syphilitic chancres of the mouth three cases

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Azithromycin SR versus minocycline in the treatment of moderate to severe acne: a phase III, multicentre, randomized, non-inferiority trial

Introduction: The primary objective of this phase III, multicentre, randomized trial was to evaluate whether azithromycin SR (azithromycin microspheres, powder for oral suspension) was non-inferior to oral minocycline in the treatment of moderate to severe acne. The primary efficacy endpoint was the change from baseline in the GAGS score. Secondary endpoints included changes from baseline in the Leeds score and quality of life (QoL). Methods: A total of 118 patients were randomized (1:1) to receive azithromycin SR (2 g/week) (n = 58) or minocycline (100 mg q.d.) (n = 60) for eight weeks. Results: The change from baseline to end of treatment in GAGS score did not differ significantly between the azithromycin SR and minocycline groups [least squares mean -8.69 (95% confidence interval [CI]: -10.33 to -7.05) and -9.16 (95% CI: -10.62 to -7.71), respectively], consistent with the noninferiority of azithromycin SR to minocycline. The lower limit of 95% confidence interval of the change from baseline to end of treatment in GAGS scores between the 2 groups (95% CI: -2.48 to 1.54) did not exceed the pre-defined non-inferiority margin of -3. In addition, there were no significant differences in improvement of acne graded by the Leeds score and QoL. Twenty-six patients (44.8%) in the azithromycin SR group and 9 patients (15%) in the minocycline group reported gastro-intestinal disorders. Conclusions: In patients with moderate to severe acne, azithromycin SR is non-inferior to minocycline for primary endpoint (GAGS score), with no significant differences in secondary endpoints

Vegetating nodules following erosions on the oral cavity : a quiz

Acta Derm Venereol 95 © 2015 The Authors. doi: 10.2340/00015555-1936 Journal Compilation © 2015 Acta Dermato-Venereologica. ISSN 0001-5555 A 68-year-old Italian man presented with a 7-month history of multiple erosions on the trunk as well as lips and oral cavity. Before admission to our department, he was treated in another institution with systemic corticosteroids (oral prednisone at the initial dose of 1 mg/kg/day, with progressively tapering dosages for 2 months) and other immunosuppressants, such as azathioprine (1.25 mg/kg/ day for 2 months), intravenous immunoglobulins (one cycle consisting of one infusion of 400 mg/kg/day for 5 consecutive days), and rituximab (one cycle consisting of one infusion of 375 mg/m2/every week for 4 weeks), achieving resolution of the cutaneous manifestations but without control of the oral involvement. Upon admission, he had multiple lip and oral erosions (Fig. 1a). In the following days, he developed erythematous-violaceous vegetating nodules that coalesced into ulcerated plaques on the lips and tongue (Fig. 1b). The patient's general condition was compromised; he was asthenic and, due to dysphagia, had lost about 15 kg in the last 3 months. Staging fibroscopy revealed nodules that induced marked stenosis of the larynx and pharynx (Fig. 1c). Within a few days, an emergency tracheotomy was required because of acute dyspnea. Biopsy specimens from a nodule were submitted for histology (Fig. 1d)

Attivazione della coagulazione nelle dermatosi bollose autoimmuni

Pemfigo volgare (PV) e pemfigoide bolloso (PB) sono dermatosi bollose di origine autoimmune che si differenziano principalmente per la sede di formazione delle bolle e per l\u2019intensit\ue0 del processo infiammatorio ad esse associato. Nel PV la bolla \ue8 infatti intraepidermica e consegue al danneggiamento delle giunzioni intercellulari dovuto al legame di autoanticorpi IgG con le desmogleine desmosomiali 3 e 1, mentre nel BP lo scollamento bolloso avviene a livello della giunzione dermoepidermica ed \ue8 causato da autoanticorpi diretti contro due antigeni emidesmosomiali, BP180 e BP 230. L\u2019infiltrato infiammatorio \ue8 denso e ricco in eosinofili nel BP e scarso nel PV. E\u2019 noto che l\u2019infiammazione attivi la cascata coagulatoria in diverse patologie. In questo studio abbiamo valutato l\u2019attivazione della coagulazione a livello sia locale che sistemico nel BP e nel PV. Sono stati studiati 20 pazienti affetti da BP (10 in fase attiva e 10 in remissione), 23 pazienti con PV (13 attivi e 10 in remissione) e 10 soggetti sani. Sono stati misurati due marcatori di attivazione della coagulazione, il frammento della protrombina F1+2 e il D-dimero, con metodiche ELISA nel plasma dei pazienti e dei controlli. L\u2019espressione del tissue factor (TF), il principale iniziatore della cascata coagulatoria, \ue8 stata valutata con metodica immunoistochimica su campioni cutanei di 10 pazienti con PV, 10 pazienti con BP attivo e sulla cute sana di 10 controlli. I livelli plasmatici di F1+2 e D-dimero erano elevati nei pazienti con BP attivo (P = 0\ub7001), mentre nel PV attivo i livelli di entrambi i parametri erano normali. In fase di remissione i livelli plasmatici di F1+2 e D-dimero erano normali sia nel BP che nel PV. E\u2019 stata dimostrata immunoreattivit\ue0 cutanea per TF nel BP attivo ma non nel PV attivo n\ue9 nella cute sana. Lo score di reattivit\ue0 del TF era pi\uf9 elevato nel BP attivo rispetto ai controlli sani e al PV attivo (P = 0\ub70001). Non vi erano differenze nello score di TF tra PV attivo e controlli. In conclusione, il BP si associa ad attivazione della coagulazione che invece \ue8 assente nel PV. I nostri dati forniscono una possibile spiegazione fisiopatologica dell\u2019aumentato rischio trombotico osservato nei pazienti con BP ma non in quelli con PV

Espressione di tissue factor da parte degli eosinofili in pazienti con orticaria cronica

Sebbene numerosi casi di orticaria cronica siano attualmente considerati di origine autoimmune e associati alla presenza di autoanticorpi circolanti che inducono il rilascio di istamina, vi sono chiare evidenze sul ruolo fisiopatologico dell\u2019attivazione della coagulazione mediata dal tissue factor (TF), il principale iniziatore della cascata coagulatoria. E\u2019 stato di recente dimostrato che gli eosinofili, peraltro presenti nella cute lesionale di pazienti con orticaria cronica, sono la maggiore fonte di TF nel sangue umano. In questo studio abbiamo valutato se gli eosinofili esprimano TF nella cute lesionale di pazienti con orticaria cronica. Abbiamo studiato 20 pazienti con orticaria cronica grave, prelevando campioni bioptici cutanei da lesioni pomfoidi attive. Come gruppo di controllo sono stati utilizzati campioni di cute sana perilesionale ottenuti dall\u2019escissione chirurgica di diversi tipi di tumori cutanei (10 casi) e varie patologie cutanee caratterizzate da infiltrati usualmente privi di eosinofili, quali vasculite leucocitoclasica (7 casi), lichen planus (8 casi) e mastocitosi (3 casi). L\u2019espressione del TF \ue8 stata valutata con metodica immunoistochimica utilizzando un anticorpo monoclonale anti-TF. Sono stati inoltre eseguiti esperimenti di colocalizzazione del TF con la proteina cationica eosinofila (ECP), considerata un marcatore classico degli eosinofili, con la tecnica del doppio marcaggio mediante due anticorpi monoclonali specifici. In tutti i campioni di cute dei pazienti con orticaria cronica \ue8 stata osservata un\u2019intensa espressione del TF che era invece assente nei controlli normali (P=0.0001) e nelle malattie cutanee non eosinofilo-mediate (P=0.001-0.0001). Le indagini di doppio marcaggio per TF e ECP hanno dimostrato che le cellule positive per TF erano eosinofili. In conclusione, gli eosinofili rappresentano la principale fonte di TF nella cute lesionale di pazienti con orticaria cronica. I nostri risultati enfatizzano il ruolo di queste cellule nella fisiopatologia dell\u2019orticaria cronica fornendo il razionale per nuove strategie terapeutiche

Instability of short arm of acrocentric chromosomes : Lesson from non-acrocentric satellited chromosomes. Report of 24 unrelated cases

Satellited non-acrocentric autosomal chromosomes (ps-qs-chromosomes) are the result of an interchange between sub- or telomeric regions of autosomes and the p arm of acrocentrics. The sequence homology at the rearrangement breakpoints appears to be, among others, the most frequent mechanism generating these variant chromosomes. The unbalanced carriers of this type of translocation may or may not display phenotypic abnormalities. With the aim to understand the causative mechanism, we revised all the ps-qs-chromosomes identified in five medical genetics laboratories, which used the same procedures for karyotype analysis, reporting 24 unrelated cases involving eight chromosomes. In conclusion, we observed three different scenarios: true translocation, benign variant and complex rearrangement. The detection of translocation partners is essential to evaluate possible euchromatic unbalances and to infer their effect on phenotype. Moreover, we emphasize the importance to perform both, molecular and conventional cytogenetics methods, to better understand the behavior of our genome

Eomesodermin controls a unique differentiation program in human IL-10 and IFN-γ coproducing regulatory T cells

Whether human IL-10-producing regulatory T cells (“Tr1”) represent a distinct differentiation lineage or an unstable activation stage remains a key unsolved issue. Here, we report that Eomesodermin (Eomes) acted as a lineage-defining transcription factor in human IFN-γ/IL-10 coproducing Tr1-like cells. In vivo occurring Tr1-like cells expressed Eomes, and were clearly distinct from all other CD4 + T-cell subsets, including conventional cytotoxic CD4 + T cells. They expressed Granzyme (Gzm) K, but had lost CD40L and IL-7R expression. Eomes antagonized the Th17 fate, and directly controlled IFN-γ and GzmK expression. However, Eomes binding to the IL-10 promoter was not detectable in human CD4 + T cells, presumably because critical Tbox binding sites of the mouse were not conserved. A precommitment to a Tr1-like fate, i.e. concominant induction of Eomes, GzmK, and IFN-γ, was promoted by IL-4 and IL-12-secreting myeloid dendritic cells. Consistently, Th1 effector memory cells contained precommitted Eomes + GzmK + T cells. Stimulation with T-cell receptor (TCR) agonists and IL-27 promoted the generation of Tr1-like effector cells by inducing switching from CD40L to IL-10. Importantly, CD4 + Eomes + T-cell subsets were present in lymphoid and nonlymphoid tissues, and their frequencies varied systemically in patients with inflammatory bowel disease and graft-versus-host disease. We propose that Eomes + Tr1-like cells are effector cells of a unique GzmK-expressing CD4 + T-cell subset

Claudin-1 Is a p63 Target Gene with a Crucial Role in Epithelial Development

The epidermis of the skin is a self-renewing, stratified epithelium that functions as the interface between the human body and the outer environment, and acts as a barrier to water loss. Components of intercellular junctions, such as Claudins, are critical to maintain tissue integrity and water retention. p63 is a transcription factor essential for proliferation of stem cells and for stratification in epithelia, mutated in human hereditary syndromes characterized by ectodermal dysplasia. Both p63 and Claudin-1 null mice die within few hours from birth due to dehydration from severe skin abnormalities. These observations suggested the possibility that these two genes might be linked in one regulatory pathway with p63 possibly regulating Claudin-1 expression. Here we show that silencing of ΔNp63 in primary mouse keratinocytes results in a marked down-regulation of Claudin-1 expression (−80%). ΔNp63α binds in vivo to the Claudin-1 promoter and activates both the endogenous Claudin-1 gene and a reporter vector containing a –1.4 Kb promoter fragment of the Claudin-1 gene. Accordingly, Claudin-1 expression was absent in the skin of E15.5 p63 null mice and natural p63 mutant proteins, specifically those found in Ankyloblepharon–Ectodermal dysplasia–Clefting (AEC) patients, were indeed altered in their capacity to regulate Claudin-1 transcription. This correlates with deficient Claudin-1 expression in the epidermis of an AEC patient carrying the I537T p63 mutation. Notably, AEC patients display skin fragility similar to what observed in the epidermis of Claudin-1 and p63 null mice. These findings reinforce the hypothesis that these two genes might be linked in a common regulatory pathway and that Claudin-1 may is an important p63 target gene involved in the pathogenesis of ectodermal dysplasias

Array-based comparative genomic hybridization analysis of aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (AECD8+L), extranodal NK/T nasal type lymphoma (ENK/T-NT) and blastic plasmocytoid dendritic cell neoplasia (BPDCN)

To better define molecular alterations involved in these proliferations, we performed an arraybased high resolution comparative genomic hybridization (aCGH) analysis on DNA extracted from skin lesions of 13 patients affected from AECD8+L, 5 patients from ENK/T-NT and 21 patients from BPDCN. In AECD8+ lymphoma, our results showed recurrent alterations of chromosomal regions found also in other CTCL, such as amplification of 3p21 (46% of patients), 7q (54%), 8q24 (54%), 16p(77%), 17q (92%), and the deletion of 9p21 (69%), and several alterations seemingly typical for AECD8+L: i.e. amplification of 11q12-q13 (69%), 22q (69%) and trisomy of 19 (69%). Within these amplified regions, the combination of duplication of JAK3 (chr. 19p13.11) and STAT3/STAT5B (chr. 17q21) might explain the hyper-activation of JAK / STAT signaling pathway, with an increased proliferation and an increased anti apoptotic activity. Interestingly, constitutive Jak3 signaling in murine lymphopoiesis, in a bone marrow transplantation model, induces an aggressive lymphoproliferative disorder characterized by the expansion of CD8+, TCR\u3b1\u3b2+ T cells. In addition chromosome 19 contains several genes that can lead to uncontrolled proliferation of cells if overexpressed, such as JUNB, JUND, KIR3DL2, AKT2, LYL1, BCL3 and RELB, alone or in combination with the proto-oncogene RELA, present in the amplified region 11q12-q13. A retrospective case study of 5 white patients affected by ENK/T lymphoma (4 PC-ENK/T-NT and 1 ENK/T-N with cutaneous involvement) was also performed. Genomic alterations were detected by aCGH hybridization that showed gains of 1q, 7q and loss of 17p in the cases of PC-ENK/T-NT lymphomas and gain of 7q and loss of 9p, 12p, 12q in the case of ENK/T-N lymphoma. In our cases, the exclusively cutaneous presentation was not associated with a better prognosis. BPDCN is a rare, often fatal disease: all patients had skin lesions, 12 with extracutaneous disease at diagnosis. By aCGH there were chromosomal imbalances in all biopsies, with an average of 7 copy number alterations/case and losses more frequent than gains (141 vs 18); large interstitial/telomeric imbalances prevailing over the entire chromosome losses/gains (127 vs 32). Common deleted regions (CDR) were found on chromosomes 5, 7, 9, 12, 13 and 14. A CDR at 9p21.3, hosting CDKN2A suppressor gene (P16INK4a, p14ARF), was present in 15 cases; 6 in biallelic status. Chromosome 13 monosomy was found in 11 cases and we identified a minimal CDR on 13q13.1-q14.3, including RB1, CCNA1 and KPNAP3. In 12 cases a monoallelic CDR encompassed 12p13.2-p13.1, hosting CDKN1B (p27/KIP1). Additionally, 4 patients had del(7)(p12), a region harbouring IKZF/Ikaros, defective in cases of acute lymphoblastic leukaemia with poor prognosis. In conclusion, AECD8+L, PC_ENK/T-NT and BPDCN are aggressive neoplastic diseases showing complex genetic alterations, involving activation, proliferations and apoptosis, that may explain the poor response to therapy. These data, complemented with gene expression analysis and immunohistochemical evaluation should help us in deciphering biologic and molecular mechanisms of these disease entities and may become important tools in diagnosis and classification or to find new therapeutic approaches