Long-term clinical impact of serum albumin in coronary artery disease patients with preserved renal function.

BACKGROUND AND AIMS: Low serum albumin level is reportedly associated with worse clinical outcomes in patients with chronic kidney disease (CKD). However, associations between decreased serum albumin level and outcomes in non-CKD patients with coronary artery disease (CAD) remain unclear. Therefore, we aimed to evaluate the prognostic value of serum albumin concentrations in stable CAD patients with preserved renal function. METHODS AND RESULTS: We studied 1316 patients with CAD and preserved renal function (estimated glomerular filtration rate ≥60 mL/min/1.73 m2) who underwent their first PCI between 2000 and 2011 and had data available for pre-procedural serum albumin. Patients were assigned to quartiles based on pre-procedural albumin concentrations. The incidence of major adverse cardiac events (MACE), including all-cause death and non-fatal myocardial infarction, was evaluated. Mean albumin concentration was 4.1 ± 0.4 g/dL. During the median follow-up of 7.5 years, 181 events occurred (13.8%). Kaplan-Meier curves revealed that patients with decreased serum albumin concentrations showed a higher event rate for MACE (log-rank, p < 0.0001). Using the highest tertiles (>4.3 g/dL) as reference, adjusted hazard ratios were 1.97 (95% CI, 1.12-3.55), 1.77 (95% CI, 0.99-3.25), and 1.19 (95% CI, 0.68-2.15) for serum albumin concentrations of <3.9, 3.9-4.0, and 4.1-4.3 g/dL, respectively. Decreased serum albumin concentration was associated with MACE even after adjusting for other independent variables (HR, 2.21 per 1-g/dL decrease; 95% CI, 1.37-3.56, p = 0.001). CONCLUSION: Decreased serum albumin concentration independently predicted worse long-term prognosis in non-CKD patients after PCI. Pre-procedural serum albumin concentration could offer a useful predictor for patients with CAD and preserved renal function.

N-[2-[(substituted chroman-8-yl)oxy]ethyl]-4-(4-methoxyphenyl)butylamines: synthesis and wide range of antagonism at the human 5-HT1A receptor.

A series of N-[2-[(substituted chroman-8-yl)oxy]ethyl]-4-(4-methoxyphenyl)butylamines was prepared and examined for their 5-HT1A receptor antagonist activity. The parent compound 3a and seven analogs bearing five kinds of substituents on the chroman ring were prepared from the corresponding 8-hydroxychroman intermediates. Radioligand binding assays proved the compounds 3a-h to have high affinity for the rat hippocampal 5-HT1A receptor with varied selectivity for adrenaline alpha1 and dopamine D2 receptors. Their antagonism was evaluated in a forskolin-stimulated adenylate cyclase assay performed with CHO cells expressing the human 5-HT1A receptor. Among the series, the C6-fluoro analog 3c showed both extremely potent affinity (Ki = 0.22 nM) and antagonism (EC50 = 13 nM) for the 5-HT1A receptor. Correlation analysis using substituent descriptors revealed a linear and negative correlation between molar refractivity of the C6-substituent and the binding affinity expressed in pKi.

Synthesis and pharmacological characterization of novel 6-fluorochroman derivatives as potential 5-HT1A receptor antagonists.

A series of novel 6-fluorochroman derivatives was prepared and evaluated as antagonists for the 5-HT1A receptor. N-2-[[(6-Fluorochroman-8-yl)oxy]ethyl]-4-(4-methoxyphenyl)butylami ne (3; J. Med. Chem. 1997, 40, 1252-1257) was chosen as a lead, and structural modifications were done on the aliphatic portion of the chroman ring, the tether linking the middle amine and the terminal aromatic ring, the aromatic ring, and lastly the amine. Radioligand binding assays proved that the majority of the novel compounds behaved as good to excellent ligands at the 5-HT1A receptor, some of which were selective with respect to alpha1-adrenergic and D2-dopaminergic receptors. The antagonist activity of the compounds was assessed in the forskolin-stimulated adenylate cyclase assays in CHO cells expressing the human 5-HT1A receptors. Among the modifications attempted, introduction of an oxo or an optically active hydroxy moiety at the chroman C-4 position was effective in ameliorating the receptor selectivity. Six analogues were selected through the in vitro screens and further evaluated for their in vivo activities. A 4-oxochroman derivative (31n), having a terminal 1, 3-benzodioxole ring, demonstrated antagonist activities toward 8-OH-DPAT-induced behavioral and electrophysiological responses in rats.

Myelin-deficiency in the cochlear nerve of the 'bt' mutant hamster.

In a previous report, we showed abnormal auditory evoked potentials in the mutant hamster, 'black tremor (bt)', with significantly prolonged wave latencies of auditory brainstem responses and prolonged N1 latencies of compound action potentials, but normal cochlear microphonics. In this report, we present the results of morphological studies supporting the results of our electrophysiological studies of the auditory pathway in bt. Observation by transmission electron microscopy revealed an abnormal myelin sheath surrounding the spiral ganglion cells, and a thinner compact myelin sheath surrounding the axons in bt than in normal hamsters. The bt hamster has a myelin deficiency not only in the brainstem, but also in the cochlear nerve.

Auditory brainstem responses, electrocochleograms, and cochlear microphonics in the myelin deficient mutant hamster 'bt'.

Electrophysiological studies of the auditory pathway were performed on the mutant hamster 'bt' which is known to have myelin deficiencies in the central nervous system. Auditory brainstem responses (ABRs), electrocochleograms (EcochGs), and cochlear microphonics (CMs) were recorded. ABRs in 'bt' demonstrated markedly transformed waveforms with significantly prolonged latencies. EcochG in 'bt' showed significantly prolonged N1 latencies of the compound action potentials (CAPs) while 'bt' showed normal CMs. The myelin deficient mutant hamster 'bt' may have myelin deficiencies not only in the brainstem auditory pathway but also in the cochlear nerve.

New quantitative methods for detection of feline parvovirus (FPV) and virus neutralizing antibody against FPV using a feline T lymphoid cell line.

Previously, we reported that a feline T lymphoid cell line, FL74 cells, was very sensitive to feline parvovirus (FPV) infection. In the present study, we developed new quantitative methods for detection of FPV and virus neutralizing antibody against FPV using FL74 cells. The methods presented here were very simple and applicable to both canine parvovirus and feline panleukopenia virus.

Serosurvey for selected virus infections of wild carnivores in Taiwan and Vietnam.

Serum samples from two leopard cats (Felis bengalensis) and four Formosan gem-faced civets (Paguma larvata taivana) in Taiwan, September 1995, and nine leopard cats in Vietnam, August and December 1997, were examined for the prevalence of antibodies against feline parvovirus, feline herpesvirus type 1, feline calicivirus and feline immunodeficiency virus. All civets and nine of 11 leopard cats were shown to have antibodies against feline parvovirus (FPV), and FPV's were isolated from mononuclear cells in the peripheral blood of the six leopard cats.

Resonantly enhanced nonlinear conductance in long quantum point contacts near pinch-off.

We report on a remarkable resonance in the differential conductance of long quantum point contacts (QPCs) that is observed as a precursor to regular quantized transport. This effect is increasingly pronounced in longer QPCs, in which the differential conductance may resonantly exceed 2e2/h. From a study of the experimental characteristics of this feature, we suggest that it may be associated with the formation of a well-resolved energy gap that opens dynamically as a result of enhanced many-body interactions in long QPCs.

Clinical studies of a perfluorochemical whole blood substitute (Fluosol-DA) Summary of 186 cases.

After the experimental and phase one studies of our so-called "artificial blood," Fluosol-DA (20%), an emulsified mixture of perfluorodecalin and perfluorotripropylamine, were successfully completed, phase two and three clinical studies were carried out on 186 patients in Japan. The initial dose was 20 ml/Kg body weight (BW), and additional 10 ml/Kg BW doses were applied as needed. Oxygen-supplying and plasma-extending effects were established. No untoward reaction was observed in any of the 186 cases except in a case that involved long-term repeated administration. Initial studies on FLuosol-DA suggest reasonable safety; however, additional clinical trials appear warranted.

Development of a perfluorochemical whole blood substitute (Fluosol-DA, 20%)--an overview of clinical studies with 185 patients.

Fluosol-DA, 20%, a perfluorochemical whole blood substitute, was infused during Phase II and Phase III clinical trials at 24 medical institutions in Japan to 185 patients for replacement of blood lost during surgery or for improvement of cerebral circulation. Its active ingredients (perfluorodecalin, perfluorotripropylamine, hydroxyethyl starch and Krebs-Ringer bicarbonate solution) give this biologically inert emulsion not only plasma-expanding properties but also a high oxygen-carrying capacity (7.2 vol.% at 37 degrees C; the oxygen carrying capacity of red blood cells is 17 to 20 vol.%). Doses given to the patients ranged from 6 to 25 ml/kg body weight. With regard to arterial blood oxygen tension, arterial blood oxygen content, blood oxygen transport, oxygen consumption, and acid-base balance, beneficial effects were generally observed after infusion of the emulsion following blood loss especially when the fractional concentration of oxygen in inspired gas (FiO2) was kept higher than 0.5. The emulsion also manifested beneficial plasma-expander effects on hemodynamics (blood pressure, pulse rate, and central venous pressure). In no case was there any anaphylactoid or other untoward reaction observed or reported during or after infusion of the emulsion. Although a slight prolongation of bleeding time (Duke) was found, the surgeons never experienced and hemorrhagic tendencies during or after their operations. Slight and transient elevations of SGOT were found but SGPT and alkaline phosphatase levels remained normal. All other hematological and biochemical parameters measured in blood, serum and urine remained within normal ranges.

Predominance of canine parvovirus (CPV) in unvaccinated cat populations and emergence of new antigenic types of CPVs in cats.

Serological, sequence, and in vitro host range analyses of feline parvovirus (FPV) isolates in Vietnam and Taiwan revealed that more than 80% of the isolates were of the canine parvovirus (CPV) type, rather than feline panleukopenia virus (FPLV). Although parvovirus isolates from three Vietnamese leopard cats were genetically related to CPV type 2a or 2b, they had a natural mutation of VP2 residue 300 Gly to an Asp, resulting in remarkable changes in their antigenic properties. These results indicated the possibility that CPV-2a/2b-type viruses can spread in cats more efficiently than conventional FPLV under natural conditions and that CPV-2a/2b viruses are further evolving in cats.

Immunohistochemical distribution of human epidermal growth factor in salivary gland tumours.

Immunohistochemical identification of human epidermal growth factor (hEGF) was carried out in a total of 152 cases of salivary gland tumours, consisting 107 pleomorphic adenomas and their variants, 13 adenolymphomas and 32 adenoid cystic carcinomas. A high percentage of pleomorphic adenomas revealed markedly positive hEGF staining of the luminal surface cells of tubuloductal structures and of modified or neoplastic myoepithelial cells. Clear cells of the tumour showed various reactivities from very slight to strong. Eosinophilic epithelial cells of adenolymphoma gave a positive reaction for hEGF in all the cases, whereas most adenoid cystic adenoma lacked hEGF staining; however some cases showed positive staining of the tumour cells. The immunohistochemical detection of hEGF in most salivary gland tumours suggests this factor to be a possible new marker of salivary glands tumours, and to have a biological role in tumour proliferation.

Immunohistochemical localization of the alpha and beta subunits of S-100 protein in pleomorphic adenoma of the salivary glands.

The immunohistochemical expression of the alpha and beta subunits of S-100 protein in reactive, modified and transformed of myoepithelial cells, salivary pleomorphic was investigated using monoclonal antibodies. With S-100 alpha, normal salivary glands showed strong staining in serous acinar cells and moderate to slight staining in ductal segments, and with S-100 beta staining was slight or negative in acinar cells, but strong in nerve fibres. In pleomorphic salivary adenomas, the immunohistochemical distribution of S-100 alpha and beta proteins indicated great variation in the tumour cells. Some neoplastic cells gave similar staining for both S-100 alpha and beta, others were strongly positive for S-100 alpha and stained only slightly for S-100 beta, or vice versa. Yet other cells were positive for S-100 alpha and negative for S-100 beta, or vice versa. Pleomorphic salivary adenomas were classified both by histopathological criteria and by their staining pattern for S-100 alpha and beta proteins. Great heterogeneity in S-100 alpha and beta protein expression was found in individual tumour cells of both ductal and myoepithelial origin, and no regular pattern was identified. The cellular origin of salivary pleomorphic adenomas is discussed in terms of S-100 alpha and beta protein immunohistochemistry. Pleomorphic adenoma cells may be transformed from reserve cells into tumour cells displaying biologic properties of myoepithelial cells, ductal cells, or a mixture of both.

Prediction of ramus fragment relationship in the surgical correction of facial asymmetries.

The Orthognathic Surgery Simulating Instrument is valuable for the presurgical evaluation of patients with dentofacial deformity asymmetry. The case report presents the use of the instrument in the presurgical workup of a patient with a severe facial asymmetry. Advantages over the use of a conventional articulator are also discussed.

Selection of 53 PFC substances for better stability of emulsion and improved artificial blood substitutes.

In order to develop a new PFC emulsion which is better than Fluosol-DA as an artificial blood substitute, 53 different kinds of PFCs were evaluated from the aspects of toxicity, excretion rate and emulsion stability. From the results of the screening test, FMOQ was selected as the best material for a new emulsion. The half-life of FMOQ in the body of rats was calculated to be 7 days which was similar to FDC in Fluosol-DA, and its emulsion stabilized with the mixture of YPL and Pluronic F68 was stable at 4 degrees C for longer than 6 months. Rats extensively exchange-transfused with this emulsion survived well for a long period, indicating a high efficacy and low toxicity of this emulsion. In conclusion the FMOQ emulsion was selected to be a hopeful candidate for a second generation of artificial blood substitutes. This work was partially supported by NHLBI Contract NO1-HB-2927.

Immunohistochemical demonstration of epidermal growth factor and nerve growth factor in experimental carcinogenesis in the mouse submandibular gland.

Immunohistochemical demonstration of epidermal growth factor (EGF) and nerve growth factor (NGF) was made during chemical carcinogenesis in the mouse submandibular gland. The granular convoluted tubule cells in the normal male submandibular gland contained larger amounts of EGF and NGF than in the female. The initial phase and early stages in chemical carcinogenesis showed degranulation of the granular convoluted tubule cells with a marked decrease in EGF and NGF. Premalignant lesions such as duct-like structures and multicystic lesions showed variable staining for EGF and were usually negative for NGF. Material secreted into the luminal spaces revealed increased staining for EGF and NGF. Scattered tumor cells of the poorly differentiated squamous-cell carcinoma type and desquamated tumor cells contained abundant EGF, but not NGF. No positive reaction for EGF or NGF was found in the induced squamous-cell carcinoma cells.

Auditory brainstem response and neuropathology in a case of systemic T-cell lymphoma with intracranial metastasis.

A 58-year-old male with systemic T-cell lymphoma involving the brainstem eccentrically, showed varying abnormal auditory brainstem responses (ABRs). The initial ABR demonstrated a prolonged V wave peak latency and an I-V IPL on admission. Four months later, all waves were absent bilaterally. Neuropathological examination at autopsy revealed that most of the nuclei and tracts associated with the auditory system were destroyed by lymphoid cell infiltration. It suggested that in the early stages of this disease, lymphoid cells could have involved the lower brainstem and, subsequently, in the advanced stages invaded the inferior colliculus.

Selective muscarinic antagonists. I. Synthesis and antimuscarinic properties of 4-piperidyl benzhydrylcarbamate derivatives.

A series of 1-substituted-4-piperidyl benzhydrylcarbamate derivatives were synthesized and evaluated for binding affinity to M1, M2 and M3 receptors, and for antimuscarinic activities. Receptor binding assays indicated that 1-benzyl-4-piperidyl benzhydrylcarbamate derivatives showed higher affinities for M1 and M3 receptors, and good selectivities for M3 over M2 receptor, than the corresponding ester analog. These results indicate that the urethane bond is a novel linker for muscarinic antagonists, and serves to lock the molecular conformation and allows the hydrophobic portion and cationic site of the molecule to bind to M1 and M3 muscarinic receptors. Among the prepared compounds, 1-(4-methylaminobenzyl)-4-piperidyl benzhydrylcarbamate monohydrochloride (18b, YM-58790) exhibited potent inhibitory activity on bladder pressure in reflexly-evoked rhythmic contraction, comparable to oxybutynin and was approximately ten times less inhibitory on oxotremorine-induced salivary secretion than oxybutynin in rats. Further evaluation of antimuscarinic effects on bradycardia and pressor in pithed rats, and on tremor in mice, demonstrated that YM-58790 can be useful for treatment of urinary urge incontinence as a bladder-selective M3 antagonist with fewer side effects.

Selective muscarinic antagonists. II. Synthesis and antimuscarinic properties of biphenylylcarbamate derivatives.

A novel series of biphenylylcarbamate derivatives were synthesized and evaluated for binding to M1, M2 and M3 receptors and for antimuscarinic activities. Receptor binding assays indicated that biphenyl-2-ylcarbamate derivatives had high affinities for M1 and M3 receptors and good selectivities for M3 receptor over M2 receptor, indicating that the biphenyl-2-yl group is a novel hydrophobic replacement for the benzhydryl group in the muscarinic antagonist field. In this series, quinuclidin-4-yl biphenyl-2-ylcarbamate monohydrochloride (8l, YM-46303) exhibited the highest affinities for M1 and M3 receptors, and selectivity for M3 over M2 receptor. Compared to oxybutynin, YM-46303 showed approximately ten times higher inhibitory activity on bladder pressure in reflexly-evoked rhythmic contraction, and about 5-fold greater selectivity for urinary bladder contraction against salivary secretion in rats. Moreover, selective antagonistic activity was also observed in vitro. Further evaluation of antimuscarinic effects on bradycardia and pressor in pithed rats, and on tremor in mice, showed that YM-46303 can be useful for the treatment of urinary urge incontinence as a bladder-selective M3 antagonist with potent activities and fewer side effects.