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Background Blood pressure (BP) variability has reportedly been a risk factor for various clinical events. To clarify the influence of BP visit‐to‐visit variability on adverse events in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐RHYTHM Registry was performed. Methods and Results Of 7406 outpatients with nonvalvular atrial fibrillation from 158 institutions, 7226 (age, 69.7±9.9 years; men, 70.7%), in whom BP was measured 4 times or more (14.6±5.0 times) during the 2‐year follow‐up period or until occurrence of an event, constituted the study group. SD and coefficient of variation of BP values were calculated as BP variability. Thromboembolism, major hemorrhage, and all‐cause death occurred in 110 (1.5%), 121 (1.7%), and 168 (2.3%) patients, respectively. When patients were divided into quartiles of systolic BP‐SD (P =0.015 for thromboembolism; HR, 2.60, 95% CI, 1.36–4.97, P =0.004 for major hemorrhage; and HR, 1.85, 95% CI, 1.11–3.07, P =0.018 for all‐cause death) after adjusting for components of the CHA 2 DS 2 ‐VASc score, warfarin and antiplatelet use, atrial fibrillation type, BP measurement times, and others. These findings were consistent when BP‐coefficient of variation was used instead of BP‐SD. Conclusions Systolic BP visit‐to‐visit variability was significantly associated with all adverse events in patients with nonvalvular atrial fibrillation. Further studies are needed to clarify the causality between BP variability and adverse outcomes in patients with nonvalvular atrial fibrillation. Registration URL: https://www.umin.ac.jp/ctr/ ; Unique Identifier: UMIN000001569.

Background Anti-programmed cell death protein 1 (PD-1) antibody monotherapy (PD1) has led to favorable responses in advanced non-acral cutaneous melanoma among Caucasian populations; however, recent studies suggest that this therapy has limited efficacy in mucosal melanoma (MCM). Thus, advanced MCM patients are candidates for PD1 plus anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) combination therapy (PD1 + CTLA4). Data on the efficacy of immunotherapy in MCM, however, are limited. We aimed to compare the efficacies of PD1 and PD1 + CTLA4 in Japanese advanced MCM patients. Patients and methods We retrospectively assessed advanced MCM patients treated with PD1 or PD1 + CTLA4 at 24 Japanese institutions. Patient baseline characteristics, clinical responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan–Meier analysis, and toxicity was assessed to estimate the efficacy and safety of PD1 and PD1 + CTLA4. Results Altogether, 329 patients with advanced MCM were included in this study. PD1 and PD1 + CTLA4 were used in 263 and 66 patients, respectively. Baseline characteristics were similar between both treatment groups, except for age (median age 71 versus 65 years; P < 0.001). No significant differences were observed between the PD1 and PD1 + CTLA4 groups with respect to objective response rate (26% versus 29%; P = 0.26) or PFS and OS (median PFS 5.9 months versus 6.8 months; P = 0.55, median OS 20.4 months versus 20.1 months; P = 0.55). Cox multivariate survival analysis revealed that PD1 + CTLA4 did not prolong PFS and OS (PFS: hazard ratio 0.83, 95% confidence interval 0.58-1.19, P = 0.30; OS: HR 0.89, 95% confidence interval 0.57-1.38, P = 0.59). The rate of ≥grade 3 immune-related adverse events was higher in the PD1 + CTLA4 group than in the PD1 group (53% versus 17%; P < 0.001). Conclusions First-line PD1 + CTLA4 demonstrated comparable clinical efficacy to PD1 in Japanese MCM patients, but with a higher rate of immune-related adverse events., Highlights • Anti-PD-1 plus anti-CTLA-4 antibody therapy (PD1 + CTLA4) is an option for patients with advanced mucosal melanoma (MCM). • Data on the efficacy of PD1 + CTLA4 compared with PD-1 monotherapy (PD1) for MCM, however, are limited. • We retrospectively analyzed data from 329 Japanese patients with advanced MCM treated with PD1 or PD1 + CTLA4. • No significant differences in objective response rate, progression-free survival, or overall survival were observed. • Immune-related adverse events resulting in treatment cessation were higher in the PD1 + CTLA4 group.

Background To clarify the influence of hypertension and blood pressure ( BP ) control on thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐ RHYTHM Registry was performed. Methods and Results A consecutive series of outpatients with atrial fibrillation was enrolled from 158 institutions. Of 7937 patients, 7406 with nonvalvular atrial fibrillation (70.8% men, 69.8±10.0 years) were followed for 2 years or until an event occurred. Hypertension was defined as a systolic BP ≥140 mm Hg, a diastolic BP ≥90 mm Hg, a history of hypertension, and/or antihypertensive drug use. Hypertension was an independent risk factor for major hemorrhage (hazard ratio 1.52, 95% CI 1.05–2.21, P =0.027) but not for thromboembolism (hazard ratio 1.05, 95% CI 0.73–1.52, P =0.787). When patients were divided into quartiles according to their systolic BP at the time closest to the event or at the end of follow‐up (Q1, CI 1.75–4.74, P CI 1.02–2.53, P =0.041) after adjustment for components of CHA 2 DS 2 ‐ VAS c score, warfarin use, and antiplatelet use. A systolic BP of ≥136 mm Hg was an independent risk factor for thromboembolism and major hemorrhage. Conclusions BP control appears to be more important than a history of hypertension and baseline BP values at preventing thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation. Clinical Trial Registration URL : http://www.umin.ac.jp/ctr . Unique identifier: UMIN 000001569.

Summary What is known and Objective: Meropenem is frequently employed as an empirical treatment for serious infections, but there has been no report on its population pharmacokinetic parameters for Japanese patients. Our aim is to undertake a population pharmacokinetic analysis of meropenem using non-linear mixed effects model (NONMEM). Methods: Data from 68 patients were analysed via NONMEM with the first-order method. The participants’ covariates, including gender, age, actual body weight, serum creatinine, serum albumin, serum total protein and creatinine clearance, were analyzed by the forward inclusion and backward elimination method to identify their potential influence on meropenem pharmacokinetics. The adequacy of the constructed model was assessed by goodness-of-fit plots and the precision of the parameter estimated at each step of the model development. To assess the robustness of the estimated parameter, bootstrap analysis was performed. Results and Discussion: The data were best described by a one-compartment model. The serum creatinine values modified by the below normal limit in our hospital (mSCR) were an influential covariate for clearance (CL): CL (L/h) = 11·1 × (mSCR/0·7)−1. The volume of distribution was estimated as 33·6 L. The coefficient of variation of the inter-individual variability of CL and the residual variability were 52·1% and 0·827% μg/mL, respectively. A comparison of the population pharmacokinetic parameters of meropenem in the final model estimated in NONMEM with original data, and 1000 bootstrap samples shows that both sets of estimates were comparable, thereby indicating the robustness of the proposed model. What is new and Conclusion: A population pharmacokinetic model that satisfactorily described the disposition and variability of meropenem in our Japanese population is described. NONMEM analysis showed that the clearance of meropenem depended on modified serum creatinine. The results of this study should help Japanese patients on meropenem by improving the prediction accuracy of dosing using the Bayesian method.

Idiopathic nodular glomerulosclerosis (ING) is characterized as diffuse nodular glomerulosclerotic lesions, closely resembling Kimmelstiel-Wilson lesions without diabetic mellitus. We report here three Japanese cases of ING and discuss the previous reports. The patients were 75-, 48- and 84-year-old males with a history of long-term hypertension. Laboratory examination revealed moderate proteinuria and mild renal dysfunction. Diabetes mellitus was excluded by repeated clinical and laboratory investigations. Renal histology revealed nodular glomerulosclerosis, and both afferent and efferent arteriolosclerosis in all patients. In electron microscopy, the glomerular basement membrane was markedly thick in all patients. A low-protein diet and potent anti-hypertensive treatment using angiotensin-converting enzyme inhibitors were initiated in all patients and urinary protein excretion significantly reduced without the progression of renal dysfunction. We reviewed 42 previously reported cases and our three cases. The analysis revealed that common clinical features of ING are being male (82.2%) of relatively advanced age (mean age 61.3 years), with hypertension (82.2%), mild renal dysfunction (mean serum creatinine 2.9 mg/dl) and moderate urinary protein excretion (mean 4.05 g/day). Common histopathological findings of ING are nodular glomerulosclerosis (100%), arterio-arteriolosclerosis (91.2 and 89.7%) and glomerular basement membrane thickening (85.7%). In conclusion, ING is one of the phenotypes of arteriosclerotic renal disease without diabetes mellitus. Severe arterio-arteriolosclerosis may contribute to the progression to glomerular nodular formation in ING. The combination of renin-angiotensin system inhibition and a low protein diet can be beneficial for the reduction of urinary protein excretion.

Objective: To reveal the C5a receptor-mediated monocyte-selective chemoattraction of the homo-dimer of guinea pig S19 ribosomal protein (RP S19), and to study the topological relationship between the RP S19 and C5a receptor genes. Methods: cDNA cloning and nucleotide sequencing, leukocyte chemotaxis measurement, and fluorescent in situ hybridization (FISH) were performed in the guinea pig. Results: The amino acid sequence of the guinea pig RP S19 deduced from the cDNA nucleotide sequence was identical to the human protein. The dimer of a recombinant RP S19 attracted guinea pig monocytes but suppressed neutrophil chemotactic movement. Both effects were C5a receptor-mediated. In the FISH analysis, the signals denoting the guinea pig RP S19 gene and C5a receptor gene completely overlapped each other. Conclusions: The guinea pig RP S19 dimer possessed a dual ligand effect, agonistic to the monocyte C5a receptor and antagonistic to the neutrophil receptor. The RP S19 and C5a receptor genes co-localized on the same chromosome.

We describe the case of a 51-year-old man with hepatitis C virus (HCV) infection and a 3-month history of facial edema. Laboratory tests upon admission for renal biopsy showed normal renal function and normocomplementemia. Serum HCV antibody (Ab) and cryoglobulin were positive. Renal biopsy specimens showed features of membranous glomerulonephritis. The likely cause was immune complex-mediated glomerulonephritis associated with HCV infection. Reports of similar cases in the literature show the normocomplementemia and negative or slightly positive cryoglobulins observed in our case as well as seropositivity for circulating immune complexes containing HCV RNA. In our case, electron microscopic examination of the subepithelial glomerular lesions revealed massive virus-like particles within unusual multilayers of electron-dense deposits (EDDs), suggesting the existence of HCV in the glomeruli. In the addition to the unique histopathological feature the presence of La/SS-B antibody in his serum indicated an abnormal immune response associated with HCV. We advise him to undergo the therapy with new type of IFN such as pegIFN-alpha2a and/or anti-viral agent like ribavirin to achieve clinical and histopathological improvement.

Two patients with a hyperkinetic syndrome contralateral to acute hemiplegia are presented. One patient showed a right-sided hemiplegia associated with abnormal movements of the left upper limb. In the other patient hemiplegia was localised on the left side while abnormal movements involved the right lower limb. Brain imaging showed acute infarctions (respectively left middle cerebral artery area and right lacunar infarctions) associated with a pre-existing contralateral infarction involving anterior non-primary motor areas. Hyperkinetic syndromes in stroke are mainly related to acute lesion of the contralateral subcortical areas. In our patients, the acute lesions were located ipsilateral to the hyperkinetic body part while the pre-existing lesions were located contralateral to the hyperkinetic side. We speculated that these pre-existing lesions might play a role in the pathophysiology of this clinical syndrome.

Probucol was given to rats made diabetic by streptozotocin. Compared with diabetic rats not receiving probucol or with nondiabetic rats, probucol lowered the plasma concentrations of triglycerides, phospholipids, cholesterol, and apolipoprotein B. The concentrations of serum chylomicrons and very low density lipoprotein (VLDL) were also reduced. In control and diabetic rats, probucol enhanced the clearance of endogenously radiolabeled VLDL from the plasma. Clearances from the plasma of rat lymph chylomicrons or chylomicron-like lipid emulsions were slow in diabetic rats. Probucol normalized chylomicron clearance in diabetic rats primarily by restoring hepatic uptake of remnants, which was decreased in diabetes. In diabetic rats, uptake of chylomicron remnants was increased in a number of extrahepatic tissues, including the heart and kidney. Probucol significantly decreased uptake in some extrahepatic tissues. Increased plasma clearance of VLDL and chylomicrons was associated with an increase in the apolipoprotein CII/CIII and apolipoprotein E/C ratios. Orally administered probucol was specifically incorporated into lymph chylomicrons, and clearance of probucol from the plasma exactly paralleled the clearance of chylomicron remnants, as traced with radiolabeled cholesteryl esters. Chylomicron-like emulsions incorporating probucol were exclusively cleared from the plasma by the liver in normal rats. We conclude that in streptozotocin diabetic rats, probucol is an effective hypolipidemic agent because it promotes the clearance of the triglyceride-rich lipoproteins.

Renal deterioration often occurs in cases of infectious endocarditis (IE), but, IE- associated nephritis with rapidly progressive glomerulonephritis (RPGN) is rare. Patients with severe infection (e.g., IE) sometimes show positivity for cytoplasmic antineutrophil cytoplasmic antibodies (C-ANCA). Therefore, diagnosis and treatment are very difficult in cases of RPGN with IE and positivity for C-ANCA. Such cases are rare, only 12 have been reported in the English literature. Herein, we describe the case of a 50-year-old man who presented with RPGN with IE and tested positively for C-ANCA. He was referred to our hospital because of leg edema, purpura and renal dysfunction. Laboratory tests revealed serum creatinine elevation and positivity for C-ANCA and proteinase 3-specific (PR3)-ANCA. RPGN and acute renal failure were diagnosed. Hemodialysis and steroid therapy were started. Streptococcus oralis was isolated by blood culture. Transthoracic echocardiography revealed grade III mitral valve insufficiency with two vegetations. Therefore, IE was diagnosed. The steroid therapy was stopped, and antibiotic therapy was begun. Because there was no improvement, surgical therapy was performed. The operation was successful, but the patient died of brain hemorrhage. Our experience in this case indicates C/PR3-ANCA positive RPGN must be ruled out in patients with infectious disease, particularly IE, together with renal symptoms, and renal biopsy should be performed.

An otherwise healthy 20-year-old woman presented with an erythematous rash on her face as well as arthralgia and anemia. She also had systemic edema, proteinuria and hypertension. Laboratory data on admission showed hypocomplementemia, human parvovirus B 19 (HPV) DNA and both immunoglobulin (Ig) M and IgG antibodies to HPV in her serum. Renal biopsy specimens showed features of endocapillary glomerulonephritis under light microscopy. Electron microscopy showed massive subendothelial electron-dense deposits. No cause was probable other than immune complex-mediated glomerulonephritis associated with HPV infection. In a review of this and similar cases reported in the literature, several characteristic features come to light: female dominance, onset in the second or third decade of life, hypocomplementemia, histologic renal endocapillary and/or mesangioproliferative glomerulonephritis with subendothelial deposits and spontaneous recovery.

Dietary oxysterols can reach the circulation and this may contribute to atherosclerosis, where lipid oxidation is thought to be important. There is also evidence that, in rats, peroxidized lipids are absorbed and transported into lymph [Aw TY, Williams MW, Gray L. Absorption and lymphatic transport of peroxidized lipids by rat small intestine in vivo: role of mucosal GSH. Am J Physiol 1992; 262: G99-G106], although the method used to detect lipid peroxides lacked specificity. We tested whether intragastric administration of vegetable oils containing triglyceride hydroperoxides (TG-OOH) to rats resulted in detectable lipid hydroperoxides in mesenteric lymph. Using sensitive HPLC with postcolumn chemiluminescence detection, we were unable to detect hydroperoxides of triglycerides, cholesterylesters or phospholipids during the course of lipid absorption, and lymph levels of ascorbate, urate, alpha-tocopherol and ubiquinol-9 did not change significantly. By contrast, we observed a striking reducing activity judged by the efficient reduction of administered ubiquinones-9 and -10 to the corresponding ubiquinols. Exposure of rat lymph and isolated chylomicrons to aqueous peroxyl radicals revealed patterns of antioxidant consumption and lipid hydroperoxide formation similar to those described previously for human extravascular fluids and isolated lipoproteins, respectively. In particular, rates of TG-OOH formation in lymph and chylomicrons were very low to undetectable as long as ascorbate and/or ubiquinols were present, but subsequently proceeded in a chain reaction despite the presence of alpha-tocopherol. These studies demonstrate that rat intestine and mesenteric lymph possess efficient antioxidant defenses against preformed lipid hydroperoxides and (peroxyl) radical mediated lipid oxidation. We conclude that dietary lipid hydroperoxides or postprandial oxidation of lipids are not likely to contribute to these particular forms of oxidized lipids in circulation and aortic tissue.

Until now, the common strategy for atopic eczema (AE) therapy is how to treat or suppress the already established eczema, or how to control the general immune responses against antigens. It has been accepted that AE shows a delayed-type hypersensitivity to exogenous antigens especially in adulthood [1]. The characteristic distribution of skin lesions, of the exposed and flexure regions, are also suggestive of dose dependency of exogenous antigen distribution over the skin. On the other hand, dry and rough surface of AE patients’ skin [2] strongly suggests decreased skin surface water content [3] and lipid [4], which was supported by the increased transepidermal water loss (TEWL) in AE patients. The increased TEWL dose does not mean simply increased transport of water, but also easier penetration of larger materials such as antigens, which is compatible to deteriorated skin barrier function. Recently, we showed the importance of epidermal ceramides in cutaneous barrier function in the essential fatty acid deficiency rat model [5]. Among the variety of ceramides, pseudo-o-acylceramide with linoleic acid (OAC) only showed significant effects in the recovery of TEWL in the rat experimental model. As we expected, topical OAC treatment on AE skin successfully suppressed TEWL close to normal level. Since the vehicle (OAC cream minus OAC) alone and white petrolatum had no significant effects in restoring of TEWL, we could confirm the effect of OAC in AE-related dry skin.

SUMMARY 1. In order to find an anaesthesia with minimum perturbation to the metabolism of chylomicrons, the effects of seven different anaesthetic agents on clearance from plasma of chylomicron-like emulsions were compared. 2. Avertin, urethane, fentanyl, and a ketamine/xylazine mixture all slowed the removal from plasma of emulsion triolein and cholesteryl oleate. The steroid anaesthetic althesin slowed the clearance of emulsion cholesteryl oleate without affecting the removal from plasma of emulsion triolein. Nembutal when injected intravenously at a hypnotic dose did not affect the clearance of emulsion triolein or cholesteryl oleate, whereas at the anaesthetic dose, nembutal slowed the clearance rate of both labelled lipids. 3. Except for althesin, which did not affect the plasma clearance of triolein, fractional clearance rates of emulsion triolein and cholesteryl oleate calculated from blood samples taken during 12 min after injection were significantly slower in the anaesthetized groups compared with controls. However, with avertin, althesin, nembutal and ketamine/xylazine, amounts of radiolabelled triolein and cholesteryl oleate remaining in plasma 25 and 30 min after injection were comparable with the control. Radioactive lipids in plasma remained much higher in rats treated with urethane and fentanyl-fluanisonium even 30 min after injection. 4. Avertin was simple to administer and produced a suitable depth of anaesthesia for minor surgery, tail vein injections and blood sampling, whereas althesin and the ketamine/xylazine mixture required supplementary doses to maintain anaesthesia towards the end of the experiment. We concluded that anaesthesia is best avoided for studies of chylomicron clearance. Avertin is the preferred agent if anaesthesia must be used, for example in newborn rats or in mice.

We have identified and characterized specific binding for calcitonin gene-related peptide (CGRP) in mouse T lymphocytes. The binding of 125I-CGRP to mouse lymphocytes was reversible and the rate of dissociation of 125I-CGRP increased with the addition of the guanine triphosphate nucleotide analog, Gpp(NH)p. Saturation experiments, and Scatchard analysis indicated two classes of binding sites for CGRP; the apparent dissociation constants (KD) were 3.5 X 10(-10)M for high affinity binding sites (Bmax, 265 sites/cell) and 4.8 X 10(-8)M for low affinity binding sites (Bmax, 13,000 sites/cell). The KD value for the high affinity binding sites is roughly comparable to the IC50 and ED50 values for inhibition of T lymphocyte proliferation and increase in the cyclic AMP concentration in these cells, respectively. 125I-CGRP bound to mouse T lymphocytes was displaced by unlabeled CGRP with an IC50 value of 3.2 X 10(-10)M; salmon or human calcitonins did not inhibit the specific binding up to 1 X 10(-6)m. Our studies suggest that CGRP may be an important immunoregulatory molecule, and implicate it in the regulation of T cell function.

A fullterm infant had fetal distress and stained amnion. He underwent an exchange blood transfusion at 12 hours after birth because of hyperbilirubinemia. He developed oliguria combined with high urine osmolality during the first 27 hours of life despite normal creatinine clearance. The diagnosis of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) was made on the basis of high urine osmolality, low plasma osmolality and elevated plasma arginine vasopressin (AVP) concentration. We determined the plasma atrial natriuretic peptide (ANP) concentration for the first 4 days of life. After 27 hours after birth, urine volume increased while plasma AVP concentration remained high. On the other hand, plasma ANP concentration gradually increased after 27 hours of life. We speculate that ANP may play an important role in producing the spontaneous diuresis in the newborn infant with SIADH.

In conscious rats with near-malignant phases of DOCA-salt (DS) hypertension, hemodynamics were studied with microspheres before and after administration of a vasopressin (VP) vasopressor antagonist in relation to plasma VP levels (pVP). Compared to the controls, the DS rats showed significant elevations in mean arterial pressure (MAP), total vascular resistance (TVR), and pVP, and a flow redistribution from kidney and spleen to skeletal muscles and heart, with increased vascular resistance in almost all organs. The antagonist elicited no significant systemic hemodynamic effects in DS rats as a whole; however, two subgroups, responders vs nonresponders, were identified according to the effects on MAP. In responders with a pVP of 29.2 +/- 2.7 (SE) pg/ml, the antagonist lowered MAP (-24.9 +/- 5.9 mm Hg) and TVR significantly, while in nonresponders with a pVP of 15.2 +/- 3.4 pg/ml, there were no effects. The major antagonist-induced regional responses were increased flow and decreased vascular resistance in skeletal muscles and skin in whole DS rats, and additionally in the gastrointestinal tract, portal organs, and testes in the responders. Significant correlations were observed between pVP, MAP, TVR, and depressor responses to the antagonist only when all data for DS and control rats were pooled. Thus, the systemic hemodynamic effects of VP are important only in responders with exceedingly elevated pVP. VP contributes significantly to the regional hemodynamic abnormalities in skeletal muscles and skin in whole DS rats, and also in several other organs in the responders.

Almost all of the conventional clinical reports on the eye-tracking test are made on the horizontal component of the smooth pursuit function of oculomotor system; few are made on the vertical component. One reason is that during the conventional vertical eye-tracking test the artifacts caused by movement of the upper eyelids often make it difficult to analyze the data. To overcome this problem the authors have developed a method to record simultaneously the horizontal and vertical components of eye movement in the eye-tracking test, and moreover, to reduce artifacts as much as possible. Our method, the circular eye-tracking test, is performed by means of an apparatus that provides a visual stimulus drawing a circle clockwise, at a rate of 120 degrees/sec, with a radius of 25.5 cm, and viewed at a distance of 70 cm.

We describe a "sandwich-type" enzyme immunoassay for insulin in serum, in which antibody Fab'-beta-D-galactosidase conjugate and an antibody-immobilized silicone rubber solid-phase are used. The interference by serum factors with the solid-phase enzyme immunoassay can now be removed by using a buffer containing gelatin. Serum samples of 50 microL can be analyzed by the enzyme immunoassay, which is as sensitive as radioimmunoassay for human insulin. Our results correlate well with those for radioimmunoassay (r = 0.97, slope = 0.92, y-intercept = 4.6 milli-int. units /L for 181 samples). Between-assay and within-assay coefficients of variation are less than 15% over the useful ranges of the assay (5--160 milli-int. units/L).

Peripheral neurological mechanisms involved in hyperuricemia following ventromedial hypothalamic electrical stimulation was studied in the conscious rat. The intensity of 0.2 mA was near the maximum intensity of stimulation current producing a linear increase in plasma uric acid throughout the 15-min period of stimulation, as well as a subsequent rise and fall of plasma allantoin. Bilateral adrenal demedullation abolished the stimulation-induced hyperuricemia and markedly impaired the accompanying rise of allantoin. Prior treatment of the animal with hexamethonium significantly inhibited the uric acid increase, but did not reduce the allantoin elevation so markedly. Moreover, propranolol eliminated both responses of these plasma purine metabolites, whereas phentolamine greatly increased the response. It is concluded therefore that the hypothalamic stimulation-induced rise of plasma uric acid is the result of acceleration of epinephrine release from the adrenal medulla and that, whereas some unknown extra-adrenal mechanism may be partially involved, the primary part of the accompanying allantoin elevation is explained by the combined effects of the increased uric acid and the hepatic uricase.

During the examination of patients who complain of vertigo or who have equilibrium disorders, it is often difficult to determine the etiology of the disorders, that is, to determine whether it is dependent on a peripheral or central vestibular disorder. To attempt to guess the etiology in these cases, we devised a new method: the caloric eye-tracking pattern test. In normal subjects and in patients with peripheral disorders, as is well known, caloric nystagmus has little influence on the eye-tracking pattern. In contrast, in patients with central vestibular disorders, caloric nystagmus evoked abnormalities on the eye-tracking pattern, either superimposed or saccades, in spite of the fact that the eye-tracking pattern before the caloric stimulation is normal. These findings result from the visual suppression mechanism to the vestibular nystagmus. We can say that the visual suppression to the vestibular nystagmus is evoked more strongly by pursuing a moving visual stimulus than by gazing at a stationary target. These results are interesting, not only from the physiological view point, but also from the clinical view point. There is a possibility of the differential diagnosis between peripheral and central vertigo.