagnosis was made by colonoscopic appearance and biopsy. A tumor measuring 0.9 x 0.6 cm was found in a resected solitary rectal ulcer. The lesion exhibited typical histological features of solitary rectal ulcer syndrome, with a well differentiated adenocarcinoma invading submucosal layers and some dysplastic glands. We believe that the adenocarcinoma represents a malignant transformation from solitary rectal ulcer syndrome, because similar to longstanding chronic idiopathic colitis, colorectal dysplasia and carcinoma may develop.

A 19-year-old woman with diabetic lipemia and maturity-onset diabetes of the young (MODY) is reported. Though her insulin secretory activity was preserved, she fell into mild diabetic ketoacidosis (DKA) and showed type V hyperlipidemia. Post-heparin plasma activity of lipoprotein lipase (LPL) was decreased even 10 days after initiating insulin injection but not deficient. The abnormalities in lipid metabolism were improved by long-term insulin treatment. Though the contribution of the genetic background to the lipid abnormalities is not clear, the characteristics of MODY in this patient including insulin secretory capacity under stress conditions such as DKA might play a role in the development of diabetic lipemia.