is a member of the skin microbiota found predominantly in regions rich in sebaceous glands. It is involved in maintaining healthy skin and has long been considered a commensal bacterium. Its ...involvement in various infections has led to its emergence as an opportunist pathogen. Interactions between
and the human host, including the human skin microbiota, promote the selection of
strains capable of producing several virulence factors that increase inflammatory capability. This pathogenic property may be related to many infectious mechanisms, such as an ability to form biofilms and the expression of putative virulence factors capable of triggering host immune responses or enabling
to adapt to its environment. During the past decade, many studies have identified and characterized several putative virulence factors potentially involved in the pathogenicity of this bacterium. These virulence factors are involved in bacterial attachment to target cells, polysaccharide-based biofilm synthesis, molecular structures mediating inflammation, and the enzymatic degradation of host tissues.
, like other skin-associated bacteria, can colonize various ecological niches other than skin. It produces several proteins or glycoproteins that could be considered to be active virulence factors, enabling the bacterium to adapt to the lipophilic environment of the pilosebaceous unit of the skin, but also to the various organs it colonizes. In this review, we summarize current knowledge concerning characterized
virulence factors and their possible implication in the pathogenicity of
.
Abstract Lichen planus (LP) is an inflammatory disease of the stratified squamous epithelia of unknown etiology. LP affects most frequently the oral mucosa, but it may also involve other mucosa and ...the skin. Oral LP (OLP) most frequently affects woman aged between 30 and 60 years. Histopathologic examination typically shows orthokeratotic hyperkeratosis, basal cell degeneration, and a dense well-defined infiltrate of lymphocytes in the superficial dermis. OLP lesions may result from the induction of keratinocytes apoptosis by cytotoxic CD8+ T cells stimulated by a yet unidentified self-antigen on a genetically predisposed patient. The association of OLP with hepatitis C virus (HCV) has been more consistently demonstrated in the Mediterranean area. Although HCV RNA and HCV-specific CD4+ and CD8+ T cells have been retrieved in the mucosal lesions of patients with chronic HCV infection and OLP, the eventual pathophysiology of HCV in OLP lesions remains unclear. Available treatments of OLP are not curative, and many have potentially prominent side effects. The objectives of OLP management should be to prevent and screen for malignant transformation and alleviate symptoms on the long-term. Avoidance of potential precipitating drugs, tobacco, alcohol, and local trauma, as well as strict oral hygiene, is essential. The first-line pharmacologic treatment relies on topical steroids. Systemic steroids should be limited to the short-term cure of severe refractory OLP. Life-long clinical follow-up, at least annually, is fundamental.
Summary Background High doses of corticosteroids are considered the standard treatment for pemphigus. Because long-term corticosteroid treatment can cause severe and even life-threatening ...side-effects in patients with this disease, we assessed whether first-line use of rituximab as adjuvant therapy could improve the proportion of patients achieving complete remission off-therapy, compared with corticosteroid treatment alone, while decreasing treatment side-effects of corticosteroids. Methods We did a prospective, multicentre, parallel-group, open-label, randomised trial in 25 dermatology hospital departments in France (Ritux 3). Eligible participants were patients with newly diagnosed pemphigus aged 18–80 years being treated for the first time (not at the time of a relapse). We randomly assigned participants (1:1) to receive either oral prednisone alone, 1·0 or 1·5 mg/kg per day tapered over 12 or 18 months (prednisone alone group), or 1000 mg of intravenous rituximab on days 0 and 14, and 500 mg at months 12 and 18, combined with a short-term prednisone regimen, 0·5 or 1·0 mg/kg per day tapered over 3 or 6 months (rituximab plus short-term prednisone group). Follow-up was for 3 years (study visits were scheduled weekly during the first month of the study, then monthly until month 24, then an additional visit at month 36). Treatment was assigned through central computer-generated randomisation, with stratification according to disease-severity (severe or moderate, based on Harman's criteria). The primary endpoint was the proportion of patients who achieved complete remission off-therapy at month 24 (intention-to-treat analysis). This study is registered with ClinicalTrials.gov , number NCT00784589. Findings Between May 10, 2010, and Dec 7, 2012, we enrolled 91 patients and randomly assigned 90 to treatment (90 were analysed; 1 patient withdrew consent before the random assignment). At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone (absolute difference 55 percentage points, 95% CI 38·4–71·7; p<0·0001. This difference corresponded to a relative risk of success of 2·61 (95% CI 1·71–3·99, p<0·0001), corresponding to 1·82 patients (95% CI 1·39–2·60) who would need to be treated with rituximab plus prednisone (rather than prednisone alone) for one additional success. No patient died during the study. More severe adverse events of grade 3–4 were reported in the prednisone-alone group (53 events in 29 patients; mean 1·20 SD 1·25) than in the rituximab plus prednisone group (27 events in 16 patients; mean 0·59 1·15; p=0·0021). The most common of these events in both groups were diabetes and endocrine disorder (11 21% with prednisone alone vs six 22% with rituximab plus prednisone), myopathy (ten 19% vs three 11%), and bone disorders (five 9% vs five 19%). Interpretation Data from our trial suggest that first-line use of rituximab plus short-term prednisone for patients with pemphigus is more effective than using prednisone alone, with fewer adverse events. Funding French Ministry of Health, French Society of Dermatology, Roche.
This paper elaborates compact MIP formulations for a discrete unit commitment problem with minimum stop and ramping constraints. The variables can be defined in two different ways. Both MIP ...formulations are tightened with clique cuts and local constraints. The projection of constraints from one variable structure to the other allows to compare and tighten the MIP formulations. This leads to several equivalent formulations in terms of polyhedral descriptions and thus in LP relaxations. We analyse how MIP resolutions differ in the efficiency of the cuts, branching and primal heuristics. The resulting MIP implementation allows to tackle real size instances for an industrial application.
PURPOSE OF REVIEWThis review is an update of the recent findings on pathophysiology of Kaposi sarcoma, the role of HHV-8 in Kaposi sarcoma pathogenesis and to summarize the recent advances in the ...treatment of Kaposi sarcoma and the role of immunity to control the disease.
RECENT FINDINGSThe causal agent of Kaposi sarcoma is HHV-8 and the mechanism by which HHV-8 drives the tumor development is unique. HHV-8 is not a classic oncogenic virus and the disease is an opportunistic tumor responding to immune restoration when it is possible.
SUMMARYFive epidemiologic types of Kaposi are recognized and HHV-8 is associated to all epidemiologic forms of Kaposi. HHV-8 is a virus favoring both angiogenesis and cellular proliferation, which are the two main histological features of Kaposi sarcoma. Although in many cases, treatment of Kaposi sarcoma is not necessary, specific chemotherapy, immunomodulation and immune stimulation are the tools for treating Kaposi sarcoma. Monochemotherapy has been shown to be as efficient as polychemotherapy and less toxic. Immune checkpoint inhibitors gave some promising results, which should be confirmed by prospective studies.
(
) has been implicated in inflammatory acne where highly mutated Christie-Atkins-Munch-Petersen factor (CAMP)1 displays strong toll like receptor (TLR)-2 binding activity. Using specific antibodies, ...we showed that CAMP1 production was independent of
phylotype and involved in the induction of inflammation. We confirmed that TLR-2 bound both mutated and non-mutated recombinant CAMP1, and peptide array analysis showed that seven peptides (A14, A15, B1, B2, B3, C1 and C3) were involved in TLR-2 binding, located on the same side of the three-dimensional structure of CAMP1. Both mutated and non-mutated recombinant CAMP1 proteins induced the production of C-X-C motif chemokine ligand interleukin (CXCL)8/(IL)-8 in vitro in keratinocytes and that of granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, IL-1β and IL-10 in ex vivo human skin explants. Only A14, B1 and B2 inhibited the production of CXCL8/IL-8 by keratinocytes and that of (GM-CSF), TNF-α, IL-1β and IL-10 in human skin explants stimulated with rCAMP1 and
. Following pretreatment with B2, RNA sequencing on skin explants identified the 10 genes displaying the strongest differential expression as
,
,
,
,
,
,
, chemokine ligand (
)
,
and colony stimulating factor (
)
. We, thus, identified a new CAMP1-derived peptide as a TLR-2 modulator likely to be a good candidate for clinical evaluation.
Background Treatment guidelines are lacking for classic Kaposi sarcoma. Objective We sought to review the evidence on efficacy of treatments for classic Kaposi sarcoma. Methods Articles published in ...English or French in MEDLINE, Trip, Cochrane Library, and Pascal databases from 1980 to December 2010 were screened. Studies reporting at least 5 patients treated for histologically confirmed classic Kaposi sarcoma were selected. Primary outcome was a decrease in the number or size of lesions or of lymphedema. We reviewed 26 articles matching the inclusion criteria for methodologic quality, classifying them according to World Health Organization criteria. Results The percentage of patients with a 50% or greater decrease in lesions was 71% to 100% for pegylated liposomal doxorubicin, 58% to 90% for vinca-alkaloids, 74% to 76% for etoposide, 93% to 100% for taxanes, 100% for gemcitabine, 97% for the combination of vinblastine and bleomycin, 71% to 100% for interferon alfa-2, 43% for thalidomide, and 12% for indinavir. For local treatments, a decrease of 50% or greater was achieved in 62% of lesions for intralesional vincristine, 50% to 90% for intralesional interferon alfa-2, 56% for imiquimod, and 25% for nicotine patches. A complete response was attained in 60% to 93% of lesions with radiotherapy. Limitations Eligible trials were of poor quality. The lack of standardized classification of disease activity and clinical outcomes precluded the comparison of studies. Conclusion The evidence for efficacy of any particular intervention is of low quality and does not support recommending any particular therapeutic strategy. Further studies are required and it will be important to standardize the assessment of disease activity and clinical response.
Although acne is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here we show that GATA6, which is expressed in the upper pilosebaceous unit ...of normal human skin, is down-regulated in acne. GATA6 controls keratinocyte proliferation and differentiation to prevent hyperkeratinisation of the infundibulum, which is the primary pathological event in acne. When overexpressed in immortalised human sebocytes, GATA6 triggers a junctional zone and sebaceous differentiation program whilst limiting lipid production and cell proliferation. It modulates the immunological repertoire of sebocytes, notably by upregulating PD-L1 and IL10. GATA6 expression contributes to the therapeutic effect of retinoic acid, the main treatment for acne. In a human sebaceous organoid model GATA6-mediated down-regulation of the infundibular differentiation program is mediated by induction of TGFβ signalling. We conclude that GATA6 is involved in regulation of the upper pilosebaceous unit and may be an actionable target in the treatment of acne.
Abstract Background Propionibacterium acnes ( P. acnes ) has been implicated in the inflammatory phase of acne vulgaris. It has been shown to activate interleukin-8 (IL-8) secretion by interacting ...with Toll-like receptor 2 (TLR-2) on the surface of keratinocytes. Nicotinamide has been shown to be an effective treatment for skin inflammation in various conditions, including acne vulgaris. Objective To investigate the molecular mechanisms underlying the anti-inflammatory properties of nicotinamide in keratinocytes stimulated by P. acnes. Methods HaCaT cells and primary keratinocyte cell lines were stimulated by P. acnes in the presence of nicotinamide. IL-8 production was monitored by ELISA on the cell culture supernatant and by qRT-PCR on total RNA extract. A luciferase reporter system assay was used to assess nicotinamide activity with the IL-8 promoter in transfected keratinocytes. We used western blotting to analyze the effect of nicotinamide on activation of the NF-κB and MAPK pathways. Results Nicotinamide significantly decreased IL-8 production in a dose-dependent manner, decreasing both mRNA and protein levels for this chemokine in immortalized HaCaT cells and primary keratinocytes. P. acnes -induced IL-8 promoter activation seemed to be downregulated by nicotinamide, which inhibited IκB degradation and the phosphorylation of ERK and JNK MAP kinases. Conclusion Our results indicate that nicotinamide inhibits IL-8 production through the NF-κB and MAPK pathways in an in vitro keratinocytes/ P. acnes model of inflammation. Keratinocytes involved in the innate immune response may be a suitable target for treatment during the early phase of inflammation.
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