Role of Soluble ST2 Biomarker in Predicting Recurrence of Atrial Fibrillation after Electrical Cardioversion or Pulmonary Vein Isolation.

This study aims to determine the predictive value of the soluble suppression of tumorigenicity 2 (sST2) biomarker in atrial fibrillation (AF) recurrence. This prospective, observational study included patients with AF referred for electrical cardioversion (ECV) or pulmonary vein isolation (PVI) procedures. Baseline characteristics were collected, and sST2 was determined at baseline and at 3 and 6 months of follow-up. sST2 was determined at baseline in a matched control group. Left atrial voltage mapping was performed in patients undergoing PVI. The sST2 maximal predictive capacity of AF recurrence was at the 3-month FU in the cohort of patients undergoing ECV with respect to 6-month AF recurrence with an AUC of 0.669, a cut-off point of 15,511 pg/mL, a sensitivity of 60.97%, and a specificity of 69.81%. The ROC curve of the sST2 biomarker at baseline and 3 months in the cohort of patients undergoing PVI showed AUCs of 0.539 and 0.490, respectively. The logistic regression model identified the rhythm (AF) and the sST2 biomarker at 3 months as independent factors for recurrence at 6 months in the ECV cohort. In the logistic regression model, sST2 was not an independent factor for recurrence at 6 months of follow-up in the PVI cohort. In patients who underwent ECV, sST2 values at 3 months may provide utility to predict AF recurrence at 6 months of follow-up. In patients who underwent PVI, sST2 had no value in predicting AF recurrence at 6 months of follow-up.

Molecular determinants of enhanced response to somatostatin receptor ligands after debulking in large GH-producing adenomas.

OBJECTIVE: Large somatotrophic adenomas depict poor response to somatostatin receptor ligands (SRLs). Debulking has shown to enhance SRLs effect in some but not all cases and tumour volume reduction has been proposed as the main predictor of response. No biological studies have been performed so far in this matter. We aimed to identify molecular markers of response to SRLs after surgical debulking in GH-secreting adenomas. DESIGN: We performed a multicenter retrospective study. PATIENTS: 24 patients bearing large GH-producing tumours. MEASUREMENTS: Clinical data and SRLs response both before and after surgical debulking were collected, and 21 molecular biomarkers of SRLs response were studied in tumour samples by gene expression. RESULTS: From the 21 molecular markers studied, only two of them predicted enhanced SRLs response after surgery. Tumours with improved response to SRLs after surgical debulking showed lower levels of Ki-67 (MKI67, FC = 0.17 and P = .008) and higher levels of RAR-related orphan receptor C (RORC) (FC = 3.1 and P Ë‚ .001). When a cut-off of no detectable expression was used for Ki-67, the model provided a sensitivity of 100% and a specificity of 52.6% with an area under the curve of 65.8%. Using a cut-off of 2 units of relative expression of RORC, the prediction model showed 100% of sensitivity and specificity. CONCLUSIONS: High levels of RORC and low levels of Ki-67 identify improved SRLs response after surgical debulking in large somatotropic adenomas. To determine their expression would facilitate medical treatment decision-making after surgery.

Pituitary Cell Turnover: From Adult Stem Cell Recruitment through Differentiation to Death.

The recent demonstration using genetic tracing that in the adult pituitary stem cells are normally recruited from the niche in the marginal zone and differentiate into secretory cells in the adenopituitary has elegantly confirmed the proposal made when the pituitary stem cell niche was first discovered 5 years ago. Some of the early controversies have also been resolved. However, many questions remain, such as which are the markers that make a pituitary stem cell truly unique and the exact mechanisms that trigger recruitment from the niche. Little is known about the processes of commitment and differentiation once a stem cell has left the niche. Moreover, the acceptance that pituitary cells are renewed by stem cells implies the existence of regulated mechanisms of cell death in differentiated cells which must themselves be explained. The demonstration of an apoptotic pathway mediated by RET/caspase 3/Pit-1/Arf/p53 in normal somatotrophs is therefore an important step towards understanding how pituitary cell number is regulated. Further work will elucidate how the rates of the three processes of cell renewal, differentiation and apoptosis are balanced in tissue homeostasis after birth, but altered in pituitary hyperplasia in response to physiological stimuli such as puberty and lactation. Thus, we can aim to understand the mechanisms underlying human disease due to insufficient (hypopituitarism) or excess (pituitary tumor) cell numbers.

Sirt1 inhibits the transcription factor CREB to regulate pituitary growth hormone synthesis.

Growth hormone (GH) is a major anabolic hormone and the primary regulator of organism growth. Its transcription is triggered by GH-releasing hormone (GHRH) through the transcription factor cAMP response element-binding protein (CREB) and by caloric intake. In contrast, the deacetylase Sirt1 is activated by caloric restriction. Therefore, the present study investigates how Sirt1 affects CREB function and GH synthesis. Sirt1 pharmacological activation with resveratrol (IC50=87 µM) suppressed GHRH-induced GH secretion from rat anterior pituitary cells in vivo and in vitro, while vehicle controls showed no effect. Resveratrol's effects were abolished after knocking down Sirt1 with RNA interference, but not in control scrambled siRNA-transfected rat somatotrophs, confirming the Sirt1 specificity. Sirt1 activation and overexpression suppressed forskolin-induced CREB-Ser(133) phosphorylation, but no effect was seen with vehicle and empty plasmid controls. The deacetylase-dead mutant Sirt1 retained CREB-Ser(133) phosphorylation by keeping protein phosphatase protein phosphatase 1 activity low. Sirt1 activation suppressed glycogen synthase kinase 3 ß acetylation, and a mutation on the GSK3ß-Lys(205) residue mimicking a hypoacetylated form revealed increased activity. In summary, this is a novel mechanism through which Sirt1 intercepts the cAMP pathway by suppressing CREB transcriptional activation, resulting in decreased GH synthesis.

Improved guidance is needed to optimise diagnostics and treatment of patients with thyroid cancer in Europe.

Although thyroid cancer (TC) is generally associated with a favourable prognosis, there are certain high-risk groups with a clear unmet therapeutic need. Unravelling the genomic landscape of TC has recently led to the development of novel effective targeted treatments. To date, these treatments have mostly been evaluated in non-randomised single-arm phase II clinical trials and are consequently non-reimbursed in several countries. Furthermore, most of these agents must be tailored to individual patient molecular characteristics, a context known as personalised cancer medicine, necessitating a requirement for predictive molecular biomarker testing. Existing guidelines, both in Europe and internationally, entail mostly therapeutic rather than molecular testing recommendations. This may reflect ambiguity among experts due to lack of evidence and also practical barriers in availability of the preferred molecular somatic screening and/or targeted treatments. This article reviews existing European recommendations regarding advanced/metastatic TC management with a special focus on molecular testing, and compares findings with real-world practice based on a recent survey involving TC experts from 18 European countries. Significant disparities are highlighted between theory and practice related to variable access to infrastructure, therapies and expertise, together with the insufficient availability of multidisciplinary tumour boards. In particular, practitioners' choice of what, how and when to test is shown to be influenced by the expertise of the available laboratory, the financing source and the existence of potential facilitators, such as clinical trial access. Overall, the need of a collaborative initiative among European stakeholders to develop standardised, accessible molecular genotyping approaches in TC is underscored.

dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe.

The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with high mortality. We show here that depletion of the PIAS2 beta isoform with a transcribed double-stranded RNA-directed RNA interference (PIAS2b-dsRNAi) specifically inhibits growth of ATC cell lines and patient primary cultures in vitro and of orthotopic patient-derived xenografts (oPDX) in vivo. Critically, PIAS2b-dsRNAi does not affect growth of normal or non-anaplastic thyroid tumor cultures (differentiated carcinoma, benign lesions) or cell lines. PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. PIAS2b depletion promotes mitotic catastrophe at prophase. High-throughput proteomics reveals the proteasome (PSMC5) and spindle cytoskeleton (TUBB3) to be direct targets of PIAS2b SUMOylation at mitotic initiation. These results identify PIAS2b-dsRNAi as a promising therapy for ATC and other aggressive anaplastic carcinomas.

Integrative clinical, hormonal, and molecular data associate with invasiveness in acromegaly: REMAH study.

INTRODUCTION: Growth hormone (GH)-secreting pituitary tumors (GHomas) are the most common acromegaly cause. At diagnosis, most of them are macroadenomas, and up to 56% display cavernous sinus invasion. Biomarker assessment associated with tumor growth and invasion is important to optimize their management. OBJECTIVES: The study aims to identify clinical/hormonal/molecular biomarkers associated with tumor size and invasiveness in GHomas and to analyze the influence of pre-treatment with somatostatin analogs (SSAs) or dopamine agonists (DAs) in key molecular biomarker expression. METHODS: Clinical/analytical/radiological variables were evaluated in 192 patients from the REMAH study (ambispective multicenter post-surgery study of the Spanish Society of Endocrinology and Nutrition). The expression of somatostatin/ghrelin/dopamine system components and key pituitary/proliferation markers was evaluated in GHomas after the first surgery. Univariate/multivariate regression studies were performed to identify association between variables. RESULTS: Eighty percent of patients harbor macroadenomas (63.8% with extrasellar growth). Associations between larger and more invasive GHomas with younger age, visual abnormalities, higher IGF1 levels, extrasellar/suprasellar growth, and/or cavernous sinus invasion were found. Higher GH1 and lower PRL/POMC/CGA/AVPR1B/DRD2T/DRD2L expression levels (P < .05) were associated with tumor invasiveness. Least Absolute Shrinkage and Selection Operator's penalized regression identified combinations of clinical and molecular features with areas under the curve between 0.67 and 0.82. Pre-operative therapy with DA or SSAs did not alter the expression of any of the markers analyzed except for DRD1/AVPR1B (up-regulated with DA) and FSHB/CRHR1 (down-regulated with SSAs). CONCLUSIONS: A specific combination of clinical/analytical/molecular variables was found to be associated with tumor invasiveness and growth capacity in GHomas. Pre-treatment with first-line drugs for acromegaly did not significantly modify the expression of the most relevant biomarkers in our association model. These findings provide valuable insights for risk stratification and personalized management of GHomas.

The Inflammatory Pattern of Chronic Limb-Threatening Ischemia in Muscles: The TNF-α Hypothesis.

Background: Vascular inflammation plays a crucial role in peripheral arterial disease (PAD), although the role of the mediators involved has not yet been properly defined. The aim of this work is to investigate gene expression and plasma biomarkers in chronic limb-threating ischemia (CLTI). Methods: Using patients from the GHAS trial, both blood and ischemic muscle samples were obtained to analyze plasma markers and mRNA expression, respectively. Statistical analysis was performed by using univariate (Spearman, t-Student, and X2) and multivariate (multiple logistic regression) tests. Results: A total of 35 patients were available at baseline (29 for mRNA expression). Baseline characteristics (mean): Age: 71.4 ± 12.4 years (79.4% male); TNF-α: 10.7 ± 4.9 pg/mL; hsCRP:1.6 ± 2.2 mg/dL; and neutrophil-to-lymphocyte ratio (NLR): 3.5 ± 2.8. Plasma TNF-α was found elevated (≥8.1) in 68.6% of patients, while high hsCRP (≥0.5) was found in 60.5%. Diabetic patients with a high level of inflammation showed significantly higher levels of NOX4 expression at baseline (p = 0.0346). Plasma TNF-α had a negative correlation with NOS3 (eNOS) expression (-0.5, p = 0.015) and plasma hsCRP with VEGFA (-0.63, p = 0.005). The expression of NOX4 was parallel to that of plasma TNF-α (0.305, p = 0.037), especially in DM. Cumulative mortality at 12 months was related to NLR ≥ 3 (p = 0.019) and TNF-α ≥ 8.1 (p = 0.048). The best cutoff point for NLR to predict mortality was 3.4. Conclusions: NOX4 and TNF-α are crucial for the development and complications of lower limb ischemia, especially in DM. hsCRP could have a negative influence on angiogenesis too. NLR and TNF-α represent suitable markers of mortality in CLTI. These results are novel because they connect muscle gene expression and plasma information in patients with advanced PAD, deepening the search for new and accurate targets for this condition.

LEAP-2 Counteracts Ghrelin-Induced Food Intake in a Nutrient, Growth Hormone and Age Independent Manner.

Data gleaned recently shows that ghrelin, a stomach derived peptide, and liver-expressed-antimicrobial peptide 2 (LEAP-2) play opposite roles on food intake. However, the data available with LEAP-2 in relation to in vivo studies are still very scanty and some key questions regarding the interplay among ghrelin and LEAP-2 remain to be answered. In this work, using rats and mice, we study fasting-induced food intake as well as testing the effect of diet exposure, e.g., standard diet and high fat diet, in terms of ghrelin-induced food intake. The anorexigenic effect of LEAP-2 on fasting induced food intake appears to be dependent on energy stores, being more evident in ob/ob than in wild type mice and also in animals exposed to high fat diet. On the other hand, LEAP-2 administration markedly inhibited ghrelin-induced food intake in lean, obese (ob/ob and DIO) mice, aged rats and GH-deficient dwarf rats. In contrast, the inhibitory effect on glucose levels can only be observed in some specific experimental models indicating that the mechanisms involved are likely to be quite different. Taken together from these data, LEAP-2 emerged as a potential candidate to be therapeutically useful in obesity.

Tackling Thyroid Cancer in Europe-The Challenges and Opportunities.

Thyroid cancer (TC) is the most common malignancy of the endocrine system that affects the thyroid gland. It is usually treatable and, in most cases, curable. The central issues are how to improve knowledge on TC, to accurately identify cases at an early stage that can benefit from effective intervention, optimise therapy, and reduce the risk of overdiagnosis and unnecessary treatment. Questions remain about management, about treating all patients in referral centres, and about which treatment should be proposed to any individual patient and how this can be optimised. The European Alliance for Personalised Medicine (EAPM) hosted an expert panel discussion to elucidate some of the challenges, and to identify possible steps towards effective responses at the EU and member state level, particularly in the context of the opportunities in the European Union's evolving initiatives-notably its Beating Cancer Plan, its Cancer Mission, and its research funding programmes. Recommendations emerging from the panel focus on improved infrastructure and funding, and on promoting multi-stakeholder collaboration between national and European initiatives to complement, support, and mutually reinforce efforts to improve patient care.

Data mining analyses for precision medicine in acromegaly: a proof of concept.

Predicting which acromegaly patients could benefit from somatostatin receptor ligands (SRL) is a must for personalized medicine. Although many biomarkers linked to SRL response have been identified, there is no consensus criterion on how to assign this pharmacologic treatment according to biomarker levels. Our aim is to provide better predictive tools for an accurate acromegaly patient stratification regarding the ability to respond to SRL. We took advantage of a multicenter study of 71 acromegaly patients and we used advanced mathematical modelling to predict SRL response combining molecular and clinical information. Different models of patient stratification were obtained, with a much higher accuracy when the studied cohort is fragmented according to relevant clinical characteristics. Considering all the models, a patient stratification based on the extrasellar growth of the tumor, sex, age and the expression of E-cadherin, GHRL, IN1-GHRL, DRD2, SSTR5 and PEBP1 is proposed, with accuracies that stand between 71 to 95%. In conclusion, the use of data mining could be very useful for implementation of personalized medicine in acromegaly through an interdisciplinary work between computer science, mathematics, biology and medicine. This new methodology opens a door to more precise and personalized medicine for acromegaly patients.

Synthesis and In Vivo Evaluation of Insulin-Loaded Whey Beads as an Oral Peptide Delivery System.

For many diabetics, daily, lifelong insulin injections are required to effectively manage blood glucose levels and the complications associated with the disease. This can be a burden and reduces patient quality of life. Our goal was to develop a more convenient oral delivery system that may be suitable for insulin and other peptides. Insulin was entrapped in 1.5-mm beads made from denatured whey protein isolate (dWPI) using gelation. Beads were then air-dried with fumed silica, Aerosil®. The encapsulation efficiency was ~61% and the insulin loading was ~25 µg/mg. Dissolution in simulated gastric-, and simulated intestinal fluids (SGF, SIF) showed that ~50% of the insulin was released from beads in SGF, followed by an additional ~10% release in SIF. The omission of Aerosil® allowed greater insulin release, suggesting that it formed a barrier on the bead surface. Circular dichroism analysis of bead-released insulin revealed an unaltered secondary structure, and insulin bioactivity was retained in HepG2 cells transfected to assess activation of the endogenous insulin receptors. Insulin-entrapped beads were found to provide partial protection against pancreatin for at least 60 min. A prototype bead construct was then synthesised using an encapsulator system and tested in vivo using a rat intestinal instillation bioassay. It was found that 50 IU/kg of entrapped insulin reduced plasma glucose levels by 55% in 60 min, similar to that induced by subcutaneously (s.c.)-administered insulin (1 IU/kg). The instilled insulin-entrapped beads produced a relative bioavailability of 2.2%. In conclusion, when optimised, dWPI-based beads may have potential as an oral peptide delivery system.

RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas.

It is unclear how loss-of-function germline mutations in the widely-expressed co-chaperone AIP, result in young-onset growth hormone secreting pituitary tumours. The RET receptor, uniquely co-expressed in somatotrophs with PIT1, induces apoptosis when unliganded, while RET supports cell survival when it is bound to its ligand. We demonstrate that at the plasma membrane, AIP is required to form a complex with monomeric-intracellular-RET, caspase-3 and PKCδ resulting in PIT1/CDKN2A-ARF/p53-apoptosis pathway activation. AIP-deficiency blocks RET/caspase-3/PKCδ activation preventing PIT1 accumulation and apoptosis. The presence or lack of the inhibitory effect on RET-induced apoptosis separated pathogenic AIP variants from non-pathogenic ones. We used virogenomics in neonatal rats to demonstrate the effect of mutant AIP protein on the RET apoptotic pathway in vivo. In adult male rats altered AIP induces elevated IGF-1 and gigantism, with pituitary hyperplasia through blocking the RET-apoptotic pathway. In females, pituitary hyperplasia is induced but IGF-1 rise and gigantism are blunted by puberty. Somatotroph adenomas from pituitary-specific Aip-knockout mice overexpress the RET-ligand GDNF, therefore, upregulating the survival pathway. Somatotroph adenomas from patients with or without AIP mutation abundantly express GDNF, but AIP-mutated tissues have less CDKN2A-ARF expression. Our findings explain the tissue-specific mechanism of AIP-induced somatotrophinomas and provide a previously unknown tumorigenic mechanism, opening treatment avenues for AIP-related tumours.

Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of Pituitary Adenoma Cells by Hampering Oncogenic Pathways and Promoting Apoptotic Signaling.

Pituitary adenomas (PAs) are intracranial tumors, often associated with excessive hormonal secretion and severe comorbidities. Some patients are resistant to medical therapies; therefore, novel treatment options are needed. Antagonists of growth hormone-releasing hormone (GHRH) exert potent anticancer effects, and early GHRH antagonists were found to inhibit GHRH-induced secretion of pituitary GH in vitro and in vivo. However, the antitumor role of GHRH antagonists in PAs is largely unknown. Here, we show that the GHRH antagonists of MIAMI class, MIA-602 and MIA-690, inhibited cell viability and growth and promoted apoptosis in GH/prolactin-secreting GH3 PA cells transfected with human GHRH receptor (GH3-GHRHR), and in adrenocorticotropic hormone ACTH-secreting AtT20 PA cells. GHRH antagonists also reduced the expression of proteins involved in tumorigenesis and cancer progression, upregulated proapoptotic molecules, and lowered GHRH receptor levels. The combination of MIA-690 with temozolomide synergistically blunted the viability of GH3-GHRHR and AtT20 cells. Moreover, MIA-690 reduced both basal and GHRH-induced secretion of GH and intracellular cAMP levels. Finally, GHRH antagonists inhibited cell viability in human primary GH- and ACTH-PA cell cultures. Overall, our results suggest that GHRH antagonists, either alone or in combination with pharmacological treatments, may be considered for further development as therapy for PAs.

A nanoemulsion/micelles mixed nanosystem for the oral administration of hydrophobically modified insulin.

The potential of nanoemulsions for the oral administration of peptides is still in its early stage. The aim of the present work was to rationally design, develop, and fully characterize a new nanoemulsion (NE) intended for the oral administration of hydrophobically modified insulin (HM-insulin). Specific components of the NE were selected based on their enhancing permeation properties as well as their ability to improve insulin association efficiency (Miglyol 812, sodium taurocholate), stability in the intestinal fluids, and mucodiffusion (PEGylated phospholipids and poloxamer 407). The results showed that the NE co-existed with a population of micelles, forming a mixed system that exhibited a 100% of HM-insulin association efficiency. The nanosystem showed good stability and miscibility in different bio-relevant media and displayed an acceptable mucodiffusive behavior in porcine mucus. In addition, it exhibited a high interaction with cell mono-cultures (Caco -2 and C2BBe1 human colon carcinoma Caco-2 clone cells) and co-cultures (C2BBe1 human colon carcinoma Caco-2 clone/HT29-MTX cells). The internalization in Caco-2 monolayers was also confirmed by confocal microscopy. Finally, the promising in vitro behavior of the nanosystem in terms of overcoming the biological barriers of the intestinal tract was translated into a moderate, although significant, hypoglycemic response (≈ 20-30%), following intestinal administration to both healthy and diabetic rat models. Overall, this information underlines the crucial steps to address when designing peptide-based nanoformulations to successfully overcome the intestinal barriers associated to the oral modality of administration.

Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis.

Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca2+ handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca2+ influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca2+ homeostasis, and WAT lipolysis in the regulation of energy balance.

Expression of exogenous proteins and short hairpin RNAs in human primary thyrocytes.

Recently, it has been shown that commercial human thyroid lines were in fact derived from colon, mammary carcinoma, or melanoma. Others have demonstrated the absence of a common pattern of gene expression between available thyroid cancer cell lines and tumors from patients. Thus, it is important to use several primary cells with a common pathological origin to achieve reproducible results, and it is necessary to find common methods for manipulation of protein expression in such various cultures. We have standardized a transfection method for efficient expression of exogenous proteins in human primary thyroid cultures. We compared lipid-based techniques with three electroporation systems (Electroporator PulseAgile [PA]-4000, Microporator MP-100, and Nucleofector II). Nucleofection was unquestionably the most efficient even for promoter regulation studies, and it was effective in cultures from different origins as normal thyroid, papillary carcinoma, or lymphoid node metastasis. We also standardized, through lentiviral infection, the short hairpin RNA downregulation of protein expression generating human thyrocytes with low levels of p27KIP1 as a model system.

Functional role of the RET dependence receptor, GFRa co-receptors and ligands in the pituitary.

The RET receptor is a tyrosine kinase receptor implicated in kidney and neural development. In the adenopituitary RET and the co-receptor GFRa1 are expressed exclusively in the somatotrophs secreting GH. RET is implicated in a clever pathway to maintain at physiological levels the number of somatotrophs and the GH production. Thus, in absence of its ligand GDNF, RET induces apoptosis through massive expression of Pit-1 leading to p53 accumulation. In the presence of the ligand GDNF, RET activates its tyrosine kinase and promotes survival at the expense of reducing Pit-1 expression and downregulating GH. Recent data suggest that RET can also have a second role in pituitary plasticity through a second co-receptor GFRa2.

Why Should Growth Hormone (GH) Be Considered a Promising Therapeutic Agent for Arteriogenesis? Insights from the GHAS Trial.

Despite the important role that the growth hormone (GH)/IGF-I axis plays in vascular homeostasis, these kind of growth factors barely appear in articles addressing the neovascularization process. Currently, the vascular endothelium is considered as an authentic gland of internal secretion due to the wide variety of released factors and functions with local effects, including the paracrine/autocrine production of GH or IGF-I, for which the endothelium has specific receptors. In this comprehensive review, the evidence involving these proangiogenic hormones in arteriogenesis dealing with the arterial occlusion and making of them a potential therapy is described. All the elements that trigger the local and systemic production of GH/IGF-I, as well as their possible roles both in physiological and pathological conditions are analyzed. All of the evidence is combined with important data from the GHAS trial, in which GH or a placebo were administrated to patients suffering from critical limb ischemia with no option for revascularization. We postulate that GH, alone or in combination, should be considered as a promising therapeutic agent for helping in the approach of ischemic disease.

Neuropsychiatric Presentation of COVID-19: A Case Report of Disinhibition in an Acute SARS-CoV-2 Infection.

Description Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral infection is notable for a high degree of symptom diversity. Emerging evidence suggests viral invasion of the central nervous system. Therefore, serious neurological and psychiatric manifestations are anticipated. We present the case of a 67-year-old male physician who has a history of stable bipolar disorder for decades and was recently hospitalized for persistent COVID-19 symptoms with documented positive serology. He presented with new and acute onset neuropsychiatric symptoms of disinhibition proximate to the viral infection. We postulate neuroinvasion as the putative origin of the patient's psychiatric instability. Furthermore, an investigation is needed to expand upon our understanding of the potential for neuropsychiatric morbidity related to SARS-CoV-2 for prompt diagnosis and appropriate management. There are also no current studies addressing the risks for neurological and psychiatric symptomatology in SARS-CoV-2 infected patients with persistent chronic mental illness.