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In pathways where acidic amino acids, such as glutamate, are thought to be the endogenous neurotransmitter, electrophysiological studies have demonstrated that L-2-amino-4-phosphonobutyrate (L-APB) is a potent antagonist of the excitatory responses [1–3]. The binding of (D, L)-[3H]APB to its putative receptor can be readily differentiated from the binding to other subclasses of glutamate receptors by its dependence upon chloride. Furthermore, binding of APB to its recognition site has been reported to be sensitive to freezing. [4].

We have previously shown that D-cycloserine displaces [3H]glycine binding to a recognition site with properties consistent with an N-methyl-D-aspartate (NMDA) receptor modulatory site. Additionally, D-cycloserine positively modulates the NMDA receptor as evidenced by its dose-dependent enhancement of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) binding to the NMDA receptor-coupled ionophore. Further evaluation of this compound indicates that the maximal stimulation of [3H]TCP binding induced by D-cycloserine is lower than that produced by other compounds acting at the NMDA receptor associated glycine modulatory site (glycine and D-serine). Moreover, the stimulation of [3H]TCP binding induced by D-cycloserine in the presence of various fixed concentrations of glycine results in a family of dose-response curves which asymptotically converge to 40-50% of the maximal stimulation induced by glycine alone. These results are consistent with D-cycloserine acting as a partial agonist of the NMDA receptor via its interaction with the coupled glycine modulatory site.

Cette experience etudie l'activite de 1-Aminocyclobutane-1-carboxylate (ACBC) sur le recepteur de N-methyl-D-aspartate (NMDA). Ce recepteur est compose d'au moins 3 sites de fixation qui ont ete caracterises par des ligands marques. Les essais de fixation realises sur des preparations de membranes synaptiques de cerveau de rat ont revele que ACBC est un antagoniste du site acide amine neutre, caracterise par la fixation de glycine marque et que cette liaison influe un autre site identifie, en diminuant son affinite pour TCP marque

Etoposide (VP-16) is a semisynthetic podophyllotoxin derivative that is active against a number of solid and hematologic malignancies. Previously reported cutaneous complications include Stevens-Johnson syndrome and radiation recall. We report 4 cases of cutaneous eruptions with distinctive histopathologic changes following etoposide therapy. Diffuse erythematous macules and papules developed 5-9 days after initiation of etoposide therapy and resolved spontaneously within 3 weeks. Histologic examination revealed epidermal maturation disturbances with scattered markedly enlarged individual keratinocytes. These cells had pale cytoplasms and fragmented, haphazardly dispersed nuclear chromatin in a starburst pattern ("starburst cells"). Many keratinocytes showed notable nuclear enlargement with multiple prominent nucleoli. In addition, numerous dyskeratotic cells and basilar mitotic figures in metaphase were present. Some of these changes have been described in condylomata acuminata treated with topical applications of podophyllin, a compound structurally related to etoposide. Starburst cells have not been reported in cutaneous eruptions produced by other chemotherapeutic agents. These cells may represent abnormal mitotic arrest secondary to podophyllin and its related compounds.

We have studied the morphological and histological effects of chronic exposure of two strains of haired mice (albino Balb/c and pigmented C3H-) to various types of radiation. UVB (280-320 nm) radiation from unfiltered sunlamp bulbs for 20 and 30 weeks produced marked epidermal acanthosis and dyskeratosis which was reversible in mice exposed for 20 weeks followed by a 20-week rest. In the dermis the elastic fibres were altered and in the pigmented mice these changes had almost completely reversed 29 weeks after cessation of exposure. Cellulose acetate-filtered sunlamp bulbs (greater than 289 nm) produced similar but less marked changes. Chronic exposure to UVA (320-400 nm) radiation produced minimal alterations in the dermis while the epidermis was normal. Visible (greater than 400 nm) radiation in large doses produced no degenerative changes. Methoxsalen/UVA radiation produced epidermal acanthosis, dermal sclerosis, and alteration of elastic fibres, which was prominent in both strains at 40 weeks. These findings suggest that the UVB component of sunlight is largely responsible for photoageing of the skin. Furthermore, chronic exposure to methoxsalen/UVA therapy is likely to potentiate solar-induced photoageing.

Recently, it was discovered that 4-hydroxy-4-androstene-3,17-dione, 4-androstene-3,6,17-trione, and 1,4,6-androstatriene-3,17-dione, compounds previously reported to be competitive inhibitors of aromatase, cause a time-dependent loss of aromatase activity in human placental microsomes. We report here that 1,4-androstadiene 3,17-dione (Ki 0.32 microM; kinact 0.91 X 10(-3)/sec) and testolactone (Ki 35 microM; kinact 0.36 X 10(-3)/sec) also cause a similar loss of aromatase activity. The mechanism which explains the unexpected loss of activity caused by these five inhibitors is neither established nor apparent from current theories of the enzyme mechanism of action of aromatase. We propose an inactivation mechanism based on a new hypothesis for estrogen biosynthesis in which the third enzyme oxidation carried out by aromatase results in the formation of an enzyme-bound intermediate. This intermediate is released as an aromatized product via a facile elimination reaction which simultaneously regenerates the unaltered active enzyme. Various structural modifications made in these five inhibitors are hypothesized to redirect this elimination reaction so that the steroid intermediate remains covalently attached to the enzyme instead of being released as an aromatized product.

The effects of acute and chronic administration of pentobarbital and ethanol and of acute administration of moprphine on the subcellular localization of calcium and magnesium were determined in brain. Acute administration of pentobarbital to mice significantly decreased the calcium content of synaptic plasma membranes, (SPM-1), while increasing the calcium content of extrasynaptosomal mitochondria. After chronic administration of pentobarbital, the calcium content of SPM-1 remained depressed but no other alterations were detected. Neither acute nor chronic treatment with pentobarbital altered the subcellular localization of magnesium in brain. Acute injection of morphine decreased the synaptosomal calcium concentration in rat brain. In contrast to these effects of pentobarbital and morphine, acute administration of ethanol to mice or rats failed to alter the calcium content of any subcellular fraction studied. In addition, acute treatment with either ethanol or morphine failed to alter the calcium or magnesium content of tissue samples from rat cortex. Chronic ethanol treatment did not alter the concentration of calcium in any subcellular fraction, but did decrease the concentration of magnesium in both myelin and serum. This finding is discussed in terms of the role of magnesium deficiency in chronic alcoholism. Taken together, these results indicate that pentobarbital, ethanol and morphine each produce distinct alterations in the subcellular localization of calcium and magnesium in brain.

Macular and papular eruptions are ascribed to various causes, often drug-related hypersensitivity or toxicity. We observed patients with cutaneous eruptions during hospital admissions for induction or augmentation chemotherapy in the treatment of leukemia. In 10 of 14 patients, macular and papular eruptions occurred in a strikingly similar pattern, at the earliest recovery of peripheral lymphocytes, after chemotherapy-induced nadir of the leukocyte count. A concomitant sharp, transient rise in temperature accompanied the eruption of lymphocyte recovery. Skin biopsy specimens were obtained from 8 of these 10 patients and showed a superficial, perivascular mononuclear cell infiltrate. Immunohistochemical analysis of the cellular infiltrate was performed. The rash of lymphocyte recovery may be due to the actual return of immunocompetent lymphocytes to the peripheral circulation and skin after the chemotherapy-induced nadir of the leukocyte count. These observations suggest that macular and papular eruptions relate to specific immunologic events.

Congenital granular-cell tumors are uncommon benign neoplasms of unknown cause that develop primarily in gingival tissue and usually do not recur after surgical excision. Untreated, these neoplasms either cease to grow or "spontaneously" regress after birth. In this report, we describe an unusual case of a child with several congenital granular-cell neoplasms that arose on the lips and continued to increase in size as the child grew. Histologic examination of the neoplasms revealed them to be composed of granular and mesenchymal cells associated with abundant collagen fibers and prominent vascular structures. Ultrastructural study disclosed typical granular cells and a preponderance of immature mesenchymal cells, some of which appeared to be transitional or early granular cells. We interpreted these findings to mean that primitive mesenchymal cells are the proliferative elements and precursors of granular cells in congenital granular-cell neoplasms. The presence of numerous immature mesenchymal cells corroborates the clinical impression that the lesions were growing. Based upon the histological and ultrastructural findings reported here, and a review of the literature, we favor a mesenchymal or endothelial-cell origin for congenital granular cell neoplasms.

Observation chez les patients de race noire atteints du SIDA, d'une pigmentation des ongles, suite a un traitement par zidovudine

The N-methyl-D-aspartate (NMDA) receptor subclass of excitatory amino acid receptors has been implicated in pathological conditions such as epilepsy, ischemia, and hypoglycemia. Antagonists of the NMDA receptor have been shown to block these conditions when induced in experimental animals. One of the most specific and potent NMDA antagonists is 2-amino-7-phosphono-heptanoate (APH), with the majority of the activity residing in the D-isomer. The racemic mixture of APH, injected intraperitoneally into mice at doses of 0.33–1.0 mmol/kg, is effective against either sound or chemically induced seizures [1]. APH has also been shown to protect against ischemia induced by bilateral carotid occlusion [2] and neuronal damage due to hypoglycemia [3]. Although these studies have demonstrated the effectiveness of APH in these pathological conditions, only limited information on the pharmacokinetics of APH is available, and it is not clear whether D,L-APH and D-APH would demonstrate different pharmacokinetic properties in blood and appearance in cerebrospinal fluid. The present study describes an analytical method for the. quantification of APH in plasma and cerebrospinal fluid. Additionally, the pharmacokinetics of D-APH and D,L-APH in the rat are reported.

Oil flow data has been obtained for Mach numbers of 2.5 and 4.0 for high lift-to-drag ratio missiles including a noncircular body, and lifting body with inlets and blended wing-body which features an M- wing. This paper compares the oil flow data with experimentally measured forces and moments, pres- sure coefficients and corresponding predictions using impact techniques. The wind tunnel model geometry and test conditions are described. A de- tailed description of the oil flow testing techni- que developed to obtain h igh quality data in a continuous flow tunnel is provided. Flow field definition and correlations between predictions and test data for spatular noses, leeside controls, trailing edge controls, flat bottoms, nose-inlet, body-inlet, body-tail and wing-body are described.

A 78-year-old man had an acute eruption of lesions that clinically resembled seborrheic keratoses. Microscopic examination of the lesions indicated acantholysis and dyskeratosis primarily in the granular layer. The patient's serum contained antibodies to intercellular substance. Direct immunofluorescence microscopy of a lesion demonstrated immunoglobulin deposition in the intercellular areas. Treatment with oral prednisone produced rapid resolution of the lesions. Patients in whom eruptive seborrheic keratoses (Leser-Trélat sign) develop should have histological examination of their lesions to rule out the diagnosis of pemphigus foliaceus.

A 14-year-old boy developed group JK corynebacteria sepsis and a generalized erythematous macular and papular skin eruption following chemotherapy for relapse of acute lymphocytic leukemia. Lesional skin biopsy demonstrated effacement of eccrine glands by numerous pleomorphic gram-positive bacilli, morphologically consistent with Corynebacterium and confirmed by culture. This is the first known report documenting the generalized skin manifestations and histopathologic features associated with Corynebacterium sepsis.

The only histologic finding common to all types of lupus erythematosus lesions is a perivascular lymphocytic infiltrate. The other histologic changes in lupus erythematosus are entirely dependent on the morphology and age of the individual lesions biopsied. We do not believe that the main clinical subsets of lupus erythematosus can be reliably diagnosed on the basis of histology alone. Some of the less common forms of lupus erythematosus have distinctive but not pathognomonic, histopathologic features. The pathogenesis of most of the histologic changes is relatively unknown, leaving room for speculation and future research.

A case of superficially invasive well-differentiated cutaneous squamous cell carcinoma containing numerous mucin-producing cells both within the epidermal and dermal components is reported. Histological, histochemical and immunohistochemical overlap exists between these cells and those of extramammary Paget's disease. The presence of mucinous metaplasia within this tumor supports an intraepidermal origin for extramammary Paget's disease.

The inactivation of human placental aromatase by 17 alpha-ethynyl-10 beta-hydroperoxy-17 beta-hydroxy-4-estren-3-one (SCH 10015) was investigated. In either the presence or absence of added NADPH, SCH 10015 (Ki = 41 microM) caused a time-dependent loss of aromatase activity (e.g. 50% loss after 20 min with 20 microM SCH 10015). Evidence for the oxidation of an active site sulfhydryl group as the molecular basis for SCH 10015 inactivation is presented. The contraceptive 17 alpha-ethynyl-substituted 19-nor steroids, norethisterone (Ki = 48 microM) and norethynodrel (Ki = 38 microM), were evaluated and found not to inactivate aromatase, suggesting that the potential conversion of either compound to SCH 10015 did not occur to a significant extent in these microsomal incubations. It is speculated that the previously observed potent contraceptive effects of SCH 10015 may have been the result of irreversible inhibition of estrogen biosynthesis.

In vitro addition of ethanol or pentobarbital to synaptosomes isolated from rat or mouse brain inhibited the depolarization-dependent uptake of calcium without affecting uptake under nondepolarizing conditions. Ethanol inhibited the uptake in a concentration-dependent manner over the range of 45 to 720 mM. Analysis of the effects of ethanol and pentobarbital on calcium uptake at different temperatures indicated that the drugs did not change the activation energy of the process but shifted the Arrhenius curves toward higher temperatures. Synaptosomes isolated from mice chronically ingesting ethanol were found to be tolerant to the inhibitory effects of ethanol and pentobarbital but not tolerant to the inhibitory effects of acetaldehyde. Synaptosomes from ethanol tolerant-dependent mice accumulated less calcium in the absence of ethanol than did synaptosomes from control mice. This depression of uptake was reversed by in vitro exposure of the synaptosomes to a low concentration of ethanol, suggesting that it represents a biochemical response to withdrawal of alcohol. A single acute injection of ethanol 1 hr before sacrifice did not alter the calcium uptake activity or the drug sensitivity of the synaptosomes. These results suggest that the known inhibitory effects of ethanol and pentobarbital on the stimulated release of neurotransmitters and the development of tolerance of these effects may be mediated by the inhibition of the depolarization-dependent influx of calcium by these drugs.

A distinctive photodermatitis is seen commonly in tourists visiting Hawaii. Analysis of 150 cases revealed that the eruption is acute in onset following exposure to sunlight, is confined to exposed areas, and mainly affects young to middle-aged white women. The clinical presentation is remarkably uniform, consisting of papules, papulovesicles, or vesicles. These findings are consistent with a diagnosis of polymorphous light eruption (PMLE) and the histologic picture supports this diagnosis. Other clinical variants of PMLE were not seen in our patients, however, which suggests that this condition is more monomorphous than polymorphous. We suggest papulovesicular light eruption as a suitable name for this common and distinctive subset of PMLE.

After receiving N,N',N''-triethylenethiophosphoramide (thiotepa) and cyclophosphamide intravenously, five women with metastatic adenocarcinoma of the breast developed a patterned hyperpigmentation confined to skin occluded by adhesive-containing materials. Determinations of thiotepa concentrations in occluded and nonoccluded skin, plasma, bandage with adhesive, and gauze containing sweat were performed. The results suggest that this alkylating agent is excreted onto the skin surface in sweat, accumulates beneath adhesive-containing bandages and electrocardiogram pads, and exerts a local toxic effect resulting in hyperpigmentation.

The presence of cardiolipin (diphosphatidyl glycerol) in lactating mammary tissue (cow and goat) was investigated. The tissue was separated into subcellular fractions by sedimentation; the identities of the fractions were confirmed by electron microscopy. Polar lipids recovered from the fractions, the whole tissues, and milks were analyzed by two-dimensional thin-layer chromatography and the percentages of cardiolipin were determined. The phospholipids of whole mammary tissue from the cow and goat contain 3-5% cardiolipin which is concentrated largely, if not exclusively, in the mitochondria. Although milk may on occasion have up to 1% cardiolipin in its phospholipids, some normal milks contain less than 0.15%. Since tissue contains 20-30 times the amount (mg/g) of phospholipids in milk, the quantitative ratio of tissue to milk cardiolipin is several hundred to one. We interpret this to mean that the mechanism of milk secretion is highly selective and insures retention of mitochondria within the cell even though they are decidedly smaller than milk fat globules which are continuously secreted. Our findings substantiate the conception that there is very little disintegration of the cell or disruption of the plasma membrane during milk secretion. The fatty acids of cardiolipin from lactating mammary tissue of cow, goat, and pig are highly unsaturated; they contain 50% or more octadecadienoic acid.

(1967). Epirus: The Geography, The Ancient Remains, The History and the Topography of Epirus and Adjacent Areas. By N. G. L. Hammond. Archaeological Journal: Vol. 124, No. 1, pp. 262-263.

The concentration of sialic acid in the anterior pituitary gland of young female rats is approximately 250 micromoles per 100 grams. After ovariectomy there is a marked and persistent rise in pituitary sialic acid; this increase is probably related to the known increase in the production of gonadotrophic hormones.