Use of Dupilumab in 543 Adult Patients With Moderate-to-Severe Atopic Dermatitis: A Multicenter, Retrospective Study.

BACKGROUND: Dupilumab has proven to be an effective treatment for patients with moderate-to-severe atopic dermatitis (AD) in clinical trials. However, real-world experience with dupilumab in a broader population is limited. METHODS: The study population comprised adult patients with moderate-to-severe AD, defined as an Eczema Area Severity Index (EASI) score of 24 or higher, treated with dupilumab at 10 Italian teaching hospitals. We analyzed physician-reported outcome measures (EASI), patient-reported outcome measures (pruritus and sleep score, Dermatology Life Quality Index [DLQI]), and serological markers (IgE and eosinophil count) after 16 weeks. RESULTS: We enrolled 543 patients with moderate-to-severe AD. Two patients (0.4%) discontinued treatment. The median (IQR) change from baseline to 16 weeks of treatment in the EASI score was -87.5 (22.0) (P<.001). The EASI-50, EASI-75, and EASI-90 response rates were 98.1%, 81.5%, and 50.8% after 16 weeks. At 16 weeks, 93.0% of the patients had achieved a 4-point or higher improvement in DLQI from baseline. During treatment with dupilumab, 12.2% of the patients developed conjunctivitis, and total IgE decreased significantly (P<.001). Interestingly, in the multivariate logistic regression model, the risk of developing dupilumab-related conjunctivitis was associated with early onset of AD (OR, 2.25; 95%CI, 1.07-4.70; P=.03) and presence of eosinophilia (OR, 1.91; 95%CI, 1.05-3.39; P=.03). CONCLUSION: This is the broadest real-life study in AD patients treated with dupilumab to date. We observed more significant improvements induced by dupilumab in adult patients with moderate-to-severe AD than those reported in clinical trials.

Thymosin ß4 and ß10 are highly expressed at the deep infiltrative margins of colorectal cancer - A mass spectrometry analysis.

OBJECTIVE: Colorectal cancer (CRC) is a complicated tumor, involving several oncogenic signaling pathways, and with a molecular mechanism not fully understood yet. The implication of thymosin ß4 (Tß4) with tumor insurgence and in migration of CRC cells was evidenced in the past with different methodologies, while Tß10 connection with CRC has been sporadically investigated. This study focused on the implication of both types of thymosin in CRC progression and invasion by analyzing the changes in their levels according to different zones of the tumor, and to Dukes stage and budding index. PATIENTS AND METHODS: Tß4 and Tß10 were analyzed in deep and superficial tumor samples, and normal mucosa from 18 patients. Concentrations of Tß4 and Tß10 have been measured by high-pressure liquid chromatography (HPLC) coupled to electrospray-ion trap mass spectrometry (ESI-IT-MS). MS data were compared by t-test and ANOVA statistical analysis. Identification of thymosin and their proteoforms has been performed by HPLC-high resolution-ESI-IT-MSMS. RESULTS: Both Tß4 and Tß10, exhibited intra-tumoral quantitative differences, being upregulated in the deep part of the CRC. They exhibited, moreover, strong association with the Dukes stage and the budding grade, being more concentrated in patients at Dukes stage B and with budding index "2". CONCLUSIONS: The results obtained in the present investigation encouraged the hypothesis that the two thymosin are involved in colorectal cancer progression, and in promoting cancer invasion. Thus, they are good candidates to be diagnostic/prognostic biomarkers and therapy targets.

Obstructive Sleep Apnea, oxidative stress, inflammation and endothelial dysfunction-An overview of predictive laboratory biomarkers.

OBJECTIVE: Obstructive Sleep Apnea (OSA) represents an emerging public health concern with great impact on cardiovascular state. Oxidative stress (OS), inflammation and altered Nitric Oxide (NO) production are recognized as prominent mechanisms of many acute and chronic diseases and even of the normal aging process. They are investigated as major pathophysiological processes in OSA through the analysis and comparison of significative and validated biomarkers. MATERIALS AND METHODS: The review is developed using as key terms "sleep apnea", "oxidative stress", "inflammation", and "endothelial dysfunction". Included studies must have followed the American Academy of Sleep Medicine guidelines according to the diagnosis and classification of OSA. Lipid, protein and DNA oxidation products, PCR, IL-6, IL-8, TNF-α, NO and nitrosative stress compounds, and endothelial functioning tests have been detected for their contribution in OSA along the last 3 decades. RESULTS: Nocturnal intermittent hypoxia has emerged to be significantly associated to oxidative/nitrosative stress, increase in pro-inflammatory markers, imbalance in NO production, and endothelium impairment. Body Mass Index (BMI) contribution needs further clarifications. Continuous Positive Airway Pressure (CPAP) therapy has demonstrated beneficial effects on vascular function and pro-inflammatory milieu in OSA. CONCLUSIONS: Oxidative stress and Inflammation significantly correlate with OSA; similarly, vascular functioning is impaired in accordance to unregulated levels of NO and derived compounds. Continuous Positive Airway Pressure markedly improves oxidative stress, inflammation and endothelial dysfunction in OSA.

Statistics of chromatin organization during cell differentiation revealed by heterogeneous cross-linked polymers.

Chromatin of mammalian nucleus folds into discrete contact enriched regions such as Topologically Associating Domains (TADs). Folding hierarchy and internal organization of TADs is highly dynamic throughout cellular differentiation, and are correlated with gene activation and silencing. To account for multiple interacting TADs, we developed a parsimonious randomly cross-linked (RCL) polymer model that maps high frequency Hi-C encounters within and between TADs into direct loci interactions using cross-links at a given base-pair resolution. We reconstruct three TADs of the mammalian X chromosome for three stages of differentiation. We compute the radius of gyration of TADs and the encounter probability between genomic segments. We found 1) a synchronous compaction and decompaction of TADs throughout differentiation and 2) high order organization into meta-TADs resulting from weak inter-TAD interactions. Finally, the present framework allows to infer transient properties of the chromatin from steady-state statistics embedded in the Hi-C/5C data.

Oral human papilloma virus infection: an overview of clinical-laboratory diagnosis and treatment.

OBJECTIVE: The aim of this review is to describe the "hot points" of current clinical governance for oral HPV comprising the use of new diagnostic molecular procedures, namely, Pyrosequencing and Next Generation Sequencing. MATERIALS AND METHODS: The data on oral HPV was collected through two levels of research. First for all, we used the canonical medical search engines, PubMed, and Medline, followed by the study of current commercial tools for HPV diagnosis, particularly within commercial companies involved in the molecular procedures for HPV detecting and genotyping. RESULTS: Different medical procedures are now described and used throughout the world in HPV diagnosis and treatment. However, the laboratory methods are often validated and used for genital infections, and, in these cases, data are missing in the literature as regards the clinical approach for oral lesions. CONCLUSIONS: Dental care units are often the front line for a clinical evaluation of a possible HPV lesion in the oral cavity, which means that correct clinical governance could avoid a viral neoplastic progression of this disease with great advantages for the patient. In this case, the problem is due to the difficulty in lesion recognition but also and more especially the absence of correct laboratory diagnosis and subsequent treatment in the clinical course.

[A case report of eccrine porocarcinoma]. / Porocarcinoma eccrino: caso clinic.

Eccrine porocarcinoma (EPC) is a rare malignant skin appendage tumour deriving from the intraepithelial ductal parts of the sweat glands. First described by Pinkus e Mehregan nel 1963 as an epidermotropic eccrine carcinoma, it is rarely reported in medical literature and represents 0.005-0.01% of all skin tumors. We report a case of a 88-year-old Caucasian female presented to our Clinic with an asymptomatic, red-brown , irregularly shaped firm nodule on the left thigh aroused 15 years earlier. The lesion has been excised and histopathological examination showed an "eccrine porocarcinoma aroused on eccrine poroma". Review of the literature on this rare condition and possible therapeutic strategies are also discussed.

A multicenter study on the prevalence of clinical patterns and clinical phenotypes in adult atopic dermatitis

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Human salivary peptides derived from histatins.

Human saliva from a healthy donor was subjected to fractionation by gel chromatography and six pools were collected and analysed by MALDI-TOF-MS and HPLC-ESI-MS. Three peptides, corresponding to 888.3, 687.3, and 524.1 amu and SNYLYDN, YLYDN, and LYDN sequences (determined by automated Edman sequencing), were isolated from pool 4. YLYDN was not previously described in human saliva. The peptides show the common C-terminal sequence of histatin 3 and histatin 1. To exclude the possibility that the three peptides were an artifact of the purification procedure, nine samples of human saliva were collected from healthy donors, immediately acidified with 0.2% TFA, and analysed by RP-HPLC-ESI-MS. The three peptides were detected in all the analyzed samples. SNYLYDN was always found at a concentration higher than that of YLYDN and LYDN. A correlation analysis performed on quantitative data indicated that the three peptides derive only from histatin 3. Other already known histatins also were searched for in the chromatogram. Histatins 1, 2, 3, 5, 6, 7, 8, and 10 were observed, although not in all samples analyzed, whereas other minor histatins were not detected.

[Relation between hypogonadism and malocclusion in beta-thalassemia major patients: analysis of 122 subjects]. / Relazione tra ipogonadismo e malocclusione dentaria in pazienti affetti da beta-talassemia major. Studio su 122 pazienti.

AIM: The type of malocclusion most often seen in beta thalassemic patients is represented by Angle's II class, which however cannot be considered significant in the patients studied in this research. The only causal factor indicated by medical literature for this pathology is medullary hyperplasia due to inefficient erythropoiesis which occurs in patients transfused at low hemoglobin levels. The aim of this research is to evaluate the influence of other factors as well, particularly sexual development, the level of seric ferritin, ALT, and age at first transfusion. METHODS: One-hundred and twenty-two b thalassemic patients and 39 homozygotes, aged between 16 and 27, undergoing treatment at the "Ospedale Regionale per le Microcitemie di Cagliari", have been analysed. RESULTS: The results of the statistic analysis have shown that hypogonadism can play an important role in determining malocclusions in male beta thalassemic patients (Odds ratio 4,5; CI 1,5-13). No other factor has shown any statistically relevant influence on dental occlusion. CONCLUSION: It would therefore be interesting to further investigate the hormonal mechanisms that can alter bone development in thalassemic youngsters: the prevention of such alterations will surely contribute to improving the quality of life in these patients, particularly now that their life expectancy has been significantly extended by the progress made in transfusional therapy and ferrochelation.

Oral Signs and HLA-DQB1∗02 Haplotypes in the Celiac Paediatric Patient: A Preliminary Study.

Celiac disease (CD) diagnosis can be extremely challenging in the case of atypical patterns. In this context, oral signs seem to play a decisive role in arousing suspicion of these forms of the disease. At the same time, the different expressions of the HLA-DQB1∗02 allele apparently seem to facilitate the interpretation of signs and highlighted symptoms. The aim of this work was to verify whether it is possible to identify a correlation between the development of oral signs and different DQ2 haplotypes in celiac pediatric patients. 44 celiac patients with a medium age of 9.9 were studied. Oral examinations were performed in order to identify recurrent aphthous stomatitis (RAS) and dental enamel defects (DED). The diagnosis of DED resulted as being related to allele expression (P value = 0.042) while it was impossible to find a similar correlation with RAS. When both oral signs were considered, there was an increase in correlation with HLA-DQB1∗02 expression (P value = 0.018). The obtained results identified both the fundamental role that dentists can play in early diagnosis of CD, as well as the possible role of HLA haplotype analysis in arousing suspicion of atypical forms of the disease.

Dental agenesis in Sardinians.

The authors report on the results of a study on the dental agenesis frequency in a sample of 420 individuals (152 males, 268 females), aged between 8 and 20 years, from Sardinia (Italy). 18.33% of the examined individuals (22 males, 55 females) show congenital absence and/or morphometric reduction of at least one tooth. The frequency of congenital absence of teeth in Sardinians lies in the middle of the range of Caucasoid populations, but the average (mean = 1.7) per individual seems to be the lowest ever reported. In some traits of agenesis Sardinians show great similarity to other isolated populations. This suggests that dental agenesis is probably affected by the same factors (e.g. isolation and inbreeding), which are responsible for the present genetic structure of the Sardinian population.

Production of bacteriolytic activity in the oral cavity by nutritionally variant streptococci.

Microorganisms from the oral flora were examined for the production of bacteriolytic substances. Among human viridans group streptococci, only one group of strains with thiol-dependent properties was shown to secrete enzymes with bacteriolytic activity on heat-killed cells of Micrococcus luteus on double-layer nutrient agar plates. By morphology, culture requirements, and biochemical properties, they were found to conform to descriptions of nutritionally variant streptococci (NVS). Bacteriolytic activity was shown to be a constant property of all of the human oral NVS isolated and a property of some reference strains of NVS from clinical sources. No other known species of viridans group streptococci demonstrated bacteriolytic activity. Analysis of bacteriolytic activity could be a useful tool for both the isolation and identification of this fastidious group of microorganisms.

Periodontal disease, oral microbial flora and salivary antibacterial factors in diabetes mellitus type 1 patients.

One hundred and thirty-one patients with diabetes mellitus type 1 (IDDM) and 20 healthy controls were checked for the presence of periodontal diseases and for some oral microbiological parameters. Results demonstrated that IDDM patients, who were well compensated from both the metabolic and clinical point of view, showed a prevalence for periodontopathies, which only differed slightly from controls. Only the presence of gingivitis was significantly higher in IDDM patients than in healthy subjects. Both anaerobic and aerobic microbial flora did not show substantial differences for either group. Among the salivary antibacterial factors studied, lysozyme was significantly decreased in diabetic patients compared to controls. It is concluded that IDDM patients undergo periodontal complications with a frequency quite close to that of non-diabetic healthy subjects, when the disease is under strict metabolic and clinical control.

Molecular differentiation of field and vaccine strains of bluetongue virus serotype 2 using the real-time polymerase chain reaction and fluorescene resonance energy transfer hybridisation probes.

As a consequence of the recent outbreaks of bluetongue (BT) disease amongst sheep in the Mediterranean Basin, and following the subsequent vaccination campaign to control further spread of the disease and its long-term maintenance, it has become most important to develop rapid and sensitive methods that can reliably differentiate between field and vaccine strains of the causative virus. The authors describe a new method to differentiate bluetongue virus serotype 2 (BTV-2) field and vaccine strains, using the VP2 gene sequence differences between the South African vaccine and the Italian field wild-type strains. The method is based on the principle that the melting temperature of a DNA duplex gives information on the sequence, which enables the identification of even single-base alterations in the amplicon. The real-time polymerase chain reaction the generation of melting curves and fluorescence detection were all performed using the light cycler system (Roche). Primers and probes were designed using VP2 gene sequences. After RT-PCR, the melting curves analysis, derived by the fluorescence resonance energy transfer (FRET) real-time PCR, was performed using the light cycler data analysis program (Roche). To assess the diagnostic value of the method, a BTV-2 vaccine strain (Onderstepoort Biological Products, South Africa) was first compared against a field strain of BTV-2 (isolated during an outbreak in 2000 in Sardinia). The ability of the method to reliably identify all the BTV-2 strains was tested using an array of eleven BTV-2 field strains isolated during outbreaks in various Italian regions between 2000 and 2002 and other serotypes (BTV-1, BTV-4, BTV-9 and BTV-16) that had been isolated during recent outbreaks of BT in the Mediterranean Basin. The method was clearly able to differentiate BTV-2 strains of vaccine virus from all wild-type strains of the same serotype tested. The resultant melting curves distinctly reveal the two strains to have differing peak values of 47.8 degrees C-/+0.6 degrees C and 60.5 degrees C-/+0.6 degrees C, respectively.

Blue-yellow perimetry in patients with ocular hypertone.

The authors report the data of the blue-yellow (B-Y) perimetry compared with the Standard perimetry in normal subjects with endocular hypertension or with initial glaucoma. With the aim of evaluating the relationship with chromatic sense deficits, precociously found in glaucoma, the F-M 100 Hue test and Lanthony D 15 Desaturé test were done. Checks were made of refraction, visual acuity, pupil diameter and assumption of medications. Sensitivity reduction in eyes with initial glaucoma is highly significant with the B-Y perimetry. Pupil diameter reduction is quite uninfluential while the chromatic sense shows some quantitative and qualitative deficits.