In vivo assessment of dopaminergic variables in schizophrenia.
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Biomedical subjects
Publications and source records attributed to F Aubin.
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The authors report a case of cutaneous pigmentation induced by minocycline. The patient (aged 59) presented with a bluish-grey pigmentation on her face, legs and nails. She had been receiving minocycline for 8 years for asthma. The cumulative dose was 400 g. Skin biopsy specimens from the pigmented areas were examined by light and electron microscopy. Light microscopy displayed hyperpigmentation with Fontana's stain in the dermis, macrophages and basal layer of the epidermis. Electron microscopy showed an increase in melanosomes within the basal keratinocytes, and dense granules in macrophages of the dermis. An X-ray microanalysis of the electron-dense granules showed the presence of larger quantities of iron and smaller quantities of sulphur and calcium. The different types of pigmentation are reviewed. Several pigments are thought to be responsible for the pigmentation but the underlying mechanism remains unclear.
Exposure of murine skin to UVB (280-320 nm) radiation accelerates the outgrowth of melanoma cells implanted into the irradiated site. Because many of the biological effects of psoralen plus UVA (320-400 nm) radiation (PUVA) resemble those of UVB radiation and because PUVA therapy is used extensively in the treatment of cutaneous diseases in humans, we determined the effect of PUVA on the growth of transplanted murine melanoma cells. Unshaved C3H/HeN(MTV-) mice were treated twice each week for 3 weeks with 0.4 mg 8-methoxypsoralen i.p. plus 4.25 kJ/m2 UVA radiation; syngeneic K1735 melanoma cells were then injected s.c. into the external ear. This treatment stimulated the outgrowth of the melanomas compared to that in untreated mice and mice treated with 8-methoxypsoralen or UVA alone. The use of a nonphototoxic, monofunctional psoralen plus UVA was equally effective, indicating that neither phototoxicity nor the ability to form DNA crosslinks was required for this effect. In vitro treatment of a murine keratinocyte cell line PAM 212 with PUVA caused the release of soluble factors that, when mixed with K1735 melanoma cells prior to injection, stimulated their outgrowth in vivo. These studies demonstrate that PUVA treatment can contribute to the pathogenesis of melanoma by exerting a stimulatory effect on the outgrowth of melanoma cells. Furthermore, they suggest that this effect may result from the ability of PUVA to cause the release of stimulatory factors from keratinocytes.
Onset of sudden death, myocardial infarction, and stroke occurs more likely in the morning hours. Similarly, a morning increase in epinephrine-induced platelet aggregation was observed accompanied by an increase in plasma catecholamines. Inhibition of the morning increase in platelet aggregation would be of therapeutic benefit. In this study the effect of the selective alpha 2-adrenergic receptor antagonist yohimbine on platelet aggregation was evaluated in healthy subjects. Yohimbine administered orally selectively antagonized epinephrine but not collagen, arachidonic acid, or adenosine diphosphate-induced ex vivo platelet aggregation. The lowest dose of yohimbine that significantly inhibited epinephrine-induced platelet aggregation was 8 mg. The inhibitory effect of yohimbine on platelet aggregation lasted 10 hours with the 12 mg dose. At the doses studied (4, 8, and 12 mg), yohimbine did not modify blood pressure, standing heart rate, or plasma catecholamine or glucose concentrations. Twelve milligrams of yohimbine moderately but significantly accelerated supine heart rate (mean maximal increase, 7 +/- 3 beats/min). Further clinical studies are needed to evaluate whether bedtime administration of 12 mg yohimbine may block the morning increase in epinephrine-induced platelet aggregation.
Although psoralens plus UVA radiation (320-400 nm) have been widely used for the treatment of dermatologic diseases, the toxic effects of these agents have led investigators to develop new photochemotherapeutic compounds. One such compound is 4,4',5'-trimethylazapsoralen (TMAP), a new bifunctional molecule. The purpose of this study was to examine the immunologic side effects of repeated treatment of C3H mice with TMAP plus UVA radiation. During this treatment, the number of ATPase+, la+, and Thy-1+ dendritic epidermal cells greatly decreased in the treated site, despite the lack of phototoxicity. The reduction in the number of detectable cutaneous immune cells was accompanied by a decrease in the induction of contact hypersensitivity to dinitrofluorobenzene applied to the treated skin, an impairment in the antigen-presenting activity of draining lymph node cells, and the presence of suppressor lymphoid cells in the spleen of unresponsive mice. Treatment with UVA radiation alone also reduced the number of ATPase+, Ia+, and Thy-1+ cells in the skin, but did not cause any detectable alterations in immune function. This implies that morphologic alterations in these cells do not necessarily indicate loss of function. Thus, although TMAP in combination with UVA radiation is not overtly phototoxic, it is highly immunosuppressive in mice.
Exposure of mice to psoralen plus ultraviolet A (320-400 nm) radiation or midrange ultraviolet B (280-320 nm) radiation causes a systemic suppression of the immune response. Although the mechanisms involved in the induction of suppression are not entirely clear, recent studies have demonstrated that ultraviolet B--irradiated keratinocytes release soluble factors that depress delayed-type hypersensitivity to alloantigens and activate the suppressor cell pathway. The purpose of this study was to determine whether PUVA-treated keratinocytes could also cause the release of such immunosuppressive factors. Treatment of keratinocytes with psoralen and UVA radiation induced the release of a factor that depressed the delayed-type hypersensitivity reaction to alloantigen. The suppressive factor was released regardless of whether the psoralen formed monofunctional or bifunctional adducts with DNA and regardless of its phototoxicity. In addition, keratinocytes treated with psoralen and lower doses of UVA radiation released a factor that inhibited contact but not delayed-type hypersensitivity, suggesting that more than one immunosuppressive factor is released following treatment of keratinocytes with appropriate doses of psoralen and UVA radiation. Our findings provide evidence that immunosuppressive factors released from keratinocytes may play a role in the induction of systemic immune suppression following PUVA treatment. Moreover, they demonstrate that PUVA treatment, unlike UVB treatment, can cause the release of more than one immunosuppressive factor from keratinocytes.
The effects of an exposure to 6 times the minimal erythemal dose of ultraviolet radiation (UV) were studied using a visual scale and a tri-stimulus colorimeter in 12 sun-tolerant (skin types III and IV) patients with type A dysplastic nevus syndrome. In such individuals, the melanocytic system would be susceptible to neoplastic transformation induced by sunlight. The cutaneous response to a marked UVB erythema has been shown to identify the high-risk patients prone to light-induced skin cancer. This study indicates that the UVB cutaneous susceptibility of patients with type A dysplastic nevi is not significantly different from control subjects, in terms of erythemal and tanning response.
Corticosteroid therapy may induce numerous psychiatric disorders. Minor changes of the euphoric mood type are observed in 75% of the patients under treatment. Major adverse effects are encountered in not more than about 5% of the cases. They consist of acute polymorphous psychotic manifestations which may be manic or depressive or, when high doses of corticosteroids are taken, of the organic confusion type. Such manifestations are particularly frequent in women and in some diseases such as lupus erythematosus or pemphigus. In the vast majority of cases they follow a favourable course when corticosteroids are reduced or discontinued and a symptomatic treatment with neuroleptic drugs is prescribed. Psychic dependence on corticosteroids and withdrawal syndromes have also been reported.
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Although some psoralens are therapeutically active in the treatment of cutaneous hyperproliferative diseases when combined with UVA (320-400 nm) radiation, the toxic effects of these compounds have led physicians to seek new photochemotherapeutic agents. One such agent is 4,4',5'-trimethylazapsoralen (TMAP), a new bifunctional psoralen compound. We investigated the effects of repetitive treatments with TMAP plus UVA radiation on the number of dendritic immune cells in murine epidermis and on the induction of phototoxicity. Mice treated 3 times per week for 4 weeks with 129 microgram TMAP plus 10 kJ/m2 UVA radiation exhibited no gross or microscopic evidence of phototoxicity. During this treatment, the numbers of ATPase+, Ia+, and Thy-l+ dendritic epidermal cells were greatly reduced, and by the end of the treatment period, few dendritic immune cells could be detected. We conclude that morphological alterations of cutaneous immune cells can occur in the absence of overt phototoxicity, and that TMAP plus low-dose UVA radiation decreases the numbers of detectable Langerhans cells and Thy-1+ cells in murine skin.
The molecular aspects of the mode of action of psoralens is not clearly understood since two types of reactions may occur simultaneously and independently of each other, when the psoralen-treated skin is exposed to ultraviolet A radiation. Type 1 is an oxygen-independent reaction, leading directly to photoaddition of psoralen to pyrimidine bases of DNA, and type 2 is an indirect oxygen-dependent reaction involving the generation of reactive oxygen species. Thus, the psoralens can damage the cell membranes, the cytoplasmic constituents and the cell nuclei resulting in the observed phototoxic effects. The molecular mechanisms underlying the generation of free radicals and DNA damages are described, and are related to the two classes of psoralens.
Hydroa vacciniform is a rare recurrent photosensitive skin condition in which deep-seated vesicles appear on sun-exposed areas and heal leaving a depressed scar. Two cases are reported, with particular emphasis on phototesting investigations. Results of blood and urine porphyrin studies were normal and no systemic abnormalities were noted. Phototesting may be viewed as an important diagnostic aid, since the induction of lesions, clinically identical to hydroa vacciniform can occur following sequential exposure to UV-A, as was the case in one of our patients.
The authors studied the bioavailability of minocycline in sebum and serum. Blood and sebum samples were collected weekly for 6 weeks from ten healthy volunteers taking 200 mg of minocycline every day for 4 weeks. Sebum was collected by direct extraction with petroleum ether from the forehead. After evaporation, sebum was weighed on a scale accurate to 10 micrograms. Determination of minocycline in serum and sebum was performed using a high performance liquid chromatography technique (HPLC), with a better detection limit at 352 nm than at 400 nm (20 ng/ml and 0.324 microgram/ml respectively). Our results contrast with other studies since no minocycline was detected in the sebum samples of treated subjects and microbiological assays of minocycline in sebum were also negative. In our opinion, the current hypothesis claiming that the effectiveness of minocycline in the treatment of acne vulgaris is based on sebaceous secretion should be reconsidered.
Lipoid proteinosis is a rare autosomal recessive condition affecting the majority of organ systems, but predominantly involving skin and mucous membranes. The mucocutaneous infiltration due to accumulation of a hyaline material is positive for both sudanophil and periodic acid-Schiff reagents. This was illustrated in a 14-year-old girl with parental consanguinity, who had classic manifestations.
The effects of an irradiation 6 times the minimal erythemal dose of UVB were studied using a visual scale from 1 to 4+ in 12 patients aged under 45 years with a past medical history of basal cell carcinoma, and in 12 sex-, age- and skin-type-matched controls. Erythema was significantly more intense at days 15 (p less than 0.01) and 22 (p less than 0.001) in patients than in controls. Pigmentation was significantly weaker at day 22 than in controls (p less than 0.005).
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