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The aim of this study was to assess exercise test results and efficacy of therapy with a β blocker (acebutolol) in ryanodine receptor type 2 (RyR2) mutation carriers with documented ventricular arrhythmias (VAs) and long-term follow-up. Twenty RyR2 mutation carriers belonging to 8 families and regularly followed at our center were analyzed using a study protocol involving electrocardiography, exercise tests off and on β-blocker therapy, 2-dimensional echocardiography, and signal-averaged electrocardiography. Off-therapy exercise testing triggered the onset of VAs at different heart rates (mean 132 ± 13 beats/min) with various patterns that worsened while exercising and disappeared immediately after stopping. The most severe VAs detected were nonsustained ventricular tachycardia in 35% and ventricular couplets in 35%. In the remaining subjects single ventricular premature beats were recorded. In 15% of patients single monomorphic ventricular premature beats were detected and identified to be linked to RyR2 mutations owing to the presence of sudden deaths of their family members and subsequent family screening. Acebutolol made the VAs disappear completely in 20% of subjects and decreased their complexity in 50%, whereas it did not change VAs appreciably in 30% of patients with less complex VAs. After 11 ± 8 years of follow-up 2 patients developed syncope. In conclusion, exercise testing was a fundamental tool for assessing the clinical phenotype and efficacy of therapy in RyR2 mutation carriers and therapy with acebutolol led in most subjects to a decreased complexity of the arrhythmic pattern or to complete suppression. [ABSTRACT FROM AUTHOR]

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a cardiac disease characterized by progressive myocardial atrophy and fibrofatty replacement. Standard electrocardiograms (ECGs) and signal-averaged ECGs (SAECGs) were relatively low cost and repeatable diagnostic tools. In this study, ECGs and SAECGs of patients with ARVC were analyzed with the aim to assess the diagnostic capability of these noninvasive techniques. A total of 205 patients with ARVC were analyzed. ECGs were abnormal in 74% of patients and SAECGs were positive in 60%, with normal ECGs mostly related to mild forms of the disease. The most common electrocardiographic abnormalities were localized right QRS prolongation, poor r wave progression in the right precordial leads, incomplete right branch bundle block, prolonged S-wave upstroke in V(1) to V(3), parietal block, ST-segment elevation in V(1) to V(3), inversion of T waves beyond V(2), and epsilon wave. Low QRS voltages in the precordial leads were frequently present in all patients with ARVC compared with a group of 120 healthy subjects (p = 0.00001). T-wave inversion beyond V(3) characterized subjects with severe right ventricular dilatation, whereas in subjects with left ventricular involvement, T-wave inversion in lateral leads was more commonly detected. Overall, the extent of electrocardiographic abnormalities was related to disease extent. In conclusion, abnormalities in ECGs and SAECGs were frequent in patients with ARVC and correlated with disease extent, even if a stereotypical electrocardiographic pattern did not exist. ECGs and SAECGs remain an important tool for the diagnosis and assessment of ARVC extent. Nonetheless, a normal ECG does not exclude the presence of the disease. [ABSTRACT FROM AUTHOR]

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease characterized by myocardial necrosis followed by fibrous-fatty replacement. The pathologic process constitutes the basis for ventricular arrhythmias due to re-entrant circuits. Even if this genetic disease is transmitted in the majority of cases with autosomal dominant trait, in all reported series ARVC is prevalent in men. In this study we investigate the impact that gender may have on clinical presentation in a large series of patients with ARVC. A total of 171 consecutive patients (mean 29 +/- 12 years, range 13 to 65) affected by ARVC were examined with family and personal history, 12-lead electrocardiogram (ECG), 24-hour ECG, signal-averaged ECG, and echocardiogram. Moreover, electrophysiological study and ventricular angiography were performed in selected cases. In the 171 subjects, 71% were men and 29% women (p = 0.02). No gender differences were found considering the age at the time of diagnosis and of study enrolment and the prevalence of index cases and family members. The genders differed in prevalence of abnormal ECG (69% vs 52%, p = 0.036) and presence of late potentials (60% vs 40%, p = 0.01). Moreover, men had larger right ventricular dimensions and practiced competitive sports more frequently (26% vs 14%, p <0.001). Nonetheless, gender was not associated with a high incidence of life-threatening ventricular arrhythmias or with a poor outcome. In conclusion, our data show that diagnosis of ARVC is less common in female patients, who present a higher prevalence of mild forms. Nonetheless, the degree of electrical instability does not differ significantly between genders in affected subjects. Even if ARVC remains mainly a male disease, gender does not have a role in patients' outcome. The cause of the under-representation of women is not clear, even if potentially important factors such as sexual hormones and physical activity could play a role. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is described as a chronic degenerative disease characterized by the loss of articular cartilage. Senescence is a natural cellular response to stressors. Beneficial in certain conditions, the accumulation of senescent cells has been implicated in the pathophysiology of many diseases associated with aging. Recently, it has been demonstrated that mesenchymal stem/stromal cells isolated from OA patients contain many senescent cells that inhibit cartilage regeneration. However, the link between cellular senescence in MSCs and OA progression is still debated. In this study, we aim to characterize and compare synovial fluid MSCs (sf-MSCs), isolated from OA joints, with healthy sf-MSCs, investigating the senescence hallmarks and how this state could affect cartilage repair. Sf-MSCs were isolated from tibiotarsal joints of healthy and diseased horses with an established diagnosis of OA with an age ranging from 8 to 14 years. Cells were cultured in vitro and characterized for cell proliferation assay, cell cycle analysis, ROS detection assay, ultrastructure analysis, and the expression of senescent markers. To evaluate the influence of senescence on chondrogenic differentiation, OA sf-MSCs were stimulated in vitro for up to 21 days with chondrogenic factors, and the expression of chondrogenic markers was compared with healthy sf-MSCs. Our findings demonstrated the presence of senescent sf-MSCs in OA joints with impaired chondrogenic differentiation abilities, which could have a potential influence on OA progression.

Aim: The aim of this study has been to measure the distress of workers at a large hospital in Rome, immediately after the lockdown with relaxed national restrictions except the indication to wear masks FP2 and to maintain the interpersonal distance of at least one meter., Method: A web-based anonymous survey has been conducted. Of the 324 responders (23-69 years; 78.09% females), 41.05% was nurse, 31.17% medical doctor, 7.72% employee with administrative function, 3.09% psychologist, 1.54% biologist, 13.58% grouped in the "other" category. 60.49% worked in a no-covid-19 ward, 20.37% in the covid-19 ward, 13.58% in outpatient clinics, and 5.56% outside the hospital. 45.06% have been exposed to covid-19 and 7.72% tested positive for covid-19. 66.67% were satisfied with the safety measures taken by the hospital. Post-traumatic stress disorder (PTSD) symptoms, as measured by IES-R, and peritraumatic distress, measured by CPDI, were frequently reported (41.05% and 43.21%, respectively). PTSD resulted independently associated with peritraumatic distress (Adjusted Odds Ratio, AOR 49.83), perception of being avoided by family and/or friends due to work performed (AOR= 4.05), low hope for the future (AOR= 2.25) and female gender (AOR= 2.90). Age and profession were considered confounding variables., Results: These results showed that even in times of reduced restrictions, the prevalence of peritraumatic distress and PTSD is high, regardless of work and professional specialization, length of service, more or less direct contact with covid-19 patients., Conclusions: Since the biological damage resulting from a PTSD is known, it is important to activate screening programs followed by specific interventions to reduce long-term risks to mental health.

Tendinopathies are at the frontier of advanced responses to health challenges and sectoral policy targets. Cell-based therapy holds great promise for tendon disorder resolution. To verify the role of stepwise trans-differentiation of amniotic epithelial stem cells (AECs) in tendon regeneration, in the present research three different AEC subsets displaying an epithelial (eAECs), mesenchymal (mAECs), and tendon-like (tdAECs) phenotype were allotransplanted in a validated experimental sheep Achilles tendon injury model. Tissue healing was analyzed adopting a comparative approach at two early healing endpoints (14 and 28 days). All three subsets of transplanted cells were able to accelerate regeneration: mAECs with a lesser extent than eAECs and tdAECs as indicated in the summary of the total histological scores (TSH), where at day 28 eAECs and tdAECs had better significant scores with respect to mAEC-treated tendons (p < 0.0001). In addition, the immunomodulatory response at day 14 showed in eAEC-transplanted tendons an upregulation of pro-regenerative M2 macrophages with respect to mAECs and tdAECs (p < 0.0001). In addition, in all allotransplanted tendons there was a favorable IL10/IL12 compared to CTR (p < 0.001). The eAECs and tdAECs displayed two different underlying regenerative mechanisms in the tendon. The eAECs positively influenced regeneration mainly through their greater ability to convey in the host tissue the shift from pro-inflammatory to pro-regenerative responses, leading to an ordered extracellular matrix (ECM) deposition and blood vessel remodeling. On the other hand, the transplantation of tdAECs acted mainly on the proliferative phase by impacting the density of ECM and by supporting a prompt recovery, inducing a low cellularity and angle alignment of the host cell compartment. These results support the idea that AECs lay the groundwork for production of different cell phenotypes that can orient tendon regeneration through a crosstalk with the host tissue. In particular, the obtained evidence suggests that eAECs are a practicable and efficient strategy for the treatment of acute tendinopathies, thus reinforcing the grounds to move their use towards clinical practice.

Purpose: To measure the prevalence and characteristics of distress and hope for the future among psycho-oncologists, who faced the coronavirus disease 2019 (COVID-19) emergency along with other healthcare workers., Methods: A web-based study was conducted among members of the Italian Society of Psycho-Oncology between May 29 and June 5, 2020., Results: A total of 237 members, aged 28-72 years, completed the COVID-19 Peritraumatic Distress Index (CPDI), Impact of Event Scale-Revised (IES-R), and HOPE questionnaires; 86.92% were female, 58.65% worked in hospitals, 21.10% were exposed to COVID-19, 11.39% experienced peritraumatic distress, and 3.38% had posttraumatic stress disorder symptoms. Peritraumatic distress was associated with living alone (adjusted odds ratio [AOR] 3.05; 95% confidence interval [CI] 1.41-8.13), using sleep remedies (AOR 3.79; 95% CI 1.41-10.21), and the perception of being avoided by family or friends because of work (AOR 2.69; 95% CI 1.02-7.11); high HOPE-Agency scores were associated with the absence of peritraumatic stress (AOR 0.40; 95% CI 0.16-0.96) after adjustment for age and sex., Conclusions: Psycho-oncologists showed greater resilience than other healthcare workers as they are trained to help others, but also to review their own values and behavior in light of stressful events. Of interest is the association between peritraumatic distress and social isolation, real or perceived. Healthcare institutions should pay attention to the mental well-being of their employees by promoting distress screening using simple tools such as the CPDI and implementing support interventions. Psycho-oncology associations should introduce policies aimed at developing a sense of social connectedness by providing an interactive system of orientation and scientific reference.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease characterized by progressive myocardial fibro-fatty replacement, arrhythmias and risk of sudden death. Its diagnosis is challenging and often it is achieved after disease onset or postmortem. In this study, we sought to identify circulating microRNAs (miRNAs) differentially expressed in ARVC patients compared to healthy controls. In the pilot study, we screened the expression of 754 miRNAs from 21 ARVC patients and 20 healthy controls. After filtering the miRNAs considering a log fold-change cut-off of ±1, p -value < 0.05, we selected five candidate miRNAs for a subsequent validation study in which we used TaqMan-based real-time PCR to analyse samples from 37 ARVC patients and 30 healthy controls. We found miR-185-5p significantly upregulated in ARVC patients. Receiver operating characteristic analysis indicated an area under the curve of 0.854, corroborating the link of this miRNA and ARVC pathophysiology.

Cellular senescence is a hallmark of ageing and it plays a key role in the development of age-related diseases. Abdominal aortic aneurysm (AAA) is an age related degenerative vascular disorder, characterized by a progressive dilatation of the vascular wall and high risk of rupture over time. Nowadays, no pharmacological therapies are available and the understanding of the molecular mechanisms that lead to AAA onset and development are poorly defined. In this study we investigated the cellular features of senescence in vascular mesenchymal stromal cells, isolated from pathological (AAA - MSCs) and healthy (h - MSCs) segments of human abdominal aorta and their implication in impairing the vascular repair ability of MSCs. Cell proliferation, ROS production, cell surface area, the expression of cyclin dependent kinase inhibitors p21 CIP1 and p16 INK4a , the activation of the DNA damage response and a dysregulated autophagy showed a senescent state in AAA - MSCs compared to h-MSCs. Moreover, a reduced ability to differentiate toward endothelial cells was observed in AAA - MSCs. All these data suggest that the accumulation of senescent vascular MSCs over time impairs their remodeling ability during ageing. This condition could support the onset and development of AAA., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Peritraumatic distress is an important predictor of post-traumatic stress disorder and although several questionnaires are available for its measurement, none of these are specific to CoViD-19. The new CoViD-19 Peritraumatic Distress Index (CPDI), developed in China, is characterized as a rapid compilation tool (10 minutes), easily understandable and appreciated by people., Aim: The objectives of this study were: (1) the validation of the Italian version of the CPDI, and (2) the measurement of the prevalence of peritraumatic distress in this phase 1 CoViD-19., Method: CPDI has been translated using a standard forward-backward-translation procedure and offered online to 329 people (191 females and 137 males, aged 46.49 ± 13.58 years). The CPDI showed an internal-consistency of Cronbach's α =0.916. Content validity was judged satisfactory by two psychologists experienced in stress and trauma. The construct validity is given by the high correlation with the dimensions of Intrusion, Avoidance and Hyperarousal as measured by the Impact of Event Scale-Revised (r=0.63, r=0.57, r=0.71, respectively)., Results: Our results are comparable to the Chinese ones. A third of people experienced symptoms of mild/moderate and severe peritraumatic distress. Females have higher scores, compared to males. Older people are more resilient, compared to younger, and those who have been in quarantine report less distress than those didn't, as evidenced by the results of the multivariate logistic regression model. High distress was associated with use of psychotropic drugs (AOR=4.28; 95% CI=1.55-11.85), sleeping remedies (AOR=4.05; 95% CI=2.07-7.94), be worried about dying in case of contagion CoViD-19 (AOR=3.33; 95% CI=1.83-6.06), female gender (AOR=2.95; 95% CI=1.58-5.53) and have a religious belief (AOR=1.97; 95% CI=1.05-3.70). To be aged 51-71 years, to have been in quarantine and to have received psychological support were variables associated with lower distress scores., Conclusions: The psychometric properties of the Italian version are satisfactory and confirm that CPDI is a tool fast, non-intrusive, administered online, and therefore 'safe' in a phase with a high risk of contagion. It allows, like a psychic thermoscan, to quickly detect the needs of the population and propose equally rapid interventions.

Amniotic membrane (AM) is considered an important medical device with many applications in regenerative medicine. The therapeutic properties of AM are due to its resistant extracellular matrix and to the large number of bioactive molecules released by its cells. An important goal that still remains to be achieved is the identification of cultural and preservation protocols able to maintain in time the membrane morphology and the biological properties of its cells. Recently, our research group demonstrated that progesterone (P 4 ) is crucial in preventing the loss of the epithelial phenotype of amniotic epithelial cells in vitro . Followed by this premise, it has been evaluated whether P 4 may also affect AM properties in a short-term culture. Results confirm that P 4 preserves AM integrity and architecture with respect to untreated AM, which showed alterations in morphology. Transmission electron microscopy (TEM) analyses demonstrate that P 4 also maintains unaltered cell-cell junctions, nuclear status, and intracellular organelles. On the contrary, an untreated AM experienced an extensive cell death and a strong reduction of immunomodulatory properties, measured in terms of anti-inflammatory cytokine expression and secretion. Overall, these results could open to new strategies to ameliorate the protocols for cryopreservation and tissue culture, which represent preliminary stages of AM application in regenerative medicine., (Copyright © 2020 Canciello, Teti, Mazzotti, Falconi, Russo, Giordano and Barboni.)

Osteoarthritis is a degenerative disease that strongly correlates with age and promotes the breakdown of joint cartilage and subchondral bone. There has been a surge of interest in developing cell-based therapies, focused particularly on the use of mesenchymal stromal cells (MSCs) isolated from adult tissues. It seems that MSCs derived from synovial joint tissues exhibit superior chondrogenic ability, but their unclear distribution and low frequency actually limit their clinical application. To date, the influence of aging on synovial joint derived MSCs' biological characteristics and differentiation abilities remains unknown, and a full understanding of the mechanisms involved in cellular aging is lacking. The aim of this study was therefore to investigate the presence of age-related alterations in synovial fluid MSCs and their influence on the potential ability of MSCs to differentiate toward chondrogenic phenotypes. Synovial fluid MSCs, isolated from healthy equine donors from 3 to 40 years old, were cultured in vitro and stimulated towards chondrogenic differentiation for up to 21 days. An equine model was chosen due to the high degree of similarity of the anatomy of the knee joint to the human knee joint and as spontaneous disorders develop that are clinically relevant to similar human disorders. The results showed a reduction in cell proliferation correlated with age and the presence of age-related tetraploid cells. Ultrastructural analysis demonstrated the presence of morphological features correlated with aging such as endoplasmic reticulum stress, autophagy, and mitophagy. Alcian blue assay and real-time PCR data showed a reduction of efficiency in the chondrogenic differentiation of aged synovial fluid MSCs compared to young MSCs. All these data highlighted the influence of aging on MSCs' characteristics and ability to differentiate towards chondrogenic differentiation and emphasize the importance of considering age-related alterations of MSCs in clinical applications., Competing Interests: The authors declare no conflict of interest.

Background: Arrhythmogenic cardiomyopathy (ACM) is associated with arrhythmias and risk of sudden death. Mutations in genes encoding proteins of cardiac intercalated discs account for ∼60% of ACM cases, but the remaining 40% is still genetically elusive., Objective: The purpose of this study was to identify the underlying genetic cause in probands with ACM., Methods: DNA samples from 40 probands with ACM, negative for mutations in the 3 major ACM genes-DSP, PKP2, and DSG2, were screened by using a targeted gene panel consisting of 15 known ACM genes and 53 candidate genes., Results: About half of patients were found to carry rare variant(s) predicted to be damaging; specifically, 9 (22.5%) showed ≥1 variants in genes associated with ACM and/or with other inherited heart diseases and 10 (25%) showed variants in candidate genes. Among the latter, we focused on 2 novel variants in TP63 and PPP1R13L candidate genes (c.796C>T, p.(R266*) and c.1858G>C, p.(A620P), respectively). The encoded proteins p63 and inhibitor of apoptosis stimulating p53 protein are known to be interacting partners. Inhibitor of apoptosis stimulating p53 protein is a shuttling multifunctional protein: in the nucleus it is critical for inhibiting p63 function, whereas in the cytoplasm it regulates desmosome integrity. According to the American College of Medical Genetics and Genomics guidelines, the variant in TP63 has been scored as likely pathogenic and the variant in PPP1R13L as a variant of uncertain significance. Importantly, the mutant TP63 allele leads to nonsense-mediated messenger RNA decay, causing haploinsufficiency., Conclusion: Our findings identify TP63 as a putative novel disease gene for ACM, while the possible involvement of PPP1R13L remains to be determined., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by progressive fibro-fatty myocardial replacement, ventricular arrhythmia, heart failure, and sudden death. Causative mutations can be identified in 60% of patients, and most of them are found in genes encoding mechanical junction proteins of the intercalated disk., Methods: Whole-exome sequencing was performed on the proband of an ACM family. Sanger sequencing was used to screen for mutations the tight junction protein 1 ( TJP1) gene in unrelated patients. Predictions of local structure content and molecular dynamics simulations were performed to investigate the structural impact of the variants., Results: A novel c.2006A>G p.(Y669C) variant in TJP1 gene was identified by whole-exome sequencing in a patient with ACM. TJP1 encodes zonula occludens 1, an intercalated disk protein interacting with proteins of gap junctions and area composita. Additional rare TJP1 variants have been identified in 1 of 40 Italian probands (c.793C>T p.(R265W)) with arrhythmogenic right ventricular cardiomyopathy and in 2 of 43 Dutch/German patients (c. 986C>T, p.(S329L) and c.1079A>T, p.(D360V)) with dilated cardiomyopathy and recurrent ventricular tachycardia. The p.(D360V) variant was identified in a proband also carrying the p.(I156N) pathogenic variant in DSP. All 4 TJP1 variants are predicted to be deleterious and affect highly conserved amino acids, either at the GUK (guanylate kinase)-like domain (p.(Y669C)) or at the disordered region of the protein between the PDZ2 and PDZ3 domains (p.(R265W), p.(S329L), and p.(D360V)). The local unfolding induced by the former promotes structural rearrangements of the GUK domain, whereas the others are predicted to impair the function of the disordered region. Furthermore, rare variants in TJP1 are statistically enriched in patients with ACM relative to controls., Conclusions: We provide here the first evidence linking likely pathogenic TJP1 variants to ACM. Prevalence and pathogenic mechanism of TJP1-mediated ACM remain to be determined.

Adult stem cells are a promising cell source for cartilage regeneration. They resided in a special microenvironment known as the stem-cell niche, characterized by the presence of low oxygen concentration. Cobalt chloride (CoCl 2 ) imitates hypoxia in vitro by stabilizing hypoxia-inducible factor-alpha (HIF-1 α ), which is the master regulator in the cellular adaptive response to hypoxia. In this study, the influence of CoCl 2 on the chondrogenic potential of human MSCs, isolated from dental pulp, umbilical cord, and adipose tissue, was investigated. Cells were treated with concentrations of CoCl 2 ranging from 50 to 400  μ M. Cell viability, HIF-1 α protein synthesis, and the expression of the chondrogenic markers were analyzed. The results showed that the CoCl 2 supplementation had no effect on cell viability, while the upregulation of chondrogenic markers such as SOX9, COL2A1, VCAN, and ACAN was dependent on the cellular source. This study shows that hypoxia, induced by CoCl 2 treatment, can differently influence the behavior of MSCs, isolated from different sources, in their chondrogenic potential. These findings should be taken into consideration in the treatment of cartilage repair and regeneration based on stem cell therapies.

Arrhythmogenic cardiomyopathy (ACM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically distinct disorders of the myocardium. Here we describe for the first time co-inheritance of mutations in genes associated with ACM or HCM in two families with recurrence of both cardiomyopathies. Among the double heterozygotes for mutations in desmoplakin (DSP) and myosin binding protein C (MYBPC3) genes identified in Family A, two were diagnosed with ACM and two with HCM. In Family B, one patient was identified to carry mutations in α-T-catenin (CTTNA3) and β-myosin (MYH7) genes, but he does not fulfill the current diagnostic criteria neither for ACM nor for HCM. Interestingly, the double heterozygotes showed a variable clinical expression of both cardiomyopathies and they do not exhibit a more severe phenotype than family members carrying only one of the two mutations.

Background: 5-fluorouracil (5-FU) based chemotherapy is the most common first line regimen used in gastric and gastroesophageal junction cancer, but development of severe toxicity is a main concern in the treatment. The present study is aimed to evaluate a novel pre-treatment assay, known as the 5-FU degradation rate (5-FUDR), as a predictive factor for 5-FU toxicity., Methods: Pre-treatment 5-FUDR and gene polymorphisms related to 5-FU metabolism (DPYDIVS14+1G>A, MTHFRA1298T or C677T, TMYS TSER) were characterized in gastro-esophageal cancer patients. Association with toxicities was retrospectively evaluated, using multivariate logistic regression analysis., Results: 107 gastro-esophageal cancer patients were retrospectively analyzed. No relation between gene polymorphisms and toxicity were detected, while low (< 5th centile) and high (> 95th centile) 5-FUDRs were associated with development of grade 3-4 toxicity (OR 11.14, 95% CI 1.09-113.77 and OR 9.63, 95% CI 1.70-54.55, p = 0.002)., Conclusions: Compared to currently used genetic tests, the pre-treatment 5-FUDR seems useful in identifying patients at risk of developing toxicity.

Aims: Whether a desmosomal (DS)-gene defect may in itself induce life-threatening ventricular arrhythmias regardless of phenotypic expression of arrhythmogenic right ventricular cardiomyopathy (ARVC) is still debated. This prospective study evaluated the long-term outcome of DS-gene mutation carriers in relation to the ARVC phenotypic expression., Methods and Results: The study population included 116 DS-gene mutation carriers [49% males; median age 33 years (16-48 years)] without prior sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). The incidence of the arrhythmic endpoint, including sudden cardiac death (SCD), aborted SCD, sustained VT, and appropriate implantable cardioverter-defibrillator (ICD) intervention was evaluated prospectively and stratified by the presence of ARVC phenotype and risk factors (syncope, ventricular dysfunction, and non-sustained VT). At enrolment, 40 of 116 (34%) subjects fulfilled the criteria for definite ARVC while the remaining were either borderline or phenotype negatives. During a median follow-up of 8.5 (5-12) years, 10 patients (9%) had arrhythmic events (0.9%/year). The event rate was 2.3%/year among patients with definite ARVC and 0.2%/year among borderline or phenotype negative patients (P = 0.002). In patients with definite ARVC, the incidence of arrhythmias was higher in those with ≥1 risk factors (4.1%/year) than in those with no risk factors (0.4%/year, P = 0.02). Mortality was 0.2%/year (1 heart failure death and 1 SCD)., Conclusions: The ARVC phenotypic expression is a prerequisite for the occurrence of life-threatening arrhythmias in DS-gene mutation carriers. The vast majority of malignant arrhythmic events occurred in patients with an overt disease phenotype and major risk factors suggesting that this subgroup most benefits from ICD therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Despite the wide use of 5-fluorouracil-based chemotherapy, development of severe toxicity that follow the treatment is not a rare event. The efforts to establish pretreatment tools for toxicity prediction, led to the development of various pharmacogenetic and biochemical assays, mainly targeted to assess the activity level of dihydropyrimidine dehydrogenase (DPD), the main metabolizing enzyme for 5-fluorouracil. Using peripheral blood mononuclear cells, we developed a biochemical assay, that is not limited to the evaluation of DPD activity, but determines the net result of all the enzymatic transformation of 5FU, in terms of the amount of drug consumed by the cells in a time unit. This parameter, named 5-fluorauracil degradation rate, presents a normal distribution inside the population and highlight the presence of an ultra-rapid metabolizers class of subjects, besides the expected poor metabolizers class. Here we will show that, in a colorectal cancer patient cohort, both poor and ultra-rapid metabolizers have significantly increased the risk of developing severe toxicity (grade3-4). Patient stratification depending on the individual 5-fluorouracil degradation rate allows to identify a 10% of the overall population at high risk of developing severe toxicity, compared to the 1.3% (as assessed in the Italian population) identified by the most commonly employed pharmacogenetic test, including the DPD polymorphism IVS14+1G>A.

Objective: Third-generation aromatase inhibitors (AI) are potent suppressors of aromatase activity. The aim of this study was to measure the incidence of adverse effects in breast cancer patients treated with AI-based adjuvant therapy and the relationship with the CYP19A1 genotypes., Materials and Methods: Forty-five postmenopausal breast cancer patients (46-85 yrs) in AI adjuvant treatment were genotyped for the rs4646 polymorphisms of CYP19A1 gene and three variations were identified. Toxicities were registered at each follow-up medical examination, and classified in accord with the Common Terminology Criteria for Adverse Events., Results: Twenty-four (53.3%) patients presented the GG genotype; 19 (42.2%) the GT, and 2 (4.4%) the TT. The AI treatment was Anastrazole for 35 patients (77.8%) and Letrozole for the others (n=10; 22.2%). Osteoporosis was significantly associated with the GG genotype (p=0.001). Treatment discontinuation (TD) was observed in 6 cases (13.3%). The only parameter able to predict TD was the appearance of severe arthralgia/myalgia (Odds Ratio, OR=23.75; p=0.009), when adjusted for age and AI treatment., Conclusion: Our results suggest that CYP19A1 polymorphic variants may influence susceptibility to develop AI-related side effects. Further prospective studies are needed to confirm the role of the aromatase gene (CYP19A1) polymorphisms in predicting adverse effects to AI-based therapy.

Dominant mutations in desmocollin-2 (DSC2) gene cause arrhythmogenic cardiomyopathy (ACM), a progressive heart muscle disease characterized by ventricular tachyarrhythmias, heart failure, and risk of juvenile sudden death. Recessive mutations are rare and are associated with a cardiac or cardiocutaneous phenotype. Here, we evaluated the impact of a homozygous founder DSC2 mutation on clinical expression of ACM. An exon-by-exon analysis of the DSC2 coding region was performed in 94 ACM index patients. The c.536A>G (p.D179G) mutation was identified in 5 patients (5.3%), 4 of which resulted to be homozygous carriers. The 5 subjects shared a conserved haplotype, strongly indicating a common founder. Genetic and clinical investigation of probands' families revealed that p.D179G homozygous carriers displayed severe forms of biventricular cardiomyopathy without hair or skin abnormalities. The only heterozygous proband, who carried an additional variant of unknown significance in αT-catenin gene, showed a mild form of ACM without left ventricular involvement. All heterozygous family members were clinically asymptomatic. In conclusion, this is the first homozygous founder mutation in DSC2 gene identified among Italian ACM probands. Our findings provide further evidence of the occurrence of recessive DSC2 mutations in patients with ACM predominantly presenting with biventricular forms of the disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The aim of the study was to validate the association between the Arg166His polymorphisms of the Fc immunoglobulin receptor 2A (FCGR2A) and the Val212Phe of FCGR3A and pathological clinical response (pCR) to trastuzumab in HER2-positive breast cancer patients., Methods: Polymorphisms were characterized by pyrosequencing in 26 patients with ductal histotype breast cancer in a neoadjuvant setting and genotype association with pCR was analyzed., Results: No association was found between the FCGR3A Val212Phe polymorphisms and pCR. In contrast, the FCGR2A GG genotype (Arg allele) was found to be positively associated with pCR (P = 0.012)., Conclusions: Our results do not support previously reported data on the effect of polymorphisms in immunoglobulin Fc receptors upon response to trastuzumab therapy.

Elastography (ES) is a technique that, when associated with traditional B mode ultrasound (US), allows the degree of elasticity of tissue to be evaluated according to a color scale system. The aims of the study were to compare the diagnostic characteristics of two widely used techniques adopted in breast cancer screening; US and color Doppler (CD), with those of the same two techniques plus ES, and assessment of the same diagnostic characteristics when the three methods were applied to lesions < or >1 cm. Methods used included subjecting 212 women to investigations aimed at the early diagnosis of breast cancer outside the screening model, whereby 395 lesions were detected by US, ES, and CD, with a definitive diagnosis proved by histological exam. The diagnostic performance of US, ES, CD, and their combinations was calculated. The results showed that comparing the diagnostic characteristics of the three methods with reference to the definitive histological results for malignant breast lesions, the best diagnostic accuracy was obtained when US, ES, and CD were combined (0.837). For lesions <1 cm, diagnostic accuracy was 0.782, and for those >1 cm, it was 0.886. In the lesions <1 cm, which were more difficult to study, a positive ES score (>4) appeared to be sufficient to deepen the diagnosis, even though 35 % of the ES or US positive lesions were not malignant. By contrast, in lesions >1 cm, the probability of having a malignant lesion when all three tests were positive was very high (97 %). It was concluded that early diagnosis is a key factor in breast cancer, so an economically sustainable, non-invasive pathway is the target of diagnostic breast imaging.

Background: The aim of the study was to assess the association of single nucleotide polymorphisms (SNPs) C677T and A1298C in the methylenetetrahydrofolate reductase gene with colorectal, esophageal/gastric and pancreatic cancer in a cohort of Italian patients., Methods: A total of 790 cancer patients and 202 healthy controls were genotyped and distributions in genotype and allele frequencies were compared by Chi-squared analysis and logistic regression analysis., Results: According to most of previous findings, we found an effect of the C677T variant, but no effect of the A1298C, in colorectal and esophageal/gastric, whereas no association was evidenced with pancreatic cancer. We found that only homozygous TT carriers of the C677T variant had an increased risk for onset of cancer., Conclusion: This result could be related to dietary and behavioral habits of the analyzed population, which could mitigate the deleterious effect of the T allele in heterozygosity and it highlights the importance to validate genetic determinant of cancer risk in different population and geographical areas., Competing Interests: The authors declare no potential conflicts of interest.

Background: Mutations in genes encoding for desmosomal proteins are the most common cause of arrhythmogenic right ventricular cardiomyopathy (ARVC). We assessed the value of genotype for prediction of lifetime major arrhythmic events and sudden cardiac death (SCD) in desmosomal gene-related ARVC., Methods and Results: The overall study population included 134 desmosomal gene mutation carriers (68 men; median age 36 years [22-52]) from 44 consecutive ARVC families undergoing comprehensive genetic screening. The probability of experiencing a first major arrhythmic event or SCD during a lifetime was determined by using date of birth as start point for the time-to-event analysis, and was stratified by sex, desmosomal genes, mutation types, and genotype complexity (single versus multiple mutations). One hundred thirteen patients (84%) carried a single desmosomal gene mutation in desmoplakin (n=44; 39%), plakophilin-2 (n=38; 34%), desmoglein-2 (n=30; 26%), and desmocollin-2 (n=1; 1%), whereas 21 patients (16%) had a complex genotype with compound heterozygosity in 7 and digenic heterozygosity in 14. Over a median observation period of 39 (22-52) years, 22 patients (16%) from 20 different families had arrhythmic events, such as SCD (n=1), aborted SCD because of ventricular fibrillation (n=6), sustained ventricular tachycardia (n=14), and appropriate defibrillator intervention (n=1). Multiple desmosomal gene mutations and male sex were independent predictors of lifetime arrhythmic events with a hazard ratio of 3.71 (95% confidence interval, 1.54-8.92; P=0.003) and 2.76 (95% confidence interval, 1.19-6.41; P=0.02), respectively., Conclusions: Compound/digenic heterozygosity was identified in 16% of ARVC-causing desmosomal gene mutation carriers and was a powerful risk factor for lifetime major arrhythmic events and SCD. These results support the use of comprehensive genetic screening of desmosomal genes for arrhythmic risk stratification in ARVC.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disease characterized by progressive myocardial loss, with fibro-fatty replacement, and high frequency of ventricular arrhythmias that can lead to sudden cardiac death. ARVC is a genetically determined disorder, usually caused by point mutations in components of the cardiac desmosome. Conventional mutation screening of ARVC genes fails to detect causative mutations in about 50% of index cases, suggesting a further genetic heterogeneity. We performed a genome-wide linkage study and a copy number variations (CNVs) analysis, using high-density SNP arrays, in an ARVC family showing no mutations in any of the desmosomal genes. The CNVs analysis identified a heterozygous deletion of about 122 kb on chromosome 12p11.21, including the entire plakophilin-2 gene and shared by all affected family members. It was not listed on any of available public CNVs databases and was confirmed by quantitative real-time PCR. This is the first SNP array-based genome-wide study leading to the identification of a CNV segregating with the disease phenotype in an ARVC family. This result underscores the importance of performing additional analysis for possible genomic deletions/duplications in ARVC patients without point mutations in known disease genes.

The aim of this study was to analyze using noninvasive cardiac examinations a series of young athletes discovered to have ventricular arrhythmias (VAs) during the preparticipation screening program for competitive sports. One hundred forty-five athletes (mean age 17 ± 5 years) were evaluated. The study protocol included electrocardiography (ECG), exercise testing, 2-dimensional and Doppler echocardiography, 24-hour Holter monitoring, signal-averaged ECG, and in selected cases contrast-enhanced cardiac magnetic resonance imaging. Results of ECG were normal in most athletes (85%). VAs were initially detected prevalently during exercise testing (85%) and in the remaining cases on ECG and Holter monitoring. Premature ventricular complexes disappeared during exercise in 56% of subjects. Premature ventricular complexes during Holter monitoring averaged 4,700 per day, predominantly monomorphic (88%), single, and/or in couplets (79%). The most important echocardiographic findings were mitral valve prolapse in 29 patients (20%), congenital heart disease in 4 (3%), and right ventricular regional kinetic abnormalities in 5 (3.5%). On cardiac magnetic resonance imaging, right ventricular regional kinetic abnormalities were detected in 9 of 30 athletes and were diagnostic of arrhythmogenic right ventricular cardiomyopathy in only 1 athlete. Overall, 30% of athletes were judged to have potentially dangerous VAs. In asymptomatic athletes with prevalently normal ECG, most VAs can be identified by adding an exercise test during preparticipation screening. In conclusion, cardiac screening with noninvasive examinations remains a fundamental tool for the identification of a possible pathologic substrate and for the characterization of electrical instability., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: Patients' care has been associated with a high burden of psychological symptoms in caregivers. This study identifies characteristics associated with mood disorders in caregivers of cancer patients., Methods: One hundred fifty-two caregivers, aged 24-78 years (average age 51; 60 % females), of cancer patients completed Family Strain Questionnaire (FSQ), Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), and Coping Orientations to the Problems Experienced. We combined this information with patient chart abstraction data., Results: Sixty-three percent of females and 38 % of males were scored as positive when screened for mood disorders, as measured by HADS (total score ≥ 16), and 17 and 5 % for emotional distress as measured by IES (total score ≥ 50). High scores in FSQ-satisfaction with family relationships and FSQ-need for more information about cancer, and low scores in FSQ-thoughts about death are reported. FSQ-emotional burden and FSQ-problems in social involvement are the areas more compromised in females, compared to males. Females, compared to males, use emotional-oriented coping strategies more frequently. Factors independently associated with mood disorders included emotional burden, problems in social involvement, and non-attendance of meeting places; help and assistance from public local services (for patients) decreased the risk of mood disorders in caregivers., Conclusions: Prevalence of mood disorders is high in cancer patients' caregivers. These results highlight the need to develop family intervention strategies to minimize the impact of patient's care on caregivers' mental health.

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a major cause of juvenile sudden death and is characterized by fibro-fatty replacement of the right ventricle. Mutations in several genes encoding desmosomal proteins have been identified in ARVC. We speculated that αT-catenin, encoded by CTNNA3, might also carry mutations in ARVC patients. Alpha-T-catenin binds plakophilins and this binding contributes to the formation of the area composita, which strengthens cell-cell adhesion in contractile cardiomyocytes., Methods and Results: We used denaturing high-performance liquid chromatography and direct sequencing to screen CTNNA3 in 76 ARVC patients who did not carry any mutations in the desmosomal genes commonly mutated in ARVC. Mutations c.281T > A (p.V94D) and c.2293&#95;2295delTTG (p.del765L) were identified in two probands. They are located in important domains of αT-catenin. Yeast two-hybrid and cell transfection studies showed that the interaction between the p.V94D mutant protein and β-catenin was affected, whereas the p.del765L mutant protein showed a much stronger dimerization potential and formed aggresomes in HEK293T cells., Conclusion: These findings might point to a causal relationship between CTNNA3 mutations and ARVC. This first report on the involvement of an area composita gene in ARVC shows that the pathogenesis of this disease extends beyond desmosomes. Since the frequency of CTNNA3 mutations in ARVC patients is not rare, systematic screening for this gene should be considered to improve the clinical management of ARVC families.

Studies on HRQOL on kidney-transplanted young adults who had a diagnosis of chronic renal failure (CRF) in the pediatric age are uncommon. We studied HRQOL and its predictors in a sample of young adults with CRF in childhood who underwent a renal transplant. We recruited patients ≥18 yr old with renal transplant. We measured HRQOL by a standardized questionnaire on lifestyle, Short Form-36 (SF-36; including a PCS and a MCS; scale: 0-100), the GHQ (for short-term changes in mental health; scale: 0-36), and the MSPSS (with scales for family, friends, and significant others; scale: 0-100). We assessed the association of potential predictors of HRQOL through multiple linear regression models. We studied 66 patients aged 18-34 yr. The average PCS score was 76.4, and the average MCS score was 73.9. The mean GHQ total score was 14.8, and the total scale MSPSS mean score was 70. Severe comorbidities significantly affected the PCS score. Individuals with severe comorbidities had lower PCS scores., (© 2012 John Wiley & Sons A/S.)

Background: Cancer leads to a complicated pattern of change in quality of life (QoL)., Objective: The aims of this study were to assess the impact of treatment-related side effects on QoL in cancer patients and to explore which other factors, and to what extent, contribute to explain low QoL scores., Methods: One hundred twenty-three cancer patients receiving chemotherapy completed the self-administered questionnaires (Medical Outcomes Short-Form-36 (SF-36) and 12-item General Health Questionnaire). Multiple regression analyses were conducted with the SF-36 physical component summary (PCS) and SF-36 mental component summary (MCS) scores as the dependent variables and demographic and clinical factors as independent variables., Results: Seventy-two percent of patients experienced treatment-related side effects, and 32% resulted positive for psychiatric diseases. Two multivariate analyses showed that worse PCS scores, like worse MCS scores, were significantly and independently predicted by treatment-related side effects (odds ratio (OR) = 5.00, 95%CI 1.29-19.45; OR = 8.08, 95%CI 2.03-32.22, respectively) and changes in health over the last 12 months (OR =2.34, 95%CI 1.47-3.76; OR = 3.21, 95%CI 1.90-5.41, respectively), after adjustment for age, gender, years of school, time from cancer diagnosis, and psychiatric disease., Conclusions: Given the new emphasis on QoL, we suggest that physicians have a responsibility to openly discuss therapy efficacy, prognosis as well as the potential for adverse events with their patients. Changes in health, as perceived by patient, should also be monitored at follow-up.

Aim: Post-traumatic emotional distress follows exposure to trauma and may be affected by atypical cerebral lateralisation. We aimed to explore the relationship between handedness and emotional dysfunction in people exposed to a nat-ural disaster., Methods: About 22 months after an earthquake, 326 exposed adults completed the Edinburgh Handedness Inventory, the Impact of Events Scale-Revised, and the Insomnia Severity Index., Results: Mixed-handed people, compared to right-handed, had a 3.3 fold increase in odds to have emotional distress. Consistent left-handers scored higher than consistent right- and mixed-handers on the ISI scale., Conclusions: Findings support that lateral preference is associated with emotion-al distress in people exposed to trauma.

Background: Depression is a potential risk factor for mortality among the aged and it is also associated with other chronic diseases and unhealthy lifestyles that may also affect mortality. The purpose of this study was to investigate the association between depressive symptoms and mortality, controlling for health, nutritional status, and life-style factors., Methods: A cohort of elderly people (N = 167) was followed-up for ten years. Information on socio-demographic characteristics, medical history, smoking, and alcohol consumption was collected. The primary outcome was all-cause mortality; the secondary outcome was cancer-specific mortality. The Geriatric Depression Scale (GDS-15) was used to assess depression. Using a multivariable Cox proportional hazards regression, we examined the association between depressive symptoms and mortality., Results: Elderly people with depression (scoring above the depression cut-off of 7) had a 53% increased risk of mortality (relative risk (RR) 1.53; 95%CI: 1.05-2.24) compared to non-depressed subjects. The combination of depressive symptoms with smoking was associated with a particularly higher risk of mortality (RR: 2.61; 95%CI: 1.28-5.31), after controlling for potential confounders., Conclusions: Depressive symptoms are associated with a significantly increased risk of all-cause mortality. The combination of depressive symptoms and smoking shorten life expectancy among the aged.

Background: The aim of this study was to describe gender differences in patients operated on for TOF and to define the impact of pregnancy in late post-surgical follow-up in women., Methods: In this research, we studied 145 patients after correction of TOF: 66 male, 79 women, 41 of which reported history of 68 pregnancies, means age 37±10 years, age at operation 7±8 years, mean duration of post-surgical follow-up 30±7 years. Selected variables were compared according to sex and according to history of pregnancy with statistical tests., Results: Men had more severe hemodynamic impairment and a higher number of cardiac reoperations than females. 41% of patients had at least one complication during pregnancy; there were 16 (67%) abortions and 39 (74%) Caesarian delivers; the recurrence of congenital heart defect was 10%. After pregnancy, there was a shift from first to second functional class: unique pregnancy determined no differences in term of morpho-functional ventricular features compared to nulliparous, but they complained fatigue and palpitation and echocardiographyc dysfunction. Left ventricular dysfunction and QRS duration at ECG were independent predictors of ventricular arrhythmias in all patients., Conclusions: There were no gender-specific differences in patients operated on for TOF using ventriculotomy. Pregnancy is an event in these patients at risk for the newborn, in terms of miscarriage, prematurity, and recurrence of birth defects, and for the mother in terms of ventricular dysfunction and electrical instability. At least a single pregnancy does not appear to significantly modify the natural history of post-surgical patients operated on for TOF.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease carrying a risk of sudden death. Information about the clinical features during childhood and the age at disease onset is scanty., Objective: The aim of the study was to describe the ARVC phenotype as its initial clinical manifestation in a pediatric population (<18 years) with desmosomal gene mutations., Methods: Fifty-three ARVC desmosomal gene mutation carriers (mean age 12.3 ± 3.9 years) were investigated by electrocardiogram (ECG), signal-averaged ECG, 24-hour Holter, echocardiogram, and contrast-enhanced cardiac magnetic resonance (CMR)., Results: None of the children ≤10 years old fulfilled the 1994 criteria, as opposed to six (33%) aged 11-14 years and eight aged >14 years (42%). At the end of follow-up (9 ± 7 years), 21 (40%) fulfilled the 1994 diagnostic criteria (mean age 16 ± 4 years). By using the 2010 criteria in subjects aged ≤18 years, 53% were unaffected, versus 62% by using the traditional criteria. More than two-thirds of affected subjects had moderate-severe forms of the disease. Contrast-enhanced CMR was performed in 21 (40%); of 13 unaffected gene mutation carriers, six showed ARVC morphological and/or tissue abnormalities., Conclusion: In pediatric ARVC mutation carriers, a diagnosis was achieved in 40% of cases, confirming that the disease usually develops during adolescence and young adulthood. The 2010 modified criteria seem to be more sensitive than the 1994 ones in identifying familial pediatric cases. Contrast-enhanced CMR can provide diagnostic information on gene mutation carriers not fulfilling either traditional or modified criteria. Management of asymptomatic gene mutation carriers remains the main clinical challenge., (Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Recent evidence suggests a relationship between psychoform and somatoform dissociation both in clinical and non clinical samples. The aim of the study was to investigate the association between the two forms of dissociation among 947 university students who completed two self-administered questionnaires, the Somatoform Dissociation Questionnaire (SDQ-20) and the Dissociative Experience Scale (DES). The main result of the study was that the association between somatoform and psychoform dissociation was strong for individuals with moderate level of DES scores (O.R.=7.0), but much stronger for individuals with high level of DES scores (O.R.=18.9)., (© 2011 Wiley Periodicals, Inc.)

Since the 20th century, psychogenic female sexual dysfunctions (FSD), like some somatoform and conversion disorders, have been considered an expression of somatoform dissociation. Several studies have reported dissociative symptoms in different somatoform and conversion disorders, but limited data are available on dissociation among patients with FSD. The aim of this study was to assess somatoform and psychoform dissociation among patients with women's orgasmic disorder, dyspareunia, and vaginismus. A battery of self-administered questionnaires (Somatoform Dissociation Questionnaire, Dissociative Experiences Scale, Hospital Anxiety and Depression Scale, Impact of Event Scale-Revised) was given to 200 gynecological outpatients to assess psychoform and somatoform dissociation and their association with FSD. A strong association between somatoform dissociation and FSD was observed (adjusted odds ratio [OR] = 5.39, 95% confidence interval [CI] = 1.15-25.32), the association between somatoform and psychoform dissociation being estimated by an adjusted OR of 4.83 (95% CI = 1.17-19.91). Our results are compatible with the idea that some forms of FSD could be regarded as somatoform dissociative disorders.

Background: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a progressive cardiomyopathy showing a wide clinical spectrum in terms of clinical expressions and prognoses., Objective: This study sought to estimate the occurrence of compound and double heterozygotes for mutations in desmosomal proteins encoding genes in a cohort of ARVC/D Italian index cases, and to assess the clinical phenotype of mutations carriers., Methods: Fourty-two consecutive ARVC/D index cases who fulfilled the International Task Force diagnostic criteria were screened for mutations in PKP2, DSP, DSG2, DSC2, and JUP genes by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing., Results: Three probands (7.1%) showing a family history of sudden death carried multiple mutations. Family screening identified an additional 7 multiple-mutation carriers. Among the 7 double heterozygotes for mutations in different genes, 2 were clinically unaffected, 2 were affected, and 3 showed some clinical signs of ARVC/D even if they did not fulfill the diagnostic criteria. Two compound heterozygotes for mutations in the same gene and 1 subject carrying 3 different mutations showed a severe form of the disease with heart failure onset at a young age. Moreover, multiple-mutation carriers showed a higher prevalence of left ventricular involvement (P = .025) than single-mutation carriers., Conclusion: Occurrence of compound and double heterozygotes in ARVC/D index cases is particularly relevant to mutation screening strategy and to genetic counseling. Even if multiple-mutation carriers show a wide variability in clinical expression, the extent of the disease is higher compared to that in single-mutation carriers.

Objective: The relationship between alexithymia and psychosocial functioning has been investigated in a few studies using indirect measures of adaptation. We aimed at directly evaluating the relationship between alexithymia and global psychosocial functioning, as measured by a standardised scale., Methods: A large, consecutive sample of dermatological inpatients (N=545) completed the 20-item Toronto Alexithymia Scale and the Skindex-29 and were administered the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I disorders and the Global Assessment of Functioning (GAF) scale., Results: Multiple regression analysis was used to control for likely determinants of psychosocial functioning such as age, sex, education, burden of skin symptoms, and psychiatric morbidity. The GAF score was associated with psychiatric morbidity (beta=-.63, P<.001), alexithymia (in particular, the difficulty identifying feelings subscale) (beta=-.19, P<.001), and burden of skin symptoms (beta=-.07, P<.05)., Conclusion: Given the well-known association between poor psychosocial functioning and several behavioural risk factors for health, our study may provide a further reason for clinicians to pay attention to alexithymic features among their patients.

Psychological distress has been frequently reported in the setting of skin disorders. The Diagnostic Criteria for Psychosomatic Research (DCPR) have been found to yield valuable integrative information, in addition to DSM-IV nosology, in a variety of medical diseases. The aim of this study was to verify whether this integration could also be helpful in dermatology. A consecutive series of 539 inpatients with various skin conditions was evaluated by means of structured interviews for DSM-IV and DCPR diagnoses. The prevalence of DSM-IV conditions was 38% (mostly depressive disorders and anxiety disorders), whereas that of DCPR clusters (mostly demoralization and somatization secondary to psychopathology) was 48%. Overall, DCPR diagnoses were significantly more frequent than DSM-IV categories, regardless of the presence or absence of a psychiatric disorder. Psychological assessment of patients with skin diseases needs to incorporate both clinical (DSM-IV) and subclinical (DCPR) methods of classification. The health status of these patients can be improved if their psychological problems are appropriately assessed and recognized.

Background: Concerns have been raised about the potential of deliberate self-harm and suicide among patients with dermatologic conditions., Objective: We sought to estimate the prevalence of suicidal ideation among patients with dermatologic conditions, and to identify demographic, clinical, and psychosocial correlates., Methods: Two samples of outpatients with dermatologic conditions (N = 294) and inpatients (N = 172) completed the 12-item General Health Questionnaire, the Skindex-29, and the Patient Health Questionnaire., Results: Forty patients (8.6%) reported suicidal ideation during the previous 2 weeks. In univariate analysis, the presence of suicidal ideation was associated with female sex, inpatient status, presence of a depressive or anxiety disorder, and higher 12-item General Health Questionnaire and Skindex-29 scores. The size of the diagnostic groups allowed reasonable prevalence estimates only for psoriasis (10%) and acne (7.1%). In multivariate analysis, only emotional distress (12-item General Health Questionnaire) and impaired social functioning (Skindex-29) were independently associated with suicidal ideation., Limitations: We lacked an observer-rated evaluation of skin condition and could rely only on the Skindex-29 symptoms subscale as a measure of disease severity. In addition, the measurement of suicidal ideation was limited as a result of the use of only one question to assess it. Furthermore, the cross-sectional design prevented causal inferences., Conclusion: Suicidal ideation is not rare among patients with dermatologic conditions. Assessing suicidality would be warranted in dermatologic practice among patients at particular risk such as women with high psychologic distress and impaired social functioning. The development of psychiatric consultation-liaison services is mandatory to provide effective treatment and careful follow-up of patients who are suicidal.