The increased severity of acute pancreatitis in the elderly is mainly related to intestinal barrier dysfunction

正To the Editor:Severeacutepancreatitisintheelderlyischaracterizedby significantmorbidityandmortalityrates,withahigherfinancial impact when compared to the same disease in younger patients [1]. There are some obvious differences between these two populations. The most glaring one is the presence of multiple co-     

VCAM-1 specific PEGylated SAINT-based lipoplexes deliver siRNA to activated endothelium in vivo but do not attenuate target gene expression

In recent years much research in RNA nanotechnology has been directed to develop an efficient and clinically suitable delivery system for short interfering RNA (siRNA). The current study describes the in vivo siRNA delivery using PEGylated antibody-targeted SAINT-based-lipoplexes (referred to as antibody-SAINTPEGarg/PEG2%), which showed superior siRNA delivery capacity and effective down-regulation of VE-cadherin gene expression in vitro in inflammation-activated primary endothelial cells of different vascular origins. PEGylation of antibody-SAINTPEGarg resulted in more desirable pharmacokinetic behavior than that of non-PEGylated antibody-SAINTPEGarg. To create specificity for inflammation-activated endothelial cells, antibodies against vascular cell adhesion molecule-1 (VCAM-1) were employed. In TNFα-challenged mice, these intravenously administered anti-VCAM-1-SAINTPEGarg/PEG2% homed to VCAM-1 protein expressing vasculature. Confocal laser scanning microscopy revealed that anti-VCAM-1-SAINTPEGarg/PEG2% co-localized with endothelial cells in lung postcapillary venules. Furthermore, they did not exert any liver and kidney toxicity. Yet, lack of in vivo gene silencing as assessed in whole lung and in laser microdissected lung microvascular segments indicates that in vivo internalization and/or intracellular trafficking of the delivery system and its cargo in the target cells are not sufficient, and needs further attention, emphasizing the essence of evaluating siRNA delivery systems in an appropriate in vivo animal model at an early stage in their development.     

Environmental and Pharmacological Modulation of Amphetamine-Induced 50-kHz Ultrasonic Vocalizations in Rats

Rats emit high-frequency 50-kHz ultrasonic vocalizations (USV) in appetitive situations like social interactions. Drugs of abuse are probably the most potent non-social elicitors of 50-kHz USV, possibly reflecting their euphorigenic properties. Psychostimulants induce the strongest elevation in 50-kHz USV emission, particularly amphetamine (AMPH), either when applied systemically or locally into the nucleus accumbens (Nacc). Emission of AMPH-induced 50-kHz USV depends on test context, such as the presence of conspecifics, and can be manipulated pharmacologically by targeting major neurotransmitter systems, including dopamine (DA), noradrenaline (NA), and serotonin (5-HT), but also protein kinase C (PKC) signaling. Several D₁ and D₂ receptor antagonists, as well as typical and atypical antipsychotics block the AMPH-induced elevation in 50-kHz USV. Inhibiting D₁ and D₂ receptors in the Nacc abolishes AMPH-induced 50-kHz USV, indicating a key role for this brain area. NA neurotransmission also regulates AMPH-induced 50-kHz USV emission given that α₁ receptor antagonists and α₂ receptor agonists exert attenuating effects. Supporting the involvement of the 5-HT system, AMPH-induced 50-kHz USV are attenuated by 5-HT_2C receptor activation, whereas 5-HT_2C receptor antagonism leads to the opposite effect. Finally, treatment with lithium, tamoxifen, and myricitrin was all found to result in a complete abolishment of the AMPH-induced increase in 50-kHz USV, suggesting the involvement of PKC signaling. Neurotransmitter systems involved in AMPH-induced 50-kHz USV emission only partially overlap with other AMPH-induced behaviors like hyperlocomotion. The validity of AMPH-induced 50-kHz USV as a preclinical model for neuropsychiatric disorders is discussed, particularly with relevance to altered drive and mood seen in bipolar disorder.     

Mechanical behavior of fixation components for periprosthetic fracture surgery

BackgroundReliable periprosthetic fracture treatment needs detailed knowledge on the mechanical behavior of the fixation components used. The holding capacity of three conventional fixation components for periprosthetic fracture treatment was systematically investigated under different loading directions.MethodsLocking compression plates were fixed to a 7 cm long part of diaphyseal fresh frozen human femur with either a single 1.7 mm cerclage cable, a 5.0 mm monocortical or a bicortical locking screw (n = 5 per group). Constructs were loaded in lateral, torsional and axial direction with respect to the bone axis in a load-to-failure test. Corresponding stress distribution around the screw holes was analyzed by finite element modeling.FindingsBoth screw fixations revealed significantly higher stiffness and ultimate strength in axial compression and torsion compared to the cerclage (all P < 0.01). Ultimate strength in lateral loading and torsion was significantly higher for bicortical screws (mean 3968 N SD 657; mean 28.8 Nm SD 5.9) compared to monocortical screws (mean 2748 N SD 585; mean 14.4 Nm SD 5.7 Nm) and cerclages (mean 3001 N SD 252; mean 3.2 Nm SD 2.0) (P ≤ 0.04). Stress distribution around the screw hole varied according to the screw type and load direction.InterpretationFixation components may be combined according to their individual advantages to achieve an optimal periprosthetic fracture fixation.     

The multiple facets of drug resistance: one history,different approaches

Some cancers like melanoma and pancreatic and ovarian cancers, for example, commonly display resistance to chemotherapy, and this is the major obstacle to a better prognosis of patients. Frequently, literature presents studies in monolayer cell cultures, 3D cell cultures or in vivo studies, but rarely the same work compares results of drug resistance in different models. Several of these works are presented in this review and show that usually cells in 3D culture are more resistant to drugs than monolayer cultured cells due to different mechanisms. Searching for new strategies to sensitize different tumors to chemotherapy, many methods have been studied to understand the mechanisms whereby cancer cells acquire drug resistance. These methods have been strongly advanced along the years and therapies using different drugs have been increasingly proposed to induce cell death in resistant cells of different cancers. Recently, cancer stem cells (CSCs) have been extensively studied because they would be the only cells capable of sustaining tumorigenesis. It is believed that the resistance of CSCs to currently used chemotherapeutics is a major contributing factor in cancer recurrence and later metastasis development. This review aims to appraise the experimental progress in the study of acquired drug resistance of cancer cells in different models as well as to understand the role of CSCs as the major contributing factor in cancer recurrence and metastasis development, describing how CSCs can be identified and isolated.