Role of major histocompatibility complex class II in the development of autoimmune type 1 diabetes and thyroiditis in rats.

Although the MHC class II 'u' haplotype is strongly associated with type 1 diabetes (T1D) in rats, the role of MHC class II in the development of tissue-specific autoimmune diseases including T1D and autoimmune thyroiditis remains unclear. To clarify this, we produced a congenic strain carrying MHC class II 'a' and 'u' haplotypes on the Komeda diabetes-prone (KDP) genetic background. The u/u homozygous animals developed T1D similar to the original KDP rat; a/u heterozygous animals did develop T1D but with delayed onset and low frequency. In contrast, none of the a/a homozygous animals developed T1D; about half of the animals with a/u heterozygous or a/a homozygous genotypes showed autoimmune thyroiditis. To investigate the role of genetic background in the development of thyroiditis, we also produced a congenic strain carrying Cblb mutation of the KDP rat on the PVG.R23 genetic background (MHC class II 'a' haplotype). The congenic rats with homozygous Cblb mutation showed autoimmune thyroiditis without T1D and slight to severe alopecia, a clinical symptom of hypothyroidism such as Hashimoto's thyroiditis. These data indicate that MHC class II is involved in the tissue-specific development of autoimmune diseases, including T1D and thyroiditis.

Increased oxygen affinity for hemoglobin Sawara: alphaA4(6) aspartic acid replaced by alanine.

The oxygen binding property of Hb Sawara (alphaA4 Asp replaced by Ala) was studied at different pH values with and without addition of 2,3-diphosphoglycerate. The oxygen affinity of Hb Sawara was shown to be increased, the difference of the log P50 value between normal and abnormal hemoglobins being 0.37 at pH 7.0. Both the magnitude of the alkaline Bohr effect and the effect of 2,3-diphosphoglycerate upon oxygen affinity of Hb Sawara were comparable to those of Hb A. The amino acid substitution of alanine for alphaA4 aspartic acid might result in the loss of a stabilizing force for ionic interaction between the alpha-amino group of NA (1)alpha1 valine and the alpha-carboxyl of HC3(141)alpha2 arginine in the deoxy-form.

Shy-Drager syndrome: neuronal loss depends on size, function, and topography in ventral spinal outflow.

We analyzed myelinated fibers and neurocytons in the ventral spinal outflow of patients with Shy-Drager syndrome. Axonal loss occurred predominantly in thin, myelinated fibers that correspond mainly to autonomic preganglionic axons. Intermediate and large myelinated fibers, mainly gamma and alpha axons, were also involved, but to a lesser degree. Neuronal and axonal loss was more prominent in caudal segments and less in rostral segments. Axonal degeneration in single teased fibers was seen frequently in ventral spinal roots.

A new series of Tc-99m-labeled hepatobiliary tracers: N'-acyl- and N'-sulfonyl ethylenediamine-N,N-diacetic acids.

Various Tc-99m-labeled N'-substituted derivatives of ethylenediamine-N,N-diacetic acid (EDDA) are evaluated as hepatobiliary imaging agents. N-substituted aromatic acyl and aromatic sulfonyl derivatives of EDDA, labeled with Tc-99m, were administered to rabbits and golden hamsters, and the distribution indicated clearance by the hepatobiliary system. N'-aromatic sulfonyl EDDAs were labeled with Tc-99m by the SnCl2 method with more than 99% yield. Clearance of Tc-99m-p-toluenesulfonyl EDDA from the blood and the liver was as rapid as that of TC-99m N-(2,6-diethylphenylcarbamoylmethyl)iminodiacetic acid (Tc-99m benzenesulfonyl EDDA lowered urinary excretion. It is concluded that the sulfonyl EDDAs provide a fruitful source for Tc-99m-labeled hepatobiliary radiopharmaceuticals.

Circular dichroism studies of the interaction between synthetic peptides corresponding to intracellular loops of beta-adrenergic receptors and phospholipid vesicles.

We previously showed that peptides corresponding to the N-terminal parts of the third intracellular loops of turkey and hamster beta-adrenergic receptors (tu beta I3N and ha beta I3N, respectively) can activate the GS protein (one of the GTP-binding regulatory proteins which couples to the beta-adrenergic receptor) reconstituted in phospholipid vesicles, and also that such activation can be greatly enhanced by a modification which increases the hydrophobicity of the peptides. These observed phenomena suggest that the interaction with phospholipid membranes is important for the activity of these peptides; hence, in the present study we employed circular dichroism to analyze the interaction of the synthetic peptides corresponding to the intracellular loops of G protein-coupled receptors with phosphatidylserine/phosphatidylcholine mixed vesicles. The tu beta I3N and ha beta I3N peptides were subsequently found to take on an alpha-helical conformation upon binding with the vesicles, whereas those corresponding to the intracellular loops of m1 and m2 muscarinic acetylcholine receptors in contrast did not interact with the vesicles. The positions of several side chains of the membrane-bound loop peptides were also determined. Our results show for the first time the interaction occurring between the intracellular loops of beta-adrenergic receptors and a phospholipid membrane.

Structure determination of an immunopotentiator peptide, cinnamycin, complexed with lysophosphatidylethanolamine by 1H-NMR1.

The three-dimensional structure of a complex of cinnamycin, a 19-amino acid residue immunopotentiator peptide, and lysophosphatidylethanolamine was determined by 1H-NMR. The complex was cylindrical in shape, 11 A in diameter and 26 A in length, excluding the acyl chain of the phospholipid. The peptide had a hydrophobic pocket surrounded by residues Phe-7 through Ala(S)-14 to bind to the head group of the ligand. Fitting of the head group to the hydrophobic pocket was so good that other than a glycerophosphoethanolamine head group would be unable to fit the pocket. The goodness of the fitting is compatible with the strict specificity of ligand binding of the peptide.

Acute exacerbation of hepatitis due to reactivation of hepatitis B virus with mutations in the core region after chemotherapy for malignant lymphoma.

A 43-year-old Japanese man who was positive for hepatitis B surface (HBs) antigen and HB e antibody, underwent chemotherapy for non-Hodgkin's lymphoma. After the chemotherapy he suffered from acute exacerbation of hepatitis because of reactivation of HBV. Recovery was achieved with interferon-alpha, glucagon-insulin therapy, and plasma exchange. Mutations were detected in codons 97, 100, 129, and 131 of the core region of HBV. The peptide encoded from the core region including such mutations possibly had greater antigenicity to induce cytotoxic T cell activity in the host. Core region mutations may be a crucial cause of the acute exacerbation of hepatitis B seen after chemotherapy.

Peripheral aneurysms of the posterior inferior cerebellar artery.

Nonmycotic peripheral posterior inferior cerebellar artery (PICA) aneurysms are rare. The authors report six cases of peripheral PICA aneurysm. Two of these are unusual; one was fusiform and another was a double aneurysm arising from the peripheral PICA. The previously reported 40 cases of peripheral PICA aneurysm are reviewed.

Amino acid similarity matrix for homology modeling derived from structural alignment and optimized by the Monte Carlo method.

In this paper, we obtained a similarity matrix for homology modeling based on the structure of proteins in a structural alignment. The alignment procedure was executed within dynamic programming generally used in alignment methods. An initial matrix derived from the structural alignment was optimized by the Markov chain Monte Carlo method at low temperature to fit its sequence alignment to the structural alignment. Structural alignment was performed on the basis of the superposition of C alpha atoms for two protein structures. The objective function in the Monte Carlo procedure was defined by entropy in the information theory, allowing us to show that the amino acid similarity matrix aligned accurately. When compared with the structural alignment, the average number of incorrect amino acid residues in the sequence alignment was 22.6 for all residues and about 3.7 for residues in structurally conserved regions. The alignment with our matrix was more similar to structural alignment than to sequence alignments using other amino acid substitution matrices.

The value of the Cytobrush for obtaining cells from the uterine cervix.

A study was undertaken to evaluate the efficacy of the Cytobrush compared with the cotton-tipped applicator for obtaining cells from the uterine cervix. Four consecutive Papanicolaou smears were obtained in 1,000 patients during a single clinic visit. In every patient, a total of four smears on two slides were submitted: one slide contained endocervical material obtained with a cotton-tipped applicator and with the Cytobrush and the other slide contained ectocervical material obtained with both a cotton-tipped applicator and the Cytobrush. In endocervical smears, the Cytobrush technique produced numerous groups and clusters of cervical columnar cells in contrast to the use of the cotton swab. This was particularly true in older patients and pregnant women. In ectocervical smears, the detection of the squamous component was also higher in the Cytobrush smear than in cotton swab smears. However, the cell yield was not influenced by the cell sampling sequence in either endocervical or ectocervical specimens. It is the conclusion of this study that the utility of the Cytobrush technique for collecting specimens for endocervical and ectocervical smears is greater and provides a higher yield of cells than the cotton swab technique. Wider use of this simple procedure is encouraged.

Cancellation of motion artifact in MRI due to 2D rigid translational motion.

A new algorithm for cancelling MRI artifact due to translational motion in the image plane is described. Unlike the conventional iterative phase retrieval algorithm, in which there is no guarantee for the convergence, a direct method for estimating the motion is proposed. In the previous approach, the motions in the readout(x-) direction and the phase encoding(y-) direction are estimated simultaneously. However, the feature of the each x- and y-directional motion is different. Based on the analysis of their features, each x- and y-directional motion is cancelled by different algorithms in two steps. First, we notice that the x-directional motion corresponds to a shift of the x-directional spectrum of the MRI signal, so the x-directional motion can be cancelled by shifting the spectrum in inverse direction. Next, the y-directional motion is cancelled using a new constraint, with which the motion component and the true image component can be separated. The algorithm is shown to be effective by simulations.

Effects of ginseng radix on sugar absorption in the small intestine.

Ginseng radix (GR) is often used in traditional Japanese kampo medicine. We studied the effect of GR on glucose and maltose transport in rat and human duodenal mucosa by Ussing's method, and on smooth muscle movement in rat duodenal muscle by Magnus' method. GR inhibited absorption of glucose or maltose in rat and human duodenal mucosa, but increased duodenal muscle movement. It suggests that the inhibition of sugar absorption by GR is more dominant than enhancement of duodenal muscle movement by GR.

[An autopsied case of type II citrullinemia--transient effectiveness with either citrate or benzoate to the consciousness disturbance].

A 44-year-old man suffered from repeated impairment of consciousness associated with flapping tremor, myoclonus and generalized convulsions, and died in coma 6 months after admission. He had had a psychosomatically underdeveloped childhood, with a propensity for legumes without a family history of the same or a record of consanguinity. On admission, he had disturbed consciousness and emaciation without other physical abnormalities. The EEG revealed diffuse slow waves with occasional appearance of triphasic waves. A high level of serum citrulline (534.7 nmol/ml) was recognized and the assay of urea cycle enzymes in the liver demonstrated decreased argininosuccinate synthetase (ASS) activity (0.062 U/g liver, 7.4% of that in normal liver), although no kinetic abnormality was found. Accordingly he was diagnosed as having type II citrullinemia. In addition, this case could be classified as cluster type of localization of the ASS in the liver by immunohistochemical study. There were characteristic findings concerning his clinical picture and laboratory data, such as a significant correlation between the grade of disturbed consciousness and arterial blood gas pH (r = 0.61, p less than 0.01). However, the blood ammonia level did not always correlate with the severity of disturbed consciousness. Oral treatment with sodium citrate and sodium benzoate was very effective, though transiently, for disturbed consciousness in this case. Pathological findings of the autopsied liver were fatty change and fibrosis. Neuropathologically, characteristic findings were brain edema with cerebellar tonsilar herniation, laminar necrosis with spongy formation in cerebral cortex, and Alzheimer type II glia. The relationship between citrullinemia and other hepatic encephalopathy was also discussed.

[Abdominal complications of V-P or L-P shunt operation --a bowel perforation and historical review (author's transl)].

We have experienced a case of shunt tube perforation into the transverse colon in which a Pudenz infantile V-A shunt tube was installed for a hydrocephalic baby. The shunt operation was performed at a year and one month of his age in this patient and bowel perforation was disclosed and corrected twenty months following the operation. From a retrospective point of view, however, slight sign of meningitis could be suspected two months earlier and judging from his symptoms of transient intracranial hypertension, the bowel perforation might be traced back even earlier. In the past twenty year history of V-P shunt maneuver, quite a number of papers on various kinds of specific complications have been reported. On reviewing these reported cases out of English and Japanese literature, numerous abdominal complications such as twenty-eight perforations, fifty CSF ascites or pseudocysts, three umbilical perforations, two vaginal perforations, five migrations into scrotum, and some volvulus and bladder perforations can be collected. These are summarized and discussed briefly in this paper.

[Effects of morphine, buprenorphine and butorphanol on airway dynamics of the rabbit].

An investigation was made on the effects of morphine, buprenorphine, and butorphanol on airway dynamics with special reference to the airway smooth muscle in rabbits. After tracheostomy under anesthesia, the animals were ventilated with a Servo 900B ventilator, and airway resistance (R) and total compliance (C) were measured according to the method of Norlander, and the effect of each drug was examined. Intravenous injection of morphine 0.2 mg.kg-1 increased R significantly at 10 and 20 minutes after its administration in nontreated animals and changed R insignificantly in animals pretreated with intravenous administration of chlorpheniramine 2.5 mg, an antihistaminic. It is considered that the increase in R after the administration of morphine in the nontreated animals is due to histamine release. Buprenorphine 0.8 micrograms.kg-1 and butorphanol 0.1 mg.kg-1 brought no significant changes in R in both nontreated and the chlorpheniramine pretreated animals. C decreased in all the groups including the control group which received mechanical ventilation alone without any drug administration.

[Chronological observation of nausea and vomiting in outpatients given oral antimetabolites as chemotherapy--two patients receiving ondansetron hydrochloride tablets].

The incidence of nausea and vomiting or anorexia was investigated in 16 outpatients receiving oral antimetabolites such as 5-FU (fluorouracil) as chemotherapy, during a maximum observation period of 28 days. In those patients who experienced the above symptoms which meet the standard defined in the study protocol, ondansetron hydrochloride tablets in a 4 mg/day dose were given based on the decision of the physician in charge, and its efficacy in those patients was examined. Nausea and emesis or anorexia was observed in six cases (37.5%) during the period of observation. Anorexia appeared in a majority of the above cases, with an incidence rate was 31.3% (5/16 cases). In two of the cases, anorexia improved after ondansetron tablets were administered. No adverse drug reaction was reported with ondansetron tablets. We conclude that although antimetabolites have low emetogenicity, as anorexia appeared in approximately 30% of the patients, the use of ondansetron tablets or other antiemetics should be considered in order to maintain patients' QOL and drug compliance.

[Clinical use of peplomycin in esophageal cancer].

A preliminary use of Peplomycin (PEP) was investigated in 14 patients with advanced esophageal cancer. PEP was given intermittently with a dose of 10 mg intravenously twice a week. As side effects there were observed fever elevation in 8 cases, stomatitis in 4 cases, erosion of the skin of the scrotum in 1 case and pigmentation in 1 case, respectively. Dyspnea associated with decrease of PaO2 was observed in 4 cases, which recovered promptly after discontinuing of the administration. Out of 10 evaluable cases, partial response was observed in 1, minor response in 1, no change in 3 and progressive disease in 5 cases, respectively. While the effect was only limited in these experiences, the local injection of PEP into or around the tumor using the external fistula of the remaining esophagus which was made at the time of by-pass operation was discussed.

[Effect of levamisole in postoperative adjuvant immunochemotherapy of stomach cancer--randomized controlled study of MMC-tegafur combination therapy with or without levamisole. 1].

The effects of levamisole used in combination with Mitomycin C and Tegafur in patients with resectable stomach cancer were investigated in 10 cooperative institutes. The patients were randomly allocated to the treatment with either control or levamisole by envelope method. Levamisole group was treated with Mitomycin C (day 0, 20 mg, day 1, 10 mg, one shot i.v.), Tegafur (600 mg/day, p.o.) and levamisole (150 mg/day, p.o.). Levamisole was administered 3 consecutive days prior to surgery, and 3 consecutive days every fortnight after surgery. The control group was administered Mitomycin C and Tegafur. The both drugs were administered by the same method as above. Two hundred and twenty-two patients were entered in this trial. However, with the exclusion of 67 patients, the eligible patients were 155, consisting of 77 in the control group and 78 in the levamisole group. In stage III patients, the disease-free interval and survival time were significantly prolonged in the levamisole group compared to the control group (generalized Wilcoxon test p less than 0.05). The side effects were observed a little more frequently in the levamisole group. However, there was no significant difference. From this result, it can be considered that levamisole is effective in delaying recurrence and in prolonging survival time of the patients when used in combination with adjuvant chemotherapy after resection of stomach cancer.