Evidence for a decrease in cardiovascular risk factors following recombinant growth hormone administration in abstinent anabolic-androgenic steroid users.

OBJECTIVES: To determine whether six days recombinant human growth hormone (rhGH) in an abstinent anabolic-androgenic steroid (AAS) group had any cardiovascular and biochemical effects compared with a control group. METHODS: Male subjects (n=48) were randomly divided, using a single blind procedure into two groups: (1) control group (C) n=24, mean+/-SD, age 32+/-11 years; height 1.8+/-0.06m; (2) rhGH using group (0.058IUkg(-1)day(-1)) (GH) n=24, mean+/-SD, age 32+/-9 years; height 1.8+/-0.07m. Physiological responses, anthropometry, arterial pulse wave velocity (APWV), blood pressure (BP), heart rate (HR), peak oxygen uptake (VO(2) peak) and biochemical indices were investigated. RESULTS: Body mass index, fat-free mass index and VO(2) peak significantly increased while body fat significantly decreased within GH (all P<0.017). Insulin like growth factor-I significantly increased within GH (P<0.017) and compared with C (P<0.05). Serum sodium significantly increased (P<0.017) and serum homocysteine, high sensitivity C-reactive protein, thyroid stimulating hormone and tetra-iodothyronine (T(4)), significantly decreased within GH (all P<0.017). T(4) significantly decreased compared with C (P<0.05). Arterial pulse wave velocity, peak and recovery systolic and diastolic BP, significantly decreased compared with C (P<0.05). Resting HR and rate pressure product (RPP) significantly increased compared with C (P<0.05). CONCLUSION: The findings of this study suggest that short term use of rhGH may have beneficial effects on endothelial function and specific inflammatory markers of cardiovascular disease in abstinent AAS users, but may have an adverse effect on the cardiovascular system, as evidenced by the increase in resting RPP.     

Are the results of electrophysiological study different in patients with a pre-excitation syndrome, with and without syncope?

AIMS: Syncope in Wolff-Parkinson-White (WPW) syndrome may reveal an arrhythmic event or is not WPW syndrome related. The aim of the study is to evaluate the results of electrophysiological study in WPW syndrome according to the presence or not of syncope and the possible causes of syncope. METHODS AND RESULTS: Among 518 consecutive patients with diagnosis of WPW syndrome, 71 patients, mean age 34.5 +/- 17, presented syncope. Transoesophageal electrophysiological study in control state and after isoproterenol infusion was performed in the out-patient clinic. Atrioventricular re-entrant tachycardia (AVRT) was more frequently induced than in asymptomatic patients (n = 38, 53.5%, P < 0.01), less frequently than in those with tachycardia; atrial fibrillation (AF) and/or antidromic tachycardia (ATD) was induced in 28 patients (39%) more frequently (P < 0.05) than in asymptomatic patients or those with tachycardia. The incidence of high-risk form [rapid conduction over accessory pathway (AP) and AF or ATD induction] was higher in syncope group (n = 18, 25%, P < 0.001) than in asymptomatic subjects (8%) or those with tachycardias (7.5%). Maximal rate conducted over AP was similar in patients with and without syncope, and higher in patients with spontaneous AF, but without syncope. Results were not age-related. CONCLUSION: Tachycardia inducibility was higher in patients with syncope than in the asymptomatic group. The incidence of malignant WPW syndrome was higher in patients with syncope than in asymptomatic or symptomatic population, but the maximal rate conducted over AP was not higher and another mechanism could be also implicated in the mechanism of syncope.     

Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of the skin, nail, oral, and genital mucosae with Candida species, mainly C. albicans. Autosomal-recessive (AR) IL-17RA and ACT1 deficiencies and autosomal-dominant IL-17F deficiency, each reported in a single kindred, underlie CMC in otherwise healthy patients. We report three patients from unrelated kindreds, aged 8, 12, and 37 yr with isolated CMC, who display AR IL-17RC deficiency. The patients are homozygous for different nonsense alleles that prevent the expression of IL-17RC on the cell surface. The defect is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. However, in contrast to what is observed for the IL-17RA– and ACT1-deficient patients tested, the response to IL-17E (IL-25) is maintained in these IL-17RC–deficient patients. These experiments of nature indicate that human IL-17RC is essential for mucocutaneous immunity to C. albicans but is otherwise largely redundant.In humans, chronic mucocutaneous candidiasis (CMC) is characterized by infections of the skin, nail, digestive, and genital mucosae with Candida species, mainly C. albicans, a commensal of the gastrointestinal tract in healthy individuals (Puel et al., 2012). CMC is frequent in acquired or inherited disorders involving profound T cell defects (Puel et al., 2010b; Vinh, 2011; Lionakis, 2012). Human IL-17 immunity has recently been shown to be essential for mucocutaneous protection against C. albicans (Puel et al., 2010b, 2012; Cypowyj et al., 2012; Engelhardt and Grimbacher, 2012; Huppler et al., 2012; Ling and Puel, 2014). Indeed, patients with primary immunodeficiencies and syndromic CMC have been shown to display impaired IL-17 immunity (Puel et al., 2010b). Most patients with autosomal-dominant (AD) hyper-IgE syndrome (AD-HIES) and STAT3 deficiency (de Beaucoudrey et al., 2008; Ma et al., 2008; Milner et al., 2008; Renner et al., 2008; Chandesris et al., 2012) and some patients with invasive fungal infection and autosomal-recessive (AR) CARD9 deficiency (Glocker et al., 2009; Lanternier et al., 2013) or Mendelian susceptibility to mycobacterial diseases (MSMD) and AR IL-12p40 or IL-12Rβ1 deficiency (de Beaucoudrey et al., 2008, 2010; Prando et al., 2013; Ouederni et al., 2014) have low proportions of IL-17A–producing T cells and CMC (Cypowyj et al., 2012; Puel et al., 2012). Patients with AR autoimmune polyendocrine syndrome type 1 (APS-1) and AIRE deficiency display CMC and high levels of neutralizing autoantibodies against IL-17A, IL-17F, and/or IL-22 (Browne and Holland, 2010; Husebye and Anderson, 2010; Kisand et al., 2010, 2011; Puel et al., 2010a).These findings paved the way for the discovery of the first genetic etiologies of CMC disease (CMCD), an inherited condition affecting individuals with none of the aforementioned primary immunodeficiencies (Puel et al., 2011; Casanova and Abel, 2013; Casanova et al., 2013, 2014). AR IL-17RA deficiency, AR ACT1 deficiency, and AD IL-17F deficiency were described, each in a single kindred (Puel et al., 2011; Boisson et al., 2013). A fourth genetic etiology of CMCD, which currently appears to be the most frequent, has also been reported: heterozygous gain-of-function (GOF) mutations of STAT1 impairing the development of IL-17–producing T cells (Liu et al., 2011; Smeekens et al., 2011; van de Veerdonk et al., 2011; Hori et al., 2012; Takezaki et al., 2012; Tóth et al., 2012; Al Rushood et al., 2013; Aldave et al., 2013; Romberg et al., 2013; Sampaio et al., 2013; Soltész et al., 2013; Uzel et al., 2013; Wildbaum et al., 2013; Frans et al., 2014; Kilic et al., 2014; Lee et al., 2014; Mekki et al., 2014; Mizoguchi et al., 2014; Sharfe et al., 2014; Yamazaki et al., 2014). We studied three unrelated patients with CMCD without mutations of IL17F, IL17RA, ACT1, or STAT1. We used a genome-wide approach based on whole-exome sequencing (WES). We found AR complete IL-17RC deficiency in all three patients.     

DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome

Juvenile ciliopathy syndromes that are associated with renal cysts and premature renal failure are commonly the result of mutations in the gene encoding centrosomal protein CEP290. In addition to centrosomes and the transition zone at the base of the primary cilium, CEP290 also localizes to the nucleus; however, the nuclear function of CEP290 is unknown. Here, we demonstrate that reduction of cellular CEP290 in primary human and mouse kidney cells as well as in zebrafish embryos leads to enhanced DNA damage signaling and accumulation of DNA breaks ex vivo and in vivo. Compared with those from WT mice, primary kidney cells from Cep290-deficient mice exhibited supernumerary centrioles, decreased replication fork velocity, fork asymmetry, and increased levels of cyclin-dependent kinases (CDKs). Treatment of Cep290-deficient cells with CDK inhibitors rescued DNA damage and centriole number. Moreover, the loss of primary cilia that results from CEP290 dysfunction was rescued in 3D cell culture spheroids of primary murine kidney cells after exposure to CDK inhibitors. Together, our results provide a link between CEP290 and DNA replication stress and suggest CDK inhibition as a potential treatment strategy for a wide range of ciliopathy syndromes.     

Comprehensive Treatment of Periorbital Region with Hyaluronic Acid

The periorbital subunit is one of the first facial regions to show signs of aging, primarily due to volume depletion of the soft tissue and bony resorption. Surgical and office-based nonsurgical procedures form an important basis for periorbital rejuvenation. It is important to make a detailed clinical evaluation of the patient to indicate the most appropriate procedure to be performed. With the objective of showing a nonsurgical procedure for the rejuvenation of the periorbital area, the authors describe a technique of applying fillers in the upper and lower periorbital regions, paying attention to the anatomy of this facial region and the type of product to be used besides the expected results of the procedure and its possible adverse effects and complications. The nonsurgical rejuvenation of the periorbicular region with hyaluronic acid is a new and innovative technique. In the opinion of the authors, it is a great aesthetic impact area and consequently brings high satisfaction to patients.Maintaining a youthful and pleasant appearance of the face in today’s culture impacts quality of life in many patients. The facial contour remodeling is being revolutionized by new nonsurgical techniques.Facial aging is a complex and dynamic process. All people age differently as a result of imbalance, disharmony, and disproportion of the aging process between the overlying soft tissue and the underlying bony frameworks.1 The upper periorbital subunit is one of the first facial regions to show signs of aging, and even minor changes in its structure and volume can distort the perceived emotions and health of patients.2 An aesthetic and youthful upper periorbital subunit is characterized by a well-defined brow of appropriate height and shape, fullness of the upper periorbit, a crisp and well-defined upper eyelid crease, minimal skin excess, and good skin quality.3,4In the aging process of this facial area, one group of patients displays signs of aging due predominantly to soft tissue ptosis of the upper eyelid, requiring surgical excision. Another group presents with volume depletion of the soft tissue and bony resorption of the orbit. The loss of septal support, leading to brow prolapse and an exacerbation of upper eyelid fullness and congestion, can also contribute to the aging process. This appearance is characterized by deflation of the upper eyelid as well as hollowing and visibility of the supraorbital bony rim, leading to a sunken, hollow, and skeletonized orbit, which can make the patient appear sickly, anorexic, and old. In recent years, modern facial rejuvenation surgery has evolved toward volume restoration in addition to tissue suspension.2Comprehensive analysis of both soft tissue and bony structural changes are essential for the periorbital rejuvenation. Surgical procedures and office-based nonsurgical procedures form an important basis for periorbital rejuvenation, including cosmeceuticals, chemical peels, laser and light treatments, neurotoxins, and fillers. Improved understanding of the pathophysiology of aging and technical advancements in nonsurgical techniques has enabled us to achieve better and more comprehensive improvement for patients.5     

Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma

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