Real-life effectiveness and safety of baricitinib in patients with severe alopecia areata: A 24-week Italian study.

BACKGROUND: Alopecia areata is an autoimmune condition characterized by rapid hair loss in the scalp, eyebrows and eyelashes, for which treatments are limited. Baricitinib, an oral inhibitor of Janus kinases 1 and 2, has been recently approved to treat alopecia areata. MATERIALS AND METHODS: We conducted a retrospective study involving 23 medical centres across Italy, enrolling patients affected by severe alopecia areata (SALT >50), for more than 6 months. Clinical and trichoscopic assessment was performed at each visit and impact on quality of life, anxiety and depression were evaluated using the Skindex-16 and the Hospital Anxiety and Depression Scale (HADS), respectively. RESULTS: A total of 118 patients were enrolled, with a mean age of 39 years and a mean SALT >95. The mean value of the SALT score decreased from an average of 96.6 (±8.23 sd) to 48 (±35.2 sd) after 24 weeks of treatment and 42.3% of patients achieved a SALT 30, 31.3% a SALT 20 and 20.3% a SALT 10 by Week 24. Trichoscopic signs showed fewer yellow dots and black dots significantly earlier than hair regrowth. Adverse events during the treatment period (mild laboratory test abnormalities) were reported in 12.7% patients. No drop-out were registered. CONCLUSION: Data on the effectiveness and safety of baricitinib are promising and support the use of this drug in severe forms of AA, also in the early stages. We also suggest performing trichoscopy in order to reveal early response to therapy.

Guidelines for training in cardiovascular magnetic resonance (CMR).

These "Guidelines for training in Cardiovascular Magnetic Resonance" were developed by the Certification Committee of the Society for Cardiovascular Magnetic Resonance (SCMR) and approved by the SCMR Board of Trustees.

Development of an improved Kelvin probe force microscope for accurate local potential measurements on biased electronic devices.

An improved setup for accurate near-field surface potential measurements and characterisation of biased electronic devices using the Kelvin Probe method has been developed. Using an external voltage source synchronised with the raster-scan of the KPFM-AM, this setup allows to avoid potential measurement errors of the conventional Kelvin Probe Force Microscopy in the case of in situ measurements on biased electronic devices. This improved KPFM-AM setup has been tested on silicon-based devices and organic semiconductor-based devices such as organic field effect transistors (OFETs), showing differences up to 25% compared to the standard KPFM-AM lift-mode measurement method.

Cutaneous vasculitis and inflammatory bowel diseases.

Extraintestinal manifestations occur in up to 40% of patients living with inflammatory bowel disease (IBD) and may precede the onset of gastrointestinal symptoms by many years. Vasculitides are considered rare cutaneous manifestations, but they often represent an important cause of morbidity and a relevant diagnostic issue in IBD. In addition, the increasing use of biological therapies for IBD may also play a pivotal role in the development of vascular disorders of different type. Hence, we provide a complete and in-depth review of the main features of cutaneous vasculitides observed in IBD, with a specific focus on their clinical presentation and possible pathophysiological mechanisms.

Edge Sharpness Assessment by Parametric Modeling: Application to Magnetic Resonance Imaging.

In biomedical imaging, edge sharpness is an important yet often overlooked image quality metric. In this work, a semi-automatic method to quantify edge sharpness in the presence of significant noise is presented with application to magnetic resonance imaging (MRI). The method is based on parametric modeling of image edges. First, an edge map is automatically generated and one or more edges-of-interest (EOI) are manually selected using graphical user interface. Multiple exclusion criteria are then enforced to eliminate edge pixels that are potentially not suitable for sharpness assessment. Second, at each pixel of the EOI, an image intensity profile is read along a small line segment that runs locally normal to the EOI. Third, the profiles corresponding to all EOI pixels are individually fitted with a sigmoid function characterized by four parameters, including one that represents edge sharpness. Last, the distribution of the sharpness parameter is used to quantify edge sharpness. For validation, the method is applied to simulated data as well as MRI data from both phantom imaging and cine imaging experiments. This method allows for fast, quantitative evaluation of edge sharpness even in images with poor signal-to-noise ratio. Although the utility of this method is demonstrated for MRI, it can be adapted for other medical imaging applications.

Use of infliximab in toxic epidermal necrolysis: a still opened challenge.

Toxic epidermal necrolysis (TEN), also known as Lyell syndrome, is a potential life-threatening muco-cutaneous disease with important systemic implications. It affects the skin and mucous membranes, with involvement of more than 30% of body surface and it is mostly caused by drugs. Although the pathogenesis is not fully elucidated, it is probably linked to the inability to detoxicate reactive metabolites of drugs, to genetic susceptibility and to immune factors leading to cellular apoptosis. Currently, there are no randomized control trials and stardardized therapeutical approaches for the management of Lyell syndrome; therefore controversial clinical responses to the most common used drug in TEN make it difficult for the clinical-therapeutic approach. The authors reported their experience on three patients affected by Lyell syndrome treated with infliximab.

Oxidative stress and psoriasis: the effect of antitumour necrosis factor-α inhibitor treatment.

BACKGROUND: Psoriasis is a chronic, inflammatory skin condition associated with a high frequency of cardiovascular events. Modifications of plasma lipids, and an increase in the levels of biochemical markers of inflammation and lipid peroxidation have been reported in subjects with psoriasis, suggesting a relationship between psoriasis, inflammation and oxidative damage. OBJECTIVES: To investigate whether modulation of inflammatory activity by tumour necrosis factor-α inhibitors in patients with psoriasis is associated with modification of lipid profiles, oxidative stress and paraoxonase (PON)1 activity. METHODS: The levels of plasma lipids and lipoprotein(a), and the levels of the markers of inflammation and lipid peroxidation were evaluated in subjects with psoriasis (n=23) before and after 24 weeks of treatment with etanercept. In the same subjects plasma total antioxidant capacity and the activity of PON1, an antioxidant and anti-inflammatory enzyme associated with the high-density lipoproteins (HDLs), were investigated. RESULTS: The results showed that clinical improvement in patients with psoriasis treated with etanercept is associated with a reduction in the levels of inflammatory markers [C-reactive protein (CRP)] and lipid peroxidation, and also with increased antioxidant capacity in the serum of patients with psoriasis. These modifications are associated with a significant increase in the activity of PON1. A significant increase in the PON1/CRP ratio has also been observed in patients with psoriasis after treatment. The significant inverse correlation between CRP and PON1 activity suggests a relationship between PON1 activity and inflammation. CONCLUSIONS: Treatment with etanercept is associated with a reduction in lipid peroxidation and an improvement in HDL antioxidant and anti-inflammatory properties.

Microvessel density and VEGF, HIF-1α expression in primary oral melanoma: correlation with prognosis.

OBJECTIVE: To understand the role of angiogenesis and hypoxia in cancer progression of primary oral melanoma (POM). MATERIALS AND METHODS: Sixteen malignant primary melanomas were immunostained with markers CD34, VEGF and HIF-1α. Stained cells were counted in the invasive front and inside the tumour, and the differences were compared and correlated with histological parameters and disease-specific survival of the patients. RESULTS: Tumour invasive front showed increased MVD and increased vessel VEGF and HIF-1α expression compared with the intratumoural compartment. No such differences were seen in tumoural melanocytes of the two compartments. Positive correlations were observed between CD34 and VEGF, CD34 and HIF-1α and VEGF and HIF-1α expression in invasive front vessels. CD34 expression was statistically correlated with the level of infiltration. A significant trend to worse disease-free survival was also determined with increased invasive front vessel expression of CD34, VEGF and HIF-1α. CONCLUSIONS: Our data highlight the importance of the invasive margin in POM biology. The high angiogenic activity and endothelial VEGF and HIF-1α expression in invasive front vessels have a significant impact on patient survival and future agents targeted against VEGF pathway may represent a novel and effective therapeutic opportunity. Larger studies are needed to further address our findings.

Antimicrobial properties of distinctin in an experimental model of MRSA-infected wounds.

The aim of this study was to evaluate the efficacy of distinctin in the management of cutaneous methicillin-resistant Staphylococcus aureus (MRSA) wound infections in an experimental mouse model. Wounds, made in the panniculus carnosus of BALB/c mice, were inoculated with 5 × 10(7) colony-forming units (CFU) of MRSA. Mice were treated with topical distinctin (1 mg/kg of body weight), topical teicoplanin (7 mg/kg of body weight), intraperitoneal teicoplanin (7 mg/kg of body weight); topical teicoplanin and daily intraperitoneal teicoplanin; topical distinctin and daily intraperitoneal teicoplanin. Bacterial cultures of excised tissues and histological examination of microvessel density and of vascular endothelial growth factor (VEGF) expression were studied. It was found that topical distinctin combined with parenteral teicoplanin inhibited bacterial growth to levels comparable with those observed in uninfected animals. Wounded areas of animals treated with distinctin were characterized by a more mature granulation tissue, with a more organized and denser type of connective tissue, compared to mice treated only with teicoplanin. Treatment with topical distinctin had a significant impact on VEGF expression and microvessel density. The combined use of distinctin with teicoplanin may be useful in the management of infected wounds by significantly inhibiting bacterial growth and accelerating the repair process.

Doxycycline-isoniazid: a new therapeutic association for recalcitrant acne agminata.

Acne agminata is a rare asymptomatic, inflammatory dermatosis, which affects adolescence and young adults, whose etiopathogenesis is already controversial. Clinically, acne agminata is characterized by red-yellow-brown papular-pustular eruption involving the central face, in particular cheeks, chin, forehead, and eyelids. The authors report a case of a 25-year-old Caucasian man affected by acne agminata treated with doxycycline and isoniazid.

Serum and tissue CTACK/CCL27 chemokine levels in early mycosis fungoides may be correlated with disease-free survival following treatment with interferon alfa and psoralen plus ultraviolet A therapy.

BACKGROUND: Neoplastic T-cell recruitment into the skin is a critical step in the pathogenesis of mycosis fungoides (MF), and the cutaneous T-cell attracting chemokine, CTACK/CCL27, might be involved. OBJECTIVES: To investigate the clinical and prognostic significance of CTACK/CCL27 levels in patients with early-stage MF. METHODS: Serum samples and skin biopsy specimens were collected from 15 patients at the time of diagnosis and after the end of treatment with psoralen plus ultraviolet A/interferon alfa-2b combination therapy. Serum samples were also collected from 20 healthy donors as controls. CTACK/CCL27 serum levels were analysed by enzyme-linked immunosorbent assays. CTACK/CCL27 tissue expression was determined by immunohistochemistry on skin biopsy specimens taken at diagnosis and after therapy. Event-free survival was taken as the primary clinical outcome. RESULTS: In patients with MF at diagnosis, CTACK/CCL27 serum levels were not significantly different from healthy controls, whereas CTACK/CCL27 expression in the skin was increased in 87% of cases compared with normal controls. After therapy, all patients obtained a clinical complete remission, serum levels did not change significantly and tissue expression remained abnormal in 80% of patients, even if complete histological remission was recorded. Serum levels were not significantly different in cases with different intensity of cutaneous immunostaining. Eight patients experienced a relapse: the combination of high CTACK/CCL27 levels both in sera and skin increased the probability of experiencing an event at 51 months from 36% to 83%. CONCLUSIONS: Our data seem to indicate that CTACK/CCL27 levels in skin and sera after therapy might be correlated with risk of recurrence.

Correlation between lipoprotein(a) and lipid peroxidation in psoriasis: role of the enzyme paraoxonase-1.

BACKGROUND: Psoriasis is a chronic, inflammatory skin disease associated with abnormal plasma lipid metabolism and with a high frequency of cardiovascular events. Modifications of plasma lipids and an increase in the levels of biochemical markers of lipid peroxidation have been reported in subjects with psoriasis, suggesting a relationship between psoriasis, lipoproteins and oxidative damage. OBJECTIVES: To investigate further the relationship between lipoproteins and oxidative stress in psoriasis. METHOD: The levels of plasma lipids, lipoprotein(a) [Lp(a)] and markers of lipid peroxidation were evaluated in subjects with psoriasis (n=23) and in controls (n=25). In the same subjects, the activity of paraoxonase-1 (PON1), an antioxidant and an anti-inflammatory enzyme associated with high-density lipoproteins, was investigated. RESULTS: The results showed higher levels of Lp(a) in the serum of patients with psoriasis compared with controls (P<0·001). Higher levels of lipid hydroperoxides (P<0·001) and lower PON1 activity were observed in the serum of patients compared with healthy subjects, confirming that psoriasis is associated with oxidative stress. The imbalance between oxidative stress and antioxidant enzymes, and the increase of Lp(a) serum levels was related to the extent and severity of psoriasis. Finally, our results demonstrated that Lp(a) levels were positively correlated with markers of lipid peroxidation and negatively related to PON1 activity, suggesting that subjects with higher levels of Lp(a) are more exposed to oxidative damage. CONCLUSIONS: Our results provide further evidence that oxidative stress and impairment of the antioxidant system in the plasma of patients may play a role in pathogenesis and progression of psoriasis and related complications.

In vitro activity and in vivo efficacy of tigecycline alone and in combination with daptomycin and rifampin against Gram-positive cocci isolated from surgical wound infection.

The aim of this work was to determine the in vitro activity of tigecycline and its bactericidal effect for a large number of Gram-positive cocci, as well as to investigate its in vitro interaction with six clinically used antibiotics. In vivo, a wound model was established through the panniculus carnosus of BALB/c mice, and then inoculated with 5 × 10(7) colony-forming units (CFU) of Staphylococcus aureus or Enterococcus faecalis. For each bacterial strain, the study included an infected or non-infected group that did not receive any treatment, three groups singly treated with tigecycline, rifampin, and daptomycin, and two groups that received tigecycline treatment plus rifampin or daptomycin. In the in vitro studies, tigecycline, daptomycin, and teicoplanin were active against all of the 48 Gram-positive isolates. The combination of tigecycline with rifampicin and daptomycin was synergistic against S. aureus and Enterococcus spp. In the in vivo studies, all groups treated with single drugs showed statistically significant results compared to the control group. The two groups treated with a combination of drugs showed the highest antimicrobial efficacy. In conclusion, our results suggested a strong activity of tigecycline alone and in combination with other antimicrobial agents against multi-resistant Gram-positive organisms isolated from wound infections.

Reciprocal altered expression of E-cadherin and P-cadherin in mucous membrane pemphigoid.

E- and P- cadherins are involved in the selective adhesion of epidermal cells. To gain insight into the role of cadherins on the acantholysis of keratinocytes and further investigate the pathogenesis of Mucous Membrane Pemphigoid, we examined the expression of P-cadherin and E-cadherin, in normal human oral mucosa, lesional and peri-lesional mucosa in MMP. Twenty-nine samples from paraffin-embedded specimens of MMP were used for the study. Five specimens of healthy oral mucosa were evaluated as control group. To evaluate the E- and P-Cadherin expression, a mean percentage of positive cells was determined from the percentage of positive cells derived from the analysis of 100 cells in ten random areas at x400 magnification. It was observed that E-cadherin was weakly and discontinuously expressed on the epithelial layers of pemphigoid mucosa, while it was intensively expressed on all keratinocytes in normal human skin. In contrast, P-cadherin was strongly expressed throughout the entire epidermal layer in MMP samples, although its expression is restricted to the basal cell layer in normal human skin. Statistical analyses showed that the percentage of E-cadherin positive cells in the epithelium of pemphigoid cases was significantly decreased compared with that in normal human mucosa. There was a significant increase in the percentage of P-cadherin positive cells in the epithelial layers of MMP compared with normal human mucosa. The present study showed that there is downregulation of E-cadherin expression and upregulation of P-cadherin expression in MMP mucosa, which may be involved in the pathogenesis of MMP.

Effectiveness of antimicrobial photodynamic therapy with a single treatment of RLP068/Cl in an experimental model of Staphylococcus aureus wound infection.

BACKGROUND: Chronic leg ulceration is a common health problem. It is well known that a clinically relevant bacterial load in chronic cutaneous wounds interferes significantly with the normal process of healing. Staphylococcus aureus is the most important representative of the staphylococcal group which causes clinically relevant infections within immunocompetent patients. OBJECTIVES: To investigate the efficacy of a single treatment of antimicrobial photodynamic therapy (APDT) with RLP068/Cl in a mouse model of a surgical wound infection induced with a methicillin-resistant strain of S. aureus (MRSA). METHODS: Wounds, established through the panniculus carnosus of BALB/c and CD1 mice, were inoculated with 5 x 10(7) c.f.u. of MRSA. Mice were randomized into four groups respectively receiving no treatment, APDT with placebo, APDT with a new phthalocyanine derivative (RLP068/Cl) and intraperitoneal teicoplanin. RESULTS: On day 2 from infection, a strong reduction of bacterial counts (≈ 3 logs) was observed in mice treated with RLP068/Cl in comparison with infected untreated mice. On day 9 from infection, a comparable and significant (≈ 2 logs) reduction of bacterial counts was found in mice treated with RLP068/Cl or with teicoplanin. At this time, histological examinations revealed that wounds treated with RLP068/Cl showed a complete re-epithelialization with a continuous epithelial lining. CONCLUSIONS: The results of the in vivo study demonstrated that APDT with RLP068/Cl may be useful in the management of chronic infected wounds, accelerating the repair process through a significant bacterial inhibition.

In vitro activity of the lipopeptide PAL-Lys-Lys-NH2, alone and in combination with antifungal agents, against clinical isolates of Candida spp.

Candida albicans is known to be the organism most often associated with serious fungal infection, but other Candida spp. are emerging as clinical pathogens associated with opportunistic infections. Among antimycotic treatments, increasing attention is currently given to anti-infective drugs based upon naturally occurring peptides, such as the short lipopeptide palmitoyl PAL-Lys-Lys-NH2 (PAL). The aim of this study is to evaluate the activity of this peptide compared to the traditional antifungal agents Fluconazole (FLU), amphotericin B (AMB) and caspofungin (CAS) on Candida spp. 24 clinical isolates of Candida spp. were tested against PAL, FLU, AMB and CAS using in vitro susceptibility tests, time killing and checkerboard assay. All of the drugs studied showed good activity against clinical isolates of candida; in particular CAS and AMB which have MICs value lower than PAL and FLU. Moreover we observed synergistic interactions for PAL/FLU (81.25%), PAL/AMB (75%) and particularly for PAL/CAS (87.5). We think that our results are interesting since synergy between PAL and CAS might be useful in clinic trails to treat invasive fungal infections.

Videocapillaroscopic pattern of alopecia areata before and after diphenylciclopropenone treatment.

Alopecia areata (AA) is an inflammatory skin disease the most effective therapy for which is diphenylcyclopropenone (DPCP). Videodermatoscopy and intra-vital capillaroscopy (IVCP) are two non-invasive techniques that help in the differential diagnosis of alopecias. It is known that, after DPCP therapy, there is a histologically proven significant increase of VEGF in hair follicle keratinocytes and a consequent increase in capillary vessels in the dermis of the same follicles. The aim of our study is to emphasize any clinical and videodermatoscopic-videocapillaroscopic changes after DPCP treatment in 20 patients affected by alopecia areata. Videodermatoscopic images and an intravital videocapillaroscopic analysis were performed at T0, T12 and T24 to emphasize clinical modifications and microscopic changes in vascular pattern before and after DPCP treatment. At T0, videodermatoscopy showed the presence of exclamation point hairs, hair follicles filled with hyperkeratotic plugs (yellow dots), hair follicles containing cadaverized hairs (black dots) and broken hairs. IVCP highlighted a pale scalp, and vessels were not visible. At 24 weeks (T24), videodermatoscopy revealed the disappearance or a statistically significant reduction of AA hallmarks and an increase of number of vellus hairs. Videocapillaroscopy showed a statistically significant increase of new vessels and, where neoangiogenesis were more marked, a major hair regrowth was evident. Our study emphasizes that, after DPCP therapy, neoangiogenesis is detectable by videocapillaroscopy and these new capillaries could be considered an initial positive attempt to compensate capillary loss of T0 alopecia areata images.