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1. Systemic (s.c. or p.o.) administration of L-threo-3,4-dihydroxyphenylserine (droxidopa, L-threo-DOPS; L-DOPS), a noradrenaline precursor, at a dose-range of 100-800 mg kg-1, produced naloxone-resistant antinociception in a dose-dependent manner in the mouse, as assessed by the tail flick test, kaolin-induced writhing test and formalin-induced nociception test. 2. Antinociception elicited by L-DOPS (400 mg kg-1, s.c.) was not affected by s.c. injection of benserazide, a peripherally preferential L-aromatic amino acid decarboxylase inhibitor, but was suppressed by its intracerebroventricular (i.c.v.) injection. 3. I.c.v. or intrathecal (i.t.) administration of the non-selective alpha-blocker, phentolamine, significantly reduced L-DOPS-induced antinociception. 4. I.c.v. administration of the alpha 1-blocker, prazosin, but not the alpha 2-blocker, yohimbine, abolished the antinociceptive effects of L-DOPS. In contrast, both blockers, when administered i.t., exhibited significant inhibitory effects. 5. These results suggest that systemic L-DOPS produces opioid-independent antinociception, mediated by supraspinal alpha 1-adrenoceptors and by spinal alpha 1- and alpha 2-adrenoceptors and may predict additional therapeutic applications of L-DOPS as an analgesic.

We measured dopamine and norepinephrine concentrations in the biopsied gastroduodenal mucosa obtained from 12 ulcer-free dyspeptic patients, nine patients with active duodenal ulcer, and eight patients with inactive (or healed) duodenal ulcer using a high-performance liquid chromatography with electrochemical detection method. Biopsy specimens were taken from endoscopically normal-appearing mucosa in the gastric body and antrum as well as in the duodenal bulb. Additional specimens were obtained from the outer edge of the ulcer margin in patients with active duodenal ulcer. The mean (+/- SD) mucosal dopamine concentrations in the gastric body and duodenum (7.6 +/- 2.8 and 6.8 +/- 2.6 pg/mg tissue) obtained from patients with inactive duodenal ulcer were significantly (P < 0.05) lower than those from dyspeptic patients (13.6 +/- 6.9 and 10.9 +/- 3.5 pg/mg tissue, respectively). In contrast, no significant differences were observed in the mean norepinephrine concentrations in these gastroduodenal tissues among the three study groups. However, the mean mucosal norepinephrine concentration in the outer edge of duodenal ulcer (86.2 +/- 125.6 pg/mg tissue) was significantly (P < 0.05 and 0.01) reduced as compared with that in the ulcer-free area of duodenum obtained from patients with inactive duodenal ulcer (257.1 +/- 188.2 pg/mg tissue) and from dyspeptic patients (276.8 +/- 138.3 pg/mg tissue). The results suggest that an alteration in the catecholaminergic system may be associated with one of the pathogenic factors of duodenal ulcer.

1. Intracerebroventricular (i.c.v.) administration of L-arginine (L-Arg), at 10-100 micrograms per mouse, produced antinociception in mice, as assessed by the tail flick test; this antinociception was reversed by pretreatment (s.c.) with naltrindole (NTI), a delta-selective opioid antagonist, and by co-administered L-leucyl-L-arginine (Leu-Arg), a kyotorphin (endogenous Met-enkephalin releaser) receptor antagonist. 2. L-NG-nitroarginine methyl ester (L-NAME), a NO synthase inhibitor, but not D-NG-nitroarginine methyl ester, given i.c.v. at 3-10 micrograms per mouse, exhibited antinociceptive activity that was resistant to naloxone (s.c.), NTI (s.c.) and Leu-Arg (i.c.v.). 3. The L-NAME (i.c.v.)-induced antinociception was not reversed by L-Arg (i.c.v.), which was antinociceptive by itself, but was abolished by combined injection of L-Arg plus Leu-Arg (i.c.v.) or by L-Arg (i.c.v.) after NTI (s.c.). 4. Methylene blue (MB), a soluble guanylate cyclase inhibitor, at 0.1-1 microgram per mouse, produced antinociception by i.c.v. administration. The antinociception induced by MB (i.c.v.) or L-NAME (i.c.v.) was reversed by co-administered dibutyryl cyclic GMP. 5. These findings suggest that L-Arg plays a dual role in nociceptive processing in the brain, being antinociceptive via the kyotorphin-Met-enkephalin pathway and nociceptive via the NO-cyclic GMP pathway.

Serum hepatocyte growth factor levels were measured in hepatectomized and nonhepatectomized surgical patients. The levels were significantly increased and reached a maximum within 7 days after surgery in both groups, returning to preoperative levels 28 days after partial hepatectomy and 7 days after other operations. Multiple regression analysis showed that such maximal hepatocyte growth factor levels were significantly related to having liver cirrhosis and postoperative maximal serum total bilirubin and alanine aminotransferase levels and peripheral white blood cell counts in the hepatectomized group and to postoperative maximal peripheral white blood cell counts and serum C-reactive protein levels in the nonhepatectomized group. However, the levels showed no relation to the resected liver volume and increment of the remaining liver volume 28 days after partial hepatectomy. It is concluded that serum hepatocyte growth factor levels were increased after partial hepatectomy in association with hepatocellular dysfunction and necrosis and systemic inflammation. It is unlikely that the increase was related to liver regeneration.

Claw nail deformities of the fingers have been repaired by many methods, but the results have been cosmetically unsatisfactory because of loss of the distal phalangeal bone and the short nail bed. We have employed a trimmed second toetip including the distal phalangeal bone and excluding the germinal matrix as a vascularised composite flap for two patients with claw nail deformity of the fingers. The advantages of this method are that the repaired nail regrows to normal size and has bilateral nail folds. We believe that, in comparison with other conventional local or island flaps, this composite flap is functionally and cosmetically ideal for the repair of claw nail deformities.

A scanning probe optical microscope using the Wiener fringe is presented. The Wiener fringe is formed by a standing wave between the incident and reflected waves on an optically reflective surface and is detected by inserting an optical fiber tip into the fringe-field region. The detected signal is used to maintain the tip-sample distance constant so that a topographic image of a sample can be obtained by a computer-assisted instrument. A spatial resolution of 200 nm has been achieved by observing a sample of known geometry.

A free paraumbilical perforator-based flap fed by a muscle perforator from the inferior deep epigastric artery and with no muscle was used in 13 patients. Among them, a free thin paraumbilical perforator-based flap with a thin layer of fat, to protect the subdermal plexus of the vessels, was used in seven patients. The dominant pedicle perforator of this thin flap is usually located around the umbilicus and a large flap can be obtained. Its critical length-to-breath ratio is considered to be 4:3. The advantages of this flap are a long and large vascular pedicle, rare postoperative abdominal herniation, little bulkiness of the flap, and a relatively large skin territory. The disadvantages are technical difficulties in dissection of the perforator and anatomical variation in the location of the perforator. We believe this flap largely overcomes the problems of the conventional rectus abdominis musculocutaneous flap.

The microvasculature of the skin of the hand in primates, including man, was examined by means of scanning electron microscopy of corrosion casts. In this study, the microvascular patterns and structures in different areas of the hand, and the changes in vascular patterns that occur with age, have been described. The typical structure of the capillary loops in the hand can be observed in the ball of the finger of the young adult monkey. The capillary loops were formed out of not just one capillary vessel, but two or three vessels. Each capillary vessel arose and divided into several branches at the papillae, and these became descending limbs. After the loop passed a hairpin turn, the descending limbs were 1.5 times larger than the ascending limbs in the intrapapillary portion, and they became extrapapillary venules. The descending limbs connected with the postcapillary venules in the postpapillary portion and with the horizontal network. The postcapillary venules fused with each other to form the primary and secondary venous arcades. The secondary venous arcades anastomosed with each other and flowed into the subpapillary venules, which run along the dermal furrow in the fingerprint. Changes in vascular patterns with age could be observed. In the infant fingerprint, the vascular systems had not yet differentiated, especially the venous system in the dermis. In the old adult finger, the capillary loops presented complicated features deviating due to aging.

Free transfers of the distal parts of the second toe for reconstruction of distal phalangeal losses of the fingers were successfully carried out. This method is believed to be the best for functional and cosmetic reasons, but major postoperative vascular problems exist. To overcome these problems, multiple vascular anastomoses were employed at operation. The indications for this method are limited in Japanese patients, and its use depends on the patient's age, sex, religious beliefs and the shape of the second toe.

The occurrence of antibodies against recombinant human interferon-alpha 2a (IFN-alpha 2a) in patients with acute viral hepatitis (AVH) was examined by ELISA. Naturally occurring IgG anti-IFN-alpha 2a were found in 50% of patients with type A, 50% of those with type B and in 8.3% of those with non-A, non-B AVH. The corresponding frequencies of IgM antibodies were 80%, 30% and 33.3%, respectively. IgM anti-IFN-alpha 2a were found more frequently in patients with AVH type A than in normal control subjects (P less than 0.01). Anti-IFN-alpha 2a were detectable at the highest frequency 3 weeks after acute onset and then became negative. An absorption experiment revealed that IgM anti-IFN-alpha 2a did not cross-react with recombinant human IFN-alpha 2b. Immunoblotting analysis confirmed the binding of antibodies to IFN-alpha 2a. Sera positive for IgG and/or IgM anti-IFN-alpha 2a were unable to neutralize IFN-alpha 2a. The appearance of anti-IFN-alpha 2a was not correlated with disease severity. There was no evidence to suggest that anti-IFN-alpha 2a impaired the elimination of hepatitis virus. This is the first study to demonstrate the occurrence of anti-IFN-alpha 2a in patients with AVH. Detection of anti-IFN-alpha 2a may be useful for clarifying any underlying immune events in various diseases.

To determine whether natural human interferon administered under the usual therapeutic dosing scheme would inhibit the hepatic drug metabolism, we performed an antipyrine test in eight patients with chronic B or non-A, non-B hepatitis before and after a subchronic interferon therapy (6 megaunits/day for 17 +/- 4 days, mean +/- SD). Six patients received interferon-beta and 2 received interferon-alpha. To circumvent a possible influence of interferon-induced fever on the hepatic drug metabolism, the antipyrine test during the interferon therapy was performed at least 14 days after the interferon-induced fever disappeared. The kinetic parameters of antipyrine were obtained from seven saliva samples over 32 hours postdose. There were no significant differences in any kinetic parameters of antipyrine observed before and during the interferon therapy. With the sample size of the study, there was only a 20% chance (i.e., beta-power = 0.8 at alpha = 0.05) that we might have missed a 17% reduction in antipyrine clearance by the interferon therapy (type II error). On the other hand, the subchronic interferon therapy lowered serum aminotransferases and DNA polymerase activity significantly (P less than .05) compared with the respective baseline values. Our results suggest that the subchronic therapeutic dosing scheme of interferon as conducted in the present study does not cause the inhibitory effect on the oxidative drug metabolism to a statistically significant or clinically relevant degree in patients with chronic hepatitis, while it improves their liver function. Further studies are required for determining if different types of interferons administered under the different dosing schemes would alter the hepatic drug metabolism and the inhibitory effect would be time-dependent.

We report a patient with acquired "double cardia" (esophagogastric fistula). She was a 76-year-old farmer's widow with severe kyphosis. She presented with postprandial heartburn one month after the initiation of nifedipine and isosorbide dinitrate. Radiologic and endoscopic examinations revealed an esophagogastric fistula, short esophagus with hiatal hernia, Barrett's esophagus with reflux esophagitis, and ulcer. This case shows that repeated reflux esophagitis and esophageal ulcer, complicated with short esophagus and hiatal hernia, can predispose to the formation of esophagogastric fistula.

Protein binding of disopyramide (D) was studied in eight patients with cancer, seven with inflammatory diseases, and seven healthy subjects. Plasma samples containing concentrations of 0.2-12.0 micrograms/ml were ultrafiltered, and the free fractions were measured with fluorescence polarization immunoassay. The mean free fractions at D concentrations ranging from 1.0 to 6.0 micrograms/ml were significantly less in patients with cancer (p less than 0.01) and those with inflammatory diseases (p less than 0.05) than in healthy subjects. Patients with cancer had a greater (p less than 0.05) D binding than those with inflammatory diseases. A multiple regression analysis revealed a significant contribution of plasma alpha 1-acid glycoprotein (AAG) (r = -0.79, p less than 0.01), but not of albumin (r = -0.096), to the overall variability in D binding at 3.0 micrograms/ml. The mean capacity constant in the two patient groups was similar, but significantly (p less than 0.01) greater than in the healthy group. Nonspecific D binding was greater in cancer patients (p less than 0.01) compared to the other two groups. Our results suggest that (a) therapeutic range of D measured as total drug concentration in patients with cancer and with inflammatory diseases would be greater than previously thought, and (b) unidentified component(s) (other than AAG and albumin) might contribute to the greater D binding in cancer patients compared to other study groups.

The use of glottal stops in continuous speech in American English has not been well studied, in spite of the common belief that they may serve as boundary markers. This paper reports the result from measurements of five speakers' readings of four stories, each arranged in both list and story form. Data were analyzed according to the difference in speakers, materials, versions, phonological situations (phoneme sequence and stress situations), grammatical conditions, and frequency of occurrence of words. Results show that higher-level factors such as speaker's reading style and difficulty of material have a strong influence than phonological and grammatical factors.

The mucus bicarbonate barrier of the duodenum has lately been reported to be one of the most important defensive factors for the duodenal mucosa. We established an in vitro system for evaluating the mucus bicarbonate barrier in the rat duodenum. Our method allows direct measurement of the pH gradient as well as the thickness of the mucus gel layer of the rat duodenum in vitro. The obtained results suggest that alkali secretion in response to acid-loading as well as the thickness of the duodenal mucus gel layer are greater than those in the stomach.

Earliest endoscopic appearance and its subsequent changes were studied in 41 cases of early gastric carcinoma where gastrocamera photographs were available for detailed analysis over the period from three months up to 10 years. The earliest appearance of polypoid carcinoma was a small area of nodularity, and that of carcinoma with mucosal depression was patchy reddening. Both types of carcinoma were thought to occur initially as a lesion without mucosal elevation or depression (IIb). In carcinoma with shallow mucosal depression (IIc and IIc-+III), there were cases believed to have remained intramucosal for an extremely long period of several years, whereas, in polypoid carcinoma (IIa and I), the growth seemed to be more rapid. In the cases with ulcer within the carcinomatous lesion, healing of the ulcer was confirmed in 37%, and "malignant cycles" were observed in 21%. Malignant transformation of gastric ulcer was suggested in one case with linear ulcer.

This study was designed to investigate the effect of luminal H+ on alkali and mucus secretion in the isolated rat stomach. At various luminal pHs, the thickness and the pH gradient of the mucus gel layer were measured. The maximum pH and calculated alkali secretion showed that the latter was stimulated in parallel with an increase in luminal H+ concentration, especially when the luminal pH became less than 3.5. Mucus secretion, however, was not significantly affected by the luminal H+ concentration. These results suggest that alkali and mucus secretion in the stomach are not regulated by the same mechanism, but different ones.

Changes in the pH gradient and thickness of the mucus gel layer in the healing of acetic acid-induced gastric ulcers in rats were investigated. The maximum of the pH gradient and the thickness of mucus gel layer at the edge of ulcers and in the regenerated mucosa were higher, decreased gradually with the healing of the ulcers and finally reached normal values. This indicates that mucus and bicarbonate are secreted actively from the mucosa surrounding an ulcer and that they play an important role in protection of the base of ulcers and in acceleration of the healing of the ulcers.

Gastric ulcers induced in dogs by transserosal injection of 1 ml of 40% acetic acid healed completely by the 7th week after ulceration and never reulcerated during the observation period up to 12 weeks. Acetic acid ulcers in the active (at 1 week), quiescent (3 weeks) or healed (at 7 weeks) stages were not influenced by the daily administration of aspirin 2 g/dog/day for for 5 consecutive weeks. All examinations were done by gastroscopy in addition to macroscopical and histological observations at autopsy.

The microvasculature of the skin of the hand of Japanese monkeys was examined by means of scanning electron microscopy of corrosion casts. The vasculature of all areas of the skin of the hand was examined and divided into three structures excluding the nail bed: (1) In the ball of the finger, the typical structure of the capillary loops was studied. Capillary loops were formed out of not just one capillary vessel, but two or three vessels. Each capillary vessel arose and divided into several branches at the papilla, and they became descending limbs. After the loop passed a hairpin turn, the descending limbs were 1.5 times larger than the ascending limbs in the intrapapillary portion, and they became extrapapillary venules. The descending limbs connected with the postcapillary venules in the postpapillary portion and with the horizontal network. The postcapillary venules fused with each other (1-5 loops) to form the primary and secondary venous arcades. (2) In the thenar eminence, the capillary loops were a little lower, and their grooves were wider than in the ball of the finger. The characteristic structure in this area was the interpapillar capillary network. (3) In the lateral side of the finger, the number of capillary loops formed by the arterial capillary network of the subepidermal layer was smaller. The capillary loops here had the lowest height and a simple structure.

The biotransformation of decanones with immobilized cells of Nicotiana tabacum led to the formation of their corresponding alcohols of high optical purity.

The outcome was studied of gastric carcinoma found in six selected mass survey groups. One-hundred-and-thirty-seven cases of gastric carcinoma were detected and followed-up postoperatively for 16 years at the longest. They consisted of 55 cases of early and 74 of advanced carcinoma with eight cases of unknown depth of involvement. Early carcinoma amounted to 42-6% of the cases with known depth of involvement. The relative five-year and 10-year survival rates calculated by the method of Ederer et al. (1961) in the 137 cases were 0-628 and 0-642, respectively, and those for early carcinoma were 0-959 and 1-016. These survival rates are remarkably high. The five-year survival rate in those who were followed-up after operation for more than five years (83 cases) was 0-554, which is much higher than that of the outpatient cases, who presented themselves for medical advice with some symptoms. The good prognosis is largely explained by a high incidence of early gastric carcinoma in the cases detected in the mass survey. Where methods of screening were concerned, the use of the gastrocamera markedly improved the detection rate of gastric carcinoma.

We measured the plasma concentration of a centrally derived noradrenaline (NA) metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), in 20 cirrhotic patients (eight with (group A) and 12 without (group B) hepatic encephalopathy (HE] and in 14 age matched healthy subjects to study if the central NA metabolism would be altered in liver cirrhosis patients, particularly in those with HE. The mean (SEM) plasma MHPG concentrations in the patient groups, group A (74.9 (8.6) pmol/l) and B (54.8 (7.2) pmol/l), were significantly (p less than 0.01) greater than in the control group (22.3 (2.0) pmol/l), and that in group A was significantly (p less than 0.05) greater than in group B. The plasma concentration of MHPG observed in these study subjects (n = 34) correlated (rs = 0.77, p less than 0.01) more strongly with the ratio of plasma catecholamine precursor amino acids (tyrosine and phenylalanine) to other neutral amino acids (tryptophan, leucine, isoleucine, and valine) known to compete with catecholamine precursor amino acids for uptake into the brain than with plasma concentration of tyrosine plus phenylalanine alone (rs = 0.63, p less than 0.01). In addition, the mean plasma MHPG concentrations measured in another group of eight cirrhotic patients (group C) during HE (79.3 (10.6) pmol/l) was significantly (p less than 0.01) greater than that measured after the recovery from HE (47.2 (5.2) pmol/l). The results suggest that the central NA metabolism may be altered in patients with liver cirrhosis, particularly in those with HE, and that the derangement in the central NA metabolism may be associated not only with an increase in plasma catecholamine precursor amino acids but also with a decrease in branched chain amino acids.

Tuning characteristics of power, intramode beat frequency, and polarization of 633-nm internal mirror lasers filled with natural Ne or (20)Ne are studied. It is found that the tuning curve of a polarization signal is S-shaped for the natural Ne laser, whereas that of the intramode beat frequency is S-shaped for the (20)Ne laser. The characteristic parameters of the tuning curve of the intramode beat frequency are determined. The axial modes of a (3)He-(20)Ne laser are collapsed into one by a transverse magnetic field and frequency stabilized by cooling the laser tube with a fan to keep the intramode beat constant. Frequency fluctuation of 3 x 10(-10) is obtained by the Allan variance analysis for the integration period range of 0.1-100 sec. Absolute accuracy and interinstrumental reproducibility of stabilized wavelengths can be expected for a (3) He-(20)Ne transverse Zeeman laser stabilized at the central frequency of the intramode beat.

The light emitted by a stabilized 633-nm He-Ne transverse Zeeman laser (STZL) is composed of two linearly polarized components that are perpendicular to each other. Optical frequencies of the two components are different, and therefore the light changes its polarization with time. The change is represented on the Poincaré sphere as a spin along the equator containing S(2) and S(3) axes of the sphere. Three types of polarimetry and two types of interferometry using an STZL are proposed and experimentally demonstrated. Comparisons of these techniques with the existing ones are also reported.

The plasma protein binding of disopyramide (D) was determined in seven patients with cirrhosis, six with nephrotic syndrome, and seven healthy subjects. Plasma samples containing concentrations of 0.2 to 12.0 micrograms/ml were ultrafiltered and the free fractions were measured with fluorescence polarization immunoassay. The mean free fractions at D concentrations ranging from 1 to 6 micrograms/ml were significantly (P less than 0.01) greater in patients with cirrhosis than in healthy subjects. No difference was observed between patients with nephrotic syndrome and healthy subjects. The free fraction at D 3 micrograms/ml correlated better with alpha 1-acid glycoprotein (r = -0.77) than with albumin (r = -0.46). Patients with cirrhosis had significantly (P less than 0.01) lower capacity constants as compared with the other two study groups. There was a significant (P less than 0.01) correlation between capacity constant and alpha 1-acid glycoprotein (r = 0.71). Our results suggest that the D therapeutic range measured as the total plasma concentration in cirrhosis, but not in nephrosis, should be approximately 50% lower than previously believed.

The paper describes a method of estimating a person's reading rate from a small sample of his speech (in other words, a short sentence). Reading rate was obtained by measuring the speaking portion of a considerable amount of reading, and dividing it by the number of phonemes in the material (this is called the grand mean). Out of 108 sentences read by four talkers, 58 having 15 words or less were selected. The ratio of unstressed to stressed syllables, and the number of syllables per occurrence of terminal lengthening were calculated for each of the 58 sentences. Sentences with both of these values in the middle range were considered to have an average phoneme duration close to the grand mean. The prediction was compared to actual readings by four talkers, with 83 percent agreement. The Summary section contains instructions for applying our method of estimating a person's reading rate. Those who are interested should read the Summary section and the Appendix first.

To study the concentration-response relationship of famotidine, we serially monitored intragastric pH and measured plasma drug concentrations simultaneously after an intravenous injection of this H2-receptor antagonist (0.1 mg/kg) in eight patients with upper gastrointestinal bleeding and in six healthy subjects. By applying the sigmoidal Emax model the mean (+/- SD) plasma famotidine concentrations associated with an intragastric pH of 4.0 in patients and healthy subjects were estimated to be 17.7 +/- 10.7 and 24.8 +/- 10.3 ng/ml, respectively (not significantly different). No significant differences were observed in the mean pharmacokinetic parameters between the two study groups. Multiple regression analysis revealed that not only a pharmacokinetic factor (i.e., elimination t1/2) but also a pharmacodynamic (or sensitivity) factor (i.e., a drug concentration associated with an intragastric pH of 4.0) contributed significantly (p less than 0.01) to the overall variability in the duration of antisecretory effect in our study subjects, with standardized partial regression coefficients of 0.54 and -0.63, respectively. Based on these data, we predict that around-the-clock control of a fasting intragastric pH above 4.0 can be attained by a continuous infusion of famotidine at rates ranging from 6 to 25 mg/day (mean +/- SD, 11 +/- 7 mg/day) in a 70 kg patient whose pharmacokinetic and pharmacodynamic characteristics are similar to those of our patients.