Generation of dyspeptic symptoms by direct acid and water infusion into the stomachs of functional dyspepsia patients and healthy subjects.

BACKGROUND: The mechanisms of the development of symptoms in functional dyspepsia (FD) patients have not been fully elucidated. We previously reported that acid directly infused into the stomach causes dyspeptic symptoms in asymptomatic healthy controls (HCs); however, the response to acid infusion of FD patients was not determined. AIM: To investigate the severity of dyspeptic symptoms induced by direct acid infusion in FD subjects and HCs. METHODS: This was a multi-centre, cross-over, randomised, double-blind study in 23 FD subjects and 32 HCs. FD was defined using the Rome III criteria. All subjects were Helicobacter pylori negative. Each subject received two tests; 0.1 mol/L hydrochloric acid and water infused into the stomach. The presence and severity of 12 dyspeptic symptoms were assessed using a visual analogue scale. RESULTS: The proportion of subjects developing symptoms by acid or water infusion was significantly greater in FD subjects than HCs. All of the FD subjects experienced at least one symptom by water or acid infusion. In the FD subjects, the severity of symptoms was significantly greater with acid infusion than water infusion. The severity of symptoms in total and the scores for eight of the 12 symptoms induced by acid infusion was significantly greater in FD subjects than in HCs. CONCLUSIONS: The severity of dyspeptic symptom generation induced by direct acid infusion into the stomach was significantly greater in functional dyspepsia subjects than in healthy controls, suggesting that hypersensitivity to acid is one of the important mechanisms of the development of symptoms in functional dyspepsia patients.

NOD1 and NOD2 mediate sensing of periodontal pathogens.

In bacterial infection, Nucleotide-binding Oligomerization Domain (NOD) 1 and NOD2 induce innate immune responses by recognizing fragments of the bacterial component peptidoglycan (PGN). To determine the roles of these receptors in detection of periodontal pathogens, we stimulated human embryonic kidney cells expressing NOD1 or NOD2 with heat-killed Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Fusobacterium nucleatum or their soluble PGNs (sPGNs). All bacteria and their sPGNs could stimulate activation of NF-kappaB. However, there were differences in NOD1- and NOD2-stimulatory activities among the species of bacteria. P. gingivalis showed weaker NOD1- and NOD2-stimulatory activities than did other bacteria. These differences in activities were confirmed by production of interleukin-8 from oral epithelial cells stimulated with sPGNs. These findings indicate that both NOD1 and NOD2 might be involved in the recognition of periodontal pathogens, and that the weak NOD-stimulatory property of P. gingivalis might be helpful for survival in the periodontal pocket.

What is the best method of detecting endometrial cancer in outpatients?-endometrial sampling, suction curettage, endometrial cytology.

OBJECTIVE: Office methods of endometrial sampling for outpatients with abnormal uterine bleeding should be minimally invasive. The purpose of this study was to determine the best method for detecting endometrial cancer in an outpatients setting. METHODS: In all, 114 symptomatic women who were suspected of having endometrial disease by their local gynaecologist were enrolled in this study. After pelvic examination and transvaginal ultrasonography, endometrial cytology, suction endometrial curettage, and four-site endometrial biopsy were performed, in this order without anaesthesia in each patient. After endometrial sampling, the patient was asked to comment on the intensity of any pain experienced during each procedure. Then the final histological diagnosis made from the surgical materials was compared with the results of the three pre-operative methods. RESULTS: Among the 114 consecutive patients, 56 had endometrial carcinoma, three had carcinosarcoma, six had endometrial hyperplasia, and 49 had benign conditions. The sensitivity of detecting malignancy was 88% (52/59) with endometrial cytology, 92% (54/59) with suction curettage, and 88% (52/59) with four-site biopsy. When endometrial cytology was combined with suction curettage, the sensitivity of detecting malignancy was increased from 92% to 98%, whereas the sensitivity was increased from 88% to 97%, when endometrial cytology was added to four-site biopsy. Suction curettage was significantly less painful than four-site biopsy. CONCLUSION: Our data indicated that suction curettage plus endometrial cytology was the best combination for pathological examination of outpatients with abnormal uterine bleeding.

Carboplatin chemotherapy in a pregnant patient with undifferentiated ovarian carcinoma: case report and review of the literature.

There are already 12 reports of women treated by chemotherapy for epithelial ovarian cancer during pregnancy. However, most cases received chemotherapy of single cisplatin or cisplatin-based regime, and only four cases received carboplatin-containing chemotherapy. We report the case of a woman treated with single-agent carboplatin during pregnancy. The patient underwent bilateral salpingo-oophorectomy at 18 weeks of gestation and was diagnosed as having stage IC undifferentiated ovarian carcinoma. She was treated with four courses of carboplatin (area under the curve = 6.0) chemotherapy during pregnancy without severe toxicity. At 33 weeks of gestation, cesarean section was performed, followed by total hysterectomy, omentectomy, and pelvic and para-aortic lymphadenectomy. No residual disease was histologically shown. The patient underwent additional chemotherapy with carboplatin and paclitaxel. After one year of follow-up, the baby shows normal growth and the patient has no evidence of disease. Postponing the termination of pregnancy by single-agent carboplatin chemotherapy during pregnancy might be considered as an option for therapy in selected women with ovarian malignancies.

Risk factors for recurrent bile duct stones after endoscopic papillotomy.

BACKGROUND: The long term outcome of endoscopic papillotomy (EPT) is not well known. The aims of this study were to clarify the clinical course of post-EPT patients and to detect predictors for bile duct stone recurrence. METHODS: A total of 1042 consecutive patients who underwent EPT for bile duct stones from December 1975 to September 1998 were prospectively followed up. Patients were divided into four groups according to gall bladder (GB) status: "acalculous GB" group, "calculous GB" group, "cholecystectomy" group, and "prior cholecystectomy" group. Reliable follow up information was obtained for 983 (94.3%) of the 1042 patients. The following factors were considered in the evaluation of predisposing risk factors for recurrence of bile duct stones: age, sex, gall bladder status, periampullary diverticulum, number of bile duct stones, diameter of bile duct stones, diameter of bile duct, lithotripsy, precutting, pneumobilia, and early complications. RESULTS: Recurrence occurred in 111 patients. The "acalculous GB" group was less prone to recurrence than the "prior cholecystectomy" group and the "calculous GB" group. The relative risks (RR) for the latter two compared with the former group were 2.26 (95% confidence interval (CI) 1.24-4.14; p=0.0078) and 2.16 (95% CI 1.21-3.87; p=0.0093), respectively. Other prognostic factors were lithotripsy (RR 2.37; 95% CI 1.47-3.81; p=0.0004) and pneumobilia (RR 1.57; 95% CI 1.01-2.43; p=0.044). CONCLUSIONS: Gall bladder status, lithotripsy, and pneumobilia were significantly related to bile duct stone recurrence after EPT.

Prognosis of acute poststreptococcal glomerulonephritis (APSGN) is excellent in children, when adequately diagnosed.

BACKGROUND: Recently, the prognosis of acute poststreptococcal glomerulonephritis (APSGN) has been reported as improved, compared with the results of previous studies. In an attempt to clarify this, we analyzed the clinical course of patients with APSGN. METHODS: A total of 220 children with acute nephritic syndrome were treated in the affiliated hospitals of our department, between January 1988 and December 1997. Among them, 138 children who were diagnosed with APSGN according to the presence of hematuria, transient hypocomplementemia and evidence of group A beta-hemolytic streptococcal infection, were studied. RESULTS: Serum creatinine and blood urea nitrogen levels at onset were 0.5 +/- 0.2 mg/dL and 20 +/-12 mg/dL, respectively. There were no patients with renal dysfunction (serum creatinine level > or = 1.5 mg/dL), but one patient with nephrotic syndrome. Blood pressure was well controlled in all patients and there were no patients with persistent hypertension. Serum complement levels were normalized within 12 weeks (100%), hematuria disappeared within 4 years (100%) and proteinuria disappeared within 3 years (100%) from the onset. CONCLUSIONS: These data indicate that the prognosis of APSGN during childhood is excellent, when adequately diagnosed and treated.

A novel human HER2-derived peptide homologous to the mouse K(d)-restricted tumor rejection antigen can induce HLA-A24-restricted cytotoxic T lymphocytes in ovarian cancer patients and healthy individuals.

A mouse HER2-derived peptide, HER2p63 (A) (TYLPANASL), can induce K(d)-restricted mouse cytotoxic T lymphocytes (CTL) and also function as a tumor rejection antigen in an in vivo assay. Since the anchor motif of mouse K(d) for peptide binding has much similarity to that of human HLA-A2402, we asked if human HER2p63 (T) (TYLPTNASL) could induce HER2-specific CTL in HLA-A2402-positive individuals. Peripheral blood mononuclear cells (PBMC) of HLA-A2402-positive individuals were sensitized in vitro with HER2p63-pulsed autologous dendritic cells prepared from PBMC. CTL clone derived from these specifically lysed HER2-expressing cell lines bearing HLA-A2402. Cytotoxic activity of the CTL clone against the HER2-expressing cell line bearing HLA-A2402 was blocked by antibodies against CD3, CD8, HLA-A24 or MHC class I, and was also inhibited by the addition of excess HER2p63-pulsed C1R bearing HLA-A2402. Killer cells were generated from PBMC of seven healthy individuals and five ovarian cancer patients, all of HLA-A2402 type, by in vitro sensitization with HER2p63-pulsed autologous antigen presenting cells. These killer cells selectively lysed HER2-expressing SKOV3 transfected with HLA-A2402 cDNA, indicating high immunogenicity of HER2p63 in all 12 individuals examined.

Changes of hemostatic molecular markers after gynecological surgery.

The authors evaluated the hemostatic abnormalities occurring in the postoperative period of eight patients with malignant tumors and compared them with those occurring in the postoperative period of eight patients with benign tumors. Two of the patients with malignant tumor presented pulmonary embolism after operation. Plasma fibrinogen and fibrin degradation product levels in patients with malignant tumors were already high before operation and further increased significantly after operation. The plasma levels of D-dimer, thrombin-antithrombin complex, and free-tissue factor pathway inhibitor were increased in both groups after operation, but they were higher in patients with malignant tumors than in patients with benign tumors. The plasma levels of protein C and antithrombin were significantly decreased in both groups after operation. but they were significantly lower in patients with malignant tumors than in those with benign tumors. The decreased activity of protein C or antithrombin may be not only a risk factor of thrombotic disease, such as pulmonary embolism, but also the cause of thrombosis. In patients with malignant tumors, the operation time was significantly longer than that in patients with benign tumors. This long operative period might cause vascular endothelial cell injury which is reflected by the plasma levels of free-tissue factor pathway inhibitor, antithrombin, and protein C.

A HER2/NEU-derived peptide, a K(d)-restricted murine tumor rejection antigen, induces HER2-specific HLA-A2402-restricted CD8(+) cytotoxic T lymphocytes.

We have identified an H-2K(d)-binding peptide, HER2p780 (PYVSRLLGI), derived from murine HER2/neu (HER2), that can induce HER2-specific murine cytotoxic T lymphocytes (CTL). Weekly vaccination of BALB/c mice by syngeneic dendritic cells pulsed with HER2p780 peptide, entirely common to murine and human HER2, suppressed growth of pretransplanted HER2-expressing syngeneic tumors. A HER2-expressing human cancer cell line SKOV3 transfected with murine H-2K(d) cDNA could also be lysed by HER2p780-specific murine CTLs, indicating that human HER2-expressing cancer cells can process and present the cognate peptide in the context of H-2K(d). Since H-2K(d) and HLA-A2402 molecules have similar anchor motifs, the possibility of inducing HER2-specific CTL activity with HER2p780 in HLA-A2402 individuals was examined. CD8(+) CTL clones specific for HER2-expressing cancer cell lines were established from peripheral blood lymphocytes with HLA-A2402 by repeatedly sensitizing with peptide-pulsed autologous dendritic cells as well as peripheral blood mononuclear cells. Detailed analysis of their specificity revealed that the cytotoxicity of CTL clones is specific for the cognate peptide with HLA-A2402 restriction. The results suggest that HER2p780 is a unique peptide that may function as a tumor rejection antigen peptide in HLA-A2402 individuals, as it was directly proven here to function in a murine tumor system.

Development of a cancer vaccine: peptides, proteins, and DNA.

Genetic changes leading to protooncogene activation qualitatively and/or quantitatively alter their gene products and are exclusively or largely restricted to transforming cells and their precursors. The overexpression of HER2 is among those changes and is often detected in adenocarcinomas such as breast, ovarian, lung, and gastric cancer. This provides a rationale for exploring the possibility that HER2 is a target of host immune responses against cancer cells. We have recently demonstrated that HER2 can be a target for tumor-rejecting immune responses against syngeneic murine HER2+ tumor cells. We defined two different peptides, HER2p63-71 and HER2p780-788, with a Kd anchor motif that can induce CD8+ cytotoxic T lymphocytes (CTLs). The growth of HER2+ syngeneic tumors was suppressed in mice immunized with HER2p63-71 or p780-788. Since murine Kd and human HLA-A24 share a similar anchor motif for peptides, HER2p63 71 and HER2p780-788 were examined for induction of CTLs in HLA-A24+ individuals. CD8+ CTL clones specific for these peptides were established and they lysed HER2+ tumor cells in a human leukocyte antigen (HLA)-A24-restricted manner. To elicit specific CD8+ T cell immune responses against cancer, the development of efficient devices to deliver tumor antigen peptides to the major histocompatibility complex (MHC) class I pathway constitutes a central issue. We have developed a novel formula of hydrophobized polysaccharide nanoparticles which can deliver a HER2 oncoprotein containing an epitope peptide to the MHC class I pathway. We designed a simple protein delivery system: cholesteryl group-bearing polysaccharides, mannan or pullulan (CHM or CHP, respectively), complexed with the truncated HER2 protein containing the 147 N-terminal amino acids. These complexes were able to induce CD8+ CTLs against HER2+ tumors. CTLs were MHC class I restricted and specifically recognized HER2p63-71, a part of a truncated HER2 protein used as an immunogen. The complete rejection of tumors also occurred when CHM-HER2 was applied early after tumor implantation. In the effector phase of in vivo tumor rejection, CD8+ T cells played a major role. The results suggest that this unique hydrophobized polysaccharide may help soluble proteins to induce cellular immunity. Such a novel vaccine may be of potential benefit in cancer prevention and cancer therapy.

[Serial cerebral computed tomography and magnetic resonance imaging in a case of hemolytic uremic syndrome with the complication of the central nervous system due to Escherichia coli O157:H7].

We report serial cerebral computed tomography (CT) and magnetic resonance imaging (MRI) in a case of hemolytic uremic syndrome (HUS) with the complication of the central nervous system due to Escherichia coli O157:H7. Although initial brain CT was normal, follow-up CT and MRI revealed lesions in the white matter and bilateral basal ganglia, representing brain edema and infarcts, respectively. Especially, lesions in the bilateral basal ganglia were very unique. Serial CT and MRI findings are useful to understand the mechanism of the complications of the central nervous system associated with HUS.

Influence of age at onset on the outcome of steroid-sensitive nephrotic syndrome.

To investigate whether age at onset of steroid-sensitive nephrotic syndrome (SSNS) is predictive of subsequent relapses, or influences outcome, we retrospectively studied 60 patients who were under 10 years of age at onset and were followed for over 10 years. They were divided into three groups according to age at diagnosis: group 1-3 (1.0-3.9 years at onset, n=24), group 4-6 (4.0-6.9 years at onset, n=22), and group 7-9 (7.0-9.9 years at onset, n=14). In the 51 patients with long-term remission, defined as remaining relapse-free over 3 years, the total number of relapses was significantly more in group 1-3 (n=18) than in group 4-6 (n=19), and the interval between onset and long-term remission was significantly longer. Group 4-6 and group 7-9 had fewer patients with active disease at 10 years, follow-up than group 1-3, as assessed by the Kaplan-Meier method. These data suggest that the age at onset of SSNS influences the clinical course (i.e., frequency of relapses) and the time to reach long-term remission. An age of less than 4 years at onset of SSNS is associated with greater likelihood for frequent relapses and a greater time interval to attain long-term remission.

[Usefulness of palliative care for the patients with recurrent gastric cancer by home-IVH].

Depending upon the type of cancer involved, the period of the end stage varies greatly, and with it decreases the quality of life (QOL). In gastric cancer, for example, the terminal stage is usually short and the QOL diminishes abruptly. Thus, it takes time keeping this decrease in QOL to minimum, despite the complications, so that the patient's last days will be even somewhat more acceptable. Improvement in QOL for the patient who cannot eat due to recurrent gastric cancer can be effectively achieved by alleviation through IVH. With this in mind, the conditions consonant with the application of home IVH are as follows: 1) The patient's pain can be kept under control at home. 2) The patient wishes to remain. 3)There is sufficient human support at home. The caretakers in the family, and especially the key person(s) must exert much effort and labor and they need rest as well. Home medical care in the terminal stage presupposes a social environment involving day care, short stay, and hospice nursing facilities of all kinds. At present, public services of this kind differ with the community, much remains uninformed to public, and clinic-hospital networking will be needed more than ever. In this difficult situation, the home-care medical services provided by the private sector are effective. These services are only for the short term, of course, and there will be a financial problem. Various measures (tax deduction, public assistance) must be considered to support the patients and caretakers.

Treatment with triiodothyronine (T3) against multinodular goiter fails to prevent the onset of Graves' disease.

We report two cases who developed hyperthyroidism and positive thyroid stimulating antibody (TSAb) while they were treated with T[3] under the diagnosis of follicular adenoma of thyroid for four or eleven years, respectively. In both cases thyroid scintigraphy revealed an increased radioiodine uptake with multinodular defects. The uptake of 131I was not suppressed by the administration of T[3]. Histological examination showed encapsulated nodule surrounded by diffuse hyperplasia. TBII or TSAb appeared in accordance with increased plasma levels of T[3] and T[4]. In spite of suppressed TSH the appearance of TSAb and subsequent manifestations of Graves' disease suggested that T[3] failed to prevent the immune mechanism which was involved in the production of TSAb.

Effect of aphidicolin on DNA synthesis in cultured human thyroid cells.

To investigate whether partial inhibition of DNA synthesis affects the growth of thyroid cells, human thyroid cells were cultured in the presence of aphidicolin for 24h. After removal of aphidicolin, the growth of thyroid cells was evaluated by [3H] thymidine uptake and analysis of cell cycle by flow cytometry. In Graves' thyroid cells, [3H] thymidine uptake and the percentage of cells in S+G2/M phase increased during 24 hours after washout of aphidicolin, whereas those were not augmented in normal thyroid cells. Thus, the acceleration of DNA synthesis occurred after the partial inhibition of it by aphidicolin in Graves' thyroid cells, but not in the normal thyroid cells. This phenomenon might, at least in part, explain the difference of growth regulation between Graves' and normal thyroid cells.

[Prolonging home residence and treatment of cancer in patients with recurrent stomach cancer].

A study was conducted on 27 patients with cancer of the stomach who died from a postoperative recurrence of the cancer, 26 of whom died in the hospital and one of whom died at home. The period from the manifestation of initial symptoms of the recurrence to confirmed diagnosis was less than two months in 20 of the 26 cases (77%). The period from confirmed diagnosis to terminal hospitalization was in excess of three months in 11 of the 26 cases (42%). Of these cases, there were some in which it appeared that the time spent at home could have been extended through means such as another operation, insertion of an intraperitoneal access apparatus, or insertion of a subselective movable catheter. Forty-six percent (46%) of the patients were notified of their diagnosis, but none of them were notified of the recurrence of the cancer, suggesting the difficulty of notifying a patient of a diagnosis of cancer recurrence. A private home-care medical system was used in the case of the patient who had died at home of terminal stomach cancer. There were no major problems with this system other than the complaint that it placed a great financial burden on the family.

[Evaluation of medicinal lymph node dissection in advanced gastric cancer].

In order to improve the results of surgical treatment in advanced gastric cancer, we performed preoperative targeted chemotherapy for metastatic lymph nodes. The solution which contained aclarubicin adsorbed on activated carbon was submucously injected around gastric tumor under endoscopic observation 2-7 days prior to the operation. We termed this method medicinal lymph node dissection (MLD). Our standard surgical treatment (SST) for gastric cancer consists of gastrectomy and extended lymph node dissection (N1 and N2 lymph nodes). Patients of curative resection with histologically positive lymph node metastasis were enrolled, as the subjects. We compared the cumulative survival rate in 47 patients treated with SST+MLD (MLD group) with that in 125 patients treated with SST only (control group). Five year survival rates in the MLD and control groups were 60% and 48%, respectively. The MLD group showed significantly higher survival rate in patients with N3, N4 and infrapyloric lymph node metastasis. A significant difference of the survival rate suggests the efficacy of SST+MLD against micrometastasis in N3 and para-aortic lymph nodes. The SST+MLD therapy is recommended to the advanced gastric cancer, especially in the lower third of the stomach.