One-Pot synthesis of N-heterocyclic compounds from cyclopropenethione derivatives

The one-pot reaction of 2-tert-butylthio-3-phenylcyclopropenethione (1a) and its 3-(2-thienyl) derivative (1b) with lithium pyrrolidinide at -70 degrees C, followed by methylation with methyl iodide, gives 6-methylthio-5-phenyl-2,3-dihydro-1H-pyrrolizine (2a) and its 5-(2-thienyl) derivative (2b), respectively. The reaction of 2-tert-butylthio-3-(pyrrolidin-1-yl)cyclopropenethione (1c) with phenyllithium gives also 2a in a high yield under similar conditions, and the reactions of 1a with N-lithium salts of 3-pyrroline, hexamethyleneimine, indoline, and carbazole, piperidine-potassium tert-butoxide mixture, and phenyllithium give 6-methylthio-5-phenyl-3H-pyrrolizine (3), 2-methylthio-3-phenyl-6,7, 8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine (5), 6-tert-butylthio-5-methylthio-4-phenyl-1,2-dihydro-6H-pyrrolo[3,2, 1-ij]quinoline (6), 4-tert-butylthio-5-methylthio-6-phenyl-4H-pyrido[3,2,1-jk]carbazole (7), 2-methylthio-3-phenyl-5,6,7,8-tetrahydroindolizine (4), and 1-tert-butylthio-2-methylthio-3-phenylindene (9), respectively. The structures of 2a and 3 were determined by X-ray analyses of their tricarbonylchromium complexes.

Long-term results of fractionated strontium-90 radiation therapy for pterygia.

PURPOSE: The long-term safety and effectiveness of fractionated strontium-90 radiation therapy (RT) for pterygium were reviewed retrospectively. METHODS AND MATERIALS: Between 1984 and 1996, 399 patients with 490 pterygia were treated with a strontium-90 eye applicator following surgical removal of the pterygium. The median follow-up period was 61 months (range 2-178). Of the 490 pterygia, 452 were fresh, 17 were recurrences after surgical removal alone, and 21 were recurrences after surgical removal plus postoperative RT. Fractionated RT of 31-42 Gy/4-5 fractions/22-29 days was given for 95.1% of the pterygia. RESULTS: In total, 58 (11.8%) local recurrences of pterygia were noted. The median time of local recurrences was 10 months, ranging from 2 to 93 months, and 16 recurrences (28%) were noted later than 24 months after treatment. The interval between surgery and the start of RT (1-3 days vs. >3 days) and recurrent pterygia were significant variables for local control in the multivariate analysis, while total RT dose (7-29 Gy vs. 31-50 Gy) was a marginally significant variable. Late toxicities that may be associated with strontium-90 RT were scleromalacia (scleral thinning) in 4 eyes, adhesion of eyelids in 3 eyes, and scleral ulcer in 2 eyes. CONCLUSION: Fractionated strontium-90 RT of approximately 40 Gy/4-5 fractions was safe and effective for preventing recurrence of pterygia, when RT was started within 3 days of surgery.

[Trend of aging on the number of teeth investigated through a survey of dental health representation in a simple equation by using a kinetic method and its application].

A survey of dental health was conducted on 6,933 residents (aged 61.8 +/- 11.1) in 4 villages Nara Prefectural Uchiyoshino Health Center administers. Examinees were divided into 7 ages groups. The mean value of present teeth at each age group was calculated. Age dependency of number of teeth was investigated with a kinetic model based on the following premise. 1. Changes between age groups can be treated as a time series occurrence. 2. Number of missing teeth can be estimated as 29 - that of present teeth. Results show that the rate of decrease of the number of present teeth is of a first order in itself and the number of missing teeth. It can be mathematically expressed as follows: -dX/dt = k.X.(29 - X).......eq. (1). in which X = number of present teeth, 29 - x = number of missing teeth k = rate constant, t = time. From this simple relationship the following are suggested 1. Tooth loss is caused by the interaction of present teeth and sites where teeth are lost. 2. Integration of eq. (1) yields ln¿(29 - X)/X¿ = 29.k.t + a.......eq. (2). in which 0 < X < 29, t = time from the youngest age group (20-29), a = constant. It appears that, from eq. (2), the dental health of a community is determined by two coefficients, 29.k and a. 3. Helping a person realize his present and future dental state and to motivate action for prevention of tooth loss by showing him his rate of decrease, "tooth age" and the predicted number of teeth a certain years later calculated from eq. (1) and eq. (2), can be of great value. 4. Eq. (2) is transformed to X = 29/¿exp(29.k.t + a) + 1¿, which represents the reverse S-shaped curve of the age dependency of the number of teeth. 5. Applying this method to cohort analysis will enable forecast of the trend of the number of teeth.

Involvement of von Willebrand factor and PGI2 in platelet binding to a partially denuded endothelial monolayer.

Platelet binding to an endothelial monolayer was examined after denudation. The binding increased for up to 10 min and thereafter declined gradually. Antibodies against von Willebrand factor (vWF) inhibited the binding. Production of prostacyclin (PGI2) occurred 10 min after endothelial denudation. This study suggests that vWF is involved in the binding during the first 10 min and that PGI2 suppresses the binding thereafter.

Long-term outcome in surgically treated spina bifida cystica.

This report describes the long-term operative outcome of 72 patients with spina bifida cystica. The period of follow-up was between 4 and 20 years. In our series, 17 patients died, with the mortality rate increasing as the lesions were more rostral. All cases involving only a meningocele are living without handicap. The cases of spina bifida cystica with hydrocephalus had higher morbidity and mortality when compared to those without hydrocephalus. We conclude that the rostro-caudal location, the content of the sac, and whether there is associated hydrocephalus are important factors influencing the long-term prognosis of spina bifida cystica.

Long-term outcome in surgically treated encephalocele.

This report describes long-term operative outcome of 24 cases with occipital encephalocele. The follow-up periods are between 4 and 20 years. Of the 24 patients with occipital encephalocele, two have died. Of the 22 living patients, 16 are living without neurological deficit, while six are disabled mentally and/or physically. Four cases of encephalocele developed hydrocephalus, and two of them died while the other two are still living with severe handicap. The presence of gross brain tissue in the sac of encephalocele and the size of the sac were also unfavorable factors for the prognosis. We conclude that the size and the content of the sac and associated hydrocephalus are the important factors that influence the long-term prognosis of occipital encephalocele.

Intercellular transport through a partially denuded arterial endothelial monolayer. Effect of platelets and PGI2.

Fluorescein Dextran (FD) was shown to be transported at increased rates through partially denuded endothelial monolayer. Platelet binding to the partially denuded monolayer lowered transport rates to those comparable with intact endothelium. Inhibition of transport by platelet binding was not affected by the addition of isocarbacyclin (a stable derivative of PGI2). This result suggests that adherent platelets at the partial denudation site are sufficient to suppress transport of FD.

Platelet adhesion to a biomimetic prosthesis prepared from canine arterial wall.

A biomimetic prosthesis was prepared from canine arterial wall by extraction with 70% formic acid. Under these conditions, the arterial architecture consisting of elastic lamella was conserved and the tensile strength was retained. Attachment of 51Cr-endothelial cells to the surface of the prosthesis was enhanced in the presence of collagen (50 micrograms/ml), fibronectin (20 micrograms/ml), and fibrinogen (500 micrograms/ml). These agents also enhanced the adhesion of 51Cr-platelets. However, preattachment of endothelial cells to prostheses prevented platelet adhesion.

Effect of PGI2 on platelet binding to partially denuded endothelial monolayer in vitro.

We have developed a new model for the investigation of platelet interaction with injured vascular endothelium. This involves the quantitative detection of platelet binding to a partially denuded endothelial cell monolayer in vitro. Porcine arterial endothelial monolayer, cultured on collagen gel containing fibrinogen and fibronectin, was partially denuded and the binding of 51Cr-platelets was measured. A synergistic increase in platelet binding was observed in the presence of fibrinogen and fibronectin. A distinct aggregation of platelets along the edge of the denuded area of the endothelial monolayer was seen. Prostacyclin (PGI2) inhibited platelet aggregation, although adhesive platelets were still present at denuded sites.

[The study on bacterial infection in chronic lower respiratory tract infection--from the viewpoints of acute and chronic infection].

Using mainly changes in the amount of sputum as an index of the infectious course of chronic lower respiratory tract infection associated with purulent sputum over years, the disease was divided into stable and acute exacerbated phases and a bacteriological investigation using transtracheal aspiration (TTA) conducted. TTA was performed 107 and 45 episodes during stable phases and acute exacerbated phases respectively. Monomicrobial and polymicrobial infection were detected most frequently during the stable and acute exacerbated phases respectively (p less than 0.01). During the stable phases, the single organisms detected most frequently were H. influenzae (26 episodes) and P. aeruginosa (20 episodes), while in the cases in which multiple organisms were detected during stable phases, combination including H. influenzae were most common (19 episodes). H. influenzae was the most frequently detected organism in cases showing single organisms during acute exacerbated phases (7 episodes). In the cases in which multiple organisms were detected as well, H. influenzae was the most commonly detected organism assumed to predispose to exacerbation (7 episodes), while P. aeruginosa was not found. These results suggest that in chronic lower respiratory tract infection. H. influenzae and P. aeruginosa are important as persistent infective organisms, while H. influenzae are important in acute exacerbation.

Hepatotoxic activity of Campylobacter jejuni.

Hepatotoxic factor(s) were isolated from whole-cell lysates of Campylobacter jejuni GIFU 8734 and purified by chromatography. A single intravenous injection of 10 micrograms of this factor reproducibly produced hepatitis in mice, as determined by histology and liver function tests. The hepatic lesions were very similar to those evoked by C. jejuni infection. Tissue-culture studies with mouse hepatocytes demonstrated that low concentrations of the factor caused release of hepatic enzymes into the medium without appreciable cytolysis. High concentrations of the factor induced cytolysis. These effects were neutralised by antiserum to the factor, but not by antisera to the lipopolysaccharide of C. jejuni or to the heat-labile enterotoxin of Escherichia coli. Among 20 clinical isolates of C. jejuni, only four evoked hepatitis in mice and produced the hepatotoxic factor.

Transcellular transport of angiotensin II through a cultured arterial endothelial monolayer.

We have studied the mechanisms of angiotensin II (A-II) transport through a cultured arterial endothelial cell monolayer. The transport of 125I-labeled A-II was inhibited by excess unlabeled A-II (50 microM) and [Sar1, Ile8]-A-II (50 microM), but was not inhibited by bradykinin (50 microM). The transport process was shown to be temperature dependent and was inhibited by 10 mM NaN3 plus 50 mM 2-deoxyglucose. Monensin (50 microM), an inhibitor of endocytotic trafficking, reduced the rate of transport of 125I-A-II. It is also shown that the specific pathway for A-II transport was unidirectional from the apical to the basolateral surface of the endothelial cell monolayer.

[A clinical study on five cases of respiratory infections caused by Neisseria meningitidis].

Five cases of the respiratory infections, in which Neisseria meningitidis was isolated upon the examination of the transtracheal aspiration (TTA), were reported. Patients studied were four males at the ages of 18, 56, 66 and 78 years, and a 18-year old female. Five cases were bronchopneumonia (two cases), acute bronchitis (two cases) and diffuse panbronchiolitis (DPB) (one case). Underlying diseases were as follows: lung cancer or acute myocardial infarction in cases of bronchopneumonia, and interstitial pneumonia or pulmonary tuberculosis in cases of acute bronchitis. There was a case in which only N. meningitidis was cultured from specimens obtained by TTA, although another different organism, in addition to N. meningitidis, was recovered from the patient of other cases. Other organisms found together with N. miningitidis were H. influenzae (2 cases), S. dysgalactiae (1 case) and M. tuberculosis (1 case). Predisposing factors were common cold in the female patient and bronchoscopic examination in the cases of lung cancer and of interstitial pneumonia. Two of the five cases occurred consecutively in the same room and so they were considered as nosocomial infections. With these findings, it can be posturated that N. meningitidis might be one of the etiological agents of the respiratory infections.

Biological functions of mouse seminal vesicle fluid. I. Suppression of blastogenic responses of lymphocytes.

The effect of mouse seminal vesicle fluid (SVF) on blastogenic response of splenocytes to mitogens was investigated. SVF significantly suppressed blastogenic response of splenocytes to concanavalin A and phytohemagglutinin in a dose-dependent manner, but blastogenic response to lipopolysaccharide was suppressed only at low, although significant, levels, even at high concentrations of SVF. Extensive dialysis did not reduce the capacity of SVF to inhibit blastogenesis of splenocytes. For elucidation of the mechanisms of suppression of blastogenic response, interleukin-2 (IL-2)-dependent cells were cultured in the presence of IL-2 and various concentrations of SVF. The presence of SVF did not inhibit the proliferative response of IL-2-dependent cells to IL-2. These results suggest that the suppression of blastogenic response of T lymphocytes to mitogens in seminal plasma is caused by an undialyzable component (or components) derived from seminal vesicle and is attributable to the alteration of receptors for mitogens or of IL-2 receptors that are expressed on stimulation by mitogens.

Enhanced interleukin production after long-term administration of erythromycin stearate.

The effects of erythromycin stearate (10 mg/kg/day) were studied on productions of interleukin (IL)-1 and -2 in mice after a long-term treatment. A 28-day treatment resulted in higher levels of IL-1 production by macrophages and of IL-2 production by splenocytes, while a 7-day treatment did not increase them. T-cell growth factor activity of IL-2 preparation prepared on day 28 of treatment as determined by HT-2 cell proliferation was reduced by about 40% in the presence of anti-murine IL-4 monoclonal antibodies, while control IL-2 activity was not reduced. Furthermore, a 28-day treatment with erythromycin stearate increased concanavalin A-induced blastogenesis of splenocytes significantly. These results suggest that long-term treatment with erythromycin stearate can stimulate host defense by increasing interleukin production.

Alterations of host resistance to mouse typhoid infection by sex hormones.

The effect on mouse typhoid infection of a 3-day treatment of female virgin mice with 1 mg/day of female sex hormones (estrogen or progesterone), maintaining the same hormonal levels observed in pregnant mice for 30 days, was investigated in order to clarify the mechanisms of altered resistance during pregnancy. Estrogen-exposed mice were more susceptible to the intraperitoneal challenge with Salmonella typhimurium as compared with the vehicle control mice, while progesterone treatment increased the survival times of mice. Estrogen exposure increased the number of peritoneal cells after treatment, but the inflammatory cellular response after infection was significantly suppressed. Although the estrogen-treated and vehicle control mice had the same degrees of peritoneal cellular responses after infection, the death rates in the estrogen-treated mice were higher than those in the vehicle control mice against challenge with 1 LD50 of S. typhimurium. On the other hand, progesterone treatment resulted in the marked influx of peritoneal cells after treatment was terminated, and also it induced a significant increase in the number of peritoneal cells after infection. Although survival times in the progesterone group were higher than those in other groups, all progesterone-treated mice died after a challenge with 1,000 LD50 of S. typhimurium. These results suggest that progesterone enhances nonspecific resistance by increasing the influx of peritoneal cells after infection, while estrogen affects the acute inflammatory responses.

Effects of mouse testicular extract on immunocompetent cells.

We investigated mouse testicular extract (TE) to clarify its biological functions in reproductive immunity. TE, at concentrations of 50-300 micrograms/ml, enhanced macrophage activities of spreading, glucose consumption, and cytostasis against a susceptible tumor cell line. On the other hand, TE inhibited concanavalin A (Con A)-induced T-cell blastogenesis in the dose range of 10-600 micrograms/ml. To elucidate the origin of TE, W/Wv mice, which genetically lack germ cells, were used. TE obtained from W/Wv mice enhanced the spreadability of macrophages and inhibited Con A-induced blastogenesis of T cells. The enhancement of macrophage spreading was only achieved by the interstitial fluid (IF), while the suppression of Con A-induced T-cell responses was detected in seminiferous tubule fluid (STF) as well as in IF. TE did not affect listerial antigen-specific responses of lymphocytes in vitro. These results suggest that TE has the capacity to regulate the biological responses associated with reproduction.

[The effect of erythromycin treatment on natural killer (NK) cell activity in patients with chronic lower respiratory tract infections].

We measured NK activity before and after administration of erythromycin in 7 cases of chronic respiratory infection, and investigated the relationship between NK activity and improvement of the clinical syndrome. 1) We saw a significant rise in NK activity after treatment of erythromycin. Values before and after ranged from 40.0 +/- 21/2% to 62.0 +/- 32.7%. 2) There was no correlation between treatment period of erythromycin and the rate of rise in NK activity in the various cases such as rapidly rising cases or slowly rising cases, etc. 3) We saw a rise in NK activity before improvement of the clinical syndrome. Therefore it is suggested that treatment of erythromycin affects a rise in NK activity.

Three dimensional observations of the palisade-shaped nerve endings of normal hair of rat's snout.

The nerve endings of normal hair of the rat's snout, partially digested with trypsin and hydrochloric acid, were studied by scanning electron microscopy. Each lanceolate structure measured ca. 10 microns in length and was arranged around the hair follicle. These palisade-shaped nerve endings were situated almost beneath the sebaceous glands, ran upward, parallel to the axis of the hair follicle, and terminated in pointed shape. 2 kinds of cells, Teloglia cell Type I showing flat profile, and Teloglia cell Type II showing spherical profile and possessing numerous caveolae in its surface were observed at the basal portion of the palisade-shaped endings. The axon was enclosed by Schwann cells in its course to the hair follicle, and was covered with Type I cells at the beginning, and with Type II cells at the end, and constituted the palisade-shaped nerve endings. The palisade structure in silver impregnated tissues observed by backscattered electron microscopy and X-ray analyzer was characterized as comprising neuronal elements. Cytochemically, the nerve endings showed cholinesterase and Mg-ATPase activities. They may be involved in the reception of the mechanical stimulation of the hair. The palisade nerve endings thus possessed appropriate 3-dimensional structure as mechanoreceptor.