Metagenomic and volatile profiles of ripened cheese obtained from dairy ewes fed a dietary hemp seed supplementation.

Chemical and organoleptic properties of dairy products largely depend on the action of microorganisms that tend to be selected in cheese during ripening in response to the availability of specific substrates. The aim of this work was to evaluate the effects of a diet enriched with hemp seeds on the microbiota composition of fresh and ripened cheese produced from milk of lactating ewes. Thirty-two half-bred ewes were involved in the study, in which half (control group) received a standard diet, and the other half (experimental group) took a diet enriched with 5% hemp seeds (on a DM basis) for 35 d. The dietary supplementation significantly increased the lactose in milk, but no variations in total fat, proteins, caseins, and urea were observed. Likewise, no changes in total fat, proteins, or ash were detected in the derived cheeses. The metagenomic approach was used to characterize the microbiota of raw milk and cheese. The phyla Proteobacteria and Firmicutes were in equally high abundance in both control and experimental raw milk samples, whereas Bacteroidetes was less abundant. The scenario changed when considering the dairy products. In all cheese samples, Firmicutes was clearly predominant, with Streptococcaceae being the most abundant family in the experimental group. The reduction of taxa observed during ripening was in accordance with the increment (relative abundance) of the starter culture Lactococcus lactis and Streptococcus thermophilus, which together dominate the microbial community. The analysis of the volatile profile in ripened cheeses led to the identification of 3 major classes of compounds: free fatty acids, ketones, and aldehydes, which indicate a prevalence of lipolysis compared with the other biochemical mechanisms that characterize the cheese ripening.

In vitro efficacy of ARQ 092, an allosteric AKT inhibitor, on primary fibroblast cells derived from patients with PIK3CA-related overgrowth spectrum (PROS).

Postzygotic mutations of the PIK3CA [phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha] gene constitutively activate the PI3K/AKT/mTOR pathway in PIK3CA-related overgrowth spectrum (PROS) patients, causing congenital mosaic tissue overgrowth that even multiple surgeries cannot solve. mTOR inhibitors are empirically tested and given for compassionate use in these patients. PROS patients could be ideal candidates for enrolment in trials with PI3K/AKT pathway inhibitors, considering the "clean" cellular setting in which a unique driver, a PIK3CA mutation, is present. We aimed to assess the effects of blocking the upstream pathway of mTOR on PROS patient-derived cells by using ARQ 092, a potent, selective, allosteric, and experimental orally bioavailable and highly selective AKT-inhibitor with activity and long-term tolerability, currently under clinical development for treatment of cancer and Proteus syndrome. Cell samples (i.e., primary fibroblasts) were derived from cultured tissues obtained from six PROS patients [3 boys, 3 girls; aged 2 to 17 years] whose spectrum of PIK3A-related overgrowth included HHML [hemihyperplasia multiple lipomatosis; n = 1], CLOVES [congenital lipomatosis, overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies, scoliosis; n = 1], and MCAP [megalencephaly capillary malformation syndrome; n = 4]. We performed the following: (a) a deep sequencing assay of PI3K/AKT pathway genes in the six PROS patients' derived cells to identify the causative mutations and (b) a pathway analysis to assess the phosphorylation status of AKT [Ser473 and Thr308] and its downstream targets [pAKTS1 (Thr246), pRPS6 (Ser235/236), and pRPS6Kß1 (Ser371)]. The anti-proliferative effect of ARQ 092 was tested and compared to other PI3K/AKT/mTOR inhibitors [i.e., wortmannin, LY249002, and rapamycin] in the six PROS patient-derived cells. Using ARQ 092 to target AKT, a critical node connecting PI3K and mTOR pathways, we observed the following: (1) strong anti-proliferative activity [ARQ 092 at 0.5, 1, and 2.5 µM blunted phosphorylation of AKT and its downstream targets (in the presence or absence of serum) and inhibited proliferation after 72 h; rapamycin at 100 nM did not decrease AKT phosphorylation] and (2) less cytotoxicity as compared to rapamycin and wortmannin. We demonstrated the following: (a) that PROS cells are dependent on AKT; (b) the advantage of inhibiting the pathway immediately downstream of PI3K to circumventing problems depending on multiple classes a PI3K kinases; and (c) that PROS patients benefit from inhibition of AKT rather than mTOR. Clinical development of ARQ 092 in PROS patients is on going in these patients.

The impact of biologic therapy in chronic plaque psoriasis from a societal perspective: an analysis based on Italian actual clinical practice.

OBJECTIVE: Psoriasis is one of the most common forms of chronic dermatitis, affecting 2-3% of the worldwide population. It has a serious effect on the way patients perceive themselves and others, thereby prejudicing their quality of life and giving rise to a significant deterioration in their psycho-physical well-being; it also poses greater difficulties for them in leading a normal social life, including their ability to conduct a normal working life. All the above-mentioned issues imply a cost for the society. This study proposes to evaluate the impact on societal costs for the treatment of chronic plaque psoriasis with biologics (etanercept, infliximab and adalimumab) in the Italian clinical practice. METHOD: A prospective observational study has been conducted in 12 specialized centres of the Psocare network, located throughout Italy. Direct and indirect costs (as well as the health-related quality of life of patients with plaque psoriasis undergoing biologic treatments) have been estimated, while the societal impact has been determined using a cost-utility approach. RESULTS: Non-medical and indirect costs account for as much as 44.97% of the total cost prior to treatment and to 6.59% after treatment, with an overall 71.38% decrease. Adopting a societal perspective in the actual clinical practice of the Italian participating centres, the ICER of biologic therapies for treating plaque psoriasis amounted to €18634.40 per QALY gained--a value far from the €28656.30 obtained by adopting a third-party payer perspective. CONCLUSION: Our study confirms that chronic psoriasis subjects patients to a considerable burden, together with their families and caregivers, stressing how important it is to take the societal perspective into consideration during the appraisal process. Besides, using data derived from Italian actual practice, treatment with biologics shows a noteworthy benefit in social terms.

Cutaneous viral infections in organ transplant patients.

Cutaneous infections might occur in up to 80% of organ transplant recipients (OTR) and viral infections are the most common them. The risk of different skin infection is among related to the intensity of immunosuppression. During the first post-transplant period, herpes viruses are most common. After some months following transplantation, human papilloma viruses represent the most significant infections among OTR. Reactivation of herpes simplex virus in OTR can become more invasive, takes longer to heal, and shows greater potential for dissemination to visceral organs compared to the general population. Specific immunosuppressive drugs (namely muromonab and mycophenolate mofetil) have been associated with an increased risk of herpes virus reactivation after transplantation. On the other hand, there is evidence that the mTOR inhibitors, such as everolimus, may be associated with a decreased incidence of herpesvirus infections in transplant recipients. The incidence of herpes zoster in OTR is 10 to 100 fold higher than the general population, ranging from 1% to 12%. The chronic immunosuppression performed in OTR may lead to persistent replication of herpesviruses, dissemination of the virus with multivisceral involvement (hepatitis, pneumonitis, myocarditis, encephalitis and disseminated intravascular coagulation) and eventually, the emergence of antiviral-drug resistance. Viral warts are the most common cutaneous infection occurring in OTR. The number of warts increases with the duration of immunosuppressive therapy. Since warts in organ recipients are frequently multiple and only rarely undergo spontaneous regression, the therapeutic management of warts in patients treated with immunosuppressive drugs might be challenging. Imiquimod, 1% cidofovir ointment, acitretin proved to be useful off-label strategies for recalcitrant cutaneous viral warts in OTR. Extensive and atypical presentation of molluscum contagiosum has been also reported in OTR, with a prevalence between 3% to 6.9%. Giant molluscum contagiosum is a clinical variant in which large nodule greater than 0.5-1 cm in diameter are observed.

Physicians' opinions and clinical practice patterns for actinic keratosis management in Italy.

AIM: We report dermatologists' opinions and clinical practice patterns about clinical factors driving decision making in the management of actinic keratosis (AK) in Italy. METHODS: We carried out a cross-sectional survey among 33 Italian dermatologists. Physicians were asked to report their management choices in consecutive patients with AK seen at their practice within 2 weeks since study initiation. We collected patients' clinical and socio-demographic characteristics with a standardized data collection form and assessed physicians' opinions on AK management with a self-reported questionnaire. RESULTS: Six hundred fifty-seven patients with new, single AK lesions without evidence of photo-damaged skin in the surrounding areas, were predominantly treated with lesion-directed therapies (primarily cryotherapy). In contrast, physicians preferentially prescribed field-directed therapies to patients with multiple lesions and evidence of photo-damaged skin in AK surrounding areas. However we observed a wide variation in treatment choices and physicians' opinions on AK management. Dermatologists underlined the importance of fostering patients' adherence and minimize therapy side effects. CONCLUSION: Overall, our results show that current guidelines regarding management of AK are only partially integrated in dermatology practice. The active dissemination of up-to-date national guidelines might help harmonize clinical decision making in this complex and fast growing therapeutic area.

The controversial management of giant congenital melanocytic nevi. When would it be better "to wait and see"?

AIM: A giant congenital nevus is a melanocytic nevus present at birth with wide extent on the skin surface. The management of this nevus remains controversial and needs to be personalized for each patient. METHODS: A retrospective multicenter study was carried out in the Dermatological Departments of Brescia, Padua, and Pavia, Italy. The inclusion criterion was the diagnosis of a giant congenital melanocytic nevus on the basis of clinical observation. RESULTS: Nine patients with giant congenital nevus are reported. None developed melanoma, whereas giant congenital nevi have been slowly fading in pigmentation. CONCLUSION: Having regard to the doubts on treatment that persist in the literature, we should consider that decisional management of giant congenital melanocytic nevi can be really complex, because of the size and depth of lesions. Indeed, the ablative surgery or other treatments might cause significant troubles and complete excision of deeper layers of the lesion is almost impossible to achieve. Moreover, the treatment does not reduce the risk of melanoma and might lead to a greater difficulty in clinical and dermoscopic observation due to the scarring occurrence after therapy. In our retrospective study, the pigmentation of giant congenital melanocytic nevi slowly faded on its own and until now none developed melanoma. Therefore, we suggest a close regular follow-up which should be focused on the exclusion of possible complications. Perhaps, it would be better "to wait and see" since other procedures do not decrease the risk of melanoma, but rather might lead the patient to underestimate it.

Optimization of systemic treatments for chronic plaque psoriasis. Recommendations for switching and transitioning.

AIM: The aim of this study was to provide practical recommendations for optimizing the use of conventional and biological systemic treatments for moderate-severe chronic plaque psoriasis, particularly in case of transitioning and switching. METHODS: A total number of 147 dermatologists from 33 different countries including Italy achieved consensus in providing practical recommendations for the use of conventional and biological treatments for moderate to severe psoriasis based on systematic literature review and/or expert opinion. RESULTS: In general, the continuous treatment regimen should be preferred in order to achieve a complete and long-term control of psoriasis. However, the treatment could be stopped or the dose reduced in case of complete disease clearance. A conventional drug could be associated to biological treatment in selected cases. Transitioning and/or switching could be considered in case of inefficacy or intolerance. A period of wash up is required if transitioning or switching is due to safety issues. CONCLUSION: This study provides practical suggestions for the optimal use of conventional and biological treatments for chronic plaque psoriasis.

CD30+ lymphoproliferative disorders of the skin: still an open question.

CD30+ lymphoproliferative disorders of the skin represent a well-defined spectrum of primary cutaneous T-cell lymphomas. They include lymphomatoid papulosis and cutaneous anaplastic large-cell lymphoma which are characterized by the common expression of the CD30 antigen, but different clinical, histological and molecular features. Recent progress in the pathobiology and identification of therapeutic targets has contributed to our current understanding of this peculiar group of cutaneous lymphoproliferative disorders. The characteristic features of this group of cutaneous lymphoproliferative disorders are reviewed with particular emphasis to their diagnosis and treatment strategies.

Consensus on the use of the fixed combination calcipotriol/betamethasone dipropionate in the treatment of plaque psoriasis.

Calcipotriol, a vitamin D analogue, and betamethasone dipropionate, a high potency corticosteroid, are complementary agents for the topical treatment of psoriasis vulgaris. Robust evidence on the efficacy and safety of their fixed combination has been provided by randomized, double-blind, controlled clinical trials involving more than 7000 patients with the ointment formulation in psoriasis of the body and more than 4000 patients with the gel formulation in scalp psoriasis. These trials have shown that the fixed combination ointment is more effective and better tolerated, not only than placebo, but also than calcipotriol and tacalcitol monotherapies. In addition, it has proved, in most instances, to be more effective than betamethasone and at least as well tolerated. The same applies to the gel for scalp and body psoriasis. Safety studies have excluded that repeated courses of treatment with the fixed combination for up to one year produce systemic effects. Studies have also shown that the fixed combination treatment improves quality of life to a significantly greater extent than calcipotriol, with the once daily regimen most appreciated by patients, in both active disease and recurrency. Because of the extensive evidence, American and European guidelines recommend the calcipotriol/betamethasone dipropionate fixed combination as first line topical treatment for mild to moderate plaque psoriasis of the body and scalp.

Health-related quality of life in psoriasis: an analysis of Psocare project patients.

AIM: Psoriasis is a common, chronic, immune-mediated skin disorder that may be complicated by psoriatic arthritis in up to one-third of patients. Psoriasis treatments are increasingly effective, yet more expensive, thus requiring rational decision-making on interventional priorities. The ability to perform cost-utility analyses is hindered by the lack of algorithms that allow the inference of utility measures, like QALY, from specific dermatological health-related quality-of-life (HR-QoL) measures (e.g. Dermatology Life Quality Index [DLQI]). This study aimed to assess whether psoriasis-related HR-QoL data (DLQI) could be used to obtain utility measures for use in economic analyses. METHODS: Psoriasis patients attending 11 Italian Psocare project treatment centers over a 19-day period were enrolled and completed a questionnaire, including several HR-QoL scales and sociodemographic/clinical data, and underwent a clinical examination. Data were subjected to a Multiple Correspondence Analysis and multiple regression analysis to determine the contribution of single items to the HR-QoL. RESULTS: DLQI and Psychological General Well-Being Index (PGWBI) scores were most closely correlated with the EuroQol health status index. Age and gender were considered confounding factors, while pain and arthritis contributed significantly to HR-QoL deterioration. For disease severity, the need for hospitalization and the number of examinations, but not the Psoriasis Area Severity Index (PASI), contributed to HR-QoL deterioration. CONCLUSION: Recent historical clinical and HR-QoL data from psoriasis patients can reproducibly define a health status index, such as the EuroQol SD-5Q, that could be used reliably to estimate QALYs for use in cost-utility analyses to compare the cost-benefit profiles of competing therapies.

Variability in human and automatic segmentation of melanocytic lesions.

In a double blind evaluation of 60 digital dermatoscopic images by 4 "junior", 4 "senior" and 4 "expert" dermatologists (dermatoscopy training respectively less than 1 year, between 1 and 5 years, and more than 5 years), a significant inter-operator variability was observed in melanocytic lesion border identification (with a disagreement of the order of 10 - 20% of the area of the lesions). Expert dermatologists showed greater agreement among themselves than with senior and junior dermatologists, and a slight tendency towards "tighter" segmentations. The human inter-operator variability was then used to evaluate the segmentation accuracy of 4 algorithms, representative of the 3 fundamental state-of-the-art automated segmentation techniques and of a fourth, novel, technique. Our evaluation methodology addresses a number of crucial difficulties encountered in previous studies and may be of independent interest. 3 of the 4 algorithms showed considerably less agreement with expert dermatologists than even senior and junior dermatologists did (with a disagreement of the order of 30% of the area of the lesions); the remaining algorithm, however, showed agreement with expert dermatologists comparable to that of other expert dermatologists.

Italian guidelines and therapeutic algorithm for actinic keratoses.

The prevalence of actinic keratosis (AK) continues to rise among white people throughout the world and it is necessary to increase the level of attention paid to it from a diagnostic and a preventive point of view. Today, AK must be considered an in situ squamous cell carcinoma and as such, must be managed using one of the available approved therapeutic alternatives. However, when multiple AKs develop on severely photodamaged skin, the treatment of the lesion together with that of the field of cancerization is part of an optimal strategy that aims not only to solve alterations clinically evident but also those in the surrounding skin field cancerization, that most likely hosts genetic alterations and is the site of initial gradual replacement of normal cells with tumoral cells. This paper reports the most recent evidences from a careful review of the literature's key articles of the treatment of AKs and suggests guidelines for the clinicians. The guidelines indicated by the authors have also been based on practical evaluations and their own clinical experience. The present conclusions may be modified by new findings in the field of oncologic research.

Generalized granuloma annulare treated with methylaminolevulinate photodynamic therapy.

Granuloma annulare (GA) is a non-infectious granulomatous dermatosis characterized by annular papules and rarely nodules and plaques, arising on the dorsa of the hands, feet, elbows and knees; it is usually chronic and asymptomatic. The aetiology of GA is unknown, although many hypotheses have been postulated. About 10% of patients affected by GA present the generalized subtype, characterized by a later age of onset and a chronic course with a low tendency to spontaneous resolution. The widespread papular eruption develops on the trunk and upper or lower limbs. Generalized GA is very disfiguring because of the extensive dissemination of the lesions. The response to various treatments, namely topical and intralesional corticosteroids, topical tacrolimus, dapsone, isotretinoin, etretinate or hydroxychloroquine, is usually unsatisfactory. We report 3 cases with long-lasting generalized GA responding to methylaminolevulinate photodynamic therapy.

Reduction of relapses of atopic dermatitis with methylprednisolone aceponate cream twice weekly in addition to maintenance treatment with emollient: a multicentre, randomized, double-blind, controlled study.

BACKGROUND: The relapsing nature of atopic dermatitis (AD) presents a challenge for its long-term treatment. Efficacy and safety of corticosteroids have been proven in the acute treatment of active AD, but their long-term efficacy and potential to reduce or prevent relapses have only partially been addressed. OBJECTIVES: To investigate long-term management (16 weeks) of AD with methylprednisolone aceponate (MPA) 0.1% cream twice weekly in addition to an emollient (Advabase((R))) after stabilization of an acute severe or very severe flare of AD with MPA cream. METHODS: Patients > or = 12 years of age with a > or = 2-year history of moderate to severe AD were eligible for this multicentre, randomized, double-blind, controlled study if they presented with an acute flare of severe or very severe AD [Investigator's Global Assessment (IGA) score > or = 4]. After successful treatment of the flare in an acute phase (AP), patients received either MPA twice weekly plus emollient or emollient alone over a 16-week maintenance phase (MP). The primary study endpoint was time to relapse of AD. Secondary endpoints included relapse rate and disease status, the patient's assessment of intensity of itch, the Eczema Area and Severity Index, the IGA score, affected body surface area, Dermatology Life Quality Index (DLQI) and children's DLQI (CDLQI), patient's and investigator's global assessment of response and patient's assessment of quality of sleep. RESULTS: Two hundred and forty-nine patients entered the AP and 221 continued into the MP. Time to relapse was longer in the MPA group than in the emollient group. The probability of remaining free from relapse after 16 weeks was 87.1% in the MPA group compared with 65.8% for the emollient. Patients treated with MPA twice weekly had a 3.5-fold lower risk of experiencing a relapse than patients treated with emollient alone (hazard ratio 3.5, 95% confidence interval 1.9-6.4; P < 0.0001). MPA was also superior to emollient for all other efficacy endpoints. Therapy with both treatments was well tolerated. CONCLUSIONS: MPA twice weekly plus an emollient provides an effective maintenance treatment regimen to control AD. Once stabilized, treatment with MPA significantly reduces the risk of relapse and the intensity of itching, and improves the overall patient status.

Prevalence of metabolic syndrome in patients with psoriasis: a hospital-based case-control study.

BACKGROUND: Psoriasis is a chronic inflammatory disease associated with an increased cardiovascular risk. Metabolic syndrome is a significant predictor of cardiovascular events. OBJECTIVE: To investigate the prevalence of metabolic syndrome in patients with psoriasis. METHODS: We performed a hospital-based case-control study on 338 adult patients with chronic plaque psoriasis and 334 patients with skin diseases other than psoriasis. RESULTS: Metabolic syndrome was significantly more common in psoriatic patients than in controls (30.1% vs. 20.6%, odds ratio 1.65, 95% confidence interval 1.16-2.35; P = 0.005) after the age of 40 years. Psoriatic patients also had a higher prevalence of hypertriglyceridaemia and abdominal obesity, whereas hyperglycaemia, arterial hypertension and high-density lipoprotein cholesterol plasma levels were similar. Although psoriasis patients were more frequently smokers, the association of psoriasis with metabolic syndrome was independent from smoking. There was no correlation between severity of psoriasis and prevalence of metabolic syndrome. Psoriatic patients with metabolic syndrome were older and had a longer disease duration compared with psoriatic patients without metabolic syndrome. CONCLUSION: Psoriatic patients have a higher prevalence of metabolic syndrome, which can favour cardiovascular events. We suggest psoriatic patients should be encouraged to correct aggressively their modifiable cardiovascular risk factors.

[Occupational contact dermatitis in metal workers and gender effect]. / Dermatiti professionali nei metalmeccanici ed effetto di genere.

Contact dermatitis is more frequent among women for anatomical reasons and for extraprofessional exposure to irritants and detergents during homeworks. In addition sensitisation to contact haptens is different in sexes. The aim of our work was to evaluate the association between patch test skin sensitizations and professional exposure to metals analyzing data for gender. Of the 15.217 patients patch tested for dermatitis, 678 were metalworkers. The statistical analysis revealed a significant association between dermatitis and sensitisation to nickel in professional exposed women (OR = 1.68; LC50% 1.11-6.50) while metal sensitisation (Cr.Ni and Co) was not relevant in men: for them a significant association between dermatitis and sensitisation was found to quaternium (OR = 3.91; LC95% 1.18-12.9), to mercaptobenzothiazole (OR = 2.69; LC50% 1.11-6.50) and to ethylendiamine dichloride (OR = 2.53; LC95% 1-6.41). The authors stress the need to evaluate patch test sensitisation considering gender effects.