Adult from of basal cell navevus syndrome: A family study

Summary A 32-year-old patient had marked reduction of visual acuity due to falciform folds of the retina and retinal detachment, and severe neurological abnormality: bilateral pyramidal involvement, fasciculation in all limbs and gait ataxia. Skull radiographs showed internal frontal hyperostosis; CT scan showed calcification of the falx cerebri, and multiple arachnoid cysts were shown by myelography. A naevoid lesion had previously been removed from the left forearm. There was a history of ophthalmological symptoms in the mother and the daughter of the propositus. His son has café au lait spot on the abdomen and dentigerous cysts. The diagnosis of an adult form of basal cell naevus syndrome with an autosomal dominant mode of inheritance is discussed.This work was supported by grants from the F.R.S.M. of Belgium no. 3.4543.77 (Prof. P. Danis) and no. 3.4538.76 (Prof. C. Coërs) and the Free University of Brussels     

Synergistic Regulation of Cytosolic Ca2+ Concentration by Adenosine and alpha1-Adrenergic Agonists in Mouse Striatal Astrocytes

Adenosine has a broad array of actions on neurons but astrocytes also possess adenosine receptors. We have previously shown that adenosine, by acting on astrocytes in the striatum, can modulate neuronal responses mediated by receptors coupled to phospholipase C through an astrocyto - neuronal interaction. In addition, adenosine was found to potentiate the alpha1-adrenergic production of inositol phosphates in astrocytes. The mechanism involved in this potentiation was further investigated by examining the effects of adenosine and alpha1-adrenergic receptor agonists on cytosolic Ca2+ in cultured striatal astrocytes from the embryonic mouse in primary culture. When used alone, methoxamine, a selective agonist of alpha-adrenergic receptors or 2-chloroadenosine, a stable analogue of adenosine, induced a transitory increase in cytosolic Ca2+, but their combined addition led to a sustained increase in cytosolic Ca2+, which seems to be due to a Ca2+ influx, because it was not observed in the absence of external Ca2+. Voltage independent Ca2+ channels contribute to this process and different blockers of voltage-operated calcium channels, such as dihydropyridines, phenylalkylamines, La3+ or Co2+ were ineffective in suppressing the sustained cytosolic Ca2+ elevation. Three observations suggest the implication of arachidonic acid in the observed potentiation: (i) arachidonic acid induced a sustained elevation of cytosolic Ca2+ similar to that evoked by the coapplication of methoxamine and 2-chloroadenosine; (ii) the addition of arachidonic acid during the calcic plateau produced by the combined application of the agonists did not increase further cytosolic Ca2+ levels; (iii) in the presence of methoxamine, 2-chloroadenosine induced a release of arachidonic acid. The stimulation of phospholipase C and the resulting activation of protein kinase C induced by methoxamine seem to be required for the potentiating effect of 2-chloroadenosine on cytosolic Ca2+. In fact, the direct activation of protein kinase C by an exogenous diacylglycerol analogue mimicked the effect of methoxamine because, in this condition, 2-chloroadenosine alone evoked a sustained elevation of cytosolic Ca2+. Therefore, methoxamine, through the successive activation of phospholipase C and protein kinase C, could allow a lipase, probably phospholipase A2, to be stimulated by 2-chloroadenosine. Arachidonic acid has already been shown to trigger the opening of K+ channels and the formation of inositol phosphates in other cell types. Therefore, in striatal astrocytes, 2-chloroadenosine, through an arachidonic acid-mediated hyperpolarization, could increase the Ca2+ driving force and thus improve Ca2+ influx through inositol phosphate-gated channels. This hypothesis is further supported by the suppressing effect of a 50 mM KCI-induced depolarization on the long lasting elevation of cytosolic Ca2+ seen in the combined presence of 2-chloroadenosine and methoxamine.     

Magnetic fields, brain and immunity: effect on humoral and cell-mediated immune responses.

Magnetic fields (MF) can influence biological systems in a wide range of animal species and humans. We report here on the influence of static MF, locally applied to the brain area, on immune system performances in the rat. In the first series of experiments two AKMA micromagnets (M) with the influx density of 600 Gauss were bilaterally implanted (with "N" polarity facing the cranial bones) and fixed to the skull posterior to the fronto-parietal suture (parietal brain exposure). Rats implanted with iron beads (I) and sham-operated (SO) rats served as controls. Animals were exposed to MF or I during different periods of time before and after immunization with several soluble or cellular antigens. We report here on the in vivo immunoregulating effects of centrally applied MF on plaque-forming cell (PFC) response, local hypersensitivity skin reactions and experimental allergic encephalomyelitis. The selective influence of MF applied to different brain regions on PFC response was evaluated, as well. For this purpose, two M were bilaterally implanted in the area of (a) frontal, (b) parietal and (c) occipital brain regions. Rats were under the influence of MF for 20 days before and 4 days after immunization with sheep red blood cells. Groups of nonimmunized rats were exposed for 14, 24 and 34 days to parietally implanted M or I, and the number of peripheral blood CD4+ and CD8+ cells determined by mouse anti-rat W3/25 and MRC OX 8 monoclonal antibodies. The results show an overall in vivo immunopotentiation of humoral and cell-mediated immune responses in rats exposed to MF. Furthermore, these immunomodulating effects of centrally applied MF depend on at least two basic parameters, time of exposure and brain region exposed. The highest immune performance was obtained after exposure of the occipital brain region for a total period of 24 days. The results provide further evidence of the complex interrelationship between the environment, the central nervous system and the immune system.     

Uptake of the daunorubicin-DNA complex in cultured fibroblasts

Summary The uptake and fate of the daunorubicin-DNA complex have been studied in cultured rat embryo fibroblasts. ¹²⁵I-DNA was digested by the cells and appeared as low molecular weight fragments in the incubation medium. Subcellular fractionation of fibroblasts, previously incubated with the complex, showed that daunorubicin was localized to nuclei and lysosomes. At a high incubation concentration (17.5 M), the accumulation of the free drug exceeded that of the complex. However, at a lower concentration (1.75 M), the accumulation of the complex was as high as that of the free drug.The results are consistent with an uptake of the complex into cultured rat embryo fibroblasts by endocytosis. However, it cannot be excluded that the complex partly dissociates in the incubation medium, and that daunorubicin and DNA thereafter enter the cells separately.     

SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.

SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.     

Effects of the Environmental Oestrogens Bisphenol A,Tetrachlorobisphenol A,Tetrabromobisphenol A, 4‐Hydroxybiphenyl and 4,4′‐Dihydroxybiphenyl on Oestrogen Receptor Binding,Cell Proliferation and Regulation of Oestrogen Sensitive Proteins in the Human Breast Cancer Cell Line MCF‐7

Abstract: Bisphenol A is extensively used in the manufacturing of epoxy resins and polycarbonate plastics, whereas several brominated and chlorinated analogues are used as flame retardants and intermediates in the plastic industry. Due to the structural relationship between these chemicals and the high production volumes, we wanted to characterize and compare their potential oestrogen‐like potency using several end‐points in MCF‐7 cells: induction of pS2 protein and progesterone receptor, reduction of oestrogen receptor level, and stimulation of cell growth. Bisphenol A, tetrachloro‐ and tetrabromo‐bisphenol A, 4‐hydroxybiphenyl and 4,4′‐dihydroxybiphenyl all showed oestrogen‐like properties in MCF‐7 cells. The chemicals tested had affinity to the oestrogen receptor isolated from MCF‐7 cells, although their EC₅₀s were 1,000 to 80,000 times higher than the EC₅₀ of 17β‐oestradiol. Bisphenol A and 4‐hydroxybiphenyl induced cell growth in MCF‐7 cells, and the highest test concentrations induced responses, apparently exceeding the cell growth induced by 17β‐oestradiol. The other chemicals tested induced less than 50% of the maximum 17β‐oestradiol‐stimulated cell growth. Bisphenol A, 4‐hydroxybiphenyl, tetrabromobisphenol A and tetrachlorobisphenol A all increased the level of the oestrogen‐regulated proteins, progesterone receptor and pS2, whereas 4,4′‐dihydroxybiphenyl showed no such effect. Bisphenol A was the only chemical tested that clearly mimicked 17β‐oestradiol in its ability to reduce the level of cytosolic oestrogen receptors in MCF‐7 cells. By measuring several oestrogen‐dependent endpoints it seems that some xeno‐oestrogens cause an imbalanced oestrogen‐response. Their ability and potency in mimicking 17β‐oestrogen in one parameter is not necessarily accompanied by a similar effect in another oestrogen‐linked parameter.     

(5) Feminist theory and pharmacy practice

This is the fifth in a series of articles highlighting the relevance of sociological theory to pharmacy practice research. The article provides an introduction to feminist theory and research as applied to health, illness and health care. The aim is to clarify the contribution made by feminist theory in developing useful conceptual tools and theories in two major areas: the specific experiences of women's health and understanding the role of women as providers of health care. We seek to contribute to a research agenda, informed by feminist thinking, for pharmacy practice. The focus of this article is on feminist theory as developed in the West, with particular emphasis on issues of concern for pharmacy practice research. We begin with a discussion of the historical context of feminism, including the women's movement and the women and health movement. This is followed by an overview of selected feminist theories. Feminist perspectives on the experience of health and illness are discussed in more detail, including issues of reproductive technologies, gender, health and morbidity; gender differences in the medical encounter; and finally the relevance of a feminist approach to pharmacy practice research, including research questions that are relevant today.     

Combined analysis of E-cadherin gene (CDH1) promoter hypermethylation and E-cadherin protein expression in patients with gastric cancer: implications for treatment with demethylating drugs.

BACKGROUND: Hypermethylation is studied as a new, relevant mechanism for silencing tumor suppressor genes. It is a potentially reversible epigenetic change and it is the target of novel anticancer compounds with demethylating activity. In this perspective, we investigated E-cadherin gene (CDH1) promoter hypermethylation in gastric carcinomas and its correlation with E-cadherin protein expression. METHODS: Consecutive cases of gastric carcinoma with assessable paraffin-embedded tumor blocks and paired normal mucosa were considered eligible for study entry. CDH1 promoter hypermethylation and E-cadherin protein expression were determined by methylation-specific polymerase chain reaction and immunohistochemistry, respectively. RESULTS: CDH1 promoter hypermethylation was found in 20 out of 70 gastric carcinomas and the epigenetic change occurred in the early, as well as in the locally advanced disease. In five cases, hypermethylation was also detected in the normal mucosa. Eighteen out of 20 hypermethylated tumors were of the diffuse histotype (P=0.0001). Of 24 tumors with reduced or negative E-cadherin expression, 19 were hypermethylated and 5 were unmethylated (P=0.0001). CONCLUSIONS: CDH1 promoter hypermethylation frequently occurs in gastric carcinomas of the diffuse histotype and it is significantly associated with downregulated E-cadherin expression. The knowledge on the hypermethylation status of tumor suppressor genes may be relevant to the development of demethylating drugs and novel chemopreventive strategies in solid tumors.     

A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin

CONTEXT: The hypothalamic-pituitary-adrenal axis is a major determinant of the host response to stress. The relationship between its activation and patient outcome is not known. OBJECTIVE: To evaluate the prognostic value of cortisol levels and a short corticotropin stimulation test in patients with septic shock. DESIGN AND SETTING: Prospective inception cohort study conducted between October 1991 and September 1995 in 2 teaching hospital adult intensive care units in France. PARTICIPANTS: A total of 189 consecutive patients who met clinical criteria for septic shock. INTERVENTION: A short corticotropin stimulation test was performed in all patients by intravenously injecting 0.25 mg of tetracosactrin; blood samples were taken immediately before the test (T0) and 30 (T30) and 60 (T60) minutes afterward. MAIN OUTCOME MEASURES: Twenty-eight-day mortality as a function of variables collected at the onset of septic shock, including cortisol levels before the corticotropin test and the cortisol response to corticotropin (delta max, defined as the difference between T0 and the highest value between T30 and T60). RESULTS: The 28-day mortality was 58% (95% confidence interval [CI], 51%-65%) and median time to death was 17 days (95% CI, 14-27 days). In multivariate analysis, independent predictors of death (P < or = .001 for all) were McCabe score greater than 0, organ system failure score greater than 2, arterial lactate level greater than 2.8 mmol/L, ratio of PaO2 to fraction of inspired oxygen no more than 160 mm Hg, cortisol level at T0 greater than 34 microg/dL and delta max no more than 9 microg/dL. Three groups of patient prognoses were identified: good (cortisol level at T0 < or = 34 microg/dL and delta max > 9 microg/dL; 28-day mortality rate, 26%), intermediate (cortisol level at T0 34 microg/dL and delta max < or = 9 microg/dL or cortisol level at T0 > 34 microg/dL and delta max > 9 microg/dL; 28-day mortality rate, 67%), and poor (cortisol level at T0 > 34 microg/dL and delta max < or = 9 microg/dL; 28-day mortality rate, 82%). CONCLUSION: Our data suggest that a short corticotropin test has a good prognostic value and could be helpful in identifying patients with septic shock at high risk for death.