Growth hormone in heart failure revisited: An old story retold

Heart failure (HF) is a disease characterized by increasing prevalence, huge direct and indirect costs, and an ominous prognosis, worse than many cancers. At the beginning of the 90s, growth hormone (GH) was proposed as potential adjunctive therapy in HF mostly due to its growth-promoting, vasodilating, and anti-apoptotic actions. However, although several uncontrolled clinical studies showed that GH therapy improved several cardiovascular parameters, two robust trials failed to confirm these findings. Dwelling upon potential explanations for such apparent discrepancy led to the hypothesis that HF patients exhibit an inhomogeneous basal activity of the GH/insulin-like growth factor 1 (IGF-1) axis, ranging from GH/IGF-1 deficiency to GH resistance. This complex phenomenon was then reconsidered in the context of the so-called multiple hormone deficiency syndrome (MHD), that is the recognition that HF is characterized not only by the hyperactivation of several signaling pathways including the adrenergic, the renin-angiotensin-aldosterone and cytokine systems, but also by a reduced anabolic drive leading to a state of anabolic/catabolic imbalance. Mounting evidence support the concept that such imbalance is not a mere epiphenomen, since it exerts a significant impact on clinical performance and more importantly, on survival. Therefore, the paradigm shift to reconsider HF as MHD represented the underpinning to implement clinical trials focused on hormone replacement therapies in congestive heart failure (CHF). With regard to GH replacement therapy, one controlled single-blind study yielded promising results, and we are currently conducting a double-blind controlled trial, as well a large Registry study to evaluate the impact of MHD on HF progression

Congenital Immunodeficiencies: novel diagnostic and therapeutic approach

The immune system is a complex integrated network of chemical and cellular mediators that developed during evolution to defend the body from any form of chemical, traumatic or infective insult to their integrity. A proper immune response relies on the innate immunity, that is responsible for a first line of defense against aggression and the aspecific recognition of a limited repertoire of antigens, and, later, on the adaptative immunity which includes chemical and cellular mediators responsible for a more powerful and specific defensive response from any form of antigen. Alterations of any part of the immune response results in failure of host defense and, in particular, of immunodeficiency, autoimmunity and cancer predisposition. Primary immunodeficiency disorders (PIDs) are rare inherited disorders characterized by poor or absent function in one or more components of the immune system, that result in chronic, recurrent and life-threatning infections if not promptly diagnosed and treated (2). Traditionally, PIDs are classified according to the component of the immune system that is primarily disrupted: innate or adaptive immunity. In the last 20 years, thanks to the progress in molecular technologies, a remarkable improvement of the knowledge in the field of PIDs, concerning both their pathogenetic mechanisms and clinical features, has been observed. Nowadays, about 300 forms of well-characterized PIDs have been identified underlying complex phenotypes which encompass a wide spectrum of clinical features ranging from recurrent bacterial infections to other unusual manifestations, such as autoimmune disorders, cancer susceptibility, allergy and auto inflammation (8, 142). However, a recent study reported that PIDs are underdiagnosed and, therefore, they are presumably more common than previously estimated. Thus far, the diagnosis of a specific PID has been based onthe demonstration of a functional immune defect and on the subsequent identification of candidate genes, which are selectively involved in the biochemical pathway implicated in that specific functional alteration. In this thesis, during the three years of my PhD program, I have contributed to elucidate “Congenital Immunodeficiencies: novel diagnostic and therapeutic approach”, through the clinical, cellular, functional and molecular study of some Immunological disorders. In particular, my research work has been focused on the study of the potential involvement of autophagy in the pathogenesis of Ataxia Telangiectasia, and the potential positive effect of glucocorticoids on the rescue of a proper cell clearance process in lymphocytes of the patients affected with this disease. Moreover, I contributed in the characterization of the potential oncogenic role of the common gamma chain (γc) in primary human hematopoietic malignant cell lines, by evaluating the molecular mechanisms by which this protein promotes tumor growth. In addition I contributed to better define the role of the epithelial cells in the immune system and of thymic stromal alterations responsible for immunological disorders. Eventually I participated to two studies focused on the application of Next Generation Sequencing technique for the diagnosis of immunodeficiencies. Overall, the results obtained during my PhD course could be useful both in the clinical practice and in the basic research of immunological diseases

Thymic stromal alterations and genetic disorders of immune system

© 2015 Pignata, D’Assante and Sousa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms

Severe combined immunodeficiency-an update

Severe combined immunodeficiencies (SCIDs) are a group of inherited disorders responsible for severe dysfunctions of the immune system. These diseases are life-threatening when the diagnosis is made too late; they are the most severe forms of primary immunodeficiency. SCID patients often die during the first two years of life if appropriate treatments to reconstitute their immune system are not undertaken. Conventionally, SCIDs are classified according either to the main pathway affected by the molecular defect or on the basis of the specific immunologic phenotype that reflects the stage where the blockage occurs during the differentiation process. However, during the last few years many new causative gene alterations have been associated with unusual clinical and immunological phenotypes. Many of these novel forms of SCID also show extra-hematopoietic alterations, leading to complex phenotypes characterized by a functional impairment of several organs, which may lead to a considerable delay in the diagnosis. Here we review the biological and clinical features of SCIDs paying particular attention to the most recently identified forms and to their unusual or extra-immunological clinical features

DiGeorge-like Syndrome in a Child with a 3p12.3 Deletion Involving MIR4273 Gene Born to a Mother with Gestational Diabetes Mellitus

Chromosome 22q11.2 deletion is the most common chromosomal alteration associated with DiGeorge syndrome (DGS), even though this is not the only underlying cause of DGS. In rare patients, mutations in a single gene, TBX1, have been described resulting in a DGS phenotype. Recently, it has been reported that at least part of the TBX1 mutant phenotype is due to excessive bone morphogenetic proteins (BMP) signaling. Evidence suggests that miRNA may modulate the expression of critical T-box transcriptional regulators during midface development and Bmp-signaling. We report on a 7-year-old Caucasian male born to a mother affected with gestational diabetes (GDM) who had a 371Kb-interstitial deletion of 3p12.3 identified by array CGH, involving the ZNF717, MIR1243 and 4273 genes. The child presented with a DiGeorge anomaly (DGA) associated with unilateral renal agenesis and language delay. The immunological evaluation revealed a severe reduction and impairment of T lymphocytes. FISH analysis and TBX1 sequencing were negative. Among the miRNA-4273 predicted target genes, we found BMP3, which is involved in several steps of embryogenesisincluding kidney and lung organogenesis and in insulin gene expression. Since DGA is not commonly found in newborns of diabetic mothers, we hypothesize that the pathogenesis of DGA associated with GDM is multifactorial, involving both genetic and/or epigenetic cofactors

Abnormal cell-clearance and accumulation of autophagic vesicles in lymphocytes from patients affected with Ataxia-Teleangiectasia

Ataxia-Teleangiectasia (A-T) is a neurodegenerative disorder due to mutations in ATM gene. ATM in the nucleus ensures DNA repair, while its role in the cytosol is still poorly clarified. Abnormal autophagy has been documented in other neurodegenerative disorders, thus we evaluated whether alteration in this process may be involved in the pathogenesis of A-T by analyzing the autophagic vesicles and the genes implicated in the different stages of autophagy. Through transmission electron microscopy (TEM) and immunofluorescence analysis we observed an accumulation of APs associated with a LC3 puncta pattern, and a reduced number of ALs. We also documented an increased expression of genes involved in AP and lysosome biogenesis and function, and a decrease of Vps18 expression, involved in their vesicular trafficking and fusion. mTORC1-controlled proteins were hyperphosphorylated in A-T, in keeping with an increased mTOR inhibitory influence of autophagy. Betamethasone is able to promote the degradation of SQSTM1, a biomarker of autophagy. Collectively, our results indicate that in cells from A-T patients, the APs maturation is active, while the fusion between APs and lysosomes is inappropriate, thus implying abnormalities in the cell-clearance process. We also documented a positive effect of Betamethasone on molecules implicated in autophagosome degradation

Unbalanced Immune System: Immunodeficiencies and Autoimmunity

Increased risk of developing autoimmune manifestations has been identified in different primary immunodeficiencies (PIDs). In such conditions, autoimmunity and immune deficiency represent intertwined phenomena that reflect inadequate immune function. Autoimmunity in PIDs may be caused by different mechanisms, including defects of tolerance to self-antigens and persistent stimulation as a result of the inability to eradicate antigens. This general immune dysregulation leads to compensatory and exaggerated chronic inflammatory responses that lead to tissue damage and autoimmunity. Each PID may be characterized by distinct, peculiar autoimmune manifestations. Moreover, different pathogenetic mechanisms may underlie autoimmunity in PID. In this review, the main autoimmune manifestations observed in different PID, including humoral immunodeficiencies, combined immunodeficiencies, and syndromes with immunodeficiencies, are summarized. When possible, the pathogenetic mechanism underlying autoimmunity in a specific PID has been explained

Klinefelter syndrome, insulin resistance, metabolic syndrome, and diabetes: review of literature and clinical perspectives

Klinefelter syndrome (KS), the most frequent chromosomic abnormality in males, is associated with hypergonadotropic hypogonadism and an increased risk of cardiovascular diseases (CVD). The mechanisms involved in increasing risk of cardiovascular morbidity and mortality are not completely understood. Insulin resistance, metabolic syndrome, and type 2 diabetes are more frequently diagnosed in KS than in the general population; however, the contribution of hypogonadism to metabolic derangement is highly controversial. Whether this dangerous combination of risk factors fully explains the CVD burden of KS patients remains unclear. In addition, testosterone replacement therapy only exerts a marginal action on the CVD system. This review summaries the current understandings of the complex relationship between KS, metabolic syndrome and cardiovascular risk in order to plan future studies and improve current strategies to reduce mortality in this high-risk population. Since fat accumulation and distribution seem to play a relevant role in triggering metabolic abnormalities, an early diagnosis and a tailored intervention strategy with drugs aimed at targeting excessive visceral fat deposition appear necessary in patients with KS

Rationale and protocol of a double-blind, randomized, placebo-controlled trial to test the efficacy, safety, and tolerability of dimethyl fumarate in Friedreich Ataxia (DMF-FA-201)

IntroductionFriedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder that causes gait and limb ataxia, dysarthria, and impaired vibratory sense, with cardiomyopathy being the predominant cause of death. There is no approved therapy, which results in the use of symptomatic treatments and the chronic support of physiotherapy. Dimethyl fumarate (DMF) is a fumaric acid ester used for the treatment of psoriasis and Multiple Sclerosis (MS). It induces Nrf2 in vitro and in vivo, and it increases frataxin in FRDA patient lymphoblasts, in mouse models, and in MS treated patients.MethodsThe aim of our study is to investigate if DMF can increase the expression of the FXN gene and frataxin protein and ameliorate in-vivo detectable measures of mitochondrial dysfunction in FRDA. The study is composed of a screening visit and two sequential 12-week phases: a core phase and an extension phase. During the first phase (core), patients will be randomly assigned to either the DMF or a placebo group in a 1:1 ratio. During the first week, patients will receive a total daily dose of 240 mg of DMF or placebo; from the second week of treatment, the dose will be increased to two 120 mg tablets BID for a total daily dose of 480 mg. During the second phase (extension), all patients will be treated with DMF. EudraCT number 2021-006274-23.EndpointsThe primary endpoint will be a change in FXN gene expression level after 12 weeks of treatment. Secondary endpoints will be frataxin protein level, cardiopulmonary exercise test outputs, echocardiographic measures, Nrf2 pathway and mitochondrial biogenesis gene expression, safety, clinical scales, and quality of life scales.ConclusionsThis is the first study aimed at exploring the ability of DMF, an already available treatment for MS and psoriasis, to correct the biological deficits of FRDA and potentially improve mitochondrial respiration in-vivo

Progressive right ventricular dysfunction and exercise impairment in patients with heart failure and diabetes mellitus: insights from the T.O.S.CA. Registry

Findings from the T.O.S.CA. Registry recently reported that patients with concomitant chronic heart failure (CHF) and impairment of insulin axis (either insulin resistance-IR or diabetes mellitus-T2D) display increased morbidity and mortality. However, little information is available on the relative impact of IR and T2D on cardiac structure and function, cardiopulmonary performance, and their longitudinal changes in CHF