Contribution of the mucosal tactile information to the mandibular position sense in patients wearing dentures.

The effects of mechanical stimulation of denture-bearing mucosa on the perception of mandibular position was tested in five patients wearing dentures. In order to produce mucosal stimulation of different intensities, five types of a punctate stimulus plate each having a different number of raised points was used. A hydraulic vertical displacement meter was also used so as to vary mandibular position. The mandibular position sense altered with changes in the physical stimulus intensity to the denture-bearing mucosa within a limit of jaw separation (less than 2.3 mm). In addition, the increases of the stimulus intensities stabilized the response regarding the mandibular position discrimination. From these results, it has been suggested that the tactile information from the denture-bearing mucosa regulates the neural mechanism concerning the mandibular position discrimination.


Level of accuracy and degree of precision in attempting to maintain steady levels of biting force.

The primary purpose of this study was to assess the level of accuracy (bias) and degree of precision for a group of 24 normal subjects attempting to maintain a constant biting force at levels of 100 gm, 500 gm, 1000 gm and 2000 gm for a period of 10 s each. Accuracy is defined as the difference between subjects' actual level of biting force and the target value they were trying to achieve. Precision is the level or range of variability demonstrated by the subjects while attempting to bite with a constant level of force. Subjects' performance relative to accuracy and precision was also compared when using the central incisors vs. the first permanent molars. Assessment of bite force was measured using a specially designed strain gauge scale which permitted subjects to visually monitor when their biting force equalled a preset resistance. Each subject was instructed to bite on the end of a plastic sheathed steel beam with enough force to activate the indicator needle on the voltage meter to its central position and to try to maintain a constant level of biting force (by attempting to keep the indicator needle steady in its central position). No significant (P > 0.05) differences were found in mean accuracy in bite force for gender or specific teeth used in the biting task. However, a significant difference (P < 0.0001) in mean accuracy in bite force was found to exist between the target levels.(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of splint therapy on TMJ position measured by the Gerber Resiliency Test.

The Gerber Resiliency Test is a clinical approach to possible evaluation of compression or distraction in the temporomandibular joints. In this study the same principle was used to check the tendency of mechanical responses of joints to the use of bite-splints. Sequences of tests were performed on 18 adult patients of the UTHSCSA clinical pool who had been previously treated for splint therapy. From this population nine patients presented one or more symptoms of TMD and nine were free of symptoms. Separation of the molars with the use of one thickness of tin foil indicated tendency to compression in the joints and three or four thicknesses to distraction. The tests were performed during delivery of the appliance and 1 week later. One sample chi-square statistical test was performed and did not show any statistically significant difference between dysfunction and non-dysfunction groups (P < .05). At delivery, there was a higher frequency of distraction in both left and right joints (P < .05) when the splint was inserted. Compression was present at very low frequency. One week later, the joints did not stay distracted in the same frequency.


Hemifacial microsomia and hypodontia: a case report.

A 6-year-old girl with hemifacial microsomia was examined. Abnormalities found were: severely malformed pinna of the right ear, right malar hypoplasia and unilateral mandibular hypoplasia. Dental examination revealed normal intraoral soft tissues with all deciduous teeth present. Radiographic examination disclosed that the maxillary and mandibular right and left second premolars were not developing. The mandibular ramus was short in length and the mandibular condyle had not developed on the right. The patient had no renal, cardiac or skeletal anomalies and her hearing was normal. No previous publications have been located which report the association of hypodontia and hemifacial microsomia.


Autoradiographic localization of endothelin-1 binding sites in human colonic cancer tissue.

Endothelin-1, a potent vasoconstrictor, has been reported to stimulate mitogenesis in various types of normal and neoplastic cells and to be involved in neurotransmission. Recently, many human cancer cell lines, including those from the human colon, have been shown to produce endothelin. In this study, the occurrence of endothelin-1 binding sites was investigated in human colonic cancer tissues using in vitro autoradiography. Specific [125I]endothelin-1 binding sites were identified over tumour vessels and stromal tissues surrounding cancer cell nests. The distribution was heterogeneous, and dense silver grains were localized, especially over clusters of fibroblasts adjacent to the cancer cell nests. Endothelin binding was minimal in the cancer cells, as in the normal crypt epithelium. Quantitative analysis of the autoradiographs demonstrated high affinity (Kd = 0.50 +/- 0.06 nM; mean +/- SEM) binding sites, with a maximum binding capacity (Bmax) of 40 +/- 3.2 amol/mm2 in the cancer tissues. Our results provide evidence that specific endothelin-1 binding sites are expressed in the stromal tissues including tumour vessels, fibroblasts, and nerve fibres. Endothelin-1 may play a modulatory role in blood supply, mitogenesis, and neurotransmission in a paracrine fashion through the stromal components in human colonic cancers.


Expression of the c-fos oncogene in chemically-induced mouse tumours and in human skin tumours.

Using a polyclonal antibody to fos oncoprotein and an immunofluorescent technique, we investigated expression of the fos oncogene in chemically-induced mouse tumours and human premalignant and malignant skin lesion. In the chemically induced tumours, the nuclei of almost all carcinoma cells stained uniformly with this antibody, while positive cells were observed in the outermost layers in the benign papillomas. In human tumours, a greater degree of nuclear staining was observed in cases of squamous cell carcinoma than in tissues from patients with Bowen's disease. Basal cell carcinoma and malignant melanoma with histological evidence of invasiveness of the tumour cells showed a higher expression of the fos gene product than that seen in histologically circumscribed tumour nests. Thus, a higher expression of the fos oncogene is closely related to the malignant progression of tumour cells, in particular, the extent of invasiveness.


L-CAM expression in normal, premalignant, and malignant colon mucosa.

L-CAM is a cell adhesion molecule which is expressed at the intercellular borders of most epithelial cells. L-CAM has been demonstrated to act as an invasion suppressor in carcinoma cell lines. In order to determine whether or not L-CAM expression might distinguish between invasive and non-invasive or metastatic and non-metastatic colon neoplasms, we studied L-CAM expression in normal colon mucosa, colon adenomas with various degrees of dysplasia, and colon carcinomas by immunohistochemistry, using the 6F9 monoclonal anti-L-CAM antibody. Normal mucosa showed evenly distributed distinct L-CAM immunoreactivity along intercellular borders. In adenomas and carcinomas, a similar though weaker expression was observed. This pattern showed a tendency to decrease in parallel with decreasing differentiation. However, no correlation was found with Dukes stage or area within the tumour. In some carcinomas, L-CAM was expressed at the luminal surface of the cells. In others, L-CAM expression was not found. These results suggest that L-CAM expression is disregulated or lost as an early event in the development of colon neoplasia and indicate that L-CAM expression does not correlate with invasive or metastatic potential.


Histological preservation after in situ hybridization to archival solid tumour sections allows discrimination of cells bearing numerical chromosome changes.

In this study, non-isotopic in situ hybridization (ISH) was used for the cytogenetic and histological examination of urological (prostatic adenocarcinoma) and endocrine (phaeochromocytoma) tumour cell nuclei in 4 microns paraffin-embedded tissue sections. In order to investigate preservation of tissue morphology, standard heat denaturation was compared with a mild enzymatic treatment for the production of single-stranded (ss)-DNA for ISH. Numerical analysis by ISH with chromosome-specific repetitive DNA probes for chromosomes 1, 7, and 11 revealed overrepresentation of chromosome 7 in the phaeochromocytoma (P < 0.01). The constitutional underrepresentation of the Y chromosome was easily detected in the prostate tumour (P << 0.01) when probed for chromosomes 7, 16, and Y. The enzymatic treatment appeared superior to heat denaturation with respect to tissue architecture in the phaeochromocytoma, while no clear difference was observed in the prostatic cancer. ISH probe patterns were similar for the two types of denaturation in both tumours (P > or = 0.20). We conclude that (1) ISH can be used for the identification of numerical cytogenetic changes in solid tumour cell nuclei within archival tissue sections; and (2) mild 'denaturation' protocols, replacing heat, are preference in retaining tissue architecture in fragile tumour specimens.


Changes in hepatic lymph vessels in endotoxaemia.

This study was undertaken into rats to investigate changes in the hepatic lymph vessels and the space of Disse in endotoxaemia and to examine their relationship with the development of endotoxin-induced hepatic injury. Lymph stasis, namely dilatation of the lymph vessels and oedema, developed rapidly in the medium-sized portal canals, the large portal canals, and the liver hilum after endotoxin injection, but not in the small portal canals. Such changes reached their maximum 4-8 h after endotoxin injection and had recovered markedly by 16 h after the injection. The space of Disse remained within normal limits during this period. These findings suggest that the intrahepatic lymph stasis in endotoxaemia may be caused by a reduction in the pumping activity of the extrahepatic and the intrahepatic large lymph vessels rather than by an increase of lymph formation in the liver lobules. There was no evidence suggesting a direct relationship between the disturbance of hepatic lymph flow and the development of hepatic injury in endotoxaemia.


Effect of cholesterol on the position of segmental lesions in unilaterally nephrectomized rats.

Different positions of segmental lesions within glomeruli may correspond to different pathogenetic mechanisms. The effect of a high cholesterol diet on the position of lesions had not previously been investigated. This was studied in rats following unilateral nephrectomy, as a change in position would suggest a different mechanism of damage. Thirty-two female WAG/ola rats had unilateral nephrectomy. Half the rats were given a diet supplemented with 4 per cent cholesterol and 1 per cent cholic acid. At death, six at 10 weeks after nephrectomy and the rest at 24 weeks, kidney sections were examined microscopically. There were significantly more segmental lesions in the cholesterol-fed rats than in the controls, and these lesions were almost entirely at the glomerular hilum in both groups. Significantly more glomeruli contained foamy cells in the cholesterol-fed group, both within lesions and away from them. These findings confirmed that in reduced renal mass, segmental lesions are mainly hilar. The diet increases the number of glomeruli affected by lesions, but these are still mainly hilar. Therefore one possibility is that hypercholesterolaemia worsens the hyperfiltration effect on glomeruli. The diet also produces foamy cells scattered throughout the glomeruli but these do not appear to develop into segmental lesions.


Polycystic kidney disease in the CBA/N immunodeficient mouse.

We describe a polycystic lesion of the kidney in the CBA/N mouse with an X-linked recessive immunodeficient syndrome. There is progressive cystic dilatation affecting all parts of the nephron. The cyst lining is composed of a single layered epithelium with focal nuclear crowding and the formation of micropapillary structures. The cystic epithelial cells show subnuclear vacuolation. Focal basement membrane thickening is also a feature. There is no significant inflammatory infiltrate present within these kidneys. Electron microscopic examination reveals that the subnuclear vacuolation is due to loss of the membrane infoldings at the basal pole of the epithelial cell with fluid accumulation within the extracellular space. The basement membrane thickening is due to expansion of the lamina densa. These changes are not present at birth but develop progressively with age. The finding of a polycystic kidney lesion in these mice offers an opportunity to investigate the relationship between the immune system and renal cyst formation.


DNA cleavage photoinduced by new water-soluble zinc porphyrins linked to 9-methoxyellipticine.

Two hybrid molecules based on a water-soluble zinc porphyrin covalently linked to 9-methoxyellipticine, 1 and 2, were studied as photoactivable DNA cleavers. The behaviour and efficiency of these photosensitizers were compared with the constitutive units of the hybrid molecules: meso-tetrakis(4-N-methylpyridiniumyl)porphyrinato-zinc(II) tetraacetate (ZnTMPyP, 3) and 9-methoxy-N2methylellipticinium acetate (9-OMe-NME, 4). On irradiation at 436 nm, the efficiency of these hybrids is similar to that of ZnTMPyP and 50-fold greater than that of haematoporphyrin derivative (HPD). This photoinduced DNA cleavage is markedly reduced in the absence of oxygen and also depends on the DNA base pair to porphyrin ratio. It is inhibited by N-acetylhistidine and sodium azide, unaffected by mannitol and superoxide dismutase (SOD) and enhanced when changing H2O for D2O. The same scavenger effects are observed on irradiation at 514 nm. At 313 nm, the efficiency of hybrids 1 and 2 is intermediate between those of ZnTMPyP and 9-OMe-NME. In these conditions, a slight inhibitory effect of mannitol is observed, suggesting the participation of radicals probably derived from partial decomposition of the porphyrins. At these three wavelengths, singlet oxygen seems to be the main species responsible for DNA cleavage. In contrast with expectation, the great affinity of these molecules for DNA does not enhance their efficiency as DNA cleavers. This effect is discussed taking into account the long lifetime of singlet oxygen which may be generated far from the target. These molecules which are only photoactivable in the presence of DNA appear to be an efficient "molecular light switch".


Comparative pharmacokinetic and photodynamic studies with zinc(II) phthalocyanine in hamsters bearing an induced or transplanted rhabdomyosarcoma.

Comparative pharmacokinetic studies in hamsters bearing an induced or first-generation transplanted rhabdomyosarcoma that were injected with liposome-incorporated zinc(II) phthalocyanine (ZnPc) show a higher drug concentration in the induced tumour. The selectivity of tumour targeting is underlined by the fact that, 24 h after injection, larger amounts of ZnPc are found in the tumour than in the liver. Photodynamic therapy investigations were carried out using 673 nm light from an argon-dye laser. On the basis of different assessment criteria (changes in mean tumour diameter with time, tumour mass regression, survival time of the treated groups of animals, and histological determination of the necrotic tissue) the photosensitizing effect of ZnPc appears to be comparable for both kinds of tumour in spite of the higher uptake of photosensitizer by the induced tumour.


Evaluation of liquid or powdered fortification of human milk on growth and bone mineralization status of preterm infants.

Thirty-five preterm (< 1500 g) infants were fed preterm human milk (PHM) supplemented with either powdered fortifier (PF) or liquid supplement (LS). Bone mineral content (BMC) of the distal third radius was measured by photon absorptiometry. Biochemical indices of nutritional and bone status were obtained every 2 weeks. The initial BMC for both feeding regimens were similar. BMC did not change over the study period for infants fed LS. Infants fed PF had BMC values greater than LS infants at weeks 2 and 4 of study. Only infants fed PF had BMC values that demonstrated a consistent increase. Serum total protein and phosphorus values were greater for PF infants at week 4 than LS infants. Weight, length, occipital-frontal circumference (OFC) gains, serum albumin, alkaline phosphatase, calcium, and vitamin D levels were similar in both groups. We conclude that products used to "enrich" PHM are adequate to meet the growth needs of the preterm infant. However, we found that infants fed the powdered fortified preterm human milk had higher bone mineralization than those fed the liquid supplemented human milk.


Plasma vitamin E concentrations of older infants fed cow's milk or infant formula.

Nutrition of older infants, though important for optimal brain development, is inadequately studied. The beverage choice markedly influences nutrient intake, but little is known regarding nutrition status of older infants, particularly for vitamin E. This study assessed vitamin E intakes and plasma tocopherol concentrations in two groups of healthy infants, 8 to 13 months of age, who had consumed either cow's milk (n = 45) or milk-based formula (n = 55) for a minimum of the 3 preceding months. Mean (+/- SEM) vitamin E intake was significantly lower (p < or = 0.001) by the infants who had consumed cow's milk (CMF) than by infants who had consumed formula (FF); 4.1 +/- 0.25 mg/day and 10.9 +/- 0.57 mg/day, respectively. Mean (+/- SEM) intake of linoleic plus linolenic acids was significantly lower (p < or = 0.005) by CMF infants (3.4 +/- 0.2 g) than by FF infants (9.9 +/- 1.0 g), although mean (+/- SEM) dietary vitamin E to polyunsaturated fat ratio (E/PUFA ratio) was the same in both FF and CMF infants (1.3 +/- 0.1). Plasma alpha-tocopherol concentration (mean +/- SD) was significantly lower (p < or = 0.005) in CMF than in FF infants (0.86 +/- 0.28 mg/dl vs. 1.14 +/- 0.42 mg/dl, respectively). Dietary vitamin E intakes were positively correlated (p < or = 0.05) with plasma alpha-tocopherol concentrations. No correlations were found between plasma alpha-tocopherol concentrations and total fat intake, dietary E/PUFA ratios, erythrocyte polyunsaturated fatty acids > or = C18:2, or number of hours postprandial that blood was drawn.(ABSTRACT TRUNCATED AT 250 WORDS)


Production of short chain fatty acids by the intestinal microflora during the first 2 years of human life.

We have followed the establishment of one group of intestinal microflora-associated characteristics, namely, the production of short chain fatty acids (SCFAs), in 30 healthy children, by gas chromatography analysis of fecal samples taken at 0, 1, 3, 6, 9, 12, 15, 18, 21, and 24 months of age. Acetic and propionic acids were the principal SCFAs at 1 and 3 months. Successively, the production of iso- and n-butyric, valeric, and caproic acids was established. At 2 years, the absolute amounts of all SCFAs with the exception of n-valeric acid had reached adult values. However, not all children had achieved a typically adult range of stool SCFAs by the end of the study. Both absolute and relative amounts of SCFAs were influenced by exposure to foods other than breast milk and exposure to antibiotic therapy. After standardization for exposure to foods other than breast milk, a positive age factor could be seen between 0 and 1 month of age for total amounts produced of SCFAs, acetic, propionic, and n-butyric acids. After this time, however, no clear age factor could be distinguished.


Parasitic infection of the gut and protein-losing enteropathy.

Parasitic infection of the gut is highly prevalent in developing countries and contributes to the severe malnutrition associated with persistent diarrhoea in children. Using random faecal alpha 1-antitrypsin measurements as an index of protein-losing enteropathy, we examined children with and without parasitic infection of the gut. Seventeen percent of children with persistent diarrhoea had evidence of protein-losing enteropathy. This was found to be associated with hypoalbuminaemia in children infected with Strongyloides stercoralis. Only a minority (2 of 17) of children infected with Giardia lamblia had raised faecal alpha 1-antitrypsin excretion and this was not associated with hypoalbuminaemia. This study emphasises the need for rapid diagnosis and treatment of Strongyloides infection in children with persistent diarrhoea and severe nutrition.


Malabsorption of different lactose loads in children with human immunodeficiency virus infection.

Thirty children infected with human immunodeficiency virus (HIV) (18 P1 and 12 P2, according to the classification system of the Centers for Disease Control) and 54 noninfected children were evaluated for lactose malabsorption with use of the hydrogen breath test after different lactose loads. Lactose malabsorption after load of 2 g/kg occurred in 75% of P2, 67% of P1, and in 46% of noninfected children. With a lower lactose load (1 g/kg), the prevalence of malabsorption was significantly higher among P2 children than P1 and noninfected cases. A similar figure was obtained after the lowest load (0.5 g/kg). Infected children with lactose malabsorption were significantly younger than noninfected malabsorbers (mean age +/- SD; 50.3 +/- 22 vs. 63.5 +/- 20.9 months) when the load of 2 g/kg was used. The use of lower lactose loads seems to be helpful in finding the dose that can be tolerated. This finding could have nutritional importance and could lead to better dietary management.


Increased serum IL-2R levels in coeliac disease are related to CD4 but not CD8 antigens.

Forty-three coeliac children, ranging from 1 year and 3 months to 14 years and 9 months, were studied. Twenty-eight patients were in an active phase of the disease, and 15 were in remission. The criteria of coeliac disease (CD) activity were established according to the results of IgA anti-endomysial antibodies (IgA-AEm). Interleukin 2 receptor (IL-2R) and CD4 and CD8 antigens were measured in serum samples by an ELISA technique using two noncompetitive monoclonal antibodies. Antigliadin antibodies of IgG (IgG-AGA) and IgA (IgA-AGA) classes were also measured. The AEm-positive coeliac patient group showed values of 1,860 +/- 948 U/ml for IL-2R, 430 +/- 228 U/ml for CD8, and 36.8 +/- 25.1 U/ml for CD4. AEm-negative patients showed values of 980 +/- 436 U/ml, 350 +/- 243 U/ml, and 24.1 +/- 20 U/ml, respectively. IL-2R levels were the only ones significantly elevated (p < 0.005) in the active coeliac group. On the other hand, IgG-AGA and IgA-AGA were both clearly increased (p < 0.001). IL-2R levels in active coeliac patients correlated with CD4 levels (p < 0.05), but not with CD8, IgG-AGA, and IgA-AGA levels. We also found a surprising negative correlation between AEm antibodies of IgA2 class with both IL-2R (r = 0.471; p < 0.05) and CD8 (r = 0.616; p < 0.05). The results show that in CD there is a lymphocyte activation affecting mainly CD4+ cells and not correlated with serum AGA levels, suggesting an independence of both immunological phenomena and probably with different locations of origin.


Gastroesophageal reflux with drifting onset in infants: a phenomenon unique to sleep.

We have characterized the gastroesophageal reflux (GER) episodes which occurred during sleep in 28 infants with pathologic gastroesophageal reflux and 10 symptomatic age-matched controls without gastroesophageal reflux. We describe three kinds of episodes during the sleeping period-awake episodes which occur completely during electroencephalogram (EEG)-defined wakefulness associated with clinical evidence of the waking state (62 episodes), episodes occurring during EEG-defined sleep which have a rapid drop in pH at their onset (119 episodes), and episodes occurring during EEG-defined sleep in which the esophageal pH drifts down slowly over a period up to 30 min (113 episodes). Only 9 of the 10 control subjects experienced any reflux episodes during monitoring. The total number of episodes of reflux in controls (34) was less than the total number in reflux subjects (260). Controls did, however, experience all three types of reflux episode. Awake episodes all had a rapid drop in pH at their onset and were characterized by a short acid clearance time (2.0 +/- 0.3 min in reflux patients and 1.0 +/- 0.2 min in controls). The sleep episodes with rapid onset had longer mean acid clearance time than the awake episodes, significantly so in GER subjects (20.1 +/- 6.8 min in reflux subjects and 2.6 + 1.3 min in controls). Body movement was noted at the onset of 93.4% of rapid-onset sleep episodes in reflux subjects and 88.9% in controls. Body movement was also common at the termination of rapid-onset sleep episodes (77.8% of rapid-onset episodes in reflux subjects and 80.0% in controls).(ABSTRACT TRUNCATED AT 250 WORDS)


Esophageal stricture in children: fiber-optic endoscopy and dilatation under fluoroscopic control.

We made a retrospective analysis of the efficacy and complication rate of 268 esophageal dilatation procedures performed under fluoroscopic control using the fiber-optic endoscope in 45 children with esophageal stricture. Antegrade and retrograde stricture dilatation was performed under general anesthetic, mainly as an outpatient procedure. Thirty-six children had an esophageal stricture following tracheoesophageal fistula and/or esophageal atresia repair, and nine children had severe corrosive stricture of the esophagus following lye ingestion. The procedure was well tolerated and effective.


Phospholipid composition and subcellular distribution in yeast and mycelial forms of Candida albicans.

Lipids were found to constitute 3.9% and 4.7% of the dry weight of yeast and mycelial forms of Candida albicans, respectively. Phospholipids were localized mainly in the microsomal fraction of both growth forms and phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and cardiolipin were the major phospholipids. Myristic acid and palmitic acid were the predominant fatty acids in the yeast form while the mycelial form contained palmitic, palmitoleic and oleic acid as major fatty acids. Yeast forms showed significantly higher specific activities of intracellular phospholipase A and lysophospholipase when compared with mycelial forms. No significant difference in the specific activity of extracellular phospholipase A was seen in either morphogenic form while the activity of extracellular lysophospholipase was higher in the yeast form. These results are discussed in the context of the virulence of this fungus.


Activity of fluconazole against Candida albicans isolates from HIV+ patients in a digestive candidosis turkey model.

Fluconazole activity against four strains of Candida albicans (three isolates from AIDS patients and one azole-resistant isolate, NCPF 3363) was studied in a turkey crop infection model. Isolate NCPF 3363 showed confirmed azole resistance in vitro and in vivo. Two isolates from AIDS patients were susceptible to fluconazole in vitro and in vivo. The third isolate was resistant to fluconazole in vitro (MIC = 100 micrograms ml-1), insensitive to 2.5 mg kg-1 but sensitive in vivo to a 5 mg kg-1 daily dose.


Glucan synthesis and its inhibition by cilofungin in susceptible and resistant strains of Candida albicans.

The lipopeptide antimycotic agent, cilofungin, at a dose of 20 micrograms ml-1, inhibited beta 1-3 glucan synthesis in a drug-susceptible strain (3153; minimum inhibitory concentration (MIC) < 1 microgram ml-1) as well as in a drug-resistant strain of Candida albicans (CA-2, derived from 3153 by nitrosoguanidine mutagenesis; MIC > 50 micrograms ml-1). This was demonstrated for both whole cells under growing and non-growing conditions, and during protoplast regeneration. However, time-effect experiments, during growth of a CA-2 culture initially exposed to an inhibitory dose of cilofungin, showed that this strain was able to progressively regain both glucan synthesis and a growth rate comparable to that of cultures that had not been treated with the drug. This recovery was not attributable to cilofungin instability or degradation within the CA-2 culture. Our study suggests the existence of an as yet unknown drug-related and/or cell-related factor(s) modulating the inhibition of glucan synthesis, and then contributing to the actual inhibitory effects of cilofungin in C. albicans.


Comparison of amphotericin B lipid complex with amphotericin B and SCH 39304 in the treatment of murine coccidioidal meningitis.

To assess the efficacy of amphotericin B lipid complex (ABLC) in the treatment of coccidioidal meningitis, we compared a wide range of doses (0.35-15 mg kg-1, intravenously (IV)) of ABLC with amphotericin B deoxycholate (AmB) (0.3-7 mg kg-1, intraperitoneally (IP)) and (IV) and a new triazole, SCH 39304 (SCH), in an experimental murine model. Survival data showed high dose ABLC to be of equal efficacy to IV and high dose IP AmB and SCH. Quantitative studies confirmed this outcome. No acute toxicity with ABLC, at the doses employed, was found. We conclude that ABLC is effective in the treatment of murine coccidioidal meningitis.


Induction of stress protein synthesis in Histoplasma capsulatum by heat, low pH and hydrogen peroxide.

It is well known that some micro-organisms synthesize proteins when stressed by heat or other factors. The function of these proteins is not yet clear, but some of them are believed to be related to resistance against a hostile environment. Histoplasma capsulatum is an intracellular pathogenic fungus that multiplies inside macrophages and resists macrophage microbicidal mechanisms. To study the defense mechanisms of H. capsulatum and mimic the hostile environment the fungus may encounter during infection, we investigated protein synthesis by H. capsulatum (isolate G217B) when stressed by heat (40 degrees C), low pH (pH 4), or oxidative products (H2O2) using [35S]-methionine labelling. Analysis of cytosol proteins by SDS-PAGE and fluorography disclosed that H. capsulatum increased synthesis of six constitutive proteins and decreased synthesis of six proteins when stressed at 40 degrees C. When stressed by pH 4 or H2O2, H. capsulatum increased the synthesis of eight and five constitutive proteins, respectively, and decreased the synthesis of three proteins. Estimation of superoxide dismutase (SOD) and catalase enzymatic activity in cytosols from stressed H. capsulatum did not reveal an increase of these enzymatic activities compared to cytosols from non-stressed H. capsulatum. These results suggest that H. capsulatum increases the synthesis of some constitutive proteins when stressed by heat, low pH or H2O2, which might relate to pathogenicity, and are thus worthy of further study. These induced proteins are apparently different from SOD or catalase.


Isolation of Cryptococcus neoformans var. gattii from an Asian patient in France: evidence for dormant infection in healthy subjects.

We report the first case of cryptococcosis due to Cryptococcus neoformans var. gattii in France. This Cambodian, non-AIDS patient had been living in France for 23 years when he developed cryptococcosis due to C. neoformans serotype B in 1985. It is possible that he was infected back in Asia or several months before, in Zaire, where he lived between 1981 and 1984. To our knowledge, this is the second case providing clinical evidence for reactivation of latent infection with C. neoformans. The mechanism is probably similar to that for C. neoformans var. neoformans.


Primary cutaneous zygomycosis due to Absidia corymbifera in a patient with AIDS.

A case of primary cutaneous zygomycosis due to Absidia corymbifera in a patient with AIDS is described. The lesions, which were located on the forehead, jaw and chest, were intradermal, extending into the subcutaneous fat and did not appear to be associated with any trauma. No deep-seated infection was evident suggesting that the superficial lesions were exogenous in origin. The possible aetiology of this infection is discussed.


Filamentous forms of Sporothrix schenckii in material from human lesions.

This paper reports the observation of the mycelial form of Sporothrix schenckii, including conidia, in dried-up purulent material from a cutaneous lesion of the face of a patient with sporotrichosis of over a year's duration.


Environmental isolation of Cryptococcus neoformans var. gattii from Eucalyptus tereticornis.

As an extension of the previously established association between Cryptococcus neoformans var. gattii and Eucalyptus camaldulensis (River red gum) we have now found a similar relationship between C. neoformans var. gattii and the closely related Eucalyptus tereticornis (Forest red gum). The global distribution of E. tereticornis is similar to that of E. camaldulensis.


Dormancy of Trichophyton mentagrophytes arthroconidia.

Arthroconidia of Trichophyton mentagrophytes demonstrated an exogenous type of dormancy under environmental conditions unsuitable for germination, provided that these conditions were not lethal. Germination did not occur at 4 degrees C unless arthroconidia were shifted up to 37 degrees C. At 45 degrees C germination was inhibited even when arthroconidia were shifted down to 37 degrees C. Germination was dependent on humidified incubation conditions. The presence of human corneocytes enhanced the germination of arthroconidia in the presence of moisture.


Fetus in fetu in the liver: case report and review of the literature.

Fetus in fetu is an extremely rare cause of abdominal mass in infancy, which most likely arises from inclusion of monozygotic diaminiotic twin. This entity is distinguished from teratoma by the presence of vertebral axis with limb bud or any other appropriately situated bones or organs. It occurs predominantly in the upper retroperitoneum, less frequently in the pelvis and ileal mesentery. Unlikely sites of occurrence such as the cranial cavity and the scrotum have been reported. In the present case the sac that contains the fetus was found in the right lobe of the liver, a site which has not been reported before. To our knowledge, and as far as the available literature is concerned, we believe this is the first report of such a case.


Fetus in fetu or giant epignathus protruding from the mouth.

A huge and extremely organoid mass, protruding from the mouth of a newborn and causing respiratory embarrassment, was resected. It was difficult to make a clear distinction whether this mass was fetus in fetu or a highly organoid epignathus dealing with the findings obtained from its gross and histological examination of the mass.


Pilomatricoma: report of two cases in children.

Two children with pilomatricoma are reported. The characteristics of this benign tumor and general principles of treatment (surgical excision) are described.


Choristoma of the submandibular gland: a rare cause of cervical swelling.

A case of choristoma of the submandibular gland excised from a 4-week-old female infant is reported. The differential diagnosis is discussed and suggestions are made for the possible etiology of the lesion.


Pyriform sinus cyst and fistula in the newborn: the value of endoscopic cannulation.

A case of pyriform sinus cyst and fistula presenting in the neonatal period is described. Endoscopic cannulation of the fistula tract was used to confirm the diagnosis and to simplify the resection.


Hungry bone syndrome in a child following parathyroid surgery.

The rare hungry bone syndrome was encountered in a 15-year-old child after the removal of a parathyroid adenoma. Contrary to the hypocalcemias caused by the removal of all parathyroid glands or transient ischemia after parathyroid surgery, in which the serum inorganic phosphorus level is usually normal, both serum calcium and inorganic phosphorus levels are decreased in hungry bone syndrome in the early postoperative period. Vigorous calcium supplementation and vitamin D are required for prolonged periods.


Giant cystic hygroma associated with venous aneurysm.

Complete excision of giant cystic hygroma requires meticulous dissection of the multilocular lymphatic cysts from the adjacent vascular and neural structures. The association of venous aneurysms with cystic hygroma is extremely rare. We report two infants with cystic hygroma in whom preoperative diagnosis of venous aneurysm was helpful in planning complete excision of the lymphatic lesions.


Kasabach-Merritt syndrome in two neonates.

Two neonates with a giant hemangioma associated with thrombocytopenia (Kasabach-Marritt syndrome) have been managed at Kure National Hospital. The first case was initially difficult to distinguish from overwhelming infection or other tumors but improved after radiotherapy. The second case was resistant to radiation and steroid therapy. Magnetic resonance imaging determined a tumor extending into the surrounding soft tissues better than did enhanced computed tomography. Subtotal excision of the tumor and various drugs were effective only transiently and 51Cr-labeled platelets sequestrated into the residual hemangioma. Severe thrombocytopenia persisted for approximately 15 months requiring extra care for head and body contusions, but finally improved by treatment with platelet-active drugs such as acetylsalicylic acid, dipyridamole, and pentoxifylline.


Primary neonatal cricopharyngeal achalasia: a case report and review of the literature.

Primary cricopharyngeal achalasia is a rare cause of dysphagia in the pediatric population. In a review of the literature, only 11 well-documented cases were discovered. We report the case of a newborn with cricopharyngeal achalasia who was successfully treated with a myotomy of the upper esophageal sphincter. A review of the literature is presented and treatment options are discussed.


Aerocele, an unusual complication of anterior cricoid split.

Since its introduction, the anterior cricoid split has proven to be a safe and effective procedure for the management of infants with acquired subglottic stenosis. In this article we report an unusual complication--an aerocele, which occurred on the 14th day following an anterior cricoid split on a 9-month-old child. The possible etiology and successful management of the aerocele are reviewed.


Chordoma presenting as a posterior mediastinal mass in a pediatric patient.

Chordomas are slow-growing malignant tumors that arise from fetal notochord cells. They are commonly found at the cranial or caudal ends of the spinal cord, but can be seen infrequently in other areas of the cord. Thoracic chordomas can present as either a posterior mediastinal mass or with cord compression symptoms. The tumors present most frequently in the 4th to 5th decade of life. It is extremely rare to see thoracic chordoma in a child. The treatment of choice for chordomas is surgery. The tumors should be totally excised when possible. If the tumor is large or invasive, debulking is indicated. Adjuvant therapy is controversial. Chordomas are very resistant to radiotherapy but there have been several reports of increased survival with high-dose radiotherapy (7,500 rad). Chemotherapy is unproven in the treatment of chordomas. Chordomas tend to recur locally quite frequently and occasionally with distant metastases. Survival ranges from 10% to 30% at 5 years.


Life-threatening respiratory distress caused by a mediastinal teratoma in a newborn.

Mediastinal teratomas rarely cause symptoms in newborns. Case reports drawing attention to this presentation have appeared in the literature. A 2-day-old baby with respiratory distress treated by intubation and mechanical ventilation underwent an urgent thoracotomy to alleviate tracheal compression that was caused by a teratoma. The clinical, radiological, and surgical features related to this case are reported.


An expandable prosthesis for stabilization of the infant mediastinum following pneumonectomy.

One possible complication in infant pneumonectomy is mediastinal shift that can fatally kink or compress airways and vessels. Rigid prostheses have been used to prevent these problems; however, they cannot be adjusted as the child grows. We report a case of expandable prosthesis implantation in a 24-day-old infant. During the 18 months postimplantation, the prosthesis was periodically injected with a saline/contrast solution to maintain the mediastinum in a midline position as the child grew. At 24-month follow-up the prosthesis was still in place, and midline position of the mediastinum maintained.


Traumatic pneumatocele.

Traumatic pneumatocele is a recognized but uncommon complication of blunt thoracic trauma. Its clinical relevance lies in the difficulty the attending surgeon encounters in differentiating the x-ray appearances from more serious pathology requiring urgent surgical intervention. We document this case because it is important that surgeons be aware of this condition and of its benign course so as to avoid unnecessary diagnostic or operative procedures.


Fibrothorax associated with a ventriculopleural shunt in a hydrocephalic child.

Ventriculopleural (VPL) shunts are considered a safe alternative to peritoneal shunts in the management of hydrocephalus. Occasionally, however, they are associated with persistent pleural effusion. We report a child, aged 3 1/2 years, who developed severe fibrothorax following the use of a VPL shunt. The shunt was removed and decortication had to be performed to alleviate his respiratory symptoms. This serious complication, never reported previously, should be borne in mind when the pleural cavity is chosen for deviation of the cerebrospinal fluid in hydrocephalic children.


Esophageal atresia with triple congenital tracheoesophageal fistulae.

The surgical management of an infant with esophageal atresia and three (2 proximal and 1 distal) congenital tracheoesophageal fistulae is described. The pitfalls in the diagnosis of proximal fistulae are discussed.


Delayed primary reconstruction of an esophageal atresia with distal esophagotracheal fistula in an infant weighing less than 500 g.

Delayed primary reconstruction of an esophageal atresia (Vogt IIIb) was undertaken in an extremely small-for-date baby (second twin, 36th week) with a birth weight of 445 g. After initial insertion of a gastrostomy under local anesthesia on the 29th day of life, ligation of the fistula and end-to-end anastomosis were performed by transpleural access (weight then, 535 g). There were no complications related to the operative procedure. The baby weighed 1,600 g at the age of 8 months.


Pneumatic perforation of the esophagus in children.

The excessive pressure in a carbonated beverage-containing plastic bottle, released by the teeth of an 11-year old boy, caused perforation of his lower pharynx. The possible mechanism is discussed.


Pyloric stenosis in a premature infant.

Workup of a case of hypertrophic pyloric stenosis in a premature infant showed absence of ultrasonic criteria for diagnosis. Transpyloric intubation for enteral feeding may delay the diagnosis of this disorder and has been thought to play a role in its development.


Prolapsed hyperplastic gastric polyp causing gastric outlet obstruction, hypergastrinemia, and hematemesis in an infant.

An infant presented with hematemesis and gastric outlet obstruction. Preoperative diagnosis of duodenal duplication cyst was based on a collaboration of radiological studies. At exploration the patient was found to have a gastric polyp that had intussuscepted into the duodenum leading to obstruction and hypergastrinemia secondary to gastric mucosa in the duodenal alkaline environment.


Heterotopic gastric mucosa and pancreatic tissue in the skin of the abdominal wall.

A lesion in the upper abdominal wall of a 10-year-old boy had been excised twice at the age of 3 years at another hospital but the lesion recurred shortly thereafter. We completely excised this lesion and histological examination showed the presence of heterotopic gastric mucosa and pancreatic tissue in the skin of the abdominal wall.


Mercury absorption following button battery ingestion.

A case of button battery ingestion with resulting disintegration of the battery, mercury spillage, and absorption of elemental mercury from the colon is reported. In the light of this case and other recorded complications following button battery ingestion, a plan of management is suggested.


Traumatic chylous ascites: conservative management.

Traumatic chylous ascites is very rare. In the majority of cases, the diagnosis is made by laparotomy. The case of a 5-year-old girl with traumatic chylous ascites is presented. The authors give their experience in nonoperative management.


Primary (retractile) mesenteritis in a child.

We report a case of primary retractile mesenteritis presenting as acute abdominal pain requiring surgery in a 3-year-old boy. At laparotomy, a hemoperitoneum was discovered and the diagnosis of primary mesenteritis was made with the aid of frozen section biopsy of the small bowel mesentery. No resection was necessary, and he made an uneventful recovery and remains well on follow-up.


Late fatal hemorrhage in pediatric liver trauma.

The cumulative evidence supports nonoperative management of hepatic trauma in children who are hemodynamically stable and who require less than 50% blood volume replacement to maintain a stable blood count. This management approach, based on the use of either serial computed tomography scans, liver/spleen scans, or ultrasonography to diagnose the injury and document resolution, achieves results that exceed those of operative management for all injuries. Late complications, which may be seen in nonoperated patients, include hemobilia, bile peritonitis, abscesses and bleeding, occur with less frequency than operated patients. We report the first case of late exsanguinating hemorrhage of a resolving hepatic injury.


Inflammatory pseudotumor of the liver in children: report of cases and review of the literature.

Two pediatric cases of inflammatory pseudotumor of liver were reported and compared with seven previously reported cases. Clinical presentation was variable but often consisted of fever and vague abdominal symptoms. These two cases were considered to be clinically malignant because angiographically one showed hypervascularity and the other showed the portal vein draining into the lesion to be occluded. There are four previous reports of similar cases complicated with occlusive phlebitis within and around the lesion. All but two of the reported cases underwent major hepatectomy or liver transplantation. However, because of the benign nature of the lesion, the treatment might be more conservative after adequate diagnostic procedures, including needle biopsy, are applied.


Isolated hepatic granuloma mimicking congenital simple cyst of the liver possibly caused by tuberculosis.

A case of hepatic granuloma resembling a simple cystic lesion of the liver in computed tomography with clinical manifestation of erythema nodosum is presented. The causes of hepatic granulomas and the importance of liver biopsy or exploratory laparotomy in their diagnosis are discussed with a review of the literature.


An unusual case of choledochal cyst causing hepatic failure requiring orthotopic liver transplantation.

The authors describe a case of orthotopic liver transplantation (OLT) in a patient with an infantile form of choledochal cyst that progressed to severe hepatic failure. Choledochal cyst must be included in the differential diagnosis of extrahepatic biliary obstruction in infants; it represents an additional reason to consider early exploratory laparotomy, both for diagnosis and to perform definitive excision. In the event that end-stage liver disease develops, OLT should be considered.


Septate gallbladder with cholelithiasis: a cause of chronic abdominal pain in a 6-year-old child.

This report describes the case of a 6-year-old girl with septate gallbladder and cholelithiasis without cholecystitis, an uncommon condition associated with chronic abdominal pain. The absence of smooth muscle components within the gallbladder septae supports an embryogenic abnormality that may have occurred early during the maturation of the gallbladder lumen. In concert with other predisposing factors, the septa may have induced gallstones and, thus, the patient's symptoms. Although rare, gallbladder abnormalities may cause abdominal pain in children and should be included in the differential diagnosis. Early ultrasound should be obtained as part of a workup if gallbladder abnormalities are suspected. Elective cholecystectomy is curative.


Discordance for anomalous pancreaticobiliary ductal junction and congenital biliary dilatation in a set of monozygotic twins.

A pair of monozygotic twins, 2-year-old Japanese girls, discordant for both anomalous pancreaticobiliary ductal junction and congenital biliary dilatation, are reported. The pathogenesis of the disease is discussed in relation to the occurrence of discordant monozygotic twins.


Simultaneous correction of biliary atresia and small bowel atresia in the neonate.

The coexistence of biliary atresia and small bowel atresia has been described. However, attempts to correct the biliary atresia at the same time as small bowel atresia repair have not been detailed. In 1986, a 2,170-g female was delivered at 36 weeks' gestation. Postpartum, duodenal obstruction was suspected after oral feedings were not tolerated. At 37 hours after birth, laparotomy showed unsuspected biliary atresia in addition to intestinal malrotation, duodenal web, and type IIIb jejunal atresia with an apple-peel configuration of the upper jejunum and mesentery supplied by the superior mesenteric artery with normal small bowel length and normal ileal mesentery. A modified Roux-en-Y hepatic portoenterostomy was performed using the blind end of the apple-peel configuration of jejunum, with a side-to-side duodenojejunostomy 25 cm from the portoenterostomy. Microscopic examination of the fibrous extrahepatic biliary tissue showed a disarray of small bile ductules. The maximal ductal size at the portoenterostomy site was 600 microns. A liver biopsy specimen showed normal architecture with eosinophils infiltrating the portal triads and periductal areas. Postoperatively, she has maintained normal growth and development with no episodes of cholangitis. Liver biopsies at 1 year and 3 years were normal. At 4 years, total and conjugated bilirubin, serum proteins, liver enzymes, coagulation factors, and trace elements were normal. We conclude that simultaneous correction of biliary atresia and small bowel atresia can be accomplished in the neonate with excellent early results.


Cystadenoma of the pancreas in a newborn.

Cystadenoma of the pancreas is a rare entity. In the pediatric population, three cases have been reported. We present a case of cystadenoma of the pancreas in a newborn. The tumor involved the head and body of the pancreas. Subtotal pancreatectomy with preservation of the duodenum, common bile duct, and pancreatic tail was performed.


Pancreatoblastoma resected by delayed primary operation after effective chemotherapy.

A case of pancreatoblastoma resected successfully after effective chemotherapy is discussed. Preoperative chemotherapy may be useful in patients with advanced unresectable pancreatoblastoma to permit complete resection of the tumor.


Intrapancreatic duodenal duplication associated with pancreatic pseudocysts.

A rare case of intrapancreatic duodenal duplication causing pancreatitis is reported. At 2 years of age, the patient presented with a recurrent pancreatic pseudocyst. Intraoperative pancreatogram showed the presence of cystic duodenal duplication in the aberrant lobe of the pancreas communication with the pancreatic duct. Since the resection of the duplication, she has been free from recurrence of pancreatitis. In this case, intraoperative pancreatography was of great value.


Obstructive jaundice associated with polysplenia syndrome in an older child.

Polysplenia syndrome includes malrotation and various forms of heterotaxy. Associated with this and malrotation are extrahepatic biliary anomalies. Actual obstruction, other than in associated biliary atresia, is extremely rare, and rarer still in older children. An 11-year-old girl presented with obstructive jaundice, malrotation, and heterotaxy, which were found in association with common bile duct anomalies and intermittent common bile duct obstruction. This case illustrates that the differential diagnosis of obstructive jaundice, even in older children, should include congenital anomalies, and that biliary anomalies should be considered in cases of malrotation and heterotaxy.


Conservative management of splenic abscesses in children.

Splenic abscesses are rare in children. The recommended treatment for this entity has been a combination of total splenectomy and appropriate antibiotic therapy. We report on the successful conservative management of two children with splenic abscesses. The patients were a girl with a single splenic abscess and a boy with multiple splenic lesions. Both were managed by parenteral antibiotic therapy followed by oral chemotherapy. Regression of the lesions was documented by repeated abdominal ultrasonographic examinations. Considering the good outcome of these patients and the importance of splenic preservation in children, we propose that management of children with single or multiple splenic abscesses should begin by a course of vigorous antibiotic therapy, reserving more aggressive surgical procedures for those who do not respond to conservative treatment or have clinical deterioration.


Primary tubercular abscess of the spleen.

A 12-year-old boy with localized tubercular abscess of the spleen is presented. The diagnosis was established on histopathologic examination. Treatment consisted of splenectomy and postoperative antitubercular therapy.


Endoscopic laser resection of a duodenal membrane.

This report documents the first resection of a duodenal membrane by laser. Subsequently, however, a laparotomy was required because of an annular pancreas. Nevertheless, it demonstrates that the laser endoscopical resection of a duodenal membrane is technically feasible.


Partial situs inversus: duodenal obstruction in a neonate with isolated levocardia.

An unusual case of duodenal obstruction in an infant with isolated levocardia is described. The following anatomic features were shown preoperatively: (1) duodenal obstruction; (2) right-sided stomach and spleen; (3) left-sided liver; (4) totally right-sided located colon in mirror image nonrotation; and (5) levocardia without any defect or dysfunction. The mentioned findings were verified intraoperatively and the cause of the duodenal obstruction was found to be an aberrant vessel. This case is a rare one regarding the lack of heart and spleen defects and the cause of duodenal obstruction. It also demonstrates the necessity of meticulous investigation and precise description of the anomaly and suggests individualization as far as the management of these cases is concerned.


Retroperitoneal jejunal diverticulum: cause of intestinal obstruction.

A 3-week-old boy presented with repeated episodes of vomiting and constipation. At laparotomy a jejunal diverticulum arising from its antimesenteric border and extending retroperitoneally was found. The narrow neck of diverticulum caused a situation similar to a Richter's hernia. The fundus of diverticulum was attached to the upper pole of left kidney. A retroperitoneal jejunal diverticulum is a new addition to the cause of neonatal intestinal obstruction.


Giant Meckel's diverticulum.

A case of incomplete intestinal obstruction caused by a giant Meckel's diverticulum in a 13-year-old girl is reported. Short resection of the ileum with the diverticulum and end-to-end anastomosis was carried out. The possibilities of diagnosis and treatment as well as the controversial classification of this rare congenital anomaly are discussed.


Chronic intussusception associated with Yersinia enterocolitica mesenteric adenitis.

An unusual case of chronic intussusception, without any digestive sign, secondary to mesenteric lymphadenitis caused by Yersinia enterocolitica is reported. Operative reduction by taxis was performed but ileopexy and antibiotic treatment were also carried out to reduce chances of recurrent intussusception.


Brown bowel syndrome: a late complication of intestinal atresia.

Two children, aged 11 years, who originally had jejunal atresia corrected in the neonatal period, developed massive dilatation of the proximal small intestine. This resulted in circular muscular hypertrophy with lipofuscin deposits giving the typical appearance of "brown bowel." The condition was associated with malnutrition and vitamin E deficiency. Because of relatively short bowel, the condition was treated by limited resection and extensive tapering of the dilated segment, end-to-end reanastomosis, vitamin E supplementation, and intensive nutritional support.


Association of Hirschsprung's disease and Müllerian inhibiting substance deficiency.

An infant who presented with Hirschsprung's disease was found to also have the clinical features of persistent Müllerian duct syndrome and on testing to have Müllerian inhibiting substance deficiency. This association has not been previously reported. While this may be a coincidence, recent reports indicate intersex conditions can be associated with Hirschsprung's disease.


Anorectal anomalies associated with Kabuki make-up syndrome.

A case report of a 3-year-old girl with Kabuki make-up syndrome (KMS) associated with anovestibular fistula is presented. To our knowledge, 62 patients with KMS have been reported in the literature, three of whom were described as having an anorectal anomaly. Including the present patient, all four KMS patients were females with anovestibular fistula.


Heterotopic hindgut duplication: a cloacal remnant associated with exstrophy of the bladder.

Lower hindgut duplications, although very rare, usually present as a cystic mass located posterior to the rectum and confined to the pelvis. Hindgut duplications are often associated with genitourinary or spinal anomalies. We describe a neonate with a previously unreported heterotopic colonic duplication presenting as an exophytic perineal mass associated with classic bladder exstrophy. The embryonic significance of these anomalies is discussed.


Neuroblastoma masquerading as a retroperitoneal Salmonella abscess.

Symptomatic Salmonella infections usually manifest as self-limited gastrointestinal distress. Patients with chronic systemic illnesses or those who are immunosuppressed may rarely present with Salmonella infection as distant suppurative abscesses. We present a previously healthy Armenian boy who came to medical attention with abdominal pain, fever, and anemia. Abdominal computed tomography (CT) scan showed a cystic suprarenal mass that was surgically explored and found to be a retroperitoneal Salmonella abscess. Postoperative CT scan showed resolving inflammation. A 6-month follow-up CT showed a large suprarenal tumor, which at exploration was found to be neuroblastoma. To our knowledge, Salmonella has never been reported presenting as a solitary retroperitoneal abscess, and neuroblastoma has not been described presenting as a Salmonella abscess. The patient is also unusual because the abscess contained a species unusual for suppurative salmonellosis.


Locally invasive aspergillosis of the bowel.

Locally invasive aspergillosis of the bowel and peritoneal cavity is a rare complication of immunosuppression, broad-spectrum antibiotic therapy, and corticosteroid administration. We present the case of a 9-year-old boy with acute lymphocytic leukemia who presented with a small bowel obstruction. Surgical treatment of the aspergillosis required multiple aggressive resections of all involved bowel segments. Parenteral nutrition and intravenous Amphotericin B and 5-Fluorocytosine therapy were also instituted. Achievement of a hematologic remission is another prerequisite for cure.


Intrauterine perineal tear: a rare birth injury.

A rare case of birth injury having intrauterine complete perineal tear is presented. Defunctioning sigmoid colostomy was undertaken because of bad perineal condition. The baby died of Pseudomonas septicemia on the 15th day before definitive surgical procedure could be undertaken.


Perinatal ovarian cyst: a nonsurgical approach.

A case of an ovarian cyst diagnosed antenatally by ultrasound and showing spontaneous resolution within 5 months after birth is presented. On the basis of this case and others reported in the literature, we recommend expectant follow-up of such lesions with operation recommended only for cysts with solid or complex components or cysts causing symptoms from large size or torsion.


Agenesis of posterior urethra in a male child and its operative reconstruction.

An 8-year-old boy passing urine through both fecal and urinary outlets since birth is reported. Investigations showed absence of the posterior urethra. A surgical procedure for reconstruction of the posterior urethra is described. The embryological explanation is also discussed.


Identity style and coping strategies.

This study examined the relationship between identity style and strategies used to cope with stressors that potentially threaten one's sense of identity. Identity style refers to differences in the way individuals construct and revise or maintain their sense of identity. An informational style involves actively seeking out, evaluating, and utilizing self-relevant information. A normative style highlights the expectations and standards of significant others. A diffuse/avoidant style is characterized by procrastination and situation-specific reactions. Late-adolescent college subjects were administered measures of identity style, ways of coping with academic stressors, and test anxiety. Within this self-as-student context, subjects with diffuse and normative identity styles employed avoidant-oriented coping strategies (wishful thinking, distancing, and tension reduction). An informational style was associated with deliberate, problem-focused coping. Findings are discussed in terms of a process model of identity development.


The impact of self-presentations on self-beliefs: effects of social identity and self-presentational context.

To examine the impact of self-presentations on private self-appraisals, subjects were induced to characterize themselves positively or negatively during a face-to-face interview, during a written interview, or on a private questionnaire. As hypothesized, subjects high in Social Identity (the tendency to root identity in social sources of experience) shifted their self-appraisals in the direction of their positive or negative role after a face-to-face interaction, but were less affected by role in their private self-characterizations. In contrast, subjects low in Social Identity were primarily affected by a private, positive self-characterization. The latter subjects were not indifferent to how they appeared to others, as indicated by their attempts to rationalize negative, face-to-face self-presentations; they simply did not define themselves in terms of their public appearance.


[Enzymes involved in metabolic activation of carcinogenic chemicals and their hormonal regulation].

Mechanisms of metabolic activation of carcinogenic chemicals, especially arylamines, are discussed together with characteristics of enzymes involved in the activation in the liver and extrahepatic tissues. In rodents, drug and carcinogen metabolizing activities often show clear age- and sex-related differences and also vary in diseased states. The current understanding of the roles of pituitary growth hormone and thyroid hormone on changes of hepatic drug metabolizing enzymes is shown in relation to the developmental changes and alteration in patho-physiological conditions.


[Synthesis of new antirusty disinfectants. I].

New quaternary ammonium salts [N-alkyl-N-2-hydroxyethyl-N,N-dimethylammonium ethyl phosphate (21, 22), isopropyl phosphate (23), n-butyl phosphate (24) and N-alkyl-N-2-hydroxy-3-phenoxypropyl-N,N-dimethylammonium ethyl phosphate (25, 26), isopropyl phosphate (27), n-butyl phosphate (28) and bis(N-alkyl-N-2-hydroxy-3-phenoxypropyl-N,N-dimethylammonium) malate (29), fumarate (30), succinate (31), adipate (32) and N-alkyl-N-2-hydroxy-3-phenoxypropyl-N,N-dimethylammonium tartrate (33)] were synthesized by alkylation of the corresponding trialkylammonium salts with various epoxy compounds. The new quaternary ammonium salts showed much greater bactericidal activities and antirusting effects than those of benzalkonium chloride. They had also good compatibilities since no precipitate was observed if the solution of any anionic surface active agents were added to the solution of these new quaternary ammonium salts. This property is the same as that of amphoteric surface active agents.


[Synthesis and antimicrobial properties of 3-O-alkyl and 3-O-haloalkyl-D-glucoses].

A series of 3-O-alkyl and 3-O-haloalkyl-D-glucoses were prepared from 1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose and their antibacterial activities were evaluated. The compounds with C12 and C14-alkyl chains were the most effective in vitro antibacterial screening, among 3-O-alkyl and 3-O-haloalkyl derivatives. The 3-O-alkyl derivatives were more effective than 3-O-haloalkyl derivatives.


[Studies on as-triazine derivatives. XVIII. Synthesis of 5,6-diaryl-1,2,4-triazine derivatives as blood platelet aggregation inhibitors].

5,6-Diphenyl-, 3,5-diphenyl-, and 3,6-diphenyl-1,2,4-triazine (as-triazine) derivatives were evaluated for inhibitory activity towards arachidonic acid-induced aggregation of rabbit blood platelet in vitro. Among the isomers, 5,6-diphenyl-as-triazine derivatives were active, therefore a phenyl substituent on the as-triazine ring at the 5- and 6-position was essential for the inhibitory activity. Thus, various 3-substituted 5,6-diaryl-as-triazines were synthesized by the nucleophilic substitution reaction of 5,6-diaryl-3-methylsulfonyl-as-triazines with O,N,C-nucleophiles. In the case of as-triazines having different aryl groups at the 5- and 6-positions, the compounds were prepared by the step-wise addition reaction of Grignard reagents with 3-methylthio-as-triazine. Among these compounds, ethyl 5-(4-methoxyphenyl)-6-phenyl-as-triazine-3-acetate (24a) and ethyl 5,6-bis(4-methoxyphenyl)-as-triazine-3-acetate (24f) showed the most potent inhibitory activity, which was almost equal to the activity of anitrazafen.


[Transport of drugs through human erythrocyte membrane. Structure-activity relationship of benzoic acid and its derivatives between membrane transport and partition coefficient].

The transport properties of benzoic acid and its eighteen derivatives such as o-, m- or p-hydroxybenzoic acid (o-, m- or p-HBA), aminobenzoic acid (o-, m- or p-ABA), toluic acid (o-, m- or p-TA), fluorobenzoic acid (o-, m- or p-FBA), chlorobenzoic acid (o-, m- or p-CBA) and bromobenzoic acid (o-, m- or p-BBA) through human erythrocyte membranes were examined. The drugs having a hydrophilic ortho-substituent and those having a hydrophobic meta- or para-substituent showed higher transport. The ratio of free drugs in erythrocytes, fuR, did not relate to the partition coefficient (P). However, fuM (the ratio of free drugs in the plasma) and Kp (the ratio of partition between erythrocytes and plasma) related to the P: fuM = -0.3128 x log P + 0.9727 (R2 = 0.8722***), Kp = -0.2558 x log P + 0.8642 (R2 = 0.8413***). In p-nitrophenol-glycosides, the fuM and the Kp that were predicted from these equations were compatible with the experimental results. It was suggested from these results that the fuM and the Kp may be predictable from the P.


[Behaviors of crystalline waters of (RS)-7-(2-aminomethylmorpholino)-1- cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid].

Physicochemical characteristics of crystalline water of (RS)-7-(2-aminomethylmorpholino)-1-cyclopropyl-6,8-difluoro-1,4-di hydro-4-oxo-3-quinoline-carboxylic acid were studied by thermal analyses and powder X-ray diffractometry. The dihydrate of the compound was stable under ambient or humidified conditions. The dihydrate converted to a monohydrate on drying under mild conditions. The mono- and dihydrates transformed into alpha-type anhydrate at 110 degrees C. These three kinds of crystals were convertible each other under appropriate conditions. At 165 degrees C, the hydrates and the alpha-anhydrate converted to beta-type anhydrate. The compressed effects on the crystalline waters were also discussed for the dihydrate by kinetic analyses.


[The effect of stationary time of punch in the process of compression on dividing properties of scored tablets].

The significance of the stationary time of punch in the process of compression on the dividing properties of scored tablets was investigated in several tablets prepared from lactose, corn starch, hydroxypropyl starch, synthetic aluminum silicate, microcrystalline cellulose or Perfiller. The dividing strength of scored tablets was not affected by the stationary time of punch. The effect of the stationary time of punch on the coefficient of variation of divided tablet weight differed in the compacting characteristics and compaction profiles of powders. In case of tablets prepared from microcrystalline cellulose, the effect of stationary time of punch was not observed. However, in the other excipients, there existed a specific stationary time of punch to minimize the coefficient of variation of divided tablet weight. The time was different due to the change of compression pressure. The coefficient of variation of divided tablet weight showed minimum at the longer stationary time of punch when tablets were compressed at the low compression pressure, and the time showed a tendency to become short with the increase of compression pressure. These results suggested that the effect of the stationary time of punch on the coefficient of variation of divided tablet weight was concerned with the compaction structure of powders produced by the movement of punch in the process of compression.


[Micellar formation and micellar structure of poly(oxyethylene)-hydrogenated castor oil].

The effects of the oxyethylene chain length of poly(oxyethylene) hydrogenated castor oil (HCOn) on the micellar formation and on the micellar structure were investigated. Some physicochemical properties of HCOn (critical micelle concentration cmc, surface tension at cmc, free energy of micellization, and surface excess) concerning surface-activity were measured. These physicochemical properties were little affected by the oxyethylene chain length of HCOn. In addition, several physical techniques have been used to study the micellar structure of HCOn. It was found that HCOn micelles were spherical or nearly spherical, and that an increase in the oxyethylene chain length led to an increase in the looseness of HCOn micelle.


[Synthesis of 6-alkylaminopyridazine-3-carboxylic acid derivatives as dopamine beta-hydroxylase inhibitors].

A series of 6-alkylaminopyridazine-3-carboxylic acid derivatives was tested for dopamine beta-hydroxylase inhibitory activity in vitro according to the method of Kruse et al. Methyl 6-alkylaminopyridazine-3-carboxylates (4) were synthesized through the reaction of methyl 6-chloropyridazine-3-carboxylate (1) with ammonia followed by the condensation with primary amines, and by the methanolysis of the resulting 6-alkylaminopyridazine-3-carboxamides (3) in methanol in the presence of boron trifluoride etherate. Among tested compounds, 6-benzylaminopyridazine-3-carboxylic acid was found to have the most potent inhibitory activity, which was in the same level of the activity of fusaric acid.


[Research and development of clarithromycin].

A series of O-alkylated derivatives of erythromycin (EM) has been prepared and their biological properties were evaluated. Among them, clarithromycin (CAM, 6-O-methylerythromycin) exhibits most potent in vitro and in vivo antibacterial activities, higher acid-stability than EM and favorable pharmacokinetic properties as an antibiotic. CAM was originally synthesized via methylation of 2'-O,3'-N-bis(benzyl-oxycarbonyl)-N-demethylerythromycin in low yield, because of the less selectivity of 6-O-methylation. The selective 6-O-methylation was achieved using the erythromycin 9-oxime derivative as a key intermediate. By the further investigation on the protective groups of 9-oxime and desosamine moiety, the production process of CAM on an industrial scale has been established via methylation of 2',4''-O-bis(trimethylsilyl)erythromycin 9-[O-(1-isopropoxycyclohexyl)oxime] in more than 45% overall yield. CAM has the same antibacterial spectra as EM and is active against aerobic Gram-positive bacteria, some Gram-negative bacteria, anaerobic bacteria, Mycoplasma and Chlamydia. The activity of CAM against clinical isolates was 1 to 16 times higher than that of EM. The efficacies of CAM were 6 to 15 times superior to those of EM against systemic infections due to Gram-positive bacteria in mice. CAM also showed more potent therapeutic efficacies than EM against respiratory tract infections caused by S. pneumoniae and H. influenzae. CAM was well absorbed after oral administration, and its distribution to various tissues was significantly higher than that of EM in animals. The level of CAM in the lung was extremely high, which accounted 69 times that of EM. CAM was found to be distributed predominantly in the alveolar wall, especially in the alveolar epithelial cells, by microautoradiography. After oral administration in human, the serum level and urinary excretion of CAM were 5 and 20 times higher than those of EM, respectively. The major and active metabolite of CAM in human, (14R)-14-hydroxyclarithromycin, existed in significant quantity in the serum and urine, suggesting that the metabolite contributes to the excellent clinical efficacy of CAM. This paper describes the synthesis, structure-activity relationships, antibacterial activities, metabolism and clinical efficacies of CAM, a new macrolide antibiotic.


[Orally active cephalosporins. I. Synthesis and structure-activity relationships of 7 beta-[2-(R)-amino-2-phenylacetamido]-3-(1H- 1,2,3-triazol-4-yl)alkylthiomethyl-3-cephem-4-carboxylic acid and related compounds].

The synthesis, antibacterial activity and oral absorbability of 7 beta-[2-(R)-amino-2-phenylacetamido]-3-(1H-1H-1,2,3-triazol- 4-yl)methylthiomethyl-3-cephem-4-carboxylic acid (1a) and related compounds (1b-p and 2) are described. The replacement of 1,2,3-triazole at the C-3 position of 1a with other heteroaromatics such as 1,2,4-triazole, imidazole and so on decreased its oral absorbability in mice (1b-j). The oral absorbability was also influenced by the spacer length between C-3 of cephem nucleus and C-4 of 1,2,3-triazole. The quantitative relationship between the bioavailability and the spacer length of cephalosporins (1a and 1k-p) is discussed. These results suggest that 1,2,3-triazole in the side chain at the C-3 position of cephems plays an important role in good oral absorption through its interaction with the transport system of small intestine.


[Studies on the baths with crude drug: the effects of Senkyu extract as skin penetration enhancer].

The effects of Senkyu (Cnidii Rhizoma and Ligustici chuanxiong Rhizoma) on the drug skin penetration were studied to clarify its effectivity as the baths. Ether and methanol extracts, and some essential oils of Senkyu (i.e. ligustilide, neocnidilide and butylidenephthalide) enhanced remarkably the skin penetration of benzoic acid. Furthermore, an appreciable correlation between the enhancing ratio and the skin/donor partition coefficient of benzoic acid was observed. These facts suggest that the constituents of Senkyu influence the skin penetration by enhancing the partition coefficient.


[Stomachic principles in ginger. II. Pungent and anti-ulcer effects of low polar constituents isolated from ginger, the dried rhizoma of Zingiber officinale Roscoe cultivated in Taiwan. The absolute stereostructure of a new diarylheptanoid].

By using the effects on HCl/ethanol-induced gastric lesions in rats, beta-sesquiphellandrene (2), beta-bisabolene (3), ar-curcumene (4) and 6-shogaol (5) were isolated as anti-ulcer active principles in ginger, the dried rhizoma of Zingiber officinale Roscoe (Shokyo in Japanese) which was cultivated in Taiwan, together with nine known compounds and a new diarylheptanoid. The absolute stereostructure of the diarylheptanoid was characterized as (3S,5S)-dihydroxy 1-(4'-hydroxy-3',5'-dimethoxyphenyl)-7-(4''-hydrox y-3''-methoxyphenyl)heptane (15) on the basis of chemical and spectroscopic evidence which included the application of the benzoate chirality method. The pungent effects of several constituents isolated from ginger were examined.


[Cell growth inhibitory compound from the culture of intestinal lactic acid bacteria].

The influence of the culture supernatants of 1000 strains of intestinal lactic acid bacteria on the growth of HeLa cells was examined. The compound from Enterococcus faecium 3463 showing the strongest cell growth inhibiting effect in these strains was isolated and identified as tyramine. The effect of tyramine was activated by the newborn bovine sera (NBS), but weakly by the fetal bovine sera (FBS). Benzylamine and beta-phenethylamine also showed the NBS-dependent cell growth inhibitory effect against HeLa cells.


[Synthesis and antitumor activities of conjugates of mitomycin C-polysaccharide from Tremella fuciformis].

The conjugates of mitomycin C (MMC) with glucuronoxylomannan (AC) from Tremella fuciformis were synthesized by the use of spacers (glycine, glycylglycine, glycylglycylglycine). In i.p.-i.p. system the antitumor activity of the conjugates (MMC-G-ACP, MMC-GG-ACP, MMC-GGG-ACP) against P388 leukemia in mice was slightly lower than that of MMC by the evaluation of life span, ILS (%). In s.c.-i.p. system the antitumor activity of the conjugates against sarcoma 180 solid tumor in mice was similar to that of MMC, except for MMC-G-ACP. The reduction of the number of leukocytes caused by MMC was suppressed by attaching MMC to AC. The conjugates did not lower the cytotoxicity of MMC against L1210 mouse leukemia cells in vitro. The release rate of MMC from the conjugates in vitro (half time of MMC release: MMC-G-ACP, 8.8 h; MMC-GG-ACP, 3.1 h; MMC-GGG-ACP, 2.9 h) was much faster than that of MMC-dextran, and differed in the length of the spacer. The results would give useful information on macromolecular carriers in drug-delivery system.


[Effects of temperature and pH on hydrolysis of monoacetoacetin in an aqueous phase].

The kinetics of hydrolysis of monoacetoacetin (MAA; 1,2-dihydroxy-3-acetoacetyloxypropane) in 300 mM phosphate buffer was studied by means of high performance liquid chromatography. MAA was hydrolyzed to glycerin (Glyc) and acetoacetate (AA), the latter of which furthermore decomposed to acetone (Acet) and CO2 at high temperature. The rate constant, k1, for the reaction of MAA-->AA+Glyc increased with increases in temperature and pH. On the other hand, another one, k2, for the reaction of AA-->Acet+CO2 increased with an increase in temperature but showed a minimum around pH 7.5 when pH was changed at a given temperature. The activation energy for k1 was almost constant in the range of studied pHs (5-8) but the pre-exponential factor, k1,0, increased with an increase in pH. It was concluded that the decomposition reaction of MAA is consecutive in a sequence of MAA-->AA-->Acet. Calculated concentrations of MAA, AA, and Acet through the obtained k1 and k2 together with a given initial concentration of MAA (= 40 mM) were compared with those experimentally observed on the time course of the hydrolysis. They were in good agreement with each other.


[Pharmacological studies on leaf of Arctostaphylos uva-ursi (L.) Spreng. V. Effect of water extract from Arctostaphylos uva-ursi (L.) Spreng. (bearberry leaf) on the antiallergic and antiinflammatory activities of dexamethasone ointment].

Effects of water extract (UW-ext) from the leaf of Arctostaphylos uva-ursi (L.) Spreng (Bearberry leaf) on the antiallergic and antiinflammatory activities of dexamethasone ointment were investigated. One or 2% UW-ext ointment did not inhibit the ear swelling by picryl chloride-induced contact dermatitis (PC-CD) and carrageenin-induced paw edema. UW-ext augmented the inhibitory effect of dexamethasone ointment (0.005 or 0.025%) on these allergic and inflammatory models, but not the side effect of it. These results suggest that Bearberry leaf increases the inhibitory effect of dexamethasone on the allergic and inflammatory models.


Marked interanimal differences in susceptibility of Sprague-Dawley rats to diquat-induced oxidative stress in the liver: correlation with hepatic uptake of diquat.

Biliary excretion of oxidized glutathione (GSSG) is used as an index of oxidative stress. We observed a marked interanimal difference in susceptibility to diquat-induced oxidative stress. When diquat injections (120 mumol/kg, i.v.) were administered to rats, a 60-fold increase in the biliary excretion of GSSG was observed in 40% of the rats (responders); however, diquat failed to increase the biliary excretion of GSSG in 60% of the animals (nonresponders). This interanimal variation is not due to differences in the hepatic metabolism or hepatobiliary transport of GSSG, as no interanimal difference was observed in the biliary output of GSSG after administration of another oxidative stress-inducing agent, t-butyl hydroperoxide (1.4 mmol/kg, i.v.). We then examined the hepatobiliary disposition of diquat (120 mumol/kg, i.v.) using a high-performance liquid chromatography procedure to quantitate diquat in blood, liver and bile. No differences in blood or biliary concentration of diquat were noted between responders and nonresponders. However, a marked difference was observed in the hepatic concentration of diquat in responders and nonresponders. The responders exhibited a 4-fold higher hepatic diquat concentration than the nonresponders (65 or 15 nmol/g, respectively) 30 min after diquat administration. In conclusion, this study demonstrates a marked interanimal variation in the susceptibility of Sprague-Dawley rats to oxidative stress produced by diquat, which appears to be due to interanimal difference in the hepatic accumulation of diquat.


Effects of social isolation on pentobarbital activity in mice: relationship to racemate levels and enantiomer levels in brain.

The effects of social isolation on hypnotic actions induced by pentobarbital (PB) were investigated pharmacokinetically in isolated and aggregated mice and rats. Animals were administered i.p. 50 mg/kg of sodium (+-)-PB, S(-)-PB or R(+)-PB. Experiments in mice indicated that the duration of sleep induced by sodium (+-)-PB was reduced in the isolated mice, while the onset of sleep or the (+-)-PB brain levels at the time of awakening did not differ significantly between isolated and aggregated mice. These results suggest that changes in pharmacokinetics of PB may underlie the difference in duration of sleep between isolated and aggregated mice. In additional experiments in mice, brain concentrations of (+-)-PB, S(-)-PB or R(+)-PB were determined at predetermined intervals after injection. These experiments demonstrated that the brain concentrations of (+-)-PB, as well as those of S(-)-PB, at each predetermined timepoint in mice sacrificed before awakening were significantly lower in the isolated mice. The brain R(+)-PB levels in the isolated mice were also significantly lower as compared with those in the aggregated mice at each timepoint after injection. Experiments in rats indicated that urinary 3'-hydroxypentobarbital (major metabolite) concentrations were higher in the isolated rats at 0 to 6 hr after injection, suggesting an increased rate of hepatic drug metabolism in the isolated rats. Take together, these findings suggest that an increased rate of metabolism of PB, especially that of the S(-)-enantiomer which is responsible for hypnotic action, in isolated rodents may be involved in the shorter duration of sleep time induced by sodium (+-)-PB.


Effects of alcohol on the hypothalamic-pituitary-gonadal axis in the developing male rat.

The ontogeny of the effects of alcohol on serum testosterone levels was examined in male rats throughout sexual maturation (25-70 days). Alcohol decreased serum testosterone levels in rats 45 days or older as expected. In contrast to these results, we found precisely the opposite effects in prepubescent male rats (25-30 days old): namely, a marked stimulation of serum testosterone. Alcohol produced dose-dependent increases in serum testosterone levels in the prepubescent animal with increases of over 300% observed. In contrast to the biphasic effects of alcohol on serum testosterone levels in the developing animal, we found either no changes or modest decreases in serum luteinizing hormone levels at all ages tested. These data indicate that the increase in testosterone occurred independently of changes in luteinizing hormone in the prepubescent animal. Thus, it appears that the primary site of action of alcohol on the hypothalamic-pituitary-gonadal axis in prepubescent male rats is the testes and that alcohol acts to directly stimulate testosterone's biosynthesis. In contrast, alcohol appears to act at both central and testicular sites in rats 45 days or older to depress the synthesis and release of testosterone. The mechanisms underlying these age-dependent, biphasic effects of alcohol on serum testosterone levels are unknown at the present time, but it seems unlikely that differences in the biodisposition of alcohol were involved.(ABSTRACT TRUNCATED AT 250 WORDS)


Oxidant-evoked release of acetylcholine from enteric neurons of the rat colon.

In the presence of halides, granulocytes generate hypochlorous acid and, subsequently, chlorinated amines (chloramines). These lipophilic, potent reactive oxygen metabolites may contribute to the mucosal pathophysiology associated with inflammatory bowel disease. A common symptom of inflammatory bowel disease is mucosal secretion of fluid and electrolytes, leading to diarrhea. Because acetylcholine (Ach) can stimulate colonic fluid secretion, we determined the effect of monochloramine (NH2Cl) on Ach release by mucosal/submucosal nerves. Mucosa from the rat colon was separated from outer muscle layers and minced before incubation with [14C]choline to label stores of Ach in cholinergic neurons. Release of [14C]Ach was evoked with NH2Cl in the absence and presence of 5-aminosalicylic acid, glutathione, nordihydroguaiarectic acid or the cyclooxygenase inhibitor piroxicam. NH2Cl produced concentration-related increases in [14C] Ach release into the medium; greater than 100% over base line was observed at 0.5 mM. Glutathione inhibited the NH2Cl-evoked release in a concentration-dependent fashion. Release induced by 0.1 mM NH2Cl was abolished by 5-aminosalicylic acid and significantly inhibited by nordihydroguaiarectic acid. Piroxicam also prevented the effect of NH2Cl on release of [14C] Ach. None of these agents alone had any effect on base line [14C]Ach release. Tetrodotoxin (5 microM) did not significantly inhibit the NH2Cl-evoked transmitter release. We conclude that NH2Cl, at concentrations believed to exist in inflamed tissue, causes the release of Ach from mucosal/submucosal nerves primarily through nonspecific neural membrane injury. Endogenous prostaglandins, possibly liberated as a consequence of the injury, may be involved in the Ach release process.


Role of endothelin-1 and big endothelin-1 in modulating coronary vascular tone, contractile function and severity of ischemia in rat hearts.

The effect of endothelin-1 (ET-1) and big ET-1 on coronary flow and contractile function was determined in isolated nonischemic and ischemic rat hearts. Both ET-1 (IC50 = 12 pMol) and big ET-1 (IC50 = 2 nMol) reduced coronary flow in a concentration-dependent manner, although ET-1 was > 100-fold more potent. Both compounds decreased contractility, an effect which was lost when coronary flow was held constant, indicating that ET-1 and big ET-1 decrease contractility secondary to reducing coronary flow. Mechanical reduction in coronary flow to levels equivalent to those seen for ET-1 or big ET-1 caused similar reductions in contractility. Both 30 pMol ET-1 and 10 nMol big ET-1 pretreatment significantly reduced the time to contracture in globally ischemic rat hearts, suggesting a proischemic effect. Phosphoramidon (100 microM, endothelin-converting enzyme inhibitor) and BQ-123 (0.3 microM, ETA receptor antagonist) abolished the preischemic increase in coronary perfusion pressure induced by big ET-1 as well as its proischemic effect, whereas only BQ-123 abolished the cardiac effect of ET-1. Neither phosphoramidon nor BQ-123 had an effect on severity of ischemia when given alone. Phosphoramidon was also given i.v. to rats subjected to coronary occlusion and reperfusion and was found to significantly reduce infarct size 24 hr postischemia. Thus, in isolated rat hearts, big ET-1 appears to be converted to ET-1 and is a potent coronary constrictor.(ABSTRACT TRUNCATED AT 250 WORDS)


Potassium channel openers dilate large epicardial coronary arteries in conscious dogs by an indirect, endothelium-dependent mechanism.

Cromakalim and pinacidil, two potassium channel openers, dilate both large and small coronary arteries in conscious dogs. Because flow-mediated dilation of large arteries is endothelium-dependent, the consequences of in vivo endothelium removal (balloon denudation) on the response of large epicardial coronary arteries to cromakalim (10 micrograms/kg) and pinacidil (30 micrograms/kg) were investigated in six dogs chronically instrumented for the measurement of arterial pressure, left circumflex coronary artery diameter and coronary blood flow. Endothelium removal abolished the dilation of large coronary arteries induced by acetylcholine (endothelium-dependent dilation) and reactive hyperemia (flow-mediated dilation), but only slightly reduced (-18%) that induced by nitroglycerin. Before endothelium removal, both cromakalim and pinacidil induced a significant decrease in coronary resistance (-71 +/- 2 and -63 +/- 2%, respectively) and a significant increase in coronary diameter (8.5 +/- 1.3 and 6.7 +/- 0.9%). After endothelium removal, the decreases in coronary resistance were unaffected, but the increases in coronary diameter were reduced by 93 and 98% as compared to predenudation responses with cromakalim and pinacidil, respectively (both P < .01). In contrast, in vitro studies performed in isolated large epicardial coronary arteries obtained from five additional dogs showed that cromakalim evoked relaxations that were not affected by prior in vivo endothelium removal. Thus, despite the presence of potassium channels in isolated denuded large coronary arteries, our data demonstrate that cromakalim- and pinacidil-induced dilation of large arteries in vivo is an indirect, flow-mediated effect which is entirely endothelium-dependent.


Induction of peroxisomal enzyme activities by di-(2-ethylhexyl) phthalate in thyroidectomized rats with parathyroid replants.

Previous studies suggest that thyroid hormones are involved in the mechanism of peroxisome proliferation. However, those studies utilized either surgically thyroidectomized animals, which are also parathyroidectomized, without calcium supplementation, or animals pretreated with antithyroid drugs, which are known to produce metabolic as well as morphometric changes in the liver. Therefore, these animal models confound conclusions drawn in previous studies. The purpose of the present study was to investigate the role of thyroid hormones in peroxisomal proliferation by the phthalate ester plasticizer, di-(2-ethylhexyl)phthalate (DEHP) in thyroidectomized rats with parathyroid replants. Using this model, it was found that DEHP-induced hepatomegaly was partially dependent on thyroid hormones. DEHP produced a thyromimetic effect, inducing the activity of malic enzyme and carnitine acetyltransferase in the absence of thyroid hormones. Additionally, DEHP-induced activities of catalase were shown to be dependent on thyroid hormones, whereas the thyroid status of the animal had no effect on DEHP-induced activities of the peroxisomal beta-oxidizing enzymes. These data further confirm that endocrine factors play variable roles in the process of induction of various peroxisomal enzymes caused by peroxisome proliferators.


Characterization of YM060, a potent and selective 5-hydroxytryptamine3 receptor antagonist, in rabbit nodose ganglion and N1E-115 neuroblastoma cells.

The 5-hydroxytryptamine (5-HT)3 receptor blocking properties of YM060, [(R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H- benzimidazole hydrochloride], were examined by electrophysiological and radioligand binding studies. Results were compared with those for ondansetron, granisetron and the enantiomer (S-form) of YM060. 5-HT and 2-methyl-5-HT, a selective 5-HT3 receptor agonist, induced dose-dependent depolarizations of rabbit nodose ganglion with ED50 values of 24.0 (19.9-29.1) and 40.1 (30.9-52.1) nmol, respectively (geometric mean, 95% CL). YM060, ondansetron, granisetron and the S-form dose-dependently inhibited 5-HT-induced depolarizations with IC50 values of 3.85 (2.47-5.98), 1.55 (1.26-1.91), 1.45 (1.18-1.79) and 13.5 (11.2-16.2) nM, respectively. Methysergide, a 5-HT1-like and 5-HT2 receptor antagonist, at a concentration of 10(-5) M had no effect on responses to 5-HT. YM060 up to 10(-5) M produced no significant depression of depolarizing responses to 1,1-dimethyl-4-phenylpiperazinium iodide and gamma-aminobutyric acid. YM060, ondansetron, granisetron and the S-form displaced specific binding of [3H]GR65630 to N1E-115 neuroblastoma cell membranes with Ki values of 0.091 (0.086-0.097), 7.03 (5.96-8.01), 2.02 (1.74-2.30) and 10.3 (9.96-10.6) nM, respectively. These results show that YM060, compared with ondansetron and granisetron, has considerably higher affinity for 5-HT3 receptors in N1E-115 cells and slightly less potent 5-HT3 receptor antagonistic activity in rabbit nodose ganglion. Moreover, the isomeric activity ratio (R-form/S-form) was approximately 112 in N1E-115 cells and no greater than 4 in the ganglion.(ABSTRACT TRUNCATED AT 250 WORDS)


Inhibition of outflow facility and accommodative and miotic responses to pilocarpine in rhesus monkeys by muscarinic receptor subtype antagonists.

The muscarinic receptor subtype antagonists 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), 11-[(2-[diethylamino)methyl]-1- piperidinyl)acetyl]-5,11-dihydro-6H-pyrido[2,3- b][1,4]benzodiazepine-6-one (AF-DX 116) and pirenzepine were used to inhibit the outflow facility and accommodative and miotic responses to near-maximal intracameral doses of pilocarpine in the living rhesus monkey eye. The pharmacologic M3 antagonist 4-DAMP was the most potent inhibitor of all three responses, with IC50 values of 41.7 nM for outflow facility (vs. 40.9 microM pilocarpine), 19.8 nM for accommodation (vs. 40.9 or 81.8 microM pilocarpine) and 3.2 nM for miosis (vs. 4.1 microM pilocarpine). The M1 antagonist pirenzepine was at least 30-fold less potent, with IC50 values of 2.2 microM for outflow facility, 1.4 microM for accommodation and 0.1 microM for miosis. The M2 antagonist AF-DX 116 was the least potent by far, with IC50 values of 15.5 microM for outflow facility, 14.2 microM for accommodation and 1.5 microM for miosis. The results suggest that these three functional responses to pilocarpine are all mediated through an M3 receptor subtype.


Cerebrospinal fluid transport and disposition of the quinolones ciprofloxacin and pefloxacin in rats.

The disposition of ciprofloxacin and pefloxacin in the rat cerebrospinal fluid (CSF) was investigated after i.v. and i.c.v. administration. After injection into the lateral ventricle, the terminal half-life of pefloxacin was shorter than that of ciprofloxacin. After i.v. infusions, the relative CSF exposure, expressed as CSF: area under the plasma concentration time curve ratio, were found to be 10.4 +/- 2.8% for ciprofloxacin and 42.4 +/- 3.0% for pefloxacin. The unit impulse response methodology was applied in order to assess the CSF transport profile. The plasma-CSF transport clearance of pefloxacin and the total amount of drug transported into the CSF were significantly higher compared with ciprofloxacin. Although pefloxacin exhibited a linear CSF transport profile, the plasma-CSF transport clearance of ciprofloxacin was found to be nonlinear at the dose level studied. Pefloxacin was converted in the brain to the active metabolite norfloxacin (N-desmethyl pefloxacin). The difference in CSF exposure of both quinolones and the presence of active metabolites of N-methylated quinolones in the CSF may be of clinical relevance in the treatment of CNS infections, but differences in antimicrobial activity have to be taken into account as well.