Clinical features and histological findings are potential indicators of activity in lesions of common vitiligo.

BACKGROUND: Unstable vitiligo lesions are usually considered to be contraindications for surgical treatment. Unfortunately, in the majority of common vitiligo cases, neither accurate clinical signs nor routine blood tests are available to determine whether or not the disease is active. OBJECTIVES: To establish a direct correlation between the clinical aspect of vitiligo lesions and their activity. METHODS: This was a prospective observational study that took place over 1 year. For each patient, a standardized evaluation included both a careful daylight and Wood's lamp examination, pictures, biopsies performed at the marginal area and histological and immunohistological studies. A second examination to assess the activity of the lesions correctly was performed 1 year after inclusion in the study. Both the clinical changes and the histological features of the lesions in actively spreading vitiligo were compared with those in stable vitiligo. RESULTS: This study included 50 patients. The lesions were classified as hypomelanotic with poorly defined borders (HPDB, 29 cases) or amelanotic with sharply demarcated borders (ASDB, 21 cases). One year after the biopsy, of the 48 patients still in the study, 20 had lesions that were considered to be stable and 28 had active lesions. Correlations were successfully obtained between clinical aspects, histological findings and vitiligo activity. The HPDB and ASDB lesions were correlated respectively with active and stable status (P < 0·001). CONCLUSIONS: A simple clinical examination including a Wood's lamp examination may allow reliable and efficient evaluation of the stability of vitiligo lesions.

Revised classification/nomenclature of vitiligo and related issues: the Vitiligo Global Issues Consensus Conference.

During the 2011 International Pigment Cell Conference (IPCC), the Vitiligo European Taskforce (VETF) convened a consensus conference on issues of global importance for vitiligo clinical research. As suggested by an international panel of experts, the conference focused on four topics: classification and nomenclature; definition of stable disease; definition of Koebner's phenomenon (KP); and 'autoimmune vitiligo'. These topics were discussed in seven working groups representing different geographical regions. A consensus emerged that segmental vitiligo be classified separately from all other forms of vitiligo and that the term 'vitiligo' be used as an umbrella term for all non-segmental forms of vitiligo, including 'mixed vitiligo' in which segmental and non-segmental vitiligo are combined and which is considered a subgroup of vitiligo. Further, the conference recommends that disease stability be best assessed based on the stability of individual lesions rather than the overall stability of the disease as the latter is difficult to define precisely and reliably. The conference also endorsed the classification of KP for vitiligo as proposed by the VETF (history based, clinical observation based, or experimentally induced). Lastly, the conference agreed that 'autoimmune vitiligo' should not be used as a separate classification as published evidence indicates that the pathophysiology of all forms of vitiligo likely involves autoimmune or inflammatory mechanisms.

Halo naevi and leukotrichia are strong predictors of the passage to mixed vitiligo in a subgroup of segmental vitiligo.

BACKGROUND: Until now, segmental vitiligo has been considered as a stable entity and mixed vitiligo, the association of segmental and nonsegmental vitiligo, has been reported rarely. OBJECTIVES: The aim of this study was to search for factors associated with the generalization of vitiligo in patients with segmental vitiligo. PATIENTS AND METHODS: This was a prospective observational study conducted in the vitiligo clinic of the Department of Dermatology of Bordeaux, France. The Vitiligo European Task Force questionnaire was completed for each patient attending the clinic with a confirmed diagnosis of segmental vitiligo after exclusion of other forms of vitiligo (focal, mucosal, not classifiable.) Thyroid function and antithyroid antibodies were screened if not obtained in the previous year. RESULTS: One hundred and twenty-seven patients were recruited: 101 had segmental vitiligo and 26 had segmental vitiligo that evolved into mixed vitiligo; 56 were male and 71 were female. Most patients had onset of segmental vitiligo before the age of 18. When conducting multivariate analysis, we found the following to be independent factors associated with the evolution of patients' disease from segmental vitiligo to mixed vitiligo: initial percentage of body surface involvement of the segment >1% [odds ratio (OR) 15·14, P=0·002], the presence of halo naevi (OR 24·82, P=0·0001) and leukotrichia (OR 25·73, P=0·0009). CONCLUSIONS: Halo naevi association and leukotrichia at first consultation in segmental vitiligo are risk factors for the progression of segmental vitiligo to mixed vitiligo. In addition, this progression of segmental vitiligo to mixed vitiligo carries a stronger link if initial segmental involvement is situated on the trunk.

Different phenotypes of segmental vitiligo based on a clinical observational study.

BACKGROUND: Segmental vitiligo and generalized vitiligo are in general considered separate entities. However, clinico-epidemiological data on segmental vitiligo are scarce compared with those of generalized vitiligo. OBJECTIVE: To analyse the clinical profile and distribution pattern of lesions in segmental vitiligo patients. METHODS: Segmental vitiligo patients were examined and questioned in a prospective and retrospective setting. The distribution and extent of the lesions were evaluated using clinical photographs. RESULTS: Different phenotypes of segmental vitiligo were found, including the unilateral segmental type (124 patients; group 1), the bilateral segmental type (three patients; group 2) and the mixed segmental and generalized type (14 patients; group 3). Furthermore, lesions were present with (10%) or without associated halo naevi. The age of onset of segmental vitiligo (median 14years) was significantly different between the three subgroups (P=0.028). Extensive involvement of segmental vitiligo lesions on trunk and extremities was significantly (P=0.031) more observed in patients with a lower age of onset, while the generalized vitiligo lesions in the mixed vitiligo group were mostly very mild. Associated autoimmune diseases were reported in 11%, whereas a positive family history for vitiligo was present in 14.9% of patients. Lesions were not strictly dermatomal nor Blaschkolinear, although a typical recurring pattern could be observed. CONCLUSION: Our data provide clinical evidence that segmental vitiligo and generalized vitiligo are parts of the same disease spectrum and that segmental vitiligo could have a polygenetic background as well. Whether different aetiopathological mechanisms underlie the different clinical phenotypes of segmental vitiligo remain to be elucidated.

Melanocyte detachment after skin friction in non lesional skin of patients with generalized vitiligo.

BACKGROUND: In vitiligo, melanocytes are gradually lost in depigmented macules of the skin. The disappearance of melanocytes has, however, not been clearly observed and consequently the aetiology of the disease (autoimmune, neural, cytotoxic) is still elusive. The starting point of vitiligo macules is frequently determined by local conditions such as wounds and excoriations, but may also follow minor traumas such as pressure or repeated friction. This prominent feature is often neglected. OBJECTIVES: To clarify the biological consequences of repeated friction on the attachment and survival of melanocytes in non lesional vitiligo skin. METHODS: Light reproducible skin friction was performed for 4 min on the volar forearm of 18 patients with extensive vitiligo and five controls with normal healthy skin. Biopsies from the test area and control skin were taken at 1, 4, 24 and 48 h following friction. Serial sections were examined with standard light microscopy, transmission electron microscopy, histochemistry and immunohistochemistry (dihydroxyphenylalanine, HMB-45, E-cadherin and an early apoptosis marker, M30 cytoDEATH antibody). RESULTS: The observation of sections at 1 and 48 h after friction on vitiligo skin and at all time points in controls revealed no changes. In contrast, in vitiligo skin at 4 and 24 h after friction, several melanocytes had undergone detachment and were found in various suprabasal positions, including the stratum spinosum, granular layer, and within and outside the stratum corneum. CONCLUSIONS: Detachment and transepidermal elimination of melanocytes following minor mechanical trauma in non lesional vitiligo skin is probably the cause of depigmentation occurring in the isomorphic response (Koebner phenomenon). We propose that transepidermal elimination of melanocytes in vitiligo should be regarded as a possible mechanism of chronic loss of pigment cells, perhaps previously damaged by another process.

A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins.

The pituitary gland has provided unique insight into molecular mechanisms and regulatory factors controlling both differentiation and gene transcription. We identified Tpit, a novel T box factor only present in the two pituitary POMC-expressing lineages, the corticotrophs and melanotrophs, and apparently in no other tissue, including hypothalamic POMC neurons. In pituitary cells, Tpit activation of POMC gene transcription requires cooperation with Pitx1, the two factors binding to contiguous sites within the same regulatory element. In gain-of-function experiments, Tpit induces POMC expression in undifferentiated pituitary cells, indicating that it can initiate differentiation into POMC-expressing lineages. TPIT gene mutations were found in patients with isolated deficiency of pituitary POMC-derived ACTH, in support of an essential role of Tpit for differentiation of the pituitary POMC lineage.

Pitx3 activates mouse tyrosine hydroxylase promoter via a high-affinity binding site.

Tyrosine hydroxylase (TH) is the rate-limiting enzyme of dopamine and (nor)adrenaline biosynthesis. Regulation of its gene expression is complex and different regulatory mechanisms appear to be operative in various neuronal lineages. Pitx3, a homeodomain-containing transcription factor, has been cloned from neuronal tissues and, in the CNS, mouse Pitx3 is exclusively expressed in midbrain dopaminergic (MesDA) neurons from embryonic day 11 (E11). TH appears in these neurons at E11.5, consistent with a putative role of Pitx3 in TH transcription. We show that Pitx3 activates the TH promoter through direct interaction with a single high-affinity binding site within the promoter and that this site is sufficient for Pitx3 responsiveness. In contrast, we did not observe an effect of Nurr1, an orphan nuclear receptor essential for normal development of MesDA neurons, on TH promoter activity. Pitx3 activation of TH promoter activity appears to be cell-dependent suggesting that Pitx3 action may be modulated by other(s) regulatory mechanism(s) and factor(s).

Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells.

Within the nuclear receptor family, Nur77 (also known as NGFI-B) distinguishes itself by its ability to bind a target sequence (the NBRE) as a monomer and by its role in T-cell receptor (TCR)-induced apoptosis in T cells. We now report on a novel mechanism of Nur77 action that is mediated by homodimers. These dimers bind a Nur77 response element (NurRE), which has been identified as a target of CRH-induced Nur77 in the pro-opiomelanocortin (POMC) gene promoter. Both halves of the palindromic NurRE are required for responsiveness to physiological signals, like CRH in pituitary-derived AtT-20 cells. Similarly, in T-cell hybridomas, TCR activation induced NurRE but not NBRE reporters. The in vivo signaling function of Nur77 thus appears to be mediated by dimers acting on a palindromic response element of unusual spacing between its half-sites. This mechanism may represent the biologically relevant paradigm of action for this subfamily of orphan nuclear receptors.

[Stress and skin: experimental approach]. / Stress et peau: approche expérimentale.

The effects of electric stress on epidermal cell mitosis, sebum production, hair growth and tumor induction, was studied in laboratory using Maynert and Levi's technique: reproducible electric stimulations were delivered in mice or hamsters in order to induce standardised stress. Such repeated stimulations increase cutaneous catecholamine concentrations in the early period. Repeated stress induce a decrease in keratinocyte and melanocyte mitoses, an increase of sebaceous excretion, and favours the development of outset of photoinduced tumors. The possible involvement of these data in human dermatopathology and clinical dermatology are discussed for each impaired cutaneous function: mitoses, hair growth, sebaceous function and anti-tumoral immunity.

Ptx1, a bicoid-related homeo box transcription factor involved in transcription of the pro-opiomelanocortin gene.

The pituitary gland contains six distinct hormone-producing cell types that arise sequentially during organogenesis. The first cells to differentiate are those that express the pro-opiomelanocortin (POMC) gene in the anterior pituitary lobe. The other lineages, which appear later, include cells that are dependent on the POU factor Pit-1 and another POMC-expressing lineage in the intermediate pituitary lobe. Using AtT-20 cells as a model for early expression of POMC in the anterior pituitary, we have defined a regulatory element conferring cell specificity of transcription and cloned a cognate transcription factor. This factor, Ptx1 (pituitary homeo box 1), contains a homeo box related to those of the anterior-specific genes bicoid and orthodenticle in Drosophila, and Otx-1 and Otx-2 in mammals. Ptx1 activates transcription upon binding a sequence related to the Drosophila bicoid target sites. Ptx1 is the only nuclear factor of this DNA-binding specificity that is detected in AtT-20 cells, and it is expressed at high levels in a subset of adult anterior pituitary cells that express POMC. However, Ptx1 is expressed in most cells of Rathke's pouch at an early time during pituitary development and before final differentiation of hormone-producing cells. Thus, Ptx1 may have a role in differentiation of pituitary cells, and its early expression pattern suggests that it may have a role in pituitary formation. In the adult pituitary gland, Ptx1 appears to be recruited for cell-specific transcription of the POMC gene.

Effect of iron and phagocytosis on murine macrophage activation in vitro.

Iron-exposed murine macrophages have a modified bactericidal activity as shown by previous observations. In order to assess the role of iron in macrophage activation, as measured by free radical production and by intracellular bacterial killing, murine peritoneal macrophages were cultivated in the presence of various sources of iron, human iron-saturated transferrin and ammonium ferric citrate, or iron chelators, Desferal, and human Apo-transferrin, and were infected with an enteropathogenic strain of E. coli. The release of nitrite (NO2-), and the production of superoxide anion (O2-) and hydrogen peroxide (H2O2) by the phagocytes were measured and compared to the production by uninfected macrophages. The synergistic action with murine r.IFN-gamma was also studied in the radical production reaction and for the bactericidal activity of macrophages. Our results show that in vitro phagocytosis of E. coli induced elevated production of NO2- and H2O2 by macrophages, and that oxygen derivatives were released independently of the presence of added iron or chelator. Despite a phagocytosis-related enhancement of NO2- release, reactive nitrogen intermediates (RNI) are not directly involved in the bactericidal mechanism, as revealed by increased intracellular killing owing to RNI inhibitors. Moreover, bacterial killing may depend on oxygen derivatives, as suggested by the effect of the antioxidant sodium ascorbate leading to both a diminished H2O2 production and a decreased bactericidal activity of macrophages.

Novel glucocorticoid receptor complex with DNA element of the hormone-repressed POMC gene.

Previous studies defined a DNA element necessary for glucocorticoid repression of the pro-opiomelanocortin (POMC) gene. The glucocorticoid receptor (GR) binds this negative glucocorticoid response element (nGRE) with an in vitro affinity similar to that of GR for positive GREs. However, whereas GR binds GREs as homodimers, a novel GR complex which forms with nGRE appears to contain three GR molecules. Biochemical characterization of this complex as well as equilibrium binding studies suggest that it is formed by sequential binding of a GR homodimer followed by binding of a GR monomer on the opposite side of the double helix. The DNA-binding domain (DBD) of GR is sufficient for differential binding of GRE and nGRE, as bacterially-expressed DBD formed unique nGRE complexes that contain three GR polypeptides. Thus, the POMC nGRE provides the first example of an interaction between GR and DNA in which GR binds otherwise than as a homodimer. Despite its high affinity for GR, the nGRE differs significantly from GREs in that it does not activate transcription in any context. As the nGRE appears insufficient on its own to confer hormone responsiveness, other POMC promoter elements are likely to be required to mediate glucocorticoid repression.

Autologous grafting with noncultured melanocytes: a simplified method for treatment of depigmented lesions.

BACKGROUND: Achromic lesions on the trunk and the extremities often do not respond to treatment and little improvement is obtained in cases of segmental vitiligo. OBJECTIVE: Transplantation of autologous noncultured melanocytes was performed to obtain a successful repigmentation. METHODS: The grafting method is carried out in two steps: production of blisters on the depigmented lesions by freezing with liquid nitrogen and injection in each blister of a suspension of epidermal cells (mainly keratinocytes and melanocytes). The cellular suspension was obtained from samples of skin of the hair scalp after trypsinization. RESULTS: Repigmentation was evident within 25 to 30 days. Coalescence of the pigmented areas was spontaneously observed or obtained after UVA stimulation. Patients with two types of leukoderma-vitiligo or nevus depigmentosus had successful repigmentation after transplantation of autologous noncultured melanocytes. CONCLUSION: This technique appears to be an effective and simple method for treating patients with achromic areas lacking melanocytes.

[Use of a disposable peroperative autotransfusion device in uncomplicated vascular surgery]. / Utilisation d'un dispositif d'autotransfusion peropératoire à usage unique en chirurgie vasculaire réglée.

We used a simple single process to recover total blood during surgery. All the process stands on a low burdensome jib and does not require additional staff in theater. Its cost is low. The indications concern all surgical operations enduring low or mean bleeding, except in septic and cancer surgery. It may be used in emergencies, even in war surgery with an incorporated source of depression.

Estrogenic regulation of murine uterine 90-kilodalton heat shock protein gene expression.

Murine uterine steady-state protein levels of the 90-kilodalton heat shock protein (HSP90) have been demonstrated recently to be increased by estrogen in a target tissue- and steroid-specific manner (C. Ramachandran, M.G. Catelli, W. Schneider, and G. Shyamala, Endocrinology 123:956-961, 1988). We now report that this regulation occurred with both the HSP86 and HSP84 forms of HSP90 as well as with the 94-kilodalton glucose-regulated protein. At the mRNA level, this response was greatest for HSP86 (15-fold). In contrast, estradiol had no significant effect on HSP70.

Effects of progesterone, promegestone and RU 486 on glucocorticoid receptor levels in primary cultures of mouse mammary epithelial cells.

Mammary epithelial cells isolated from midpregnant mice and cultured on collagen gels contain glucocorticoid receptors whose levels are modulated by a variety of steroids. In the absence of any added steroid to the cell culture medium, the levels of glucocorticoid receptors in the cells decline during culture, which is counteracted by the addition of a variety of glucocorticoid agonists. The effectiveness of the glucocorticoid in preventing the loss of glucocorticoid receptors is in turn counteracted by the addition of the synthetic progestin promegestone and the synthetic antiglucocorticoid RU 486. Of the two, RU 486 is the most potent in antagonizing the effect of cortisol on the GR levels. Promegestone antagonizes the effect of cortisol, too, although higher concentrations are necessary. Progesterone was without a clear effect either as a glucocorticoid agonist or an antagonist. Progesterone, however, was extensively metabolized by mammary epithelial cells in culture. Based on these observations we conclude that in mammary epithelial cells glucocorticoids positively regulate the metabolism of their own receptors and that antiglucocorticoids, such as RU 486 and progestins, can antagonize that effect.

[Intraoperative autotransfusion of traumatic hemoperitoneum in emergency surgery]. / L'auto-transfusion per-opératoire d'hémopéritoines traumatiques en chirurgie d'urgence.

The système à lavage globulaire was used for intraoperative auto-transfusion of adult patients with traumatic hemoperitoneum. This method provides a rapid supply of blood of large amount and of quality superior to that supplied by a blood-bank: a massive autologous transfusion carries less risk of complications than a homologous transfusion. Although this procedure is without risk to patients it is essential to comply with its contraindications (rupture of a hollow organ for the septic risk and existence of a neoplasm for the dissemination risk) and also its precautions in use, mainly the combined use of frozen fresh plasma beyond a certain autotransfused quantity of blood (about 1,200 cc). This latter problem of supplementary supply of coagulation factor is identical to that raised by massive homologous transfusion.