Masahiko Sakai

Measurement of Portal Vascular Resistance in Patients With Portal Hypertension

Portal vascular resistance was measured percutaneously in 60 patients with chronic liver disease and in 5 control subjects. The portal vascular resistance (PVR) was calculated, using the following equation, from the portal blood flow (QPV), portal venous pressure (PPV), and hepatic venous pressure (PHV): PVR = (PPV - PHV)/QPV. The portal blood flow was measured using an ultrasonic Doppler duplex system, and the portal venous and hepatic venous pressures were measured using percutaneous transhepatic catheterization and venous catheterization, respectively. The wedged hepatic venous pressure was measured by occluding the hepatic venous branch using a balloon catheter. The portal vascular resistance was 0.25 +/- 0.13 mmHg X ml-1 X min X kg body weight (mean +/- SD, n = 5) in the control group, 0.64 +/- 0.29 mmHg X ml-1 X min X kg body wt (n = 13) in the chronic active hepatitis group, 1.34 +/- 0.79 mmHg X ml-1 X min X kg body wt (n = 30) in the cirrhosis group, and 0.85 +/- 0.69 mmHg X ml-1 X min X kg body wt (n = 13) in the idiopathic portal hypertension group.

A conserved epitope on H+,K+-adenosine triphosphatase of parietal cells discerned by a murine gastritogenic T-cell clone

BACKGROUND/AIMS H+,K(+)-adenosine triphosphatase (H+,K(+)-ATPase) of parietal cells is an organ-specific enzyme recognized by autoantibodies found in human and murine autoimmune gastritis (AIG). Murine AIG can be induced in BALB/c mice by thymectomy 3 days after birth and is a T cell-mediated disease. This study examined the specificity of T cells that cause AIG and the role of H+,K(+)-ATPase in this disease. METHODS From an AIG mouse, a gastritogenic T-cell clone (II-6) was established, and its reactivity to synthetic peptides of H+,K(+)-ATPase was tested. RESULTS II-6 cells are CD4+, V beta 14+, and interferon gamma producers. Adoptive transfer of II-6 cells to syngeneic nude mice resulted in AIG without the production of autoantibodies to parietal cells. The II-6 cells were responsive not only to murine but also to human and porcine parietal cells. Their proliferation was also induced by amino acids 891-905 (alpha 891) and 892-906 (alpha 892) of the alpha subunit of porcine and human H+,K(+)-ATPase, respectively. CONCLUSIONS The T-cell response to a single epitope of H+,K(+)-ATPase, the amino acid sequence of which is conserved among at least three mammals tested, is sufficient to cause AIG. Autoantibodies to parietal cells are not detected in these AIG mice.

A possible involvement of Fas-Fas ligand signaling in the pathogenesis of murine autoimmune gastritis.

BACKGROUND & AIMS A Th1 clone, II-6, established from an autoimmune gastritis BALB/c mouse that underwent thymectomy 3 days after birth, recognized a 15 mer peptide constructing the alpha subunit of H+, K(+)-adenosine triphosphatase as antigen and induced gastritis in nu/nu mice by adoptive transfer. The aim of this study was to examine the molecular mechanism of target (parietal cells) destruction in either thymectomized or II-6 cell-transferred nu/nu mice. METHODS Expression of Fas, major histocompatibility complex class II, and intercellular adhesion molecule 1 molecules on the gastric mucosa of these mice were immunohistochemically examined. In situ DNA fragmentation in these thymectomized or nu/nu mice was tested by the terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine triphosphate nick end label (TUNEL) method. Moreover, activity of II-6 cells to induce apoptosis was tested by using the 15 mer peptide-pulsed B lymphoma cells, A20.2J, as the target. RESULTS A portion of parietal cells in gastritis-bearing thymectomized or nu/nu mice at an early stage expressed Fas, major histocompatibility complex class II, and intercellular adhesion molecule 1 molecules and was TUNEL positive. Fas-ligand message was induced on activated II-6 cells and caused DNA fragmentation of the antigen-pulsed A20.2J cells. CONCLUSIONS Cognate interaction between Fas antigen on the target and Fas ligand on the effector seems to be one possible mechanism for the target cell destruction in organ-specific autoimmune gastritis.

Parietal cell autoantigens involved in neonatal thymectomy-induced murine autoimmune gastritis. Studies using monoclonal autoantibodies

Autoimmune gastritis accompanied by autoantibodies to parietal cells was induced in BALB/c nu/+ mice by neonatal thymectomy 2-4 days after birth. Three monoclonal autoantibodies, designated as 2B6 (IgG1), 2G10 (IgG2b), and 1H9 (IgG1), were obtained from one of these mice. All three reacted specifically with parietal cells, 2G10 recognizing species-specific antigenic determinants and 2B6 and 1H9 recognizing interspecies-specific antigenic determinants. All three recognized antigens on the membrane of intracellular secretory canaliculi and the cytoplasmic tubulovesicular system of parietal cells. At least two different molecular groups were recognized by these antibodies; 2B6 recognizing a 65,000-79,000-mol wt group and 1H9 recognizing a 92,000-120,000-mol wt group. Sera of most mice with autoimmune gastritis reacted with either or both groups. Both groups were consistently coprecipitated by any of the three antibodies when solubilized in NP-40. Sera, from patients with pernicious anemia, containing anti-parietal cell antibodies could also precipitate these two groups of antigens. Competition assay and physicochemical studies showed that the epitopes recognized by the three monoclonal antibodies are different.

Quantitative measurement of portal blood flow in patients with chronic liver disease using an ultrasonic duplex system consisting of a pulsed doppler flowmeter and B-mode electroscanner

SummaryPortal blood flow (PBF) can be measured quantitatively using a B-mode combined pulsed Doppler (BCD) system. This system combines a real time B-mode linear type electroscanner and a pulsed Doppler (D-mode) flowmeter. Since both modes are displayed in realtime, Dopper blood flow signals can be retrieved at will from any depth. The blood flow velocity determined by the Doppler spectrogram and the vascular cross-sectional area measured from the B-mode tomographic image enables the quantitative calculation of blood flow volume. Using this system,PBF was measured quantitatively in 88 healthy adults, 54 patients with chronic hepatitis, 65 with cirrhosis of the liver, 27 with primary hepatoma and 12 with idiopathic portal hypertension (IPH). Results ofPBF volume measurement were as follows: 889±284 ml/min (mean ± S.D.) for healthy adults, 851 ± 237 ml/min for patients with chronic hepatitis, 870 ± 289 ml/min for cirrhosis of the liver, 966 ± 375 ml/min for primary hepatoma and 1,047 ± 381 ml/min forIPH.These preliminary results demonstrated that this ultrasonic Duplex system is clinically useful to determine the quantitative amount of PBF.

Decreased glucose effectiveness but not insulin resistance in glucose-tolerant offspring of Japanese non—insulin-dependent diabetic patients: A minimal-model analysis

The aim of the study was to estimate insulin sensitivity (SI), insulin secretion, and glucose effectiveness (SG) in 10 subjects with normal glucose tolerance (eight men and two women) with a family history of non-insulin-dependent diabetes mellitus (NIDDM offspring). Ten glucose-tolerant subjects (eight men and two women) without a family history of NIDDM served as control subjects. All subjects were Japanese. They underwent a modified frequently sampled intravenous glucose tolerance test (FSIGT): glucose (300 mg/kg body weight) was administered, and insulin (20 mU/kg over 5 minutes) was infused from 20 to 25 minutes after glucose. SI and SG were estimated by Bergmans minimal-model method. No significant difference was observed in body mass index (22.6 +/- 1.5 v 21.5 +/- 0.6 kg/m2) and fasting glucose (5.1 +/- 0.1 v 5.2 +/- 0.1 mol/L) and insulin (40.7 +/- 6.3 v 42.6 +/- 6.7 pmol/L). SI was not different between the two groups (0.83 +/- 0.11 v 0.94 +/- 0.15 x 10(-1).min-1.pmol/ L-1, P > .05). The acute insulin response to glucose (AIRglucose) estimated by intravenous glucose tolerance testing was significantly lower in the offspring than in the normal controls (2,139 +/- 265 v 3,438 +/- 318 pmol/L.min, P < .05). The glucose disappearance rate (KG) and SG were significantly diminished in the offspring versus normal controls (KG, 1.50 +/- 0.22 v 2.10 +/- 0.15 min-1, P < .05; SG, 0.016 +/- 0.003 v 0.023 +/- 0.002 min-1, P < .05). Thus, glucose-tolerant Japanese NIDDM offspring with normal insulin sensitivity are characterized by a reduced AIRglucose and diminished SG. This is the first report that glucose resistance but not insulin resistance already exists in glucose-tolerant Japanese NIDDM offspring.

Endosonographic characterization of duodenal elevated lesions

BACKGROUND Endoscopic diagnosis of duodenal elevated lesions is problematic for two reasons. Endoscopic biopsy often fails to confirm a histologic diagnosis of submucosal lesions. Moreover, a biopsy specimen is often insufficient to verify a differential diagnosis of mucosal lesions. In this study, we evaluated the usefulness of endosonography in the resolution of these problems. METHODS The endoscopic and endosonographic features of 15 duodenal elevated lesions that had been confirmed histologically in our hospital were reviewed retrospectively. RESULTS Of the 15 cases, 8 were submucosal lesions (lipoma, Brunners gland hyperplasia, lymphangioma, carcinoid tumors, leiomyoma, and malignant lymphoma); the rest were mucosal lesions. A correct histologic diagnosis based on endoscopic biopsies was obtained in only 6 cases (three submucosal lesions and three mucosal lesions). On the other hand, ultrasonography was useful in the characterization of all submucosal lesions based on their echo level, layer of origin, and tissue homogeneity. As for mucosal lesions, the depth of infiltration was correctly estimated with endosonography. Either endoscopic resection or surgery was selected on the basis of endosonographic information. CONCLUSIONS We conclude that endosonography is useful in the differential diagnosis of submucosal lesions and in determining suitable treatment methods for duodenal mucosal and submucosal lesions.

Genetic studies on experimental autoimmune gastritis induced by neonatal thymectomy using recombinant inbred strains between a high-incidence strain, BALB/c, and a low-incidence strain, DBA/2

Thymectomy on day 3 after birth induced autoimmune gastritis (AIG) at the age of 2 months in 51–73% of BALB/c mice, and in only 3–5% of DBA/2 mice. AIG was detected by histological and serological (immunofluorescence staining for detecting anti‐parietal cell autoantibody) examination. However, autoantibody was weakly positive in almost all of these DBA/2 mice when measured by ELISA using extract of murine gastric mucosa as the antigen. To investigate genetically the mechanism controlling the incidence of AIG, 11 recombinant inbred strains established by brother‐sister mating of (BALB/c x DBA/2) F2 mice (C x D2 strains) were used. Among 26 markers tested, the Mls‐1 locus on BALB/c chromosome 1 and the Hc locus coding a complement component (C5) on BALB/c chromosome 2 were found to be associated with high susceptibility to AIG. However, if one or both of the loci were of DBA/2 origin, mice showed medium or low susceptibility to AIG. For further analysis, F1, F2 and back‐cross generations of these two strains were tested, but segregation of a single susceptibility or insusceptibility gene was not obtained. Taken together, it seems probable that two or more genes are involved in the induction mechanism of AIG. We did not detect C5 deposition in AIG lesions, nor complement‐dependent cytotoxic antibody to parietal cells in serum from AIG mice. However, injection of irradiated spleen cells of DBA/2 mice into BALB/c mice thymectomized on day 3 augmented the incidence of AIG from 71 to 100%, but not that of oophoritis (33%). A relationship between Mls‐1a determinants and the pathogenesis of AIG was further suggested from the fact that Vβ6 TcR‐expressing T cells increased in number in AIG‐bearing compared with normal BALB/c mice.

Retroflexed endoscopic multiple band ligation of symptomatic internal hemorrhoids

Abstract Background Elastic band ligation is a well-established nonoperative method for treatment of internal hemorrhoids that give rise to symptoms. This study assessed the efficacy and safety of retroflexed endoscopic multiple band ligation, a procedure that involves extensive ligation of internal hemorrhoids, and the immediately proximal normal rectal mucosa, by means of a retroflexed endoscope. Methods Eighty-two patients with symptoms caused by internal hemorrhoids (15, stage I; 19, stage II; 47, stage III; 1, stage IV) were treated by retroflexed endoscopic multiple band ligation. Symptoms (prolapse, bleeding, pain with defecation) were graded from 0 to 3. Range and form of the internal hemorrhoids were evaluated endoscopically. Retroflexed endoscopic multiple band ligation was performed by using a flexible endoscope with an attached band ligation device in the retroflexed position. Results A mean of 8 bands (range 4-14) were placed per treatment session. Seventy-six patients were treated in a single session, 5 in two sessions, and one in 3 sessions. Symptom and endoscopic scores improved at 4 weeks after the retroflexed endoscopic multiple band ligation: bleeding, from 1.26 to 0.53 ( p p p =0.67); Goligher classification, from 2.41 to 1.09 ( p p p Conclusions Retroflexed endoscopic multiple band ligation is a safe and effective method for treatment for patients with symptoms caused by internal hemorrhoids.

Choices of Japanese patients in the face of disagreement

BACKGROUND Patients in different countries have different attitudes toward self-determination and medical information. Little is known how much respect Japanese patients feel should be given for their wishes about medical care and for medical information, and what choices they would make in the face of disagreement. METHODS Ambulatory patients in six clinics of internal medicine at a university hospital were surveyed using a self-administered questionnaire. RESULTS A total of 307 patients participated in our survey. Of the respondents, 47% would accept recommendations made by physicians, even if such recommendations were against their wishes; 25% would try to persuade their physician to change their recommendations; and 14% would leave their physician to find a new one. Seventy-six percent of the respondents thought that physicians should routinely ask patients if they would want to know about a diagnosis of cancer, while 5% disagreed; 59% responded that physicians should inform them of the actual diagnosis, even against the request of their family not to do so, while 24% would want their physician to abide by their familys request and 14% could not decide. One-third of the respondents who initially said they would want to know the truth would yield to the desires of the family in a case of disagreement. INTERPRETATION In the face of disagreement regarding medical care and disclosure, Japanese patients tend to respond in a diverse and unpredictable manner. Medical professionals should thus be prudent and ask their patients explicitly what they want regarding medical care and information.