Nonlinear mixed effect modeling of the pharmacodynamics of natriuretic peptides in rats

Natriuretic peptides have not only natriuretic/diuretic but also hypotensive activities, and the decreased renal perfusion caused by the excessive hypotension is known to attenuate the diuretic actions. The present study was designed to examine the relationship between the dosing (intravenous constant infusion) rates and the diuretic actions of -rat atrial natriuretic peptide (-rANP) and rat brain natriuretic peptide (rBNP) in rats, and population (nonlinear mixed effect model) analysis was applied to these complicated diuretic actions. The intrinsic diuretic activities of -rANP and rBNP could be analyzed, and the effects of blood pressure, heart rate, and also inhibition of degradation enzyme on the diuresis of natriuretic peptides were estimated simultaneously. The population analysis was useful for analyzing such pharmacodynamic data for which the individual analysis could not be applied easily.     

Fibrinogen osaka IV: A congenital dysfibrinogenemia found in a patient originally reported in relation to surgery,now defined to have an Aα arginine-16 to histidine substitution

We discovered a congenital heterozygous dysfibrinogen in a patient and reported this case in relation to surgery some time ago (Jpn J Surg (1988) 18:43–46).³ Further studies on the isolated abnormal population of fibrinogen derived from this patient have revealed that fibrinopeptide A was not cleaved by ancrod, a snake venom-derived thrombin-like enzyme, but by thrombin, slowly but completely. The released fibrinopeptide A components, being the A, AY, and AP peptides, were all found to be abnormal, as evidenced by slightly earlier elution positions on high-performance liquid chromatography, compared with the normal counterparts. By analyzing their amino acid sequence, we have identified an arginine to histidine substitution at position 16 of the A chain, the thrombin cleavage site. Utilizing insolubilized abnormal fibrinogen, we confirmed that the polymerization site assigned to the central E domain, the A site, was exposed by thrombin, but not by ancrod. This dysfibrinogen, designated as fibrinogen Osaka IV, is the second abnormal molecule with an A arginine-16 to histidine substitution identified among Japanese families.     

Role of Laryngeal Movement and Effect of Aging on Swallowing Pressure in the Pharynx and Upper Esophageal Sphincter

Objectives Describe contribution of laryngeal movement to pressure changes at the upper esophageal sphincter (UES) and the effect of aging on the swallowing function. Study Design Manofluorography on 56 nondysphagic adults divided into three age groups: the 21‐ to 31‐year‐old group (n = 32), the 61‐ to 74‐year‐old group (n = 12) and the 75‐ to 89‐year‐old group (n = 12). Analyses of the bolus transit time, the amplitudes and durations of pharyngeal pressures, the timing of a pressure fall at the UES and the laryngeal movements. Methods Intraluminal strain‐gauge sensors recorded pressure changes in the oropharynx, hypopharynx and the UES. Motion pictures of the videotapes were fed into a personal computer, and movements of the hyoid bone were measured in both the horizontal and vertical directions as an indication of laryngeal movement. Results In 26‐ and 70‐year‐old men with calcification of the thyroid cartilage, it was determined that the larynx and hyoid bone moved in consonance until the end of the rapid hyoid movements in both the superior and anterior directions. In the 21‐ to 31‐year‐old group, the magnitude of the pressure fall at the UES was maximal before or almost at the same time as the bolus arrival, in preparation for smooth passage of the bolus from the pharynx to the esophagus. The rapid superior movements of the hyoid bone started significantly early as compared with its anterior movements (P = .0001). The rapid anterior movements of the hyoid bone started simultaneously with the pressure fall at the UES. In the elderly, all segmental transit times were significantly increased. The timing of the pressure fall at the UES was significantly delayed and the UES pressure reached its minimum value after arrival of the bolus at the UES. The minimum pressure at the UES increased to a significantly positive value. The rapid anterior movements of the hyoid were significantly delayed, suggesting that this delay causes the delay in the pressure fall at the UES. Conclusions The rapid superior and anterior movements of the hyoid bone are considered to start at the same time as those of the larynx. In the young group, it is suggested that superior laryngeal movement protects the lower airway prior to the anterior laryngeal movement, causing the pressure fall at the UES to enable the passage of a bolus into the UES. In the elderly, smooth passage of the bolus from the pharynx to the esophagus is hindered and the system that prevents aspiration is rendered inefficient by changes in the swallowing pressures and laryngeal movements with aging.     

Familial hyperextensible proximal interphalangeal joints

Summary Hyperextensibility of the proximal interphalangeal joints was noted in 3 males and 6 females in 3 generations of a Japanese family. The proposita, a 14-year-old girl, had hyperextensible proximal interphalangeal joints of the 2nd, 3rd, 4th, and 5th fingers giving swan-neck appearance during the extension. She was asymptomatic and had no other features of skin involvement. Her father, younger sister, grandmother, two aunts, and three cousins on the father's side had hyperextensible proximal interphalangeal joints. No instance of male to male transmission was present. The condition was thus inherited as an autosomal or X-linked dominant trait.     

Neurotoxicity and pharmacokinetics of ventriculolumbar perfusion of methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-gluco-pyranoside (MCNU) in dogs

Summary Ventriculolumbar perfusion of methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU), a water soluble nitrosourea with log P-0.71, may be efficacious in the treatment of subarachnoid dissemination of malignant glioma. We used 2 dogs to study the neurotoxicity and pharmacokinetics of MCNU. MCNU (1 mg), dissolved in 10 ml of artificial CSF, was administered via the right lateral ventricle during a period of 18 to 42 min and the CSF was drained by lumbar puncture. The perfusion was repeated once a week for 10 consecutive weeks. No neurological and systemic symptoms were noted after perfusion. Histological examination of the brain and spinal cord showed local denudation of the ependyma and local subependymal spongy degeneration and gliosis in the lateral ventricle into which MCNU was administered in one dog and local denudation of the ependyma in the other. When administration was over a period of 21 to 38 min, the MCNU concentration in the lumbar CSF peaked at 11.11 to 50.67 g/ml, in 28 to 78 min. The area under the drug concentration-time curve (AUC) was 1152 g×min/ml on average, significantly larger than that of ACNU. The elimination phase followed linear kinetics and the half-time was 41.1 min on average, significantly longer than that of ACNU. These findings suggest that ventriculolumbar perfusion of MCNU may be effective in the treatment of subarachnoid dissemination of malignant glioma notwithstanding some local histological changes.     

Complete nucleotide sequence of mouse mammary tumor virus from jyg chinese wild mice: Absence of bacterial insertion sequences in the cloned viral gag gene

Mammary tumors of a newly isolated strain of Chinese wild mouse (JYG mouse) harbor exogenous mouse mammary tumor virus (MMTV). The complete nucleotide sequence of exogenous JYG-MMTV was determined on the proviral 5' long terminal repeat (LTR)(partial)-gag-pol-env-3' LTR (partial) fragment cloned into a plasmid vector and the cDNA sequence from JYG-MMTV producing cells. Similarly to the other MMTV species the LTR of JYG-MMTV contains an open reading frame (ORF). The amino acid sequence of the JYG-MMTV ORF resembles that of SW-MMTV (92% identity) and endogenous Mtv-7 (93% identity) especially at the C-terminal region. Thus, a functional similarity in T-cell receptor V beta recognition as a superantigen is implicated among these MMTV species. Analysis of the viral gag nucleotide sequence revealed that this gene is not disrupted by the bacterial insertion sequence IS1 or IS2, which have been reported to be present in the majority of the plasmids containing the gag region. Comparison of amino acid sequences of JYG-MMTV with those of BR6-MMTV showed that over 96% of the amino acids of gag, pol, protease and env products are identical. These results suggest the intact nature of the nucleotide sequence of the near full-length MMTV genome cloned in the plasmid.     

Impaired glucose tolerance, diabetes mellitus, and gallstone disease: An extended study of male self-defense officials in Japan

Few studies have investigated the relation between glucose tolerance status and ultrasonographically determined gallstone disease. Using a 75-g oral glucose tolerance test, we examined the association of impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) with gallstone disease in Japanese men. Subjects were men aged 48 to 59 of the Japan Self-Defense Forces who received a preretirement health examination between October 1986 to December 1994. After exclusion of 12 men under insulin treatment in the consecutive series of 7637 men, 174 were found to have gallstones; 103 were at the state of postcholecystectomy, and 6899 had normal gallbladder. IGT and NIDDM were associated with a modestly increased risk of gallstone disease; adjusted odds ratios were 1.3 (95% confidence interval [CI]: 0.9–1.8) for IGT and 1.3 (95% CI: 0.8–2.0) for NIDDM after adjustment for hospital, rank, smoking, alcohol use, and body mass index. Adjusted odds ratio for IGT and NIDDM combined was 1.3 (95% CI: 1.0–1.7, p=0.08). When prevalent gallstones and postcholecystectomy were considered separately, NIDDM showed a significant, positive association with postcholecystectomy, but not with prevalent gallstones. The findings add to evidence that glucose intolerance is associated with a modest increase in the risk of gallstone disease.     

Three-Dimensional Echocardiographic Reconstruction of the Left Ventricle by a Transesophageal Tomographic Technique: In Vitro and In Vivo Validation of its Volume Measurement

Accurate determination of left ventricular (LV) volume has important therapeutic and prognostic implications in patients with cardiac disease. Volume estimations by two-dimensional techniques are not very accurate due to geometric assumptions. OBJECTIVES: To validate LV volume determinations by a new transesophageal three-dimensional echocardiographic technique. We performed three-dimensional reconstruction of the LV using an echo-computed tomographic (CT) technique based on serial pullback parallel slice imaging technique in both in vitro and in vivo settings. Fourteen latex balloons with various sizes (30-235 mL) and shapes (conical, pear shaped, round, elliptical, and aneurysms in various locations) filled with known volumes of water were imaged in a water bath. From the static three-dimensional image, the LV long axis was defined and the LV was sectioned perpendicular to this axis into 2-mm slices. The volume of each slice was calculated with the observer blinded to the actual volume as the product of the slice thickness and the manually traced perimeter of the slice and the LV volume as the sum of the volumes of the slices (Simpson's method). The calculated LV volume closely correlated with the actual volume (r = 0.99, P < 0.0001, calculated volume = 1.06x - 11.3, Deltavolume = -5.7 +/- 10.0 cc). Using the same system, transesophageal echocardiographic (TEE) images of the LV were obtained in 15 patients gated to respiration and ECG. Satisfactory dynamic three-dimensional reconstruction of the LV was possible in ten patients. The three-dimensional LV volumes (systolic and diastolic) using Simpson's method correlated well with those obtained from biplane or multiplane TEE images using the area length method (r = 0.89, p < 0.0001, y = 12.7 + 0.84x, Deltavolume = 1.3 +/- 18.1 cc). The LV major-axis diameters by the two methods showed very close correlations as well (r = 0.86, P < 0.0001, y = 19 + 0.74x, Deltadiameter = 1.0 +/- 7.2 mm). We conclude that three-dimensional LV volume calculation by the echo-CT technique is intrinsically sound, is independent of LV geometry, and with some limitations, is applicable in vivo. (ECHOCARDIOGRAPHY, Volume 13, November 1996)     

Histopathological grading and clinical features of patients with mucoepidermoid carcinoma of the salivary glands]

In the 22 years between March 1979 and February 2001, we treated 16 patients--10 men and 6 women aged 10-80 years (mean: 44 years)--with mucoepidermoid carcinoma (MEC) of the salivary gland, evaluating them clinically and histopathologically. Tumor sites included 12 at the parotid gland, 3 at the submandibular gland, and 1 at the minor salivary gland. All tumors were graded histopathologically based on the criteria of Goode et al. as follows: low grade (n = 10), intermediate grade (n = 1), and high grade (n = 5). Female gender was associated with low grade MEC and male gender with high grade MEC (P < 0.05). The age at onset in high grade MEC was older than that in low grade MEC (P < 0.005). Lymph-node metastasis was detected in 7 out of the 16 patients (44%) associated significantly with high grade MEC (P < 0.05). Distant metastasis was detected in 4 of 16 patients (25%). Distant metastasis was significantly associated with high grade MEC (P < 0.05). Local recurrence was detected in 3 of 15 patients undergoing surgery (20%). No difference was seen in local recurrence frequency between low and high grade MEC. Survival was calculated with Kaplan-Meier's method. In all 16, 5-year survival was 86% and 10-year survival 75%. Five-year survival in low grade MEC was 100%, whereas that in high grade MEC was 67% (P < 0.05). In MEC of the salivary gland, it was suggested that the histopathological MEC grade evaluated by Goode's criteria significantly correlated with gender, age, lymph-node metastasis, distant metastasis, and 5-year survival.     

Effect of a selective inducible nitric oxide synthase inhibitor on intraocular nitric oxide production in endotoxin-induced uveitis rabbits: in vivo intraocular microdialysis study

Inducible nitric oxide (NO) synthase (iNOS) is believed to contribute to the pathogenesis of endotoxin-induced uveitis (EIU). In the present study, we investigated the inhibitory effects of N(G)-nitro-L-arginine methyl ester (L-NAME), a non-selective NOS inhibitor, and S,S'-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBITU), a potent and selective iNOS inhibitor, on intraocular NO production in EIU rabbits using an in vivo intraocular microdialysis technique. The flare level in the anterior chamber increased from 1h after the injection of 100 micro g/kg lipopolysaccharide (LPS), and continued to increase for 24h. Aqueous humor protein concentrations were significantly increased at 24h after LPS-injection. These changes were significantly reduced by L-NAME (10mg/kg) and PBITU (1mg/kg), but not by D-NAME (10mg/kg). The increase in NO(2)(-) and NO(3)(-) levels in the dialysate induced by LPS was significantly inhibited by L-NAME (10mg/kg) and PBITU (1mg/kg), but not by D-NAME (10mg/kg). These results suggest that activation of iNOS may play a key role in the development of EIU, and selective inhibitors of iNOS may have therapeutic applications in the treatment of EIU.