Paraviral cutaneous manifestations associated to SARS-CoV-2 Omicron variant.

BACKGROUND: The spreading of the SARS-CoV-2 Omicron variant is probably due to its increased transmissibility and ability to escape from neutralising antibodies. Cutaneous manifestations have been reported after infection with the Omicron strain, consisting mainly of generalised urticarial eruption and prickly heat rash, also known as miliaria, that can persist for several days. Here the impact of Omicron SARS-CoV-2 on skin was investigated. METHODS: The case series of 10 patients with SARS-CoV-2 Omicron variant-related cutaneous manifestations were described; moreover, skin derived cells were challenged in vitro with SARS-CoV-2 Omicron variant. RESULTS: The main clinical cutaneous features observed were urticarial lesions lasting more than 24 h, mainly involving the trunk and sometimes extending to the extremities, and miliaria presenting with clusters of small sweat-filled vesicles, sometimes surrounded by slight erythema. HaCaT keratinocytes, BJ fibroblast cell lines and outer root sheath (ORS) keratinocytes were not susceptible to SARS-CoV-2 Omicron variant infection; they also did not present any evident cytopathic effect or modification of cells viability. CONCLUSION: Our findings suggests that, despite the high number of nucleotide mutations in the spike protein of SARS-CoV-2 Omicron variant, responsible to the higher transmissibility of this virus, and the increased reports of cutaneous manifestation in COVID-19 affected patients, the virus is not able to directly infect and damage the keratinocytes and fibroblasts, thus suggesting an indirect virus-induced activation of the immune system as the major pathogenetic driver.

A rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a multifactorial aetiology that involves a strict interplay between genetic factors, immune dysregulation and lifestyle. Familial forms represent around 40% of total HS cases and show an autosomal dominant mode of inheritance of the disease. In this study, we conducted a whole-exome sequence analysis on an Italian family of 4 members encompassing a vertical transmission of HS. Focusing on rare damaging variants, we identified a rare insertion of one nucleotide (c.225dupA:p.A76Sfs*21) in the DCD gene encoding for the antimicrobial peptide dermcidin (DCD) that was shared by the proband, his affected father and his 11-years old daughter. Since several transcriptome studies have shown a significantly decreased expression of DCD in HS skin, we hypothesised that the identified frameshift insertion was a loss-of-function mutation that might be associated with HS susceptibility in this family. We thus confirmed by mass spectrometry that DCD levels were diminished in the affected members and showed that the antimicrobial activity of a synthetic DCD peptide resulting from the frameshift mutation was impaired. In order to define the consequences related to a decrease in DCD activity, skin microbiome analyses of different body sites were performed by comparing DCD mutant and wild type samples, and results highlighted significant differences between the groins of mutated and wild type groups. Starting from genetic analysis conducted on an HS family, our findings showed, confirming previous transcriptome results, the potential role of the antimicrobial DCD peptide as an actor playing a crucial part in the etio-pathogenesis of HS and in the maintenance of the skin's physiological microbiome composition; so, we can hypothesise that DCD could be used as a novel target for personalised therapeutic approach.

Aquaporins Are One of the Critical Factors in the Disruption of the Skin Barrier in Inflammatory Skin Diseases.

The skin is the largest organ of the human body, serving as an effective mechanical barrier between the internal milieu and the external environment. The skin is widely considered the first-line defence of the body, with an essential function in rejecting pathogens and preventing mechanical, chemical, and physical damages. Keratinocytes are the predominant cells of the outer skin layer, the epidermis, which acts as a mechanical and water-permeability barrier. The epidermis is a permanently renewed tissue where undifferentiated keratinocytes located at the basal layer proliferate and migrate to the overlying layers. During this migration process, keratinocytes undertake a differentiation program known as keratinization process. Dysregulation of this differentiation process can result in a series of skin disorders. In this context, aquaporins (AQPs), a family of membrane channel proteins allowing the movement of water and small neutral solutes, are emerging as important players in skin physiology and skin diseases. Here, we review the role of AQPs in skin keratinization, hydration, keratinocytes proliferation, water retention, barrier repair, wound healing, and immune response activation. We also discuss the dysregulated involvement of AQPs in some common inflammatory dermatological diseases characterised by skin barrier disruption.

Unraveling the Role of Sex Hormones on Keratinocyte Functions in Human Inflammatory Skin Diseases.

The skin exerts several fundamental functions that are the first physical, chemical and immune barriers to the human body. Keratinocytes, the main cell type of the epidermis, provide mechanical defense, support skin integrity and actively endorse cutaneous immune responses. Not surprisingly, considering these crucial activities, alterations in keratinocyte functions are associated with different inflammatory skin diseases. Recent findings indicate that the skin should not only be regarded as a target for hormones but that it should also be considered as an endocrine peripheral organ that is directly involved in the synthesis and metabolism of these chemical messengers. Sex hormones have multiple effects on the skin, attributed to the binding with intracellular receptors expressed by different skin cell populations, including keratinocytes, that activate downstream signaling routes that modulate specific cellular functions and activities. This review is aimed at reorganizing the current knowledge on the role exerted by sex hormones on keratinocyte function in five different inflammatory skin diseases: Hidradenitis suppurativa; Acne vulgaris; Atopic dermatitis; progesterone hypersensitivity; psoriasis. The results of our work aim to provide a deeper insight into common cellular mechanisms and molecular effectors that might constitute putative targets to address for the development of specific therapeutic interventions.

Electrocardiograms of Children and Adolescents Practicing Non-competitive Sports: Normal Limits and Abnormal Findings in a Large European Cohort Evaluated by Telecardiology.

OBJECTIVE: The objective of this study was to derive normal electrocardiographic values and to report the abnormal findings in a large contemporary European cohort of physically active children and young adolescents. METHODS: In a 3-month period, data derived from subjects aged between 3 and 14 years and referred to the Telecardiology Centre (Genoa, Italy) for electrocardiogram (ECG) evaluation as pre-participation screening for non-competitive sports were analyzed. RESULTS: A total of 2060 ECGs were recorded. Of those, 1962 did not show any morphological abnormality and were used to derive normality ranges for heart rate, PR interval, QRS duration, corrected QT interval, and voltage of R wave as measured in V1 according to age and sex. Findings and clinical implications of the 98 ECGs with abnormal findings were also reported. Abnormal ECG findings were not as uncommon as expected in this population, being manifest in about 5 % of subjects. However, major ECG anomalies (diffuse negative T-waves, pre-excitation) were present in just ten subjects (0.5 %). Lower mean heart rate values (from 90-100 bpm at 3 years of age to 80-85 bpm at 14 years of age) and lower rates of the prevalence of negative T-waves in the V3 lead (from 55-60 % at 3 years of age to 8-10 % at 14 years of age) were observed with increasing age. CONCLUSIONS: This is the first work reporting derived normal limits and abnormal ECG findings in a large contemporary European cohort of children and adolescents aged 3-14 years practicing non-competitive sports. Clear pathological alterations are extremely uncommon, deserving, when encountered, additional examinations. Even in a physically active population, the common features of an adult athlete's ECG are absent.

[ECG for non-competitive sports in childhood: strengths and disputes]. / ECG per l'idoneità all'attività sportiva non agonistica in età pediatrica: punti di forza e controversie.

BACKGROUND: Sport is very important for health promotion and conservation. Active lifestyle and regular exercise reduce cardiovascular disease incidence. The Italian Ministry of Health issued the Law Decree no. 243 (10/18/2014) concerning "guidelines for certification about non-competitive sports" to promote safety in sports. This regulation defines the activities for which a certificate is required, the professional actors involved and the clinical exams to be performed according to the patient's health status. In particular, the Law Decree recommends to perform an electrocardiogram (ECG) "at least once in a lifetime", introducing much greater news into pediatric practice. METHODS: We proposed a survey evaluating frequency of ECG implementation for non-competitive sports and cardiovascular diseases incidence was administered to 7 Ligurian pediatricians. RESULTS: The number of ECG/year for pediatrician increased from 10 ECG/year to 50 ECG/year with an indication of suitability to non-competitive sports. One case of QT prolongation and 2 cases of type 1 Brugada ECG pattern were diagnosed. In addition, 3 patients had an atrial septal defect and 3 children had a ventricular septal defect. Forty-three percent of the pediatricians considered useful performing the ECG. CONCLUSIONS: ECG in children has enhanced the positive effects on the community health. However, it remains to be defined in agreement with scientific societies the age at which to perform ECG, the sports for which ECG is required and the cost-benefit ratio for the National Health System and families.

[Enhanced prognostic stratification of cad patients with dilated left ventricle by stress and rest functional parameters and 99mTc-tetrofosmin Gated-SPECT].

PURPOSE: To evaluate whether the post-stress and rest functional parameters, measured by Gated-SPECT, have incremental prognostic value compared with perfusion parameters in predicting cardiac events (CE), in a population of CAD patients with dilated LV. MATERIALS AND METHODS: A total of 670 consecutive patients (mean age: 62; range 29-86 yrs.) underwent conventional diagnostic 2-day gated-SPECT with 99mTc-tetrofosmin (55% exercise stress test, 45% dip stress): 605 patients (mean age: 62 yrs., range: 34-86 yrs.) had known or suspected CAD, whereas 65 (mean age: 60 yrs, range: 29-80 yrs) had low pre-test likelihood of CAD (<10%), a normal post-stress perfusion scan and no hypertension. Fifty-three percent of CAD patients had a history of MI. Perfusion was analyzed on ungated images using 20 segments scored on a 5-point scale (0=normal, 4=no uptake), while wall thickening was assessed visually on stress/rest end-systolic images using a 4-point score (0=normal, 3=absence of WT). LVEF and volumes were calculated using an automatic algorithm. Post-stress and rest ratio were determined for both end-diastolic and end-systolic volume, while the post-stress LVEF change (d-LVEF) was calculated according to the following formula: (Stress LVEF-rest LVEF)/rest LVEF*100. RESULTS: By using a cutoff value of 126 ml for rest-EDV, and of 68 ml for rest-ESV we found a LV dilation in 129/605 patients (21%). These thresholds were the mean values plus two standard deviations obtained in the control group. 111/129 (86%) were followed up for a mean period of 147.0 months. 83 of 111 (75%) patients had a history of MI and forty three (39%) had undergone surgical revascularizations. During the follow-up, 21 events (5 cardiac deaths, 3 nonfatal MI, 13 late revascularizations) occurred. All post-stress perfusion and functional parameters were more compromised in patients with CE compared with patients without events, but only rest EDV, rest ESV, post-stress ESV and WT-SSS reached statistical significance (201 ml vs 176 ml; p=0.035; 137 ml vs 113 ml; p=0.047; 143 ml vs 117 ml; p=0.034, 19 vs 15; p=0.048, respectively). Multivariate Cox proportional analysis demonstrated that stress ESV added significantly prognostic information over WT-SSS in predicting CE (p=0.046). CONCLUSIONS: Stress ESV has incremental prognostic value compared with wall thickening in predicting CE, in CAD patients with dilated cardiomyopathy. Perfusion parameters failed to show prognostic information in these patients.

Treatment of atherosclerotic renal artery stenosis.

The increasing prevalence of atherosclerotic renal artery stenosis (ARAS) has prompted in recent years a more aggressive treatment of this condition for reducing BP and for preserving the jeopardized renal function. Percutaneous transluminal renal angioplasty (PTRA), alone or in conjunction with stent implantation, may be useful for both these goals. However, despite the methodological improvements that make this procedure much safer than surgery, caution must be applied before PTRA is extended to all patients with ARAS. Indeed, PTRA is associated with a 23% rate of major/minor complications and with a 20% rate of restenosis, even in arteries implanted with stent. Moreover the cure rate of hypertension achievable with PTRA is, at best, around 10%, with a 40% rate of improvements. Even for rescuing the ischemic kidney, PTRA/stent implantation are not always effective; only 35% of patients with ARAS have some improvement in renal function. These data indicate that there is an urgent need of rigorous criteria for selecting among the many patients with ARAS those who may actually benefit from the dilation procedure.

Increased oxidative stress and platelet activation in patients with hypertension and renovascular disease.

BACKGROUND: Hypertensive patients with renovascular disease (RVD) may be exposed to increased oxidative stress, possibly related to activation of the renin-angiotensin system. METHODS AND RESULTS: We measured the urinary excretion of 8-iso-prostaglandin (PG) F2alpha and 11-dehydro-thromboxane (TX) B2 as indexes of in vivo lipid peroxidation and platelet activation, respectively, in 25 patients with RVD, 25 patients with essential hypertension, and 25 healthy subjects. Plasma renin activity in peripheral and renal veins, angiotensin II in renal veins, cholesterol, glucose, triglycerides, homocysteine, and antioxidant vitamins A, C, and E were also determined. Patients were also studied 6 months after a technically successful angioplasty of the stenotic renal arteries. Urinary 8-iso-PGF2alpha was significantly higher in patients with RVD (median, 305 pg/mg creatinine; range, 124 to 1224 pg/mg creatinine) than in patients with essential hypertension (median, 176 pg/mg creatinine; range, 48 to 384 pg/mg creatinine) or in healthy subjects (median, 123 pg/mg creatinine; range, 58 to 385 pg/mg creatinine). Urinary 11-dehydro-TXB2 was also significantly higher in RVD patients compared with healthy subjects. In RVD patients, urinary 8-iso-PGF2alpha correlated with 11-dehydro-TXB2 (r(s)=0.48; P<0.05) and renal vein renin (r(s)=0.67; P<0.005) and angiotensin II (r(s)=0.65; P=0.005) ratios. A reduction in 8-iso-PGF2alpha after angioplasty was observed in RVD patients with high baseline levels of lipid peroxidation. Changes in 8-iso-PGF2alpha were related to baseline lipid peroxidation (r(s)=-0.73; P<0.001), renal vein angiotensin II (r(s)=-0.70; P<0.01) and renin (r(s)=-0.63; P<0.05) ratios. CONCLUSIONS: Lipid peroxidation is markedly enhanced in hypertensive patients with RVD and is related to activation of the renin-angiotensin system. Moreover, persistent platelet activation triggered or amplified by bioactive isoprostanes may contribute to the progression of cardiovascular and renal damage in this setting.