A disalicylic acid-furanyl derivative inhibits ephrin binding to a subset of Eph receptors

Eph receptor tyrosine kinases and ephrin ligands control many physiological and pathological processes, and molecules interfering with their interaction are useful probes to elucidate their complex biological functions. Moreover, targeting Eph receptors might enable new strategies to inhibit cancer progression and pathological angiogenesis as well as promote nerve regeneration. Because our previous work suggested the importance of the salicylic acid group in antagonistic small molecules targeting Eph receptors, we screened a series of salicylic acid derivatives to identify novel Eph receptor antagonists. This identified a disalicylic acid-furanyl derivative that inhibits ephrin-A5 binding to EphA4 with an IC(50) of 3 μm in ELISAs. This compound, which appears to bind to the ephrin-binding pocket of EphA4, also targets several other Eph receptors. Furthermore, it inhibits EphA2 and EphA4 tyrosine phosphorylation in cells stimulated with ephrin while not affecting phosphorylation of EphB2, which is not a target receptor. In endothelial cells, the disalicylic acid-furanyl derivative inhibits EphA2 phosphorylation in response to TNFα and capillary-like tube formation on Matrigel, two effects that depend on EphA2 interaction with endogenous ephrin-A1. These findings suggest that salicylic acid derivatives could be used as starting points to design new small molecule antagonists of Eph receptors.     

Emerging issues in smoking among adolescent and adult cancer survivors: a comprehensive review

The number of cancer survivors is significantly increasing, thereby prioritizing the importance of identifying and preventing adverse health outcomes within this high-risk population. Cigarette smoking is of particular salience as it places both adolescents and adults with a cancer history at risk for various health problems, including second malignancies. The purpose of this article is to provide a comprehensive review of the smoking literature as it relates to adolescents and adults on-treatment and surviving cancer. In particular, the article reviews the prevalence, risk factors, and health outcomes associated with smoking, in addition to the prevention and smoking cessation interventions available to adolescent and adult oncology patients. Furthermore, efficacious cessation strategies have recently emerged from the smoking literature in healthy populations, and their application to oncology populations is discussed.     

Remifentanil at induction of general anesthesia for cesarean section: Double blind,randomized clinical trial

Introduction:

Remifentanil, with its rapid activity onset and short duration of action, may be more effective than other opioids for providing hemodynamic stability during obstetric anesthesia. However, there is some evidence of adverse effects on neonatal respiratory function. We investigated maternal and fetal effects of Remifentanil during cesarean section surgery.

Methods:

Eighteen women with singleton term pregnancies, and physical class status of I or II as defined by the American Society of Anesthesia (ASA), who were undergoing general anesthesia for semi-elective cesarean section were randomized into two groups (40 in each group) that received either an intravenous bolus of 0.5 µg/kg Remifentanil or the same dose of saline as a placebo. Maternal hemodynamic variables and neonatal umbilical artery pH and Apgar score at first and fifth min were evaluated in both groups.

Results:

Systolic and diastolic blood pressure were significantly lower after tracheal intubation and skin incision in the Remifentanil group as compared with the control group (p <0.05). There were no significant differences regarding heart rate between groups at any time (p > 0.05). Apgar scores at first and fifth min were not significantly different among groups (p>0.05). No neonate required assisted ventilation or naloxan administration.

Conclusion:

Remifentanil may be a safe and effective drug for the induction of general anesthesia and surgical stimulation without subsequent neonatal depression.     

The influence of the haemodialysis procedure on platelets, coagulation and fibrinolysis

In end-stage renal disease, in particularly when treated with haemodialysis, the function of platelets, coagulation and fibrinolytic systems can be disturbed, thus contributing to either thrombotic or bleeding complications. It is important to know whether the currently used haemodialysis procedure itself (by biocompatible membranes and better anticoagulation with nandroparin) affects platelets, coagulation or fibrinolysis. In 15 patients who had been treated with chronic haemodialysis, we measured and compared platelet aggregation (induced by adenosine diphosphate, collagen and epinephrine), the markers of coagulation and fibrinolysis activation (thrombin-antithrombin complexes, thrombin fragments F1+2, D-dimer), and fibrinolytic parameters, i.e. fibrinogen, plasminogen, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 antigen and activity, before and immediately after the regular haemodialysis sessions. We did not find differences between pre- and post-haemodialysis platelet aggregation induced with all agents. Markers of coagulation and fibrinolysis activation remained unchanged during the process of haemodialysis. However, in post-haemodialysis samples, t-PA activity was significantly increased. Other fibrinolytic parameters remained unchanged. In conclusion, our results showed that the current technique of haemodialysis procedure does not affect platelet aggregation or activate coagulation, and therefore, does not contribute to a thrombotic tendency. However, it does directly affect fibrinolysis through activation of t-PA, which might be clinically relevant since this could increase the bleeding tendency in some haemodialysis patients.     

A hippocampal interneuron associated with the mossy fiber system

Network properties of the hippocampus emerge from the interaction of principal cells and a heterogeneous population of interneurons expressing gamma-aminobutyric acid (GABA). To understand these interactions, the synaptic connections of different types of interneurons need to be elucidated. Here we describe a type of inhibitory interneuron of the hippocampal CA3 region that has an axon coaligned with the mossy fibers. Whole-cell patch-clamp recordings, in combination with intracellular biocytin filling, were made from nonpyramidal cells of the stratum lucidum under visual control. Mossy fiber-associated (MFA) interneurons generated brief action potentials followed by a prominent after-hyperpolarization. Subsequent visualization revealed an extensive axonal arbor which was preferentially located in the stratum lucidum of CA3 and often invaded the hilus. The dendrites of MFA interneurons were mainly located in the strata radiatum and oriens, suggesting that these cells are primarily activated by associational and commissural fibers. Electron microscopic analysis showed that axon terminals of MFA interneurons established symmetric synaptic contacts predominantly on proximal apical dendritic shafts, and to a lesser degree, on somata of pyramidal cells. Synaptic contacts were also found on GABAergic interneurons of the CA3 region and putative mossy cells of the hilus. Inhibitory postsynaptic currents (IPSCs) elicited by MFA interneurons in simultaneously recorded pyramidal cells had fast kinetics (half duration, 3.6 ms) and were blocked by the GABA(A) receptor antagonist bicuculline. Thus, MFA interneurons are GABAergic cells in a position to selectively suppress the mossy fiber input, an important requirement for the recall of memory traces from the CA3 network.     

Food anthocyanins decrease concentrations of TNF-α in older adults with mild cognitive impairment: A randomized,controlled, double blind clinical trial

Background & aimsVascular function, blood pressure and inflammation are involved in the pathogenesis of major chronic diseases, including both cardiovascular disease (CVD) and mild cognitive impairment (MCI). This study investigated the effects of food anthocyanins on microvascular function, 24-h ambulatory blood pressure (ABP) and inflammatory biomarkers in older adults with MCI.Methods and resultsThirty-one participants with MCI [19 female, 12 male, mean age 75.3 (SD 6.9) years and body mass index 26.1 (SD 3.3) kg/m²], participated in a randomized, controlled, double-blind clinical trial (Australian New Zealand Clinical Trials Registry: ACTRN12618001184268). Participants consumed 250 mL fruit juice daily for 8 weeks, allocated into three groups: a) high dose anthocyanins (201 mg); b) low dose anthocyanins (47 mg); c) control. Microvascular function (Laser Speckle Contrast Imaging combined with a post-occlusive reactive hyperaemia test), 24h ABP and serum inflammatory biomarkers were assessed before and after the nutritional intervention.ResultsParticipants in the high anthocyanins group had a reduction in serum tumor necrosis factor alpha (TNF-α) (P = 0.002) compared to controls and the low anthocyanins group (all P's > 0.05). Serum IL-6, IL-1β, c-reactive protein, and parameters of microvascular function and 24h ABP were not altered by any treatment.ConclusionA daily high dose of fruit-based anthocyanins for 8 weeks reduced concentrations of TNF-α in older adults with MCI. Anthocyanins did not alter other inflammatory biomarkers, microvascular function or blood pressure parameters. Further studies with a larger sample size and longer period of follow-up are required to elucidate whether this change in the immune response will alter CVD risk and progression of cognitive decline.