[TMPRSS2-Erg/AR-V7: Prognostic value of tests in urine and biopsy rince material in prostate cancer]. / TMPRSS2-Erg/AR-V7 : valeur diagnostique des tests urinaires et sur liquides biopsiques dans le cancer prostatique.

INTRODUCTION: Nowadays, diagnostic biomarker research is oriented on a genomic characterisation of prostate cancer (PCa). This study evaluated diagnostic values of TMPRSS2-Erg fusion transcripts expression (TE) and androgen receptor variant 7 (AR-V7) on urine (tU) and biopsic rince material (tLRB) samples. MATERIALS AND METHODS: TE and AR-V7 have been tested by RT-PCR and RT-qPCR on urine and biopsies' rince liquid on 372 patients referred for prostate biopsies. RESULTS: Two hundred thirty-three patients (62%) were diagnosed with PCa. tU.AR-V7 was positive for 15 healthy patients (28%) and 30 patients diagnosed with PCa (37%). tLRB.AR-V7 was positive for 66 patients (42%) diagnosed with PCa. Concerning TE for patients diagnosed with PCa, tU was positive for 59 patients (54%) and tLRB for 132 (55%). TE and TE/AR-V7 combination were significantly associated with PCa (P<0.001), as tLRB.AR-V7 (P<0.001). Sensitivity and specificity for TE/AR-V7 combination for PCa were respectively: tU.TE/AR-V7 67% and 70%, tLRB.TE/AR-V7 68.8% and 71%, and, tUtLRB.TE/AR-V7 83% and 60%. There was no benefit for AR-V7 and TE association versus TE alone when comparing AUC. CONCLUSION: AR-V7 is not specific of PCa because of detection on healthy patients. This study did not managed to show a sufficient diagnostic value for TE/AR-V7 combination on urine and biospic rince material tests. LEVEL OF EVIDENCE: 3.

Prolactin decreases LPS-induced inflammatory cytokines by inhibiting TLR-4/NFκB signaling in the human placenta.

Prolactin (PRL) plays an important role in trophoblast growth, placental angiogenesis and immunomodulation within the feto-maternal interface, where different cell types secrete PRL and express its receptor. During pregnancy, inflammatory signalling is a deleterious event that has been associated with poor fetal outcomes. The placenta is highly responsive to the inflammatory stimulus; however, the actions of PRL in placental immunity and inflammation remain largely unknown. The aim of this study was to evaluate PRL effects on the TLR4/NFkB signalling cascade and associated inflammatory targets in cultured explants from healthy term human placentas. An in utero inflammatory scenario was mimicked using lipopolysaccharides (LPS) from Escherichia coli. PRL significantly reduced LPS-dependent TNF-α, IL-1ß and IL-6 secretion and intracellular levels. Mechanistically, PRL prevented LPS-mediated upregulation of TLR-4 expression and NFκB phosphorylation. In conclusion, PRL limited inflammatory responses to LPS in the human placenta, suggesting that this hormone could be critical in inhibiting exacerbated immune responses to infections that could threaten pregnancy outcome. This is the first evidence of a mechanism for anti-inflammatory activity of PRL in the human placenta, acting as a negative regulator of TLR-4/NFkB signaling.

Growth hormone and prolactin regulate human neural stem cell regenerative activity.

We have previously shown that the growth hormone (GH)/prolactin (PRL) axis has a significant role in regulating neuroprotective and/or neurorestorative mechanisms in the brain and that these effects are mediated, at least partly, via actions on neural stem cells (NSCs). Here, using NSCs with properties of neurogenic radial glia derived from fetal human forebrains, we show that exogenously applied GH and PRL promote the proliferation of NSCs in the absence of epidermal growth factor or basic fibroblast growth factor. When applied to differentiating NSCs, they both induce neuronal progenitor proliferation, but only PRL has proliferative effects on glial progenitors. Both GH and PRL also promote NSC migration, particularly at higher concentrations. Since human GH activates both GH and PRL receptors, we hypothesized that at least some of these effects may be mediated via the latter. Migration studies using receptor-specific antagonists confirmed that GH signals via the PRL receptor promote migration. Mechanisms of receptor signaling in NSC proliferation, however, remain to be elucidated. In summary, GH and PRL have complex stimulatory and modulatory effects on NSC activity and as such may have a role in injury-related recovery processes in the brain.

Prolactin and human tumourogenesis.

The involvement of prolactin in human tumourogenesis has been long debated. The reason is that the evidence supporting the role of circulating prolactin in promoting breast cancer was mainly obtained using rodent models, whereas most of the studies performed in human species in the 1980s have remained inconclusive. Things have now started to change because two alternative mechanisms of prolactin actions in tumour growth have emerged since the beginning of the 21st Century. The first involves locally-produced prolactin, which acts by an autocrine/paracrine mechanism. Genetically-modified mouse models have demonstrated the tumourigenic potential of local prolactin on the prostate and the mammary gland, and arguments are now emerging in humans also. The second mechanism involves genetic variants of the receptor. Although no genetic disorder has been reported for prolactin or its receptor, a variant of the prolactin receptor exhibiting constitutive activity has been recently identified in patients presenting with breast tumours, suggesting that sustained prolactin signalling may participate in breast tumourogenesis. Recent data regarding these two nonclassical mechanisms of prolactin action are discussed. Finally, we address the question of their inhibition in future cancer therapy, both in light of other findings that have revealed novel actions of prolactin in breast cancer cells, and with respect to the compounds currently available to target prolactin receptor signalling.

A four-generation Ehlers-Danlos syndrome with vascular dissections. Skin ultrastructure and biomechanical properties.

Ehlers-Danlos syndrome (EDS) is heterogenous with regard to genetic traits, clinical manifestation, the biomechanical and microscopic properties of connective tissues, and basic molecular defects. We report on nine relatives of four generations who suffered from large vessel dissections and cutaneous microscopic changes consistent with EDS. Measurements of the mechanical properties of skin were performed using a computerized suction device (Cutometer). Morphological and biomechanical alterations suggestive of EDS were present in all examined subjects. A loose network of collagen bundles was admixed with clumsy elastic fibres. Factor XIIIa-positive dermal dendrocytes looked almost normal but were slim and rarefied in four subjects. The severity in ultrastructural alterations of the collagen network differed among the subjects. The group with the most prominent changes showed the most striking biomechanical alterations characterized by increased biologic elasticity without any excess in skin extensibility. A positive correlation was found between skin extensibility and elasticity. In conclusion, distinct alterations in the collagen scaffolding were found to be correlated to variable severity in biomechanical alterations of the skin. The predictive value of these changes for large vessel dissections in some families at risk remains to be settled.

[How I explore...cheilitis]. / Comment j'explore...une chéilite.

A cheilitis is an inflammatory disease confined to the lips. Several origins are recognized. Their nature is often different in children and adults. Some are spongiotic due to irritation or allergic reaction. Other lesions are keratotic and can evolve to leucoplasia and epidermoid carcinoma.

Physico-chemical and biological characterizations of two human prolactin analogs exhibiting controversial bioactivity, synthesized in Chinese hamster ovary (CHO) cells.

The synthesis, purification and characterization of G129R-hPRL and S179D-hPRL, the two better-studied antagonists of human prolactin (hPRL), is described. Both of these have been expressed for the first time, in their authentic form, by a stable CHO cell line, at secretion levels of 7.7 and 4.3 microg/10(6) cells/day, respectively. Previous studies had shown that these hPRL analogs, when produced in bacterial cytoplasm, consistently contained misfolded forms and multimers according to the specific denaturation, refolding and purification conditions. These versions also have an N-terminal extra methionine. An extensive physico-chemical characterization was carried out after a practical two-step purification process and included SDS-PAGE and Western blotting analysis, matrix-assisted laser-desorption ionization time-of-flight mass spectral (MALDI-TOF-MS) analysis, high-performance size-exclusion chromatography (HPSEC) and reversed-phase high-performance liquid chromatography (RP-HPLC). This last technique revealed a considerable difference in hydrophobicity due to a single amino acid substitution, with S179D-hPRL less (t(RR) = 0.85 +/- 0.010) and G129R-hPRL more (t(RR) = 1.10 +/- 0.013) hydrophobic than hPRL, where t(RR) is the relative retention time. The biological characterization was based on further refinement of a sensitive proliferation assay using the pro-B murine cell line (Ba/F3) transfected with the long form hPRL receptor cDNA such that the minimal detectable dose was 0.04 ng of hPRL/mL, the Ba/F3-LLP assay. On the basis of this assay, the relative residual agonistic activity of these two products, determined against a hPRL international standard in four independent assays, was 53 x 10(-3) for S179D-hPRL and 70 x 10(-5) for G129R-hPRL. We believe that the present synthesis and characterization could be extremely helpful for studies of these two proteins, which have been reported to antagonize tumor growth-promoting effects of hPRL in vivo in animal models of breast and prostate cancer.

[How I treat...acne in adolescents: a strategic algorithm without antibiotic]. / Comment je traite...l'acné de l'adolescent: un algorithme stratégique sans antibiotique.

Acne is a multifaceted disorder. Its clinical presentation differs according to the age and gender of the subjects. Acne of the adolescent is a frequent disorder. Some topical and oral antibiotics have proven their efficacy. However, the risk of bacterial resistance may be a concern for the clinicians and their patients. Hence, a therapeutic strategy without antibiotics merits to be considered. Retinoids have a place of choice in this therapeutic strategy. Benzoyl peroxide and miconazole are also active and valuable agents in this therapeutic algorithm.

Breast inflammatory gigantomastia in a context of immune-mediated diseases.

CONTEXT: Localized breast lesions have been described in lupic or diabetic patients. However, the description of breast gigantomastia in women presenting with autoimmune diseases has not been reported. SETTING: The study took place within the Department of Endocrinology and Reproductive Medicine, Necker Hospital, Paris, France. PATIENTS: We describe eight patients with inflammatory gigantomastia, occurring in a context of immune-mediated diseases: myasthenia, chronic arthritis, or thyroiditis. MAIN OUTCOME MEASURES: Together with hormonal, immunological, and breast magnetic resonance imaging (MRI) evaluation, breast histology enabled us to perform immunocytochemical and indirect immunofluorescence studies. Control sera were obtained from patients with (n = 10) and without (n = 7) antinuclear antibodies. RESULTS: Six of the eight patients developed gigantomastia either at puberty or during pregnancy. Neither a hormonal oversecretion nor a specific immunological pattern was observed. All patients except one presented antinuclear antibodies. Histological study revealed a diffuse, stromal hyperplasia and a severe atrophy of the lobules. A rarefaction of adipocytes was also noted, as previously suggested on MRI. There was a perilobular lymphocytic infiltrate made of CD3+ lymphocytes. Study of sera from five of six cases of gigantomastia showed a nuclear immunofluorescence pattern in normal mammary ductal and lobular glandular epithelium, as well as in kidney and intestine epithelial cells. In control sera, a nuclear signal was observed only when antinuclear antibodies were present. CONCLUSIONS: We suggest that breast tissue may be a target tissue in autoimmune diseases, this process being favored by the hormonal milieu. However, the precise mechanism of such association is not individualized. The fact that stromal hyperplasia is the main histological feature justifies the search for the involvement of growth factors in such a process.

[Photoexacerbated dermatoses]. / Dermatoses photo-aggravées.

A series of viral and bacterial diseases are photoaggravated. Some autoimmune connective tissue disorders including lupus erythematosus and dermatomyositis are also affected. This category of photoexacerbated diseases also encompasses some cases of atopic dermatitis, lichen and rosacea.

[Laser and pulsed light treatments]. / Traitements par lasers et lumiere pulsée.

Numerous types of lasers can exert different and specific effects in the skin. Devices delivering high intensity of pulsed light can exert similar effect.

[How I explore ... an enlarged red leg]. / Comment j'explore ... une grosse jambe rouge.

A consultation motivated by an enlarged red leg is a common situation. The causes are multiple and the diagnosis primarily relies on case history and physical examination distinguishing inflammatory red legs from erythemato-violaceous presentations. Additional diagnostic search cannot be described as a single standardized procedure. Each disease calls for specific and different paraclinical investigations. The most frequent cause is erysipelas or a thrombophlebitis. Some vascular malformations and some functional circulatory disturbances are also possible, as well as sequelae of panniculitis or borreliosis.

A mutant receptor with enhanced dominant-negative activity for the blockade of human prolactin signalling.

An effective mechanism for interfering with prolactin signalling would provide a powerful tool for clarifying the importance of prolactin in breast cancer, as well as for investigating functions of prolactin in other tissues. Based on our previous identification of a dominant-negative mutation in the growth hormone receptor that causes familial short stature, we investigated the potential for using a similar truncated mutant of the prolactin receptor (PRLR1-242). Like the mutant growth hormone receptor, PRLR1-242 exerts an exceptionally powerful dominant-negative effect. A probable explanation for the strong dominant-negative activity of this class of mutation is that, lacking internalisation motifs, the truncated mutants accumulate at the cell surface and form non-functional heterodimers with wild-type receptors. In accordance with evidence for heterodimer formation between the two receptors, PRLR1-242 also blocks signalling by the growth hormone receptor. When expressed from an adenoviral vector, PRLR1-242 inhibits activation of STAT5 (signal transducer and activator of transcription 5) by prolactin in T47-D breast cancer cells, and blocks the ability of prolactin to induce proliferation in these cells. Thus PRLR1-242 provides an effective means of blocking the responsiveness of target tissues to human prolactin.

[Medication of the month. Lowette, a contraceptive for treating acne in young women]. / Le médicament du mois. Lowette, un contraceptif pour traiter l'acné de la jeune femme.

Acne is a multifactorial disorder affecting the vast majority of adolescents and young adults. Among the therapeutic armamentum, estroprogestative contraception can be offered to young women. The choice must, however, be carefully targeted because the estroprogestative associations do not show similar anti-acne efficacy. A new contraceptive associating 20 micrograms of ethinyl estradiol and 100 micrograms of levonorgestrel (Lowette) has proven its clinical efficacy in this indication.

Responsive corneosurfametry following in vivo skin preconditioning.

Skin is subjected to many environmental threats, some of which altering the structure and function of the stratum corneum. Among them, surfactants are recognized factors that may influence irritant contact dermatitis. The present study was conducted to compare the variations in skin capacitance and corneosurfametry (CSM) reactivity before and after skin exposure to repeated subclinical injuries by 2 hand dishwashing liquids. A forearm immersion test was performed on 30 healthy volunteers. 2 daily soak sessions were performed for 5 days. At inclusion and the day following the last soak session, skin capacitance was measured and cyanoacrylate skin-surface strippings were harvested. The latter specimens were used for the ex vivo microwave CSM. Both types of assessments clearly differentiated the 2 hand dishwashing liquids. The forearm immersion test allowed the discriminant sensitivity of CSM to increase. Intact skin capacitance did not predict CSM data. By contrast, a significant correlation was found between the post-test conductance and the corresponding CSM data. In conclusion, a forearm immersion test under realistic conditions can discriminate the irritation potential between surfactant-based products by measuring skin conductance and performing CSM. In vivo skin preconditioning by surfactants increases CSM sensitivity to the same surfactants.

[How I treat ... the athlete's foot and its non-mycotic cutaneous pathology]. / Comment je traite ... le pied du sportif et sa pathologie cutanée non mycosique.

Skin and nails of the foot of sport practitioners of various disciplines are subjected to the effects of benign but invalidating pathologies. Microtraumatisms are frequently involved. Beside dermatomycoses and onychomycoses, a dozen of typical disorders are identified.

[Aroma and perfume allergy: anathema for some epicurean appeal?]. / L'allergie aux arômes et parfums: anathème sur un attrait épicurien?

Aromas and fragrances are present in many cosmetics, some topical drugs, food and various hygiene, household and industrial products. They can be responsible for contact dermatitis. Multiple sensitizations can even involve in various combinations some fragrance compounds, a given degradation product or a contaminant. The diagnosis relies on clinical examination and oriented anamnesis. A histological examination is sometimes necessary. Specific path testing brings insight on the culprit chemical compounds.

[How I explore ... A cutaneous scleroderma using noninvasive methods]. / Comment j'explore.... Une sclérodermie cutanée d'une manière non invasive.

There exists several clinical types of scleroderma. Most of them show cutaneous manifestations. Skin involvement may be isolated (morphea) or be part of a multi-organ systemic disease. Objective non-invasive functional methods are useful in order to better assess the severity and evolution of the disease and the effects of treatments. Measurements of the thickness and mechanical properties of the skin as well as the visualization of the cutaneous blood flow prove to be informative.

Nudging hair shedding by antidandruff shampoos. A comparison of 1% ketoconazole, 1% piroctone olamine and 1% zinc pyrithione formulations.

Hair shedding and hair thinning have been reported to be affected by dandruff and seborrhoeic dermatitis. The present study was conducted in 150 men presenting with telogen effluvium related to androgenic alopecia associated with dandruff. They were randomly allocated to three groups receiving each one of the three shampoos in the market containing either 1% ketoconazole (KTZ), 1% piroctone olamine (PTO) or 1% zinc pyrithione (ZPT). Shampoos had to be used 2-3 times a week for 6 months. Hair shedding during shampoo was evaluated semiquantitatively. Hair density on the vertex was evaluated on photographs using a Dermaphot. Trichograms were used for determining the anagen hair percentage and the mean proximal hair shaft diameter using computerized image analysis. The sebum excretion rate (SER, mug cm(-2) h(-1)) was also measured using a Sebumeter. The three treatments cleared pruritus and dandruff rapidly. At end point, hair density was unchanged, although hair shedding was decreased (KTZ: -17.3%, PTO: -16.5%, ZPT: -10.1%) and the anagen hair percentage was increased (KTZ: 4.9%, PTO: 7.9%, ZPT: 6.8%). The effect on the mean hair shaft diameter was contrasted between the three groups of volunteers (KTZ: 5.4%, PTO: 7.7%, ZPT: -2.2%). In conclusion, telogen effluvium was controlled by KTZ, PTO and ZPT shampoos at 1% concentration. In addition, KTZ and PTO increased the mean hair shaft thickness while discretely decreasing the sebum output at the skin surface.