Dual growth factor delivery from degradable oligo(poly(ethylene glycol) fumarate) hydrogel scaffolds for cartilage tissue engineering.

This work describes the development of a non-invasive means of simultaneously delivering insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta1 (TGF-beta1) to injured cartilage tissue in a controlled manner. This novel delivery technology employs the water-soluble polymer, oligo(poly(ethylene glycol) fumarate) (OPF), in the fabrication of biodegradable hydrogels which encapsulate gelatin microparticles. Release studies first examined the effect of gelatin isoelectric point (IEP) and crosslinking extent on IGF-1 release from these microparticles. In the presence of collagenase, highly crosslinked, acidic gelatin (IEP=5.0) provided sustained release of IGF-1, 95.2+/-2.9% cumulative release at day 28, while less crosslinked microparticles and microparticles of alternate IEP exhibited similar release values after only 6 days. Encapsulation of these highly crosslinked microparticles in a network of OPF provided a means to further control release, reducing final cumulative release to 70.2+/-4.7% in collagenase-containing PBS. Final release values from OPF-gelatin microparticle composites could be altered by incorporating less crosslinked, non-loaded microparticles within these constructs. Finally, this technology was extended to the dual delivery of IGF-1 and TGF-beta1 by loading these growth factors into either the OPF hydrogel phase or gelatin microparticle phase of composites. Release profiles were successfully manipulated by altering the phase of growth factor loading and microparticle crosslinking extent. For instance, by loading TGF-beta1 into the gelatin microparticle phase, a burst release of 10.8+/-0.7% was achieved, while loading this growth factor into the OPF hydrogel phase resulted in a burst release of 25.2+/-1.5%. With either system, simultaneous, slow release of IGF-1 over a 4-week period was accomplished by selectively loading this protein into highly crosslinked, encapsulated microparticles. These results demonstrate the utility of these systems in future studies to assess the interplay and time course of multiple growth factors in cartilage repair.     

Prediction of atrial fibrillation development and progression:current perspectives

Atrial fibrillation(AF) is the most common arrhythmia in clinical practice. Several conventional and novel predictors of AF development and progression(from paroxysmal to persistent and permanent types) have been reported. The most important predictor of AF progression is possibly the arrhythmia itself. The electrical, mechanical and structural remodeling determines the perpetuation of AF and the progression from paroxysmal to persistent and permanent forms. Common clinical scores such as the hypertension, age ≥ 75 years, transient ischemic attack or stroke, chronic obstructive pulmonary disease, and heart failure and the congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category scores as well as biomarkers related to inflammation may also add important information on this topic. There is now increasing evidence that even in patients with so-called lone or idiopathic AF, the arrhythmia is the manifestation of a structural atrial disease which has recently been defined and described as fibrotic atrial cardiomyopathy. Fibrosis results from a broad range of factors related to AF inducing pathologies such as cell stretch, neurohumoral activation, and oxidative stress. The extent of fibrosis as detected either by late gadolinium enhancement-magnetic resonance imaging or electroanatomic voltage mapping may guide the therapeutic approach based on the arrhythmia substrate. The knowledge of these risk factors may not only delay arrhythmia progression, but also reduce the arrhythmia burden in patients with first detected AF. The present review highlights on the conventional and novel risk factors of development and progression of AF.     

Concomitant Use of Direct Oral Anticoagulants with Antiplatelet Agents and the Risk of Major Bleeding in Patients with Nonvalvular Atrial Fibrillation

Purpose

Patients with nonvalvular atrial fibrillation commonly have comorbidities requiring concurrent use of oral anticoagulants and antiplatelets. There are no real-world data on the comparative safety of concomitant antithrombotic treatments in the era of direct oral anticoagulant (DOACs). Thus, we compared the incidence of intracranial hemorrhage, gastrointestinal bleeding, and other major bleeding between concomitant DOAC-antiplatelet use and concomitant vitamin K antagonist (VKA)-antiplatelet use in patients with nonvalvular atrial fibrillation.

Neuroendocrine differentiation in embryonal type hepatoblastoma

Hepatoblastoma, a malignant tumor which arises occasionally in older children but very rarely in adults, exhibits divergent differentiation with embryonal cells, fetal hepatocytes and immature elements. This report describes an embryonal type hepatoblastoma with neuroendocrine differentiation in a 16‐year‐old patient, which was diagnosed postoperatively. Clinical and radiologic work‐up failed to reveal a primary gastrointestinal malignancy and no primary lesions were detected in any other organ. This feature of hepatoblastoma is considered to be a multidirectional differentiation of the small epithelial or stem cells of the liver. At 2‐year follow up, the patient remains symptom‐free, with normal laboratory and diagnostic imaging studies, and no recurrent or metastatic disease identified.     

The role of functional social support in treatment retention and outcomes among outpatient adult substance abusers

Aims The goals of this study were: (1) to compare patients with high and low functional social support at intake and 6 months later on various risk factors; (2) to test the stress‐buffering role of functional social support on treatment outcomes, and (3) to determine whether levels of functional social support at intake predicted treatment retention. Design Consecutive admissions to an outpatient treatment program were assessed at intake (n = 206) and at 6 month follow‐up (n = 172) using the Addition Severity Index (ASI). Patients completed questionnaires pertaining to social support, stress and psychological functioning both at intake and at 6 months. Findings Both high and low social support groups experienced marked declines in negative affect and in the severity of substance abuse over time. There were some group differences: for example, symptoms of depression and psychological distress were higher among patients with low social support at intake and at 6 months. Patients with low social support at intake reported higher severity of alcohol and drug abuse at 6 months. Hierarchical regression analyses showed that functional social support was a modest predictor of reductions in the severity of alcohol abuse at follow‐up, after controlling for the number of days in treatment. Higher levels of social support explained a modest (6%) proportion of the variance in alcohol‐related outcomes, but did not predict reductions in drug abuse. Survival analysis demonstrated that the rate of dropping out of treatment was significantly higher for patients with low social support. Conclusions Higher functional social support at intake is a positive predictor of retention in treatment, and a modest predictor of reductions in alcohol intake, but not in drug use. Overall, social support accounts for a small percentage of the variance in drug/alcohol‐related outcomes, underscoring the need for further research into variables accounting for treatment success and failure.     

The effect of aspirin and various iontophoresis solution vehicles on skin microvascular reactivity.

The two main objectives of this study were: (1) to examine the effect of aspirin on the endothelial function in healthy subjects and (2) to examine the effect of deionized water and 5% NaCl as iontophoresis solution vehicles. The skin microcirculation was evaluated at the forearm level of healthy subjects. A laser Doppler scanner was employed to measure vasodilation in response to the iontophoresis of 1% acetylcholine (endothelium-dependent) and 1% sodium nitroprusside (endothelium-independent). In the first experiment, nine healthy subjects were given 500 mg aspirin daily for 3 days. The microvascular reactivity was measured at the beginning and the end of the study. In the second experiment, the response to iontophoresis of acetylcholine and sodium nitroprusside as 1% solutions of deionized water was compared to the responses that were achieved after the iontophoresis of deionized water or 5% NaCl solution. After 3 days of aspirin intake, there were no changes in the vasodilatory response to acetylcholine (endothelium-dependent vasodilation) [81 +/- 11 vs 77 +/- 10 (% of increase over baseline at the beginning vs the end of the study, mean +/- SE), P = NS] or sodium nitroprusside (endothelium-independent vasodilation) (69 +/- 8 vs 64 +/- 12, P = NS). There was also a negligible response after the iontophoresis of 5% NaCl (3 +/- 4) and deionized water (6 +/- 4) in anodal mode (the mode employed for the iontophoresis of acetylcholine). In cathodal mode, employed for the iontophoresis of sodium nitroprusside, the response to 5% NaCl was still negligible but a considerable response was found after the iontophoresis of deionized water. In normal healthy subjects, aspirin administration has no effect on forearm skin microvascular reactivity, including both endothelium-dependent and endothelium-independent vasodilation. In addition, a NaCl solution would be preferable to deionized water as the iontophoresis solution vehicle.     

Plasma pituitary adenylate cyclase activating polypeptide (PACAP) levels in chronic hepatitis B patients under lamivudine treatment

OBJECTIVE: Lamivudine is a nucleoside analogue with potent antiviral activity against hepatitis B virus (HBV). Plasma pituitary adenylate cyclase activating polypeptide (PACAP) is a multifunctional neuropeptide that is produced within the lymphoid microenvironment and induces the production of Th2-type cytokines. The aim of our study was to investigate the possible alterations of plasma PACAP-38 levels in chronic hepatitis B (CHB) patients during lamivudine treatment and to compare them with biochemical, virological and histological data. METHODS: Plasma PACAP-38 levels were measured using competitive radio-immune analysis (RIA) in 25 CHB patients before and after completion of a 52-week lamivudine treatment period and in 22 healthy blood donors. Biochemical evaluation was done at baseline and every three months during treatment. Virological evaluation (HBV-DNA) was performed at baseline and at weeks 24 and 52 of treatment. Baseline liver histology was assessed for all patients at the beginning and at week 52 of the study for histological comparison with the pretreatment biopsy, according to the Ishak scoring system. Statistical evaluation of data was done using analysis of variance and Student's t-test. RESULTS: Virological breakthrough was observed in seven (28%) patients at week 52 of treatment. Histological improvement was observed in 21 (84%) CHB patients, despite the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) mutations. Plasma PACAP-38 levels were significantly lower in CHB patients at baseline than in healthy blood donors. Significant elevation of plasma peptide levels was observed in CHB patients after the completion of lamivudine treatment period, even in the subgroup of those who exhibited YMDD variants. CONCLUSION: The elevation of plasma PACAP-38 levels in treated CHB patients following lamivudine-induced elimination of viraemia suggests a possible alteration of T-cellular immune response, resulting in biochemical and histological remission of liver disease, even in patients who exhibited virological breakthrough.     

Operation of the voltage sensor of a human voltage- and Ca2+-activated K+ channel

Voltage sensor domains (VSDs) are structurally and functionally conserved protein modules that consist of four transmembrane segments (S1–S4) and confer voltage sensitivity to many ion channels. Depolarization is sensed by VSD-charged residues residing in the membrane field, inducing VSD activation that facilitates channel gating. S4 is typically thought to be the principal functional component of the VSD because it carries, in most channels, a large portion of the VSD gating charge. The VSDs of large-conductance, voltage- and Ca²⁺-activated K⁺ channels are peculiar in that more gating charge is carried by transmembrane segments other than S4. Considering its “decentralized” distribution of voltage-sensing residues, we probed the BK_Ca VSD for evidence of cooperativity between charge-carrying segments S2 and S4. We achieved this by optically tracking their activation by using voltage clamp fluorometry, in channels with intact voltage sensors and charge-neutralized mutants. The results from these experiments indicate that S2 and S4 possess distinct voltage dependence, but functionally interact, such that the effective valence of one segment is affected by charge neutralization in the other. Statistical-mechanical modeling of the experimental findings using allosteric interactions demonstrates two mechanisms (mechanical coupling and dynamic focusing of the membrane electric field) that are compatible with the observed cross-segment effects of charge neutralization.     

Symptomatic Hyperglycemia in a Patient with Dialysis Ascites

An anuric woman with ascites rapidly developed extreme hyperglycemia and seizures after hemodialysis. During development of hyperglycemia, the decrease in serum sodium concentration (Δ[Na]) was nearly twice the value predicted by a formula accounting for the degree of hyperglycemia and the intracellular-to-extracellular volume ratio. The prediction assumed that ascitic fluid is part of the extracellular volume. Potential contributors to the development of seizures include the rapid development of severe hypertonicity, a remote history of seizure disorder and development of dialysis disequilibrium syndrome. Observations in peritoneal dialysis suggest that fluid with sodium concentration lower than in the ascitic fluid is transferred from the abdominal cavity into the blood during rapid development of hyperglycemia. In this case, Δ[Na], which determines the tonicity level expected after correction of hyperglycemia, resulted from exit of both intracellular and ascitic fluid into the extracellular compartment and, therefore, ascitic fluid functions as an extension of the intracellular fluid.