Effectiveness of guselkumab in patients with facial and/or genital psoriasis: Interim analysis results at Week 12 from the GULLIVER study.

BACKGROUND: Facial (FP) and genital psoriasis (GP) significantly affect patients' quality of life. Despite the advances in treatments, limited data on efficacy and safety are available on these difficult-to-treat areas. Guselkumab is an interleukin (IL)-23 inhibitor which has been proven effective in treating patients with moderate-to-severe plaque psoriasis. OBJECTIVES: The aim of this interim analysis was to report the efficacy and safety of guselkumab in the treatment of patients with FP and/or GP. MATERIALS AND METHODS: GULLIVER is a 52-week Italian observational study to evaluate the effectiveness and safety of guselkumab in a real-life setting in patients with FP and/or GP. Adult patients with facial and/or genital moderate-to-severe psoriasis (sPGA score ≥ 3) were included. The primary endpoint of this analysis was the percentage of patients achieving a facial or genital sPGA score of 0 (clear) or 1 (almost clear), at Week 12. The change in the score of the facial or genital sPGA components in patients with a score ≥3 for each sPGA component was assessed. PASI score in patients with a baseline PASI above or below 10 was evaluated. RESULTS: Overall, 351 patients were included in the study; 83.3% of FP and 76.5% of GP patients achieved the primary endpoint. Similar response rates were observed for the facial or genital sPGA components in patients with a baseline facial or genital sPGA score ≥3 in each component. Among patients with a baseline PASI score >10, mean PASI score improved from 19.0 (SD 8.3) to 2.2 (SD 4.8). Forty-four AEs were observed in 32 patients; two mild and transient AEs (fatigue and nausea) were considered treatment related. No SAEs were observed. CONCLUSIONS: Guselkumab, showing to be effective and safe in treating FP and GP, may be a valid therapeutic option for patients with psoriasis localized in these difficult-to-treat areas.

Autoantibody profile and clinical patterns in 619 Italian patients with cutaneous lupus erythematosus.

BACKGROUND: Anti-nuclear antibodies (ANA), anti-extractable nuclear antigens (ENA) and anti-dsDNA antibodies are often associated with cutaneous lupus erythematosus (CLE), with variable frequency depending on skin subtype. However, specific data based on large case-series on the pathogenetic, diagnostic and prognostic meaning of such autoantibodies are still lacking. OBJECTIVE: To characterize the correlations between CLE subtypes as well as LE-non-specific skin lesions and their autoantibody pattern. METHODS: Epidemiological, clinical and immunopathological data of 619 Italian patients with CLE and LE-non-specific skin lesions were analysed. Differences in age, sex, clinical features and autoantibody profile were evaluated in each LE subgroup. RESULTS: Anti-nuclear antibodies (P < 0.0001), anti-dsDNA (P < 0.0001), ENA (P = 0.001), anti-Sm (P = 0.001), anti-RNP (P = 0.004) and anti-histone (P = 0.005) antibodies were associated with SLE. A strong association between ANA (P < 0.0001) and anti-dsDNA (P < 0.0001) and female gender was also found: positive ANA and positive anti-dsDNA had a higher prevalence among females. Chronic CLE resulted to be negatively associated with ENA (OR = 0.51, P < 0.0001), anti-Ro/SSA (OR = 0.49, P < 0.0001) and anti-dsDNA (OR = 0.37, P < 0.0001). Intermittent CLE resulted to be negatively associated with ENA (OR = 0.50, P = 0.007) and ANA (OR = 0.61, P = 0.025). Subacute CLE resulted to be associated with ENA (OR = 5.19, P < 0.0001), anti-Ro/SSA (OR = 3.83, P < 0.0001), anti-Smith (OR = 2.95, P = 0.004) and anti-RNP (OR = 3.18, P = 0.007). Acute CLE resulted to be strongly associated with anti-dsDNA (OR = 6.0, P < 0.0001) and ANA (OR = 18.1, P < 0.0001). LE-non-specific skin lesions resulted to be significantly associated with systemic involvement. Livedo reticularis was significantly associated with ENA (P = 0.007) and anti-Ro/SSA (P = 0.036). Palpable purpura and periungual telangiectasia were significantly associated with ANA. CONCLUSION: According to our findings, some well-known associations between CLE subtypes and autoantibody profile were confirmed; moreover, specific association between autoantibodies and LE-non-specific skin lesions was highlighted. A strict association between anti-ENA and anti-Ro/SSA antibodies and livedo reticularis, ANA and palpable purpura, and ANA and periungual telangiectasia was evidenced.

Evaluating the critical strain energy release rate of bioactive glass coatings on Ti6Al4V substrates after degradation.

It has been reported that the adhesion of bioactive glass coatings to Ti6Al4V reduces after degradation, however, this effect has not been quantified. This paper uses bilayer double cantilever (DCB) specimens to determine GIC and GIIC, the critical mode I and mode II strain energy release rates, respectively, of bioactive coating/Ti6Al4V substrate systems degraded to different extents. Three borate-based bioactive glass coatings with increasing amounts of incorporated SrO (0, 15 and 25mol%) were enamelled onto Ti6Al4V substrates and then immersed in de-ionized water for 2, 6 and 24h. The weight loss of each glass composition was measured and it was found that the dissolution rate significantly decreased with increasing SrO content. The extent of dissolution was consistent with the hypothesis that the compressive residual stress tends to reduce the dissolution rate of bioactive glasses. After drying, the bilayer DCB specimens were created and subjected to nearly mode I and mode II fracture tests. The toughest coating/substrate system (one composed of the glass containing 25mol% SrO) lost 80% and 85% of its GIC and GIIC, respectively, in less than 24h of degradation. The drop in GIC and GIIC occurred even more rapidly for other coating/substrate systems. Therefore, degradation of borate bioactive glass coatings is inversely related to their fracture toughness when coated onto Ti6A4V substrates. Finally, roughening the substrate was found to be inconsequential in increasing the toughness of the system as the fracture toughness was limited by the cohesive toughness of the glass itself.

Quantifying the mode II critical strain energy release rate of borate bioactive glass coatings on Ti6Al4V substrates.

Bioactive glasses have been used as coatings for biomedical implants because they can be formulated to promote osseointegration, antibacterial behavior, bone formation, and tissue healing through the incorporation and subsequent release of certain ions. However, shear loading on coated implants has been reported to cause the delamination and loosening of such coatings. This work uses a recently developed fracture mechanics testing methodology to quantify the critical strain energy release rate under nearly pure mode II conditions, GIIC, of a series of borate-based glass coating/Ti6Al4V alloy substrate systems. Incorporating increasing amounts of SrCO3 in the glass composition was found to increase the GIIC almost twofold, from 25.3 to 46.9J/m2. The magnitude and distribution of residual stresses in the coating were quantified, and it was found that the residual stresses in all cases distributed uniformly over the cross section of the coating. The crack was driven towards, but not into, the glass/Ti6Al4V substrate interface due to the shear loading. This implied that the interface had a higher fracture toughness than the coating itself.

New insights into potential risk factors and associations in genital lichen sclerosus: Data from a multicentre Italian study on 729 consecutive cases.

BACKGROUND: Limited data are available on risk factors associated with lichen sclerosus and no data are available on gender differences in genital lichen sclerosus (GLS). OBJECTIVE: This multicentre study aimed at identifying potential risk factors for GLS, through data collection from a large, mixed-sex sample of patients comparing gender-related differences in relation to data from the general population. METHODS: This was a cross-sectional study on 729 subjects (53.8% females, 46.2% males) affected with GLS, consecutively observed within a network of 15 Italian dermatology units. The following information was collected: demographic data, anthropometric measures, comorbidities, family history of LS, clinical features and symptoms related to GLS. RESULTS: Overweight and obesity, blood hypertension, hypothyroidism and an educational attainment equal or above upper secondary school level were more frequent among the study patients than among the general Italian population. Moreover, a family history of GLS was reported more frequently than expected among GLS patients. These factors were similar in males and females. The disease tended to occur later in females than in males. CONCLUSIONS: Our findings suggest that metabolic factors, and possibly a sedentary lifestyle, may play a role in GLS pathogenesis in genetically predisposed patients, and that risk profile is similar in males and females despite some difference in the onset of symptoms.

Phenotypical characterization of circulating cell subsets in pyoderma gangrenosum patients: the experience of the Italian immuno-pathology group.

BACKGROUND: No data are available as to the phenotype of circulating lymphocyte subsets in pyoderma gangrenosum (PG). AIM: To analyse the expression of different chemokine receptors associated to T-helper (Th)1 (CCR5), Th2 (CCR4) and Th17 (CCR6), as well as the regulatory T-cell subset (Treg) and dendritic cell polarization in the blood of newly diagnosed untreated PG patients. MATERIALS AND METHODS: Multi-parameter flow cytometry was performed on blood samples from 10 PG patients collected at first diagnosis among centres belonging to the Italian Immuno-pathology Group. Blood samples from 10 age- and sex-matched healthy controls (HC) were used as controls. RESULTS: PG patients are characterized by an over-expression in the blood of the CD4+CCR5+ and CD4+CCR6+ and a down-regulation of CD4+CCR4+ counts with respect to healthy subjects. Moreover, they show increased levels of myeloid derived dendritic cells type1 and reduced levels of the Treg CD4+CD25highFOXP3+ subset. CONCLUSIONS: The pattern of chemokine expression argues in favour of a Th1 (CCR5+) and Th17 (CCR6+) polarization with a down-regulation of Th2 (CCR4+).

Function of the centromedial amygdala in reward devaluation and open-field activity.

The present research aimed at determining the role played by the amygdala in reward devaluation using transient inactivation induced by lidocaine microinfusions into the centromedial region. Two situations involving reward devaluation were tested in rats: consummatory successive negative contrast (cSNC) and anticipatory negative contrast (ANC). In cSNC, rats exposed to a downshift from 32% to 4% sucrose consume less 4% sucrose than rats always exposed to 4% sucrose. Extensive evidence suggests that reward devaluation in the cSNC situation is accompanied by negative emotion. In ANC, rats consume less 4% sucrose when each session is closely followed by access to 32% sucrose rather than by 4% sucrose. Evidence suggests that reward devaluation in the ANC situation does not involve negative emotions; rather, ANC appears to involve Pavlovian anticipation of the higher value solution. To test the effects of lidocaine microinfusions in a situation known to induce negative emotion, but unrelated to reward devaluation, animals were also exposed to a lighted open field. Centromedial amygdala inactivation reduced the cSNC effect and increased exploratory behavior in the open field, both effects consistent with a reduction in negative emotional state. However, no detectable effects of amygdala inactivation were observed in the ANC situation. These results suggest that, first, the function of the amygdala is not unique to reward devaluation and, second, it is concerned with tagging the devaluation experience with aversive valence.

A project by the SIDeMaST Immunopathology Group on cutaneous vasculitis.

Vasculitides are a challenge to the clinician, in terms of both diagnosis and therapy. Multiple classification systems have been implemented and the numerous classification schemes reflect the complexity of establishing a simple classification that could be functional for daily care. Although vasculitis classification has become increasingly elaborated, some areas remain ill defined. Some forms of vasculitis are still difficult to assign to a specific disease entity. Generally accepted operational criteria are available for many vasculitides, but for some entities there are no effective criteria. Moreover, diagnostic criteria for vasculitis with sufficient strength and/or confidence that can be universally accepted are not yet available. The need for diagnostic criteria validated and agreed upon is particularly relevant in the context of cutaneous vasculitis. The project of the SIDeMaST Italian Group of Immunopathology on cutaneous vasculitis is a national prospective observational study designed to develop and validate diagnostic criteria and to improve and validate classification criteria for cutaneous small vessel vasculitis also known as leukocytoclastic vasculitis (CLV). Primary objective of the study will also be that of developing the CUtaneous VAsculitis Severity Index (CUVASI). Secondary objectives of the project will be: 1) definition of the etiological agents that are most frequently associated with CLV; 2) search for possible correlations between causative agent and peculiar clinical and/or histopathological aspects; 3) evaluation of immunofluorescence pattern observed in this specific group of primitive cutaneous vasculitis in order to characterize the diagnostic sensitivity and specificity of this technique; 4) identification of a set of clinical investigations and laboratory tests to be performed for a correct CLV assessment. Actually 15 Italian dermatological clinics are contributing to the project and anticipated recruiting >100 patients with CLV. A pilot retrospective study to assess the feasibility of the project is going to be launched and if its results are positive then the prospective study will be started and it promises to be a unique opportunity to evaluate a large database on CLV in Italian population.

Vasculitis associated with connective tissue diseases.

Vasculitis in connective tissue disease (CTD) is quite rare, it is reported in approximately 10% of patients with CTD; systemic lupus erythematosus (SLE) shows the highest association rate. Vessels of any size may be involved, but mainly small vessels vasculitis is reported. At present the classification of these vasculitis is unsatisfactory. According to the 2012 revised International Chapel Hill Consensus Conference, vasculitides secondary to CTD are a well identified entity and are classified under the category of "vasculitis associated with systemic disease". However only lupus vasculitis and rheumatoid vasculitis are explicitly listed, while the remaining are generically included under the heading "others". Petechiae, purpura, gangrene and ulcers are the most frequent cutaneous manifestations that should investigated in order to rule out potentially dangerous systemic involvement, especially if cryoglobulinemic or necrotizing vasculitis are suspected. This review will focus on the cutaneous involvement in CTD associated vasculitis.

Differences in clinicopathological features and distribution of risk factors in Italian melanoma patients.

BACKGROUND: No studies are available in the literature on the distribution of different melanoma features and risk factors in the Italian geographical areas. OBJECTIVE: To identify the differences in clinical-pathological features of melanoma, the distribution of risk factors and sun exposure in various Italian macro-areas. METHODS: Multicentric-observational study involving 1,472 melanoma cases (713 north, 345 centre, 414 south) from 26 referral centres belonging to the Italian Multidisciplinary Group for Melanoma. RESULTS: Melanoma patients in northern regions are younger, with thinner melanoma, multiple primaries, lower-intermediate phototype and higher counts of naevi with respect to southern patients; detection of a primary was mostly connected with a physician examination, while relatives were more involved in the south. Northern patients reported a more frequent use of sunbeds and occurrence of sunburns before melanoma despite sunscreen use and a lower sun exposure during the central hours of the day. CONCLUSIONS: The understanding of differences in risk factors distribution could represent the basis for tailored prevention programmes.

Validation of an original questionnaire for patients with psoriatic arthritis: the Psoriatic Arthritis Impact Profile (PAIP).

BACKGROUND AND AIMS: There is a wide evidence that Psoriatic Arthritis (PsA) as well as Psoriasis (Ps) lead to significant health problems and interfere with the patient quality of life (QoL). Even though a validated questionnaire for Ps is available, no questionnaire for PsA is currently present in literature. The aim of our work has been to confirm the efficacy of our original questionnaire as well as to validate it, through the comparison with other existing recognised and accepted questionnaires, such as MOF-SF36, HAQ, McGill Pain Questionnaire, and Zeung Self-Rating Depression and Anxiety Scales. MATERIALS AND METHODS: We have realized a questionnaire for PsA (Psoriatic Arthritis Impact Questionnaire, PAIP), in terms of psychological and rheumatological evaluation, QoL, social and economic assets. RESULTS: The statistical comparisons between PAIP and the accepted questionnaires (see above) confirm that PAIP is widely validated and represents a useful tool suitable for clinical evaluation and management of patients with PsA. CONCLUSIONS: The indexes of the correlation among the different parts of PAIP and the other questionnaires have shown positive correlations. Moreover, PAIP presents a dedicated unit for the economical and therapeutic parameters, The short time for compilation (15 minutes), the easy of comprehension of the questions, and - above all - the validation of PAIP, make our questionnaire a useful tool, suitable for the clinical management of the patients with PsA.

Flow cytometric analyses of circulating regulatory T cells in patients with dermatitis herpetiformis and other immune mediated dermatoses.

Regulatory T cells (Tregs) play a crucial role by maintaining the peripheral tolerance and inhibiting autoimmunity. In recent years, numerous autoimmune and immune-mediated diseases have been shown to present significant number depletion and/or function impairment of this subset. In the present study, we present a brief overview of the results obtained by our group in association with the centers belonging to the Italian Immunopathology Group, as to the expression levels and biological significance of circulating regulatory CD4+CD25+brightFOXP3+ T cells in a variety of immune-mediated skin diseases (such as psoriasis, scleroderma, bullous pemphigoid and GvHD), together with preliminary results achieved in patients with inflammatory bowel disease-related dermatoses. This review shows that this series of different cutaneous diseases characterised by an immune-mediated pathogenesis, share a significant down-regulation of circulating FOXP3+ Treg cells, whilst the treatment and the achievement of clinical response are generally associated with an opposite phenomenon with up-regulation of Treg cells. Future studies are mandatory to identify the effective role of these modifications in the disease pathogenesis as well as its relationship with the clinical response.

Stratigraphic context and paleoenvironmental significance of minor taxa (Pisces, Reptilia, Aves, Rodentia) from the late Early Pleistocene paleoanthropological site of Buia (Eritrea).

The Buia Homo site, also known as Wadi Aalad, is an East African paleoanthropological site near the village of Buia that, due to its very rich yield from the late Early Pleistocene, has been intensively investigated since 1994. In this paper, which reports on the finds of the 2010-2011 excavations, we include new fossil evidence on previously identified taxa (i.e., reptiles), as well as the very first description of the small mammal, fish and bird remains discovered. In particular, this study documents the discovery of the first African fossil of the genus Burhinus (Aves, Charadriiformes) and of the first rodent from the site. This latter is identified as a thryonomyid rodent (cane rat), a relatively common taxon in African paleoanthropological faunal assemblages. On the whole, the new occurrences documented within the Buia vertebrate assemblage confirm the occurrence of taxa characterized by strong water dependence. The paleoenvironmental characteristics of the fauna are confirmed as fully compatible with the evidence obtained through sedimentology and facies analysis, documenting the sedimentary evolution of fluvio-deltaic and lacustrine systems.

Dermatophytosis in animals: epidemiological, clinical and zoonotic aspects.

AIM: Dermatophytosis are the most frequent fungal infections of pets and livestock and play an important role in animal and human health due to their zoonotic potential. Another important aspect of these infections is linked to the economic consequences in farm animal and fur production systems. An overview of dermatophytosis in animals is described in this paper. Epidemiological, clinical and zoonotic aspects are addressed, considering individual species, both pets and farmed animals. METHODS: In particular, most recent investigations in the field of animal mycology, carried out in Central Italy, are reported, with particular reference to rabbit, ruminants, horse, dog, cat and some wild species. RESULTS: The information in this article show how dermatophytes infect a wide range of animals which may be in contact with human beings either directly or indirectly. Consequently they are frequently a source of infection for human beings who, vice versa, may sometimes become contagious for animals. CONCLUSION: Fungal pathogens derive their power to spread from contamination of the animal's habitat - whether the animal is a conventional pet or not, a farm animal or living in the wild. Thus if treatment of the animal or human patient is to achieve optimal efficacy, it needs to be associated with adequate environmental measures.

Skin and nail mycoses in patients with diabetic foot.

Diabetes mellitus affects all socioeconomic and age groups and its incidence is rapidly increasing worldwide. The diabetic foot complication represents one of the most complex and serious complications in these patients. Fungal infections can also contribute to the severity of the diabetic foot. The aim of the present study was to evaluate the prevalence of foot skin and toenail mycosis in a group of 75 patients with diabetic foot complication and in a matched control group. Diabetic patients showed onychomycosis in 53.3% and foot skin mycosis in 46.7% of the cases, with a prevalence of both fungal infections significantly higher than that observed in the control group. At least one type of these fungal infections was present in 69.3% of diabetic subjects with a highly significant difference compared to control group (P<0.001). Trichophyton rubrum and Trichophyton interdigitale were the most common species responsible of both nail and skin infections. Candida spp, Fusarium spp, Aspergillus spp and other moulds. were found in about 1/3 onychomycosis. Previous toe amputation was significantly associated with both skin and nail mycosis. The present study confirms that both tinea pedis and onychomycosis have a high prevalence in subjects suffering from diabetic foot complication, and that the problem of fungal infections of the foot in diabetic subjects is still highly underestimated. Consequently, there is an important clinical rationale for careful mycological examination of diabetic foot and an adequate treatment tailored for each individual patient according to the fungal species involved.

Herpes genitalis without frontiers: from clinical aspects to viral identification.

Genital herpes simplex virus infection is a recurrent, lifelong disease with no cure. The strongest predictor for infection is a person's number of lifetime sex partners. HSV-2 is the commonest responsible, although infections caused by HSV-1 are rapidly increasing, particularly in adolescents, women and men who have sex with men. The natural history includes first-episode of mucocutaneous infection, establishment of latency in the dorsal root ganglion, and subsequent reactivation. Most infections are transmitted via asymptomatic viral shedding. Atypical manifestations are common. Genital HSV-2 recurs six times more frequently than type 1. Laboratory confirmation of the clinical diagnosis is recommended in all patients in order to guide a correct counselling and management. Real-time PCR and viral culture represent the gold standard for diagnosis. Serologic testing can be useful in persons with a questionable history. Counselling patients about the risk of transmission is crucial and helps prevent the spread of disease and neonatal complications.

Field distribution and activity of chlorinated solvents degrading bacteria by combining CARD-FISH and real time PCR.

Nowadays several advanced molecular techniques are applied for quantifying bacteria involved in contaminant degradation processes. However, despite the fact that significant efforts have been taken to make these tools more reliable and specific, their application for the analysis of field samples is hardly ever applied. In this study, a combination of three methods (CARD-FISH, qPCR and RT-qPCR) was successfully applied to evaluate the distribution and the activity of known chlorinated solvent dechlorinating bacteria in a contaminated site where no remedial actions have been undertaken. CAtalysed Reporter Deposition Fluorescence In Situ Hybridization (CARD-FISH) specifically provided the cell densities of known dechlorinating bacteria and was found to be more sensitive than quantitative PCR (qPCR) for the quantification of 'Dehalococcoides' cell numbers in the aquifer. Among the screened dechlorinators, 'Dehalococcoides' spp. were mainly found and nearly homogenously distributed in the aquifers at concentrations ranging from 8.1×10(5)±1.2×10(5) to 2.5×10(7)±5.6×10(6)cells per liter of groundwater (with a relative abundance out of the total Bacteria of 0.7-15%). Further, the dechlorination potentialities of 'Dehalococcoides' species living in the aquifer were evaluated by analyzing the abundance and the expression of 16S rRNA genes and reductive dehalogenase (RDase) encoding functional genes by qPCR and Reverse Transcription qPCR (RT-qPCR). 'Dehalococcoides'tceA gene, known to be associated to strains capable of reducing chlorinated solvents beyond cis-DCE, was found and expressed in the field. Overall, this study proved the existence of a well-established dechlorinating microbial community able to use contaminants as substrates for their metabolic activity and indicated the occurrence of reductive dechlorination at the site.

Evaluation of the constitutive properties of native, tissue engineered, and degenerated articular cartilage.

BACKGROUND: Conventional models to evaluate degenerated cartilage do not consider nonlinear permeability and proteoglycan viscous effects. Some models also utilize spring elements to represent the viscous effects of the fibers, thus application tothe modeling of nonuniform deformations such as those that occur in indentation tests. The purpose of this study was to assess the changes in the mechanical behavior of tissue engineered and degraded cartilage while addressing these shortcomings and limitations. METHODS: An inverse finite element method was used to determine the material properties of native and tissue engineered cartilage from indentation test data. The engineered cartilage was evaluated 3 and 9 months after implantation into osteochondral defects in the trochlear groove of sheep stifles. The strain rate dependent responses of the engineered and native cartilage in unconfined compression were also determined for strain rates ranging from 0 to 20% s(-1). The material properties of bovine cartilage before and after proteoglycan depletion and collagen degradation were also compared using unconfined compression test data from the literature. FINDINGS: For a given strain, the stiffness of the engineered cartilage was approximately one tenth of that of the native cartilage both at 3 and 9 months. The model appeared to be able to predict the equilibrium and transient mechanical function of degenerated cartilage, and discerned the proteoglycan loss from collagen degradation. INTERPRETATION: The model can be used for high strain and dynamic analysis of cartilage, and may in the future allow the determination of the load bearing capability of engineered cartilage.