Role of lymph node dissection in the treatment of urothelial carcinoma of the upper urinary tract: multi-institutional relapse analysis and immunohistochemical re-evaluation of negative lymph nodes.

AIM: To determine the role of lymph node dissection (LND) in the treatment of urothelial carcinoma (UC) of the upper urinary tract (UUT). PATIENTS AND METHODS: [Study-1] A retrospective multi-institutional study evaluated 293 patients undergoing predominantly nephroureterectomy for UC of the UUT. Of 293 patients, 267 patients had pure UC and 26 demonstrated other histological components. Regarding the pathological node status, 130 patients had pN0 disease, 141 patients had pNx disease and 22 patients had pN+ disease. The sites of initial recurrence and time to first recurrence were reviewed. The sites of recurrence were classified as locoregional or distant recurrence. The relationship between node status and future recurrence was analyzed. [Study-2] Fifty-one patients treated by nephroureterectomy at Hokkaido University Hospital were included. All had LND and all LNs were negative on hematoxylin and eosin staining. We re-evaluated the presence of micrometastasis in LND specimens by anti-cytokeratin immunohistochemistory. RESULTS: [Study-1] Of 293 patients, 76 developed disease relapse. Regional lymph node recurrence was the most common site (34 patients). On multivariate analyses that adjusted for the effect of tumor stage and tumor grade, pNx (skipping LND) was an adverse factor not only for locoregional recurrence, but also for distant relapse. [Study-2] Immunohistochemistry identified micrometastases in 7 (14%) of 51 patients. Regarding survival, 5 of these 7 patients with micrometastases were alive at last follow-up. CONCLUSIONS: On relapse analysis, skipping LND was an adverse factor not only for locoregional recurrence, but also for distant relapse. Immunohistochemistry detected micrometastases in about 14% of patients previously diagnosed as pN0. These findings further support a potential therapeutic benefit of LND by eliminating micrometastases.

Immunization against intestinal bacterial endotoxin prevents alcoholic fatty liver in rats.

Accumulating evidences indicate that an endotoxin originating from intestinal gram-negative bacteria may be involved in alcohol-induced liver injury including fatty liver. Therefore, whether immunization against intestinal bacterial endotoxin blocked fatty liver induced by chronic alcohol and diet including much-unsaturated fatty acid was investigated in rats. The titer of antibody against the endotoxin increased significantly after 13 weeks of continuous immunization. Daily alcohol treatment was initiated at 12 weeks and continued for 4 weeks. Plasma glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT) and triglyceride (TG) levels increased significantly in non-immunized rats receiving alcohol, but not in immunized rats. Continuous alcohol treatment gradually decreased the survival rate to 60% from 13 days after beginning administration in non-immunized, but not immunized, rats. A histochemical study revealed that continuous treatment with alcohol and unsaturated fatty acids caused fatty liver in non-immunized, but not immunized, rats. This study strongly supports the hypothesis that alcohol-induced fatty liver is due to a circulating endotoxin, and suggests that immunization for endotoxin prevent the alcoholic fatty liver.

Versatility of the accessory C proteins of Sendai virus: contribution to virus assembly as an additional role.

The P/C mRNA of Sendai virus (SeV) encodes a nested set of accessory proteins, C', C, Y1, and Y2, referred to collectively as C proteins, using the +1 frame relative to the open reading frame of phospho (P) protein and initiation codons at different positions. The C proteins appear to be basically nonstructural proteins as they are found abundantly in infected cells but greatly underrepresented in the virions. We previously created a 4C(-) SeV, which expresses none of the four C proteins, and concluded that the C proteins are categorically nonessential gene products but greatly contribute to viral full replication and infectivity (A. Kurotani et al., Genes Cells 3:111-124, 1998). Here, we further characterized the 4C(-) virus multiplication in cultured cells. The viral protein and mRNA synthesis was enhanced with the mutant virus relative to the parental wild-type (WT) SeV. However, the viral yields were greatly reduced. In addition, the 4C(-) virions appeared to be highly anomalous in size, shape, and sedimentation profile in a sucrose gradient and exhibited the ratios of infectivity to hemagglutination units significantly lower than those of the WT. In the WT infected cells, C proteins appeared to colocalize almost perfectly with the matrix (M) proteins, pretty well with an external envelope glycoprotein (hemagglutinin-neuraminidase [HN]), and very poorly with the internal P protein. In the absence of C proteins, there was a significant delay of the incorporation of M protein and both of the envelope proteins, HN and fusion (F) proteins, into progeny virions. These results strongly suggest that the accessory and basically nonstructural C proteins are critically required in the SeV assembly process. This role of C proteins was further found to be independent of their recently discovered function to counteract the antiviral action of interferon-alpha/beta. SeV C proteins thus appear to be quite versatile.

Non-purulent meningoencephalomyelitis of a Pacific striped dolphin (Lagenorhynchus obliquidens). The first evidence of morbillivirus infection in a dolphin at the Pacific Ocean around Japan.

On March 22, 1998, a mature, male, hyposthenic Pacific striped dolphin (Lagenorhynchus obliquidens) was stranded at Aoshima Beach in Miyazaki prefecture, Japan. A necropsy performed 14 hr after death revealed mild diffuse congestion and edema of the leptomeninges and mild pulmonary atelectasis. Histopathologically, non-purulent inflammatory were observed throughout the cerebrum, thalamus, midbrain, pons, medulla oblongata, and spinal cord. Hematoxylin and eosin stain revealed no viral inclusion bodies. Immunohistochemistry using a monoclonal antibody against nucleoprotein of canine distemper virus (CDV-NP) revealed a number of CDV-NP-positive granular deposits in the cytoplasm and cell processes of the degenerating or intact neurons. The present paper is a first report of spontaneously occurred morbillivirus infection in a dolphin at the Pacific Ocean around Japan.

Spinal oligodendroglioma with diffuse arachnoidal dissemination in a Japanese Black heifer.

A gelatinous focus with cystic spaces, was found in the posterior funiculus of the 2nd to 3rd lumbar levels of the spinal cord of a Japanese Black heifer, 2 years old, with clinical signs of severe dysstasia. Histopathological examination revealed that the spinal lesion consisted of multifocal and diffuse proliferation of round cells with abundant vacuolar cytoplasm and hyperchromatic nuclei. In the lesions there was a number of cystic spaces containing aggregates of small round cells. The neoplastic foci showed a honeycomb structure divided by thin blood vessels, representing typical lesions of oligodendroglioma. Diffuse and multifocal proliferation of these round cells were also recognized in the subarachnoidal space in the sacral spinal cord. Immunohistochemically, the proliferating round cells were negative for glial fibrillary acidic protein. Based on these morphological features, the case was diagnosed as lumbar spinal oligodendroglioma with diffuse arachnoidal dissemination.

Obui-himo syndrome.

Normal variants of the venous system are relatively common and rarely cause severe symptoms. We report the case of a 5-month-old baby who displayed cyanotic color and swelling of arms whenever she was carried on the mother's back with a special band "Obui-himo". It was demonstrated by venography that the symptoms were caused by the absence of a cephalic vein and compression of axillary veins with the Obui-himo. In any country with a custom similar to the Obui-himo, these symptoms, if clinically encountered, are an indication that venography should be performed.

Cefotiam-induced IgE-mediated occupational contact anaphylaxis of nurses; case reports, RAST analysis, and a review of the literature.

Cefotiam (CTM) is one of the most popular cephem antibiotics in Japan. Recently we experienced two cases of nurses with CTM-induced contact anaphylaxis. When they were preparing drip infusions of antibiotics or working around other nurses doing so, they suddenly fell into shock with other symptoms such as flushing, urticaria, abdominal distress, vomiting, dyspnoea and/or loss of consciousness. The symptoms never occurred after they avoided exposure to CTM. Passive cutaneous or open patch tests were positive for CTM. Histamine release was induced by CTM from washed leucocytes. RAST analysis using CTM-human serum albumin-coupled discs showed high % RAST count, suggesting that these reactions were mediated by IgE antibodies. A RAST inhibition test suggested that the methyl-thiotetrazole side-chain was the main antigenic determinant. Both patients had hand dermatitis that had appeared preceding the episodes of anaphylaxis. Although the dermatitis had been resistant to treatments, it also disappeared after they avoided exposure to CTM. It seemed likely that it was also induced or exacerbated by CTM and facilitated the penetration of CTM to cause anaphylaxis. The literature is also reviewed.

Impact of stress on serum gastrin in Zollinger-Ellison syndrome.

We report an impressive case with Zollinger-Ellison syndrome (ZES), in which stress-induced sympathetic discharge influenced serum gastrin. Our patient was a 35-yr-old female who complained of frequent and massive vomiting (more than 4000 ml of gastric juice) which was aggravated especially by psychosocial stress. Basal hypergastrinemia (1900 pg/ml) was found after the admission. The most striking finding was that laboratory stress dramatically increased serum gastrin (from 1900 to 5400 pg/ml) and plasma noradrenaline (from 180 to 1130 pg/ml). Mental arithmetic stress further enhanced hypergastrinemia (5800 pg/ml) with a concomitant increase in plasma noradrenaline (1240 pg/ml). Neostigmine (10 micrograms/kg im) also increased serum gastrin up to 6100 pg/ml but propranolol (40 micrograms/kg i.v.) reduced these elevations (noradrenaline: 990 pg/ml, gastrin: 5000 pg/ml). In this case, the effect of stress on serum gastrin mimicked the effect of catecholamine infusion in ZES. These findings suggest that psychological stress induces serum gastrin secretion via beta-adrenoceptor with exacerbation of symptoms in some cases with ZES.

Brain-gut response to stress and cholinergic stimulation in irritable bowel syndrome. A preliminary study.

To investigate the influence of the brain-gut interactions on the pathophysiology of irritable bowel syndrome (IBS), we compared such patients (n = 10) with healthy control subjects (n = 11) by measuring the pressure of the colon and small intestine simultaneously with analysis of power spectrum of the electroencephalography (EEG) under mental stress and administration of neostigmine. Stress slightly increased the colonic motility index, reduced the percentage of alpha power, and increased the percentage of beta and theta power of the EEG in the patients with IBS more than in the controls (p < 0.05). The patients with IBS had a longer phase II (p < 0.01) and shorter phase I (p < 0.02) of fasting duodenal motor activity than the controls. Neostigmine (10 micrograms/kg) caused a significant difference in the colonic motility index (p < 0.01) and power spectra of EEG (p < 0.05) in the patients with IBS compared to the controls. Significant positive correlation was detected between colonic motility and power spectral change induced by stress (r = 0.46, p < 0.05) or neostigmine (r = 0.51, p < 0.01). These results suggest that patients with IBS have exaggerated responsivity of the gut and the brain to mental stress and cholinergic stimulation. Moreover, there is a possibility that these exaggerated responses are related.

Case report: reversal of severe leukopenia by granulocyte colony-stimulating factor in anorexia nervosa.

Recent attempts to reduce weight by patients with anorexia nervosa have sometimes led to life-threatening hematologic complications. This report describes an instance in which a patient with anorexia nervosa and pancytopenia drastically improved with treatment that included administration of granulocyte colony-stimulating factor. The patient had lost 27 kg of body weight within 8 months. Even after admission, the blood cell count continued to decrease rapidly as follows: platelet, from 244 x 10(3)/microliters to 44 x 10(3)/microliters; erythrocyte, from 4.04 x 10(6)/microliters to 2.58 x 10(6)/microliters; and leukocyte, from 4.8 x 10(3)/microliters to 1.6 x 10(3)/microliters (granulocyte, 0.8 x 10(3)/microliters). Complications included pneumomediastinum, pneumothorax, purpura, petechiae, hepatomegaly, fever, gangrenous stomatitis, and somnolence. Bone marrow aspiration disclosed absence of fat cells, marrow hypoplasia, and infiltration of the mature lymphocytes. Intravenous hyperalimentation, blood transfusion, gamma-globulin, and antibiotics were administered, but leukopenia and fever remained. However, administration of recombinant human granulocyte colony-stimulating factor dramatically reversed the leukopenia and fever. With careful nutrition therapy, the patient's blood cell count and bone marrow normalized by the time of discharge. It was concluded that severe hematologic disorders may occur in patients with anorexia nervosa, and advanced treatment may be required to save the patient's life.

[Brain-gut interactions in irritable bowel syndrome: physiological and psychological aspect].

Recent advances in the investigation of brain-gut interaction in irritable bowel syndrome (IBS) were reviewed. Brain is suggested to play an important role in the pathophysiology of IBS on the basis of the following evidence. (1) Stress often induces major symptoms of IBS patients (Drossman et al., 1982), simultaneously with colonic hypermotility (Fukudo et al., 1987) or dysmotility of the small intestine (Kumar et al., 1985). (2) IBS patients rarely express symptoms or small intestinal dysmotility during sleep (Kellow et al., 1990). (3) IBS patients complain of more pain with balloon distension of the colon or rectum than normal controls; visceral perception is enhanced in IBS (Whitehead et al., 1990). (4) IBS patients often show psychoneurotic symptoms and extra-colonic somatic symptoms (Young et al., 1976). (5) There are some animal (Williams et al, 1987) or human (Dinan et al, 1990) experiments which indicate the possible involvement of brain peptide or brain monoamine in IBS. (6) Dysrhythmia or increased beta power in electroencephalogram is observed more often in IBS patients than in the normal controls (Fukudo et al, 1991) in addition to abnormal REM sleep in IBS patients (Kumar et al., 1992). These observations support our hypothesis that not only the gut but also the brain show dysfunction and exaggerated responsivity to the stimuli in IBS. Further research on brain-gut interaction in IBS is warranted.

Accentuated vagal antagonism of beta-adrenergic effects on ventricular repolarization. Evidence of weaker antagonism in hostile type A men.

BACKGROUND: Prior research has suggested a weaker parasympathetic antagonism of sympathetic effects on the heart in type A (coronary-prone) men. To confirm this phenomenon and extend our understanding of it, we investigated the effects of prior muscarinic blockade on the electrocardiogram T wave and other cardiovascular and neuroendocrine responses to isoproterenol in type A and type B (non-coronary-prone) men. METHODS AND RESULTS: Responses to two 5-minute intravenous isoproterenol infusions (0.01 micrograms/kg/min and 0.02 micrograms/kg/min) were evaluated in six type A and six type B men after pretreatment with either dextrose placebo or atropine (1.2 mg). Atropine significantly potentiated T wave attenuation in the recovery period after isoproterenol infusion (0.30 +/- 0.07 mV) compared with placebo (0.54 +/- 0.09 mV, p less than 0.001). Atropine also potentiated the heart rate increase to isoproterenol (39 +/- 3 beats per minute versus 20 +/- 2 beats per minute after placebo). Atropine enhanced decreases in systolic, diastolic, and mean arterial pressures as well as pulse pressure to isoproterenol. Atropine enhancement of many of these responses was increased among subjects with high scores on various hostility/anger scales. Isoproterenol alone produced greater T wave attenuation in type A than in type B men. However, atropine enhancement of T wave attenuation and blood pressure falls by isoproterenol was present only in type B men. CONCLUSIONS: These findings indicate that there is accentuated parasympathetic antagonism of T wave attenuation and blood pressure responses induced by beta-adrenergic stimulation. Relative weakness of this antagonism of sympathetic effects on the heart in hostile type A individuals may contribute to their higher coronary disease risk.

Topical thrombin-induced IgE-mediated anaphylaxis: RAST analysis and skin test studies.

Bovine topical thrombin (BTT) is a heterologous plasma thrombin concentrate that has been frequently used for the hemostasis since the 1940s. Recently, three patients in Japan went into shock after the topical application of BTT at lesion sites, and two of these patients had received BTT repeatedly. The clinical symptoms and the increased anti-BTT percent RAST counts suggest that these reactions were shock mediated by anti-BTT IgE antibodies. The RAST-inhibition analysis suggested that the antigenic substance(s) were bovine-specific moiety(ies) mainly involved in the contaminant rather than bovine thrombin itself. The skin tests were studied to predict such allergic reactions. The intracutaneous test provoked nonspecific reactions even at the low concentrations of BTT. The prospective study on the predictive value of the prick test with 1000 U/ml (1 mg/ml) of BTT in 192 patients suggested that it is useful to detect highly sensitive patients. In addition, the increased levels of anti-BTT IgE antibodies in patients 1 month after the single administration of BTT suggested the immunogenicity of the topical application of BTT.

Beta and alpha adrenergic reactivity elicitable stress study with special reference of electrocardiographic T-wave amplitude.

Twenty-six healthy young Caucasian males were defined into high hostile (Hi-Ho) group and low hostile (Lo-Ho) group assessed by Cook-Madley's Hostility (Ho) scale. Mental arithmetic task (MA) and forehead cold stimulus task (FCS) were loaded to both Hi-Ho and Lo-Ho groups. Electrocardiographic T-wave amplitude (TWA), heart rate (HR) and coefficient of variance of 100 R-R intervals (CVR-R) were measured continuously during MA and FCS task periods. Greater TWA attenuation was found in Hi-Ho group (p less than 0.05). Although no significant intergroup difference was represented in HR and CVR-R, HR increased significantly (p less than 0.01) in whole subjects and CVR-R was tend to be suppressed during MA period. In addition, comparison of these physiological responses were performed between Type-A and Type-B groups classified by Jenkins' Activity Survey Form-T (JAS-T). There was no significant difference in reactivity of TWA, HR and CVR-R to both two tasks between high and low Type-A scored groups. Previous data suggested that the TWA reactivity in Hi-Ho subjects to cognitive stress showed similar pattern in Type-A individuals. However, autonomic nervous interaction could not be clarified in Hi-Ho subjects. The differentiation of method for assessment of behavioral pattern was also discussed.

Influence of environmental factors on IgE production.

The prevalence of atopic diseases appears to have increased rapidly, especially in industrialized countries. The increase may be explained by a change in certain environmental factors. This article focuses on the influence of environmental factors on IgE production. Epidemiological or experimental reports have shown that tobacco smoke, virus infection and mercuric chloride may enhance IgE production. We demonstrated the enhancing effect of diesel-exhaust particulates (DEP), which seem to have increased in urban environments, on IgE antibody production. The IgE antibody responses in mice immunized by intraperitoneal injection of antigens mixed with DEP were higher than those in animals immunized with the antigens alone. DEP also had an adjuvant activity for IgE antibody production in mice after entry via the respiratory tract (the natural mode of entry). The enhancing effect of DEP on IgE antibody responses was demonstrated even when a small dose such as 1 micrograms of DEP was given intranasally at three-week intervals. Our further study has indicated that suspended particulate matter including materials other than DEP has an adjuvant activity for IgE antibody production.