2,007 research outputs found
Therapeutic advances in ADPKD: the future awaits
Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder included in ciliopathies, representing the fourth cause of end stage renal disease (ESRD), with an estimated prevalence between 1:1000 and 1:2500. It is mainly caused by mutations in the PKD1 and PKD2 genes encoding for polycystin 1 (PC1) and polycystin 2 (PC2), which regulate differentiation, proliferation, survival, apoptosis, and autophagy. The advances in the knowledge of multiple molecular pathways involved in the pathophysiology of ADPKD led to the development of several treatments which are currently under investigation. Recently, the widespread approval of tolvaptan and, in Italy, of long-acting release octreotide (octreotide-LAR), represents but the beginning of the new therapeutic management of ADPKD patients. Encouraging results are expected from ongoing randomized controlled trials (RCTs), which are investigating not only drugs acting on the calcium/cyclic adenosin monoposphate (cAMP) pathway, the most studied target so far, but also molecules targeting specific pathophysiological pathways (e.g. epidermal growth factor (EGF) receptor, AMP-activated protein kinase (AMPK) and KEAP1-Nrf2) and sphingolipids. Moreover, studies on animal models and cultured cells have also provided further promising therapeutic strategies based on the role of intracellular calcium, cell cycle regulation, MAPK pathway, epigenetic DNA, interstitial inflammation, and cell therapy. Thus, in a near future, tailored therapy could be the key to changing the natural history of ADPKD thanks to the vigorous efforts that are being made to implement clinical and preclinical studies in this field. Our review aimed to summarize the spectrum of drugs that are available in the clinical practice and the most promising molecules undergoing clinical, animal, and cultured cell studies. Graphical abstract: [Figure not available: see fulltext.
Clinical findings and prognosis of interference injuries to the palmar aspect of the forelimbs in Standardbred racehorses: A study on 74 cases
Information on interference injuries in racehorses is lacking
Indeterminacy of Spatiotemporal Cardiac Alternans
Cardiac alternans, a beat-to-beat alternation in action potential duration
(at the cellular level) or in ECG morphology (at the whole heart level), is a
marker of ventricular fibrillation, a fatal heart rhythm that kills hundreds of
thousands of people in the US each year. Investigating cardiac alternans may
lead to a better understanding of the mechanisms of cardiac arrhythmias and
eventually better algorithms for the prediction and prevention of such dreadful
diseases. In paced cardiac tissue, alternans develops under increasingly
shorter pacing period. Existing experimental and theoretical studies adopt the
assumption that alternans in homogeneous cardiac tissue is exclusively
determined by the pacing period. In contrast, we find that, when calcium-driven
alternans develops in cardiac fibers, it may take different spatiotemporal
patterns depending on the pacing history. Because there coexist multiple
alternans solutions for a given pacing period, the alternans pattern on a fiber
becomes unpredictable. Using numerical simulation and theoretical analysis, we
show that the coexistence of multiple alternans patterns is induced by the
interaction between electrotonic coupling and an instability in calcium
cycling.Comment: 20 pages, 10 figures, to be published in Phys. Rev.
Oral Sucrosomial® iron versus intravenous iron for recovering iron deficiency anaemia in ND-CKD patients: a cost- minimization analysis.
Stepwise shortening of agalsidase beta infusion duration in Fabry disease: Clinical experience with infusion rate escalation protocol
Background: Although enzyme replacement therapy with agalsidase beta resulted in a variety of clinical benefits, life-long biweekly intravenous infusion may impact on patients’ quality of life. Moreover, regular infusions are time-consuming: although a stepwise shortening of infusion duration is allowed up to a minimum of 1.5 hr, in most centers it remains ≥3 hr, and no data exists about the safety and tolerability of agalsidase beta administration at maximum tolerated infusion rate. Methods: In this study, we reported our experience with a stepwise infusion rate escalation protocol developed in our center in a cohort of 53 Fabry patients (both already receiving and treatment-naΪve), and explored factors predictive for the infusion rate increase tolerability. Results: Fifty-two patients (98%) reduced infusion duration ≤3 hr; of these, 38 (72%) even reached a duration ≤2 hr. We found a significant difference between the mean duration reached by already treated and naΪve patients (p <.01). More severely affected patients (male patients and those with lower enzyme activity) received longer infusions for higher risk of infusion-associated reactions (IARs). A significant correlation between anti-agalsidase antibodies and IARs was found. Conclusion: Our infusion rate escalation protocol is safe and could improve patient compliance, satisfaction and quality of life
Characterization of Evidence for Human System Risk Assessment
Understanding the kinds of evidence available and using the best evidence to answer a question is critical to evidenced-based decision-making, and it requires synthesis of evidence from a variety of sources. Categorization of human system risks in spaceflight, in particular, focuses on how well the integration and interpretation of all available evidence informs the risk statement that describes the relationship between spaceflight hazards and an outcome of interest. A mature understanding and categorization of these risks requires: 1) sufficient characterization of risk, 2) sufficient knowledge to determine an acceptable level of risk (i.e., a standard), 3) development of mitigations to meet the acceptable level of risk, and 4) identification of factors affecting generalizability of the evidence to different design reference missions. In the medical research community, evidence is often ranked by increasing confidence in findings gleaned from observational and experimental research (e.g., "levels of evidence"). However, an approach based solely on aspects of experimental design is problematic in assessing human system risks for spaceflight. For spaceflight, the unique challenges and opportunities include: (1) The independent variables in most evidence are the hazards of spaceflight, such as space radiation or low gravity, which cannot be entirely duplicated in terrestrial (Earth-based) analogs, (2) Evidence is drawn from multiple sources including medical and mission operations, Lifetime Surveillance of Astronaut Health (LSAH), spaceflight research (LSDA), and relevant environmental & terrestrial databases, (3) Risk metrics based primarily on LSAH data are typically derived from available prevalence or incidence data, which may limit rigorous interpretation, (4) The timeframe for obtaining adequate spaceflight sample size (n) is very long, given the small population, (5) Randomized controlled trials are unattainable in spaceflight, (6) Collection of personal and environmental data on the astronaut population may create opportunities for advanced analytics and human-environment modeling that goes beyond that achieved in isolated experimental designs; and (7) Translation of relevant research to operations is a complex, transdisciplinary enterprise in which the approach must apply across the physical, biological, behavioral, and social sciences. The approach to synthesizing evidence must address both source and fidelity of data, and reflect the most general attributes of quality of evidence in science and engineering: reliability and validity. The authors are developing a two-factor approach which includes the various kinds of evidence required to understand risks and for the integrated interpretation of all evidence that is essential to develop standards and countermeasures. A unified framework for aggregating and assessing different kinds of evidence provides a consistent, traceable, evidence-based decision-making process to translate research to operations in an environment where engineers, scientists, physicians, and managers all engage in analyzing the trade space of vehicle design, standards, requirements and solutions for spaceflight
Human dental pulp stem cells produce mineralized matrix in 2D and 3D cultures
The aim of this study was to characterize the in vitro osteogenic differentiation of dental pulp stem cells (DPSCs) in 2D cultures and 3D biomaterials. DPSCs, separated from dental pulp by enzymatic digestion, and isolated by magnetic cell sorting were differentiated toward osteogenic lineage on 2D surface by using an osteogenic medium. During differentiation process, DPSCs express specific bone proteins like Runx-2, Osx, OPN and OCN with a sequential expression, analogous to those occurring during osteoblast differentiation, and produce extracellular calcium deposits. In order to differentiate cells in a 3D space that mimes the physiological environment, DPSCs were cultured in two distinct bioscaffolds, Matrigelâ„¢ and Collagen sponge. With the addition of a third dimension, osteogenic differentiation and mineralized extracellular matrix production significantly improved. In particular, in Matrigelâ„¢ DPSCs differentiated with osteoblast/osteocyte characteristics and connected by gap junction, and therefore formed calcified nodules with a 3D intercellular network. Furthermore, DPSCs differentiated in collagen sponge actively secrete human type I collagen micro-fibrils and form calcified matrix containing trabecular-like structures. These neo-formed DPSCs-scaffold devices may be used in regenerative surgical applications in order to resolve pathologies and traumas characterized by critical size bone defects
Adverse Outcome of Early Recurrent Ischemic Stroke Secondary to Atrial Fibrillation after Repeated Systemic Thrombolysis
Background. Recurrent ischemic stroke is associated with adverse neurological outcome in patients with atrial fibrillation. There is very scarce information regarding the neurological outcome of atrial fibrillation patients undergoing repeated systemic thrombolysis after early recurrent ischemic stroke. Clinical Case and Discussion. We describe a case of a 76-year-old woman with known paroxysmal atrial fibrillation who was admitted because of an acute right middle cerebral artery ischemic stroke and who underwent repeated systemic thrombolysis within 110 hours. The patient underwent systemic thrombolysis after the first ischemic stroke with almost complete neurological recovery. On the fourth day after treatment, an acute left middle cerebral artery ischemic stroke was diagnosed and she was treated with full-dose intravenous recombinant tissue plasminogen activator. A hemorrhagic transformation of the left middle cerebral artery infarction was noted on follow-up cranial computed tomographic scans. The patient did not recover from the second cerebrovascular event and died 25 days after admission. Conclusion. To the best of our knowledge, this is the second case reporting the adverse neurological outcome of a patient with diagnosis of atrial fibrillation undergoing repeated systemic thrombolysis after early recurrent ischemic stroke. Our report represents a contribution to the scarce available evidence suggesting that repeated systemic thrombolysis for recurrent ischemic stroke should be avoided
Failure by congestion of pedicled and free flaps for reconstruction of lower limbs after trauma: the role of negative-pressure wound therapy
Lower limb reconstruction with pedicled or free flaps can be commonly compromised by venous insufficiency. This complication often leads to partial/complete flap necrosis and increases the risk of superinfection. Negative-pressure wound therapy (NPWT) is known to increase local blood flow, decrease edema, promote tissue granulation, and reduce the likelihood of soft tissue infection. This study aims to evaluate the effectiveness of NPWT in the treatment of congested pedicled and free flaps of the lower limb after reconstructions in lower limb traumas. A retrospective analysis was performed on four congested (pedicled and free) flaps on the lower limbs. NPWT was applied in all cases after partial flap debridement. NPWT was able to improve and resolve tissue edema and venous insufficiency, avoid further flap necrosis, and promote granulation. On NPWT removal, a split-thickness skin graft was applied on the wound, achieving complete and uneventful healing. NPWT is a useful instrument in managing flaps affected by venous insufficiency in lower limb reconstruction, although larger studies are necessary to better define the effectiveness and indications of NPWT in this setting
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