Reconstruction of the Terminal of an Abandoned Fractured Unipolar Coronary Sinus Lead: a Feasible Solution to Restore Effective Cardiac Resynchronization Therapy

AbstractComplications related to coronary sinus lead are not infrequent in recipients of cardiac resynchronization devices. We describe the case of a patient with a biventricular implantable cardioverter defibrillator with persistent phrenic nerve stimulation, previous coronary sinus lead fracture, and severe left subclavian vein stenosis. The reimplantation of a new coronary sinus lead on the left side, ipsilateral to the original implant, was unsuccessful. In order to avoid more complex and risky procedures, we performed the repair of the fractured abandoned lead with the reconstruction of the unipolar lead terminal. Effective biventricular pacing was obtained with satisfactory electrical parameters and it was maintained at twelve months follow-up

Evidence for Altered Ca2+ Handling in Growth Associated Protein 43-Knockout Skeletal Muscle

Neuronal growth-associated protein 43 (GAP43) has crucial roles in the nervous system, and during development, regeneration after injury, and learning and memory. GAP43 is expressed in mouse skeletal muscle fibers and satellite cells, with suggested its involvement in intracellular Ca2+ handling. However, the physiological role of GAP43 in muscle remains unknown. Using a GAP43-knockout (GAP43-/-) mouse, we have defined the role of GAP43 in skeletal muscle. GAP43-/- mice showed low survival beyond weaning, reduced adult body weight, decreased muscle strength, and changed myofiber ultrastructure, with no significant differences in the expression of markers of satellite cell and myotube progression through the myogenic program. Thus, GAP43 expression is involved in timing of muscle maturation in-vivo. Intracellular Ca2+ measurements in-vitro in myotubes revealed GAP43 involvement in Ca2+ handling. In the absence of GAP43 expression, the spontaneous Ca2+ variations had greater amplitudes and higher frequency. In GAP43-/- myotubes, also the intracellular Ca2+ variations induced by the activation of dihydropyridine and ryanodine Ca2++ channels, resulted modified. These evidences suggested dysregulation of Ca2+ homeostasis. The emerging hypothesis indicates that GAP43 interacts with calmodulin to indirectly modulate the activities of dihydropyridine and ryanodine Ca2+ channels. This thus influences intracellular Ca2+ dynamics and its related intracellular patterns, from functional excitation-contraction coupling, to cell metabolism, and gene expression. © 2016 Caprara, Morabito, Perni, Navarra, Guarnieri and Mariggiò

The Landscape of lncRNAs in Multiple Myeloma: Implications in the “Hallmarks of Cancer”, Clinical Perspectives and Therapeutic Opportunities

Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that are not translated into proteins. Nowadays, lncRNAs are gaining importance as key regulators of gene expression and, consequently, of several biological functions in physiological and pathological conditions, including cancer. Here, we point out the role of lncRNAs in the pathogenesis of multiple myeloma (MM). We focus on their ability to regulate the biological processes identified as “hallmarks of cancer” that enable malignant cell transformation, early tumor onset and progression. The aberrant expression of lncRNAs in MM suggests their potential use as clinical biomarkers for diagnosis, patient stratification, and clinical management. Moreover, they represent ideal candidates for therapeutic targeting

MICA-129 dimorphism and soluble MICA are associated with the progression of multiple myeloma

Natural killer (NK) cells are immune innate effectors playing a pivotal role in the immunosurveillance of multiple myeloma (MM) since they are able to directly recognize and kill MM cells. In this regard, among activating receptors expressed by NK cells, NKG2D represents an important receptor for the recognition of MM cells, being its ligands expressed by tumor cells, and being able to trigger NK cell cytotoxicity. The MHC class I-related molecule A (MICA) is one of the NKG2D ligands; it is encoded by highly polymorphic genes and exists as membrane-bound and soluble isoforms. Soluble MICA (sMICA) is overexpressed in the serum of MM patients, and its levels correlate with tumor progression. Interestingly, a methionine (Met) to valine (Val) substitution at position 129 of the α2 heavy chain domain classifies the MICA alleles into strong (MICA-129Met) and weak (MICA-129Val) binders to NKG2D receptor. We addressed whether the genetic polymorphisms in the MICA-129 alleles could affect MICA release during MM progression. The frequencies of Val/Val, Val/Met, and Met/Met MICA-129 genotypes in a cohort of 137 MM patients were 36, 43, and 22%, respectively. Interestingly, patients characterized by a Val/Val genotype exhibited the highest levels of sMICA in the sera. In addition, analysis of the frequencies of MICA-129 genotypes among different MM disease states revealed that Val/Val patients had a significant higher frequency of relapse. Interestingly, NKG2D was downmodulated in NK cells derived from MICA-129Met/Met MM patients. Results obtained by structural modeling analysis suggested that the Met to Val dimorphism could affect the capacity of MICA to form an optimal template for NKG2D recognition. In conclusion, our findings indicate that the MICA-129Val/Val variant is associated with significantly higher levels of sMICA and the progression of MM, strongly suggesting that the usage of soluble MICA as prognostic marker has to be definitely combined with the patient MICA genotype

DRD1 and DRD2 Receptor Polymorphisms: Genetic Neuromodulation of the Dopaminergic System as a Risk Factor for ASD, ADHD and ASD/ADHD Overlap

The dopaminergic system (DS) is one of the most important neuromodulator systems involved in complex functions that are compromised in both autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD), conditions that frequently occur in overlap. This evidence suggests that both disorders might have common neurobiological pathways involving the DS. Therefore, the aim of this study was to examine the DRD1 and DRD2 dopamine receptor single nucleotide polymorphisms (SNPs) as potential risk factors for ASD, ADHD, and ASD/ADHD overlap. Genetic data were obtained from four groups: 75 ASD patients, 75 ADHD patients, 30 patients with ASD/ADHD overlap, and 75 healthy controls. All participants were between 2 and 17 years old. We compared the genotypic and allelic frequency of 18 SNPs among all of the study groups. Moreover, in the case of statistically significant differences, odds ratios (OR) were obtained to evaluate if the presence of SNPs might be a risk factor of developing a specific clinical phenotype. This study found that DRD1 and DRD2 receptors SNPs might be considered as potential risk factors for ASD and ADHD. However, only DRD2-12 (rs7131465) was significantly associated with a higher risk for the ASD/ADHD overlap. These data support the hypothesis of the genetic neuromodulation of the DS in the neurobiology of these conditions

RCCS™ bioreactor-based modelled microgravity induces significant changes on in vitro 3D neuroglial cell cultures

We propose a human-derived neuro-/glial cell three-dimensional in vitro model to investigate the effects of microgravity on cell-cell interactions. A rotary cell-culture system (RCCS) bioreactor was used to generate a modelled microgravity environment, and morphofunctional features of glial-like GL15 and neuronal-like SH-SY5Y cells in three-dimensional individual cultures (monotypic aggregates) and cocultures (heterotypic aggregates) were analysed. Cell survival was maintained within all cell aggregates over 2 weeks of culture. Moreover, compared to cells as traditional static monolayers, cell aggregates cultured under modelled microgravity showed increased expression of specific differentiation markers (e.g., GL15 cells: GFAP, S100B; SH-SY5Y cells: GAP43) and modulation of functional cell-cell interactions (e.g., N-CAM and Cx43 expression and localisation). In conclusion, this culture model opens a wide range of specific investigations at the molecular, biochemical, and morphological levels, and it represents an important tool for in vitro studies into dynamic interactions and responses of nervous system cell components to microgravity environmental conditions

S100A1: A Multifaceted Therapeutic Target in Cardiovascular Disease

Cardiovascular disease is the leading cause of death worldwide, showing a dramatically growing prevalence. It is still associated with a poor clinical prognosis, indicating insufficient long-term treatment success of currently available therapeutic strategies. Investigations of the pathomechanisms underlying cardiovascular disorders uncovered the Ca2+ binding protein S100A1 as a critical regulator of both cardiac performance and vascular biology. In cardiomyocytes, S100A1 was found to interact with both the sarcoplasmic reticulum ATPase (SERCA2a) and the ryanodine receptor 2 (RyR2), resulting in substantially improved Ca2+ handling and contractile performance. Additionally, S100A1 has been described to target the cardiac sarcomere and mitochondria, leading to reduced pre-contractile passive tension as well as enhanced oxidative energy generation. In endothelial cells, molecular analyses revealed a stimulatory effect of S100A1 on endothelial NO production by increasing endothelial nitric oxide synthase activity. Emphasizing the pathophysiological relevance of S100A1, myocardial infarction in S100A1 knockout mice resulted in accelerated transition towards heart failure and excessive mortality in comparison with wild-type controls. Mice lacking S100A1 furthermore displayed significantly elevated blood pressure values with abrogated responsiveness to bradykinin. On the other hand, numerous studies in small and large animal heart failure models showed that S100A1 overexpression results in reversed maladaptive myocardial remodeling, long-term rescue of contractile performance, and superior survival in response to myocardial infarction, indicating the potential of S100A1-based therapeutic interventions. In summary, elaborate basic and translational research established S100A1 as a multifaceted therapeutic target in cardiovascular disease, providing a promising novel therapeutic strategy to future cardiologists

Group IV Phospholipase A2α Controls the Formation of Inter-Cisternal Continuities Involved in Intra-Golgi Transport

The enzyme phospholipase A2 (cPLA2α) is involved in the formation of intercisternal tubules that mediate transport of proteins within the Golgi complex

Reproducible surface-enhanced Raman quantification of biomarkers in multicomponent mixtures

A.C.D.L. is supported by an AIRC Start-up Grant 11454 and a FIR project RBFR12WAPY. A.D.F. is supported by an EPSRC Career Acceleration Fellowship (EP/I004602/1). D.C. is supported by an AIRC Grant IG10341 and the projects PON01-00117 and PON01-00862. S.M. is supported by a PRIN project 2012CK5RPF_05.Direct and quantitative detection of unlabeled glycerophosphoinositol (GroPIns), an abundant cytosolic phosphoinositide derivative, would allow rapid evaluation of several malignant cell transformations. Here we report label-free analysis of GroPIns via surface-enhanced Raman spectroscopy (SERS) with a sensitivity of 200 nM, well below its apparent concentration in cells. Crucially, our SERS substrates, based on lithographically defined gold nanofeatures, can be used to predict accurately the GroPIns concentration even in multicomponent mixtures, avoiding the preliminary separation of individual compounds. Our results represent a critical step toward the creation of SERS-based biosensor for rapid, label-free, and reproducible detection of specific molecules, overcoming limits of current experimental methods.PostprintPeer reviewe