Changes in energy during treatment of depression: an analysis of duloxetine in double-blind placebo-controlled trials.

AIMS: The aim of this study was to assess how quickly and effectively duloxetine improves energy compared with placebo in patients with major depressive disorder (MDD). METHODS: Data from 10 randomised, double-blind, placebo-controlled clinical trials examining duloxetine (40-60 mg/day) vs. placebo in patients diagnosed with MDD were analysed. Change from baseline at Week 1 through Week 8 in Hamilton Depression Rating Scale (HAM-D) retardation subscale score (Item 1 - depressed mood, Item 7 - work and activities, Item 8 - retardation and Item 14 - genital symptoms) was assessed with mixed model repeated measures analysis. Positive predictive values and negative predictive values were calculated for predictor analysis. RESULTS: Patients treated with duloxetine (N = 1522) experienced statistically significantly (p ≤ 0.05) greater reductions in HAM-D retardation subscale scores vs. placebo (N = 1180) starting at Week 1 throughout Week 8 of treatment. Of the patients with early energy improvement (≥ 20% reduction in HAM-D retardation subscale scores) at Week 1, 48% achieved remission (HAM-D total score ≤ 7) at Week 8; 48% and 46% of patients who experienced early energy improvement at Weeks 2 and 4, respectively, achieved remission at Week 8. DISCUSSION: We demonstrated that treatment with duloxetine, quickly and with increasing magnitude over treatment time, improves low energy symptoms. As early as 1 week after starting treatment with duloxetine, improvement of low energy may serve as a predictor of remission at end-point. CONCLUSIONS: Treatment with duloxetine improves energy in patients with MDD and early response in retardation may serve as a modest predictor of remission at end-point. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov. Study Identifiers: NCT00036335; NCT00073411; NCT00406848 and NCT00536471. Studies HMAQa, HMAQb, HMATa, HMATb, HMBHa and HMBHb predate the registration requirement. DATA POSTING: ClinicalTrials.gov. Study Identifiers: NCT00406848; NCT00536471.

Factors associated with self-assessed masticatory ability among community-dwelling elderly Japanese.

UNLABELLED: Self-assessed masticatory ability has been shown to be significantly related to general health among elderly persons. OBJECTIVE: To identify oral factors associated with the self-assessed masticatory ability. BASIC RESEARCH DESIGN: Cross-sectional study. PARTICIPANTS: A total of 736 community-dwelling elderly persons. MAIN OUTCOME MEASURES: Data on background factors and the self-assessed masticatory ability were collected by questionnaire. An intraoral examination examined the pattern of posterior occluding pairs of natural teeth (POPs), the WHO Community Periodontal Index of Treatment Needs (CPI) and denture-related factors such as use of dentures, pain when using dentures and stability and retention of dentures. Chi-squared tests examined the relationships between the self-assessed masticatory ability and the background factors and oral conditions. Ordinal regression models were constructed with the self-assessed masticatory ability as the dependent variable and oral conditions as the principal independent variables, to adjust for the potential confounding variables. RESULTS: Self-assessed impairment of masticatory ability was associated with lost POPs (p < 0.001) and CPI (p = 0.012). In the participants with lost POPs, self-assessed impairment of masticatory ability was associated with not using dentures and pain when using dentures (p < 0.001). In the totally edentulous subjects, impairment of masticatory ability was not associated with stability and retention of dentures (p = 0.070). CONCLUSIONS: Factors affecting self-assessed masticatory ability include the pattern of POPs, periodontal status, denture use and pain when using dentures.

Self-assessed masticatory ability and hospitalisation costs among the elderly living independently.

The escalating medical costs are a social problem in many countries. Masticatory ability is thought to be related to the general health conditions. The purpose of this study was to show relationships between self-assessed masticatory ability and medical costs among the elderly living independently in community. Data on background factors and self-assessed masticatory ability were collected from 702 Japanese elderly persons by questionnaires. An intra-oral examination was performed to examine the number of remaining teeth. Self-assessed masticatory ability was classified into one of three categories: ability to chew all kinds of food (Good), ability to chew only slightly hard food (Fair) or ability to chew only soft or pureed food (Poor). Data on the annual medical excluding dental costs were obtained from the Japanese National Health Insurance system. The Kruskal-Wallis test was used to examine differences in outpatient costs and hospitalisation costs among the three groups of self-assessed masticatory ability. Univariate unconditional logistic regression models and multivariate logistic regression models were used with medical costs as the dependent variable and self-assessed masticatory ability as the principal independent variable. A significant difference (P=0·039) in hospitalisation costs but not outpatient costs was found among the three groups of self-assessed masticatory ability. The multivariate logistic regression analysis showed that severely impaired masticatory ability (Poor) was significantly related to higher costs of hospitalisation. Self-assessed impairment of masticatory ability may be a significant and independent indicator of higher costs of hospitalisation among community-dwelling elderly persons.

Impaired host defence against Mycobacterium avium in mice with chronic granulomatous disease.

Patients with chronic granulomatous disease (CGD), an inherited disorder of phagocytic cells, often contract recurrent life-threatening bacterial and fungal infections. CGD is considered to arise from a functional defect of the O(2)-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes. To determine whether or not NADPH oxidase is crucial to the host defence against Mycobacterium avium, we investigated the response against M. avium using CGD model mice (gp91-phox(-)) of C57BL/6 strain. A tracheal injection of 1 x 10(7) colony-forming units (CFU)/head of M. avium strain FN into the CGD mice resulted in a pulmonary infection, while also increasing the mortality rate. In contrast, normal C57BL/6 mice injected with same dose of the organisms did not develop severe pulmonary infection and were able to survive through 2 months of observation. The macrophages obtained from the CGD mice were observed to have a higher burden of the bacterial growth than macrophages from normal C57BL/6 mice. These results suggest that the defect of the NADPH oxidase function impairs the host defence against M. avium infection.

Binding characteristics and distribution of lactoferrin receptors in the gut and choroid plexus in newborn calves.

Lactoferrin (Lf), an iron-binding multifunctional glycoprotein, abundantly present in colostrum and milk of different species such as humans, bovines, and mice has been shown that bovine colostral Lf is transported into the CSF via plasma in newborn calves. Specific Lf-receptors (Lf-R) are present in different cells of different species. In the present study, we report for the first time, the presence and distribution of Lf-R in the intestine and choroid plexus in newborn calves. Brush-border membrane vesicles (BBMV) were prepared from the mucosa of duodenum, jejunum, ileum, colon, epithelium overlying Peyer's patches (EOPP) in jejunum (EOPPJ) and ileum (EOPPI), and choroid plexus membranes. Receptor binding assays were carried out using 125I labeled bovine Lf. Specific and saturable Lf-R were found in BBMV of all the intestinal segments and choroid plexus examined. Nonlinear regression and Scatchard plot analyses clearly revealed that EOPP had the highest binding maximal (Bmax), and lowest in colon. The maximum dissociation constant (Kd) 0.7 microM was in colon while, Bmax and Kd in choroid plexus membrane were 16.87 nmol/mg protein and 0.34 microM, respectively. All these findings together strongly suggested that Lf was transported into CSF via plasma through receptor mediated transcytosis.

Stimulation of renin secretion from the intact kidney and from isolated glomeruli by the calcium ionophore A23187.

The ionophore A23187 evoked a dose-dependent release of renin from the isolated perfused cat kidney, which was inhibited by calcium deprivation and adrenergic blockade. The latter finding indicates that the effects of A23187 on the intact kidney are mediated mainly by catecholamine release from sympathetic nerve endings. Ionophore also elicited a concentration-dependent enhancement of renin secretion from a pure preparation of glomeruli isolated from cat kidney; this stimulation was still manifest when the glomeruli were superfused with a calcium-free solution. These findings indicate that A23187 evokes renin secretion from juxtaglomerular cells by mobilizing cellular calcium and support the view that an increase in intracellular calcium is intimately involved in the mechanism of renin secretion.

Aldosterone production is activated in failing ventricle in humans.

BACKGROUND: Recent reports have indicated that aldosterone is produced in extra-adrenal tissues in animals. The present study was designed to examine whether aldosterone is produced in human heart. METHODS AND RESULTS: Plasma levels of aldosterone, BNP, and angiotensin-converting enzyme were measured in anterior interventricular vein (AIV), coronary sinus (CS), and aortic root (Ao), respectively, in 20 patients with left ventricular systolic dysfunction (LVSD), 25 patients with LV diastolic dysfunction (LVDD), and 23 control subjects. Aldosterone levels were significantly higher in AIV and CS than Ao in LVSD (98+/-10 versus 72+/-9 pg/mL, P:<0.001, and 97+/-11 versus 72+/-9 pg/mL, P:<0.001, respectively) and LVDD (87+/-10 versus 71+/-9 pg/mL, P:<0.01, and 84+/-10 versus 71+/-9 pg/mL, P:<0.01, respectively) groups, but no differences were observed in levels for these sites in the control group. Levels of ACE activity and BNP also were higher in AIV than Ao in both LV dysfunction groups. The difference in aldosterone levels between AIV and Ao and those in BNP and angiotensin-converting enzyme had a significant positive correlation with LVEDP and a significant negative correlation with LV ejection fraction in the LVSD group. CONCLUSIONS: Production of aldosterone, angiotensin-converting enzyme, and BNP are activated in failing human ventricle in proportion to severity.

Aldosterone induces angiotensin-converting-enzyme gene expression in cultured neonatal rat cardiocytes.

BACKGROUND: The cardiac renin-angiotensin-aldosterone system is activated in failing hearts in proportion to the severity of the disease. We hypothesized that a positive feedback mechanism might exist within this system and contribute to the progression of the heart failure. Methods and Results-- To test this hypothesis, we examined whether angiotensin II or aldosterone induces the expression of angiotensin-converting-enzyme (ACE) mRNA in cultured neonatal rat ventricular cardiocytes. Expression of ACE mRNA was detected and quantified using real-time reverse transcription-polymerase chain reaction. Exposure to angiotensin II (10(-5) mol/L) for 24 hours had no significant effect on the expression of ACE mRNA (0.7+/-0.5-fold versus control, P=NS), but similar treatment with aldosterone (10(-5) mol/L) induced a 23.3+/-7.9-fold increase (P<0.01) in ACE mRNA expression. The effect of aldosterone was both time- (maximal effect, 24 hours) and dose-dependent (EC(50), 4x10(-7) mol/L), and it was significantly (P<0.01) inhibited by spironolactone, a specific mineralocorticoid receptor antagonist. CONCLUSIONS: Aldosterone upregulates ACE mRNA expression, which is blocked by spironolactone in neonatal rat cardiocytes. Thus, spironolactone may suppress the progression of heart failure by blocking the effects of aldosterone and angiotensin II.

Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with myocardial infarction.

OBJECTIVES: We examined the possible association between the missense Glu298Asp variant of the endothelial nitric oxide synthase (eNOS) gene and myocardial infarction (MI). BACKGROUND: Endothelium-derived nitric oxide (NO) plays a key role in the regulation of vascular tone. Recently, we reported that a missense Glu298Asp variant in exon 7 of the eNOS gene is a possible genetic factor involved in the pathogenesis of coronary spasm. Endothelium-derived NO also has vasoprotective effects by suppressing platelet aggregation, leukocyte adhesion and smooth muscle cell proliferation. METHODS: We screened 285 patients with an MI and 607 control subjects in Kumamoto Prefecture, Japan. Genotypes were determined by polymerase chain reaction-restriction fragment-length polymorphism analysis. RESULTS: The frequency of the missense Glu298Asp variant was significantly higher in the MI group than in the control group (21.1% vs. 13.3%, p = 0.003, odds ratio 1.73 for the dominant effect of the eNOS T allele). Multiple logistic regression analysis showed that the missense Glu298Asp variant was an independent risk factor for MI, as was diabetes mellitus, hypertension, cigarette smoking, hypercholesterolemia and body mass index. CONCLUSIONS: There was a significant association of the missense Glu298Asp variant of the eNOS gene with MI. This marker-disease association may be due to the impaired effects of NO on the cardiovascular system: dysregulation of vascular tone, platelet aggregation and leukocyte adhesion and smooth muscle cell proliferation, all of which promote coronary atherosclerosis and thrombosis.

Cloning of cDNA encoding the rice 22 kDa protein of Photosystem II (PSII-S) and analysis of light-induced expression of the gene.

Cloning of rice cDNA encoding the chlorophyll-binding 22 kDa protein of Photosystem II (PSII-S) and the light-induced expression of the gene are reported. One of the light-responsive cDNA clones, isolated by screening with a light-specific subtracted cDNA probe, was shown to encode PSII-S of rice. Genomic Southern analysis suggested that the PSII-S gene, psbS, is a single-copy gene in rice. A brief exposure to red light induced a severalfold increase in the steady state level of PSII-S transcripts in etiolated seedlings. The red light effect was reversed by far-red light, suggesting involvement of phytochrome in the PSII-S gene regulation. Prolonged exposure (3 h) to blue light, however, revealed a much stronger effect than red light on the accumulation of PSII-S transcripts in the etiolated seedlings. In dark-adapted green plants, prolonged exposure to blue light induced re-accumulation of transcripts encoding PSII-S, whereas red light had little effect.

Plasma levels of A- and B-type natriuretic peptides in patients with hypertrophic cardiomyopathy or idiopathic dilated cardiomyopathy.

We investigated the relation between left ventricular structure and the secretion patterns of A- and B-type natriuretic peptides (ANP and BNP) by comparing their plasma levels in patients with hypertrophic cardiomyopathy (HC) and patients with idiopathic dilated cardiomyopathy (IDC). The secretion of ANP and BNP was much higher in patients with HC than in those with IDC; this shows that left ventricular cavity size is a key factor that regulates the secretion of ANP and BNP.

T(-786)--> C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with myocardial infarction, especially without coronary organic stenosis.

Recently, we discovered a T(-786)-->C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene that is associated with coronary spasm. The precise mechanism(s) of myocardial infarction (MI), especially without coronary organic stenosis, has not been elucidated, but it seems possible that coronary spasm plays a key role in the mechanism. In this study, we examined the frequency with which the T(-786)-->C mutation occurred in 359 patients with MI who were compared with 195 controls. In the MI group, the frequency of C/C, C/T, and T/T genotypes was 1%, 22%, and 77%, respectively. In the control group, the frequency of C/C, C/T, and T/T genotypes were 0%, 8%, and 92%, respectively. The frequency of the C allele was significantly higher in the MI group than in the control group (p < 0.001). In the MI group, 30 of 359 patients (8%) with MI had no stenosed vessels angiographically, 158 (44%) had 1 stenosed vessel, 80 (22%) had 2 stenosed vessels, and 91 (25%) exhibited 3 stenosed vessels. Total and low-density lipoprotein cholesterol levels and the incidence of diabetes mellitus increased as the number of stenosed vessels increased (p < 0.01, respectively). The frequency of the T(-786)-->C mutation was significantly higher in MI patients with no stenosed vessels (50%) than in those with stenosed vessels (p < 0.003). In conclusion, the T(-786)-->C mutation was strongly associated with MI, especially without coronary arterial stenosis, in Japanese patients. The association may be due to the impaired effects of nitric oxide in the cardiovascular system.

A T-786-->C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene and coronary arterial vasomotility.

In the endothelium, synthesis of nitric oxide (NO) from the amino acid L-arginine is catalyzed by the endothelial NO synthase (eNOS), and the continuously generated NO serves to maintain basal vascular tone. Recently, we discovered a T-786-->C mutation in the 5'-flanking region of the eNOS gene; this mutation reduced the promoter activity of the eNOS gene and was associated with coronary spasm. We examined the vasomotility of the epicardial coronary artery in subjects with and without T-736-->C mutation. We examined vasomotility in 32 consecutive subjects who were heterozygotes for the T-786-->C mutation and in 68 subjects without the T-786-->C mutation who had equivalent age, sex, and smoking status at the proximal and distal segments of the left descending coronary artery by performing quantitative coronary angiography. In subjects with the mutant allele (-786C allele), basal diameters of proximal and distal segments before intracoronary injection of acetylcholine (ACh) were less than diameters in subjects without the mutant allele (p <0.05), although there was no difference between subjects with and without the mutant allele in the diameters of coronary arteries after isosorbide dinitrate (ISDN) administration. When we compared the changes in diameters, both ACh-induced vasoconstriction and ISDN-induced vasodilatation in subjects with the mutant allele were significantly increased in the proximal (p <0.01, p <0.001, respectively) and distal segments (p <0.03, p <0.01, respectively). Taken together, these findings strongly suggest that the T-786-->C mutation increases the basal tone of the coronary artery, and enhances the response to the constrictor effects of ACh and the dilator effect of ISDN because of reducing the endothelial NO synthesis.

Interaction on metabolic clearance between A-type and B-type natriuretic peptides in patients with heart failure.

A-type and B-type natriuretic peptides (ANP and BNP) are secreted into the systemic circulation via the coronary sinus. Plasma levels of ANP and BNP at the coronary sinus should directly determine the systemic circulating levels. However, the metabolic clearance of these hormones are dependent on similar systems, natriuretic peptide clearance receptor (NPR-C) and neutral endopeptidase 24.11 (NEP), suggesting a possible interaction between ANP and BNP on metabolic clearance. In this study, we examined the interaction on metabolic clearance in patients with heart failure. We obtained blood samples from the coronary sinus and aortic root in 100 patients with heart failure and 28 control subjects. The difference in ANP and BNP levels between the coronary sinus and the aortic root is reflected partly by the metabolic clearance in the pulmonary circulation. In this study, we examined the possible interaction on metabolic clearance between ANP and BNP using a statistical procedure. The ratio of the level of BNP to ANP (BNP/ANP) was significantly higher in the aortic root than in the coronary sinus at any stage of heart failure. We performed multiple regression analysis using ANP and BNP levels at the coronary sinus as independent variables (X1 and X2, respectively) and the ANP level at the aortic root as a dependent variable (Y). The analysis showed that both X1 and X2 were significant variables in the equation. On the other hand, we performed the same analysis using the BNP level at the aortic root as a dependent variable (Y). The analysis showed that only X2 was a significant variable in the equation. This study suggests that (1) the metabolic clearance in the pulmonary circulation is higher for ANP versus BNP and (2) the amount of ANP cleared in the pulmonary circulation depends on the amount of both ANP and BNP secreted from the heart, whereas the amount of BNP cleared in the pulmonary circulation is dependent solely on the amount of BNP secreted from the heart.

Postnatal development of EEG patterns, catecholamine contents and myelination, and effect of hyperthyroidism in Suncus brain.

The postnatal development of the central nervous system (CNS) in house musk shrew in the early stage of maturation was studied. The electroencephalogram (EEG) and visual evoked potential (VEP) in association with catecholamine contents and myelin basic protein (MBP) immunoreactivity were carried out from the 1st to the 20th day of postnatal age. Different EEG patterns which were specific to behavioral states (awake and drowsy) were first recorded on the 5th day, and the total power which was obtained by power spectrum analysis increased after this stage. The latencies of all peaks in VEP markedly shortened between the 5th and the 7th day. Noradrenalin (NA) content of the brain showed a slight increase after the 3rd day, and reached maximum levels on the 7th day, which was delayed a few days compared to dopamine (DA). In hyperthyroidism, the peak latency of VEP was shortened and biosynthesis of NA in cerebral cortex and DA in hippocampus was accelerated. The most obvious change in MBP-immunoreactivity of the telencephalon occurred from the 7th to the 10th day. These morphological changes in the brain advanced at the identical time-course to those in the electrophysiological development and increment of DA and NA contents.

Cytochrome reduction induced by increase in extracellular potassium and by electrical stimulation in isolated perifused neurohypophysis of guinea pig under mild hypoxic conditions.

Parallel reduction of cytochromes, a(a3), b and c + c1 was recorded under mild hypoxic conditions when the neurohypophysis was electrically stimulated and extracellular KCl concentration was increased. The electrically stimulated reduction was abolished by tetrodotoxin and by replacement of NaCl with LiCl. The reduction was not influenced by removal of extracellular Ca2+, or by application of a Ca ionophore, A23187. These results show that cytochrome reduction correlates with K+-influx in the resting state, and with Na+-influx followed by activation of the neurosecretory terminals contained in the neurohypophysis.

Relationships between activity of daily living, and oral cavity care and the number of oral cavity microorganisms in patients with cerebrovascular diseases.

We examined the relationships among the activity of daily living (ADL), oral cavity care, and the number of oral cavity microorganisms in 40 patients with cerebrovascular diseases (CVD). The CVD patients were classified into 4 groups, I, II, III and IV based on their ADL and the method used for oral cavity care. The ADL was highest in group I and lowest in group III. Only the patients of only group III could not eat by themselves and were receiving naso-esophageal feeding. Oral cavity care was performed by the patients themselves in groups I and IV, but was performed by caregivers in groups II and III. The group IV patients had no teeth, but could eat by themselves using full dentures. The numbers of microorganisms in the pharyngeal swabs from the 4 groups were measured and expressed as colony-forming units (cfu). The numbers of both Staphylococci spp. and Candida spp. were significantly higher in group III than in the other groups. Moreover, Pseudomonas aeruginosa was isolated only from patients of group III (in about 66%). The oral cavity care by caregivers was almost the same in groups II and III, but the numbers of oral cavity microorganisms were significantly higher in group III than in group II. These results indicated that microorganisms grow more easily in the oral cavities of CVD patients with low ADL compared with CVD patients with higher ADL, and that eating is thought to be important for the prevention of an increase of microorganisms in the oral cavity.

Developmental changes in the regional Na+/glucose transporter mRNA along the small intestine of suckling rats.

We investigated the postnatal development of Na(+)-dependent glucose transporter (SGLT1) as a change in the level of the gene expression of the transporter during the suckling period in rats. We measured the changes in the expression of SGLT1 mRNA in various regions of the intestine during the development of rat pups, using a Northern blot analysis. We found a pronounced gradient in SGLT1 mRNA, with a high level in the duodenum declining gradually, but significantly, to a relatively low level near the ileocecal junction. The level of SGLT1 mRNA in the jejunum region increased in proportion to postnatal age. SGLT1 mRNA was not found at the colon. These data indicate that the glucose uptake in the small intestine of rat pups changes according to regional and age-related transporter activity.

Inhibitory influence of amino acids on secretagogues induced exocrine secretion in isolated perfused rat pancreas.

Influence of amino acids upon pancreatic exocrine secretion has been investigated in the isolated perfused pancreas of rats. Arg produced significant and dose-related inhibition of pancreatic juice flow, protein output and amylase output evoked by CCK-PZ (1.25 pM). The secretory response evoked by CCK-PZ was inhibited by other amino acids (Ala, Asp, Asn, Gly, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Val, in each 20 mM). A similar inhibitory pattern was observed using 10 mixed amino acids of 2 mM each (Pro, Phe, Thr, Met, Lys, Asp, Leu, Trp, Val, Gly). Gly at a concentration of 20 mM produced significant inhibition of exocrine secretion evoked by ACh (50 nM) or GRP (36 pM). The inhibitory response induced by amino acids could not be repeated by using exogenous insulin (1 microM) and glucagon (280 nM). The inhibitory response was also not changed by increased extracellular Ca (5 or 10 mM). However, Gly (20 mM) produced inhibition of exocrine secretion evoked by Ca reintroduction into a pancreas which was pretreated with A 23187. It was suggested that the inhibitory effects of some amino acids on exocrine secretion are mainly caused by suppression of Ca influx in a stimulus-secretion coupling process.

Comparison of pancreatic exocrine secretion via endogenous secretin by intestinal infusion of hydrochloric acid and monocarboxylic acid in anesthetized piglets.

The secretory response of the exocrine pancreas via endogenous secretin (IRS) by intraduodenal instillation of hydrochloric acid (HCl) and various monocarboxylic acid solutions was studied in anesthetized piglets. The secretion induced by HCl solutions of various concentrations containing 250 mM NaCl occurred when pH of the solutions was lower than 1.5. After instillation of the HCl solution of pH 1.0, juice flow and protein output increased 26 times and 9 times, respectively, as compared with basal levels. Such pancreatic responses paralleled an increase in plasma IRS concentration in the portal vein. The pancreatic response induced by a lactic acid solution occurred when pH of the solutions was lower than 3.8. The juice flow and protein output stimulated by a lactic acid solution of 250 mM and pH 2.0 were 16 and 8 times higher than the basal levels. The responses to the lactic acid solution of pH 2.0 increased concentration dependently, and were followed by an increase in IRS concentration in the portal vein. The pancreatic exocrine responses induced by other monocarboxylic acid solutions (250 mM) of pH 2.0 were in the following order: formic acid greater than lactic acid greater than pyruvic acid much greater than acetic acid greater than butyric acid greater than propionic acid. Lactamide, an analogous substance of lactic acid, did not evoke any pancreatic secretion. The results indicate the possibility that pancreatic exocrine response induced by HCl is dependent upon hydrogen ion, while the response induced by monocarboxylic acid is not always dependent on dissociation constant of acid.