Snail peptide expression pattern in the nervous system of the medicinal leech

Distribution of neurons immunopositive to antibodies against the "command neuron peptides" (CNPs) encoded by the snail Helix Command-Specific 2 (HCS2) gene was investigated in the nervous system of medicinal leech Hirudo. Immunopositive neurons were found in the leech segmental ganglia, brain and tail ganglionic masses, and peripheral ganglia. The CNPs immunopositive fibers were observed in neuropils of all ganglia and in some nerves. The role of CNPs immunopositive cells in animal behavior and the putative functions of the CNPs neuropeptide family are discussed.     

Effects of fluorine-containing opener of ATP-sensitive potassium channels, pinacidil-derivative flocalin, on cardiac voltage-gated sodium and calcium channels

Fluorine-containing pinacidil-derivative flocalin is an effective adenosine triphosphate-sensitive potassium (K_ATP)-channel opener with pronounced vasodilatory, cardioprotective effects and low general toxicity. By activating cardiac K_ATP channels, flocalin hyperpolarizes cardiac myocytes, decreases their excitability, reduces Ca²⁺ entry, and inhibits Ca²⁺-dependent signalling processes. Since our previous studies indicated that the drug also influences the rate of rise and amplitude of the cardiomyocyte’s action potential, here we have investigated its possible actions on depolarizing inward currents through voltage-gated sodium (VGSC) and L-type calcium (VGCC) channels. Experiments were conducted on cultured cardiac myocytes prepared from the whole hearts of neonatal rats and maintained in culture for 1–3?days using whole-cell patch-clamp technique with no distinction of myocyte’s type. Flocalin concentration dependently inhibited the Na⁺ inward current through VGSCs with IC₅₀?=?17.4?μM and a maximal extent of 0.54, slowed down its inactivation kinetics, and hyperpolarized steady-state inactivation by 5.6?mV. The drug also inhibited calcium current through L-type VGCCs with IC₅₀?=?24.1?μM and a maximal block of 0.38, without affecting its inactivation but producing 5.3-mV hyperpolarization shifting of steady-state activation. Inhibition of both depolarizing currents by flocalin in addition to its ability to open K_ATP channels enhances the suppressive action of the drug on cardiac excitability and broadens its pharmacological effects. Since, according to our previous data, cardiac K_ATP-channel opening by flocalin occurs with ЕC₅₀?=?8?μM, the possibility of partial blockade of VGSC and L-type VGCCs should be considered when determining the therapeutic concentrations of the compound during its use as a cardioprotector.     

Pulmonary pattern in systemic vasculitis: granulomatosis,lung cancer or both?

As clinical manifestations of systemic vasculitides share many common features with other conditions, the rate of diagnostic errors and delayed diagnoses is high. Hence we performed an analysis of the available data regarding misdiagnosis of vasculitis as lung cancer and vice versa, as well as coexistence of vasculitis and lung cancer. The present case-based review highlights the diagnostic challenges encountered when granulomatosis with polyangiitis (GPA) mimics lung cancer. The importance of a multidisciplinary team approach to patients with pulmonary involvement and multisystem manifestations is essential for appropriate planning of further diagnostic steps and for minimizing the delay in correct diagnosis and treatment. In the present case, although computed tomography raised suspicion for lung cancer, further biopsies and laboratory screening for systemic vasculitides rejected malignancy and confirmed the diagnosis of GPA.     

Regulation of transmitter release by Ca(2+) and synaptotagmin: insights from a large CNS synapse

Transmitter release at synapses is driven by elevated intracellular Ca(2+) concentration ([Ca(2+)](i)) near the sites of vesicle fusion. [Ca(2+)](i) signals of profoundly different amplitude and kinetics drive the phasic release component during a presynaptic action potential, and asynchronous release at later times. Studies using direct control of [Ca(2+)](i) at a large glutamatergic terminal, the calyx of Held, have provided significant insight into how intracellular Ca(2+) regulates transmitter release over a wide concentration range. Synaptotagmin-2 (Syt2), the major isoform of the Syt1/2 Ca(2+) sensors at these synapses, triggers highly Ca(2+)-cooperative release above 1μM [Ca(2+)](i), but suppresses release at low [Ca(2+)](i). Thus, neurons utilize a highly sophisticated release apparatus to maximize the dynamic range of Ca(2+)-evoked versus spontaneous release.     

Synthesis and Anti-Platelet Activity of Thiosulfonate Derivatives Containing a Quinone Moiety

Thiosulfonate derivatives based on quinones were synthesized for studying “structure-activity relationship” compounds with an acylated and a free amino-group. Anti-platelet activity of the synthesized compounds was determined and the influence of substituents on the activity of the derivatives was assessed.     

Cardiotoxicity of anticancer treatments: Epidemiology,detection, and management

Answer questions and earn CME/CNE Cancer and heart disease are the leading causes of morbidity and mortality in the industrialized world. Modern treatment strategies have led to an improvement in the chances of surviving a diagnosis of cancer; however, these gains can come at a cost. Patients may experience adverse cardiovascular events related to their cancer treatment or as a result of an exacerbation of underlying cardiovascular disease. With longer periods of survival, late effects of cancer treatment may become clinically evident years or decades after completion of therapy. Current cancer therapy incorporates multiple agents whose deleterious cardiac effects may be additive or synergistic. Cardiac dysfunction may result from agents that can result in myocyte destruction, such as with anthracycline use, or from agents that appear to transiently affect left ventricular contractility. In addition, cancer treatment may be associated with other cardiac events, such as severe treatment‐induced hypertension and vasospastic and thromboembolic ischemia, as well as rhythm disturbances, including QTc prolongation, that may be rarely life‐threatening. Early and late effects of chest radiation can lead to radiation‐induced heart disease, including pericardial disease, myocardial fibrosis, cardiomyopathy, coronary artery disease, valvular disease, and arrhythmias, in the setting of myocardial fibrosis. The discipline of cardio‐oncology has developed in response to the combined decision making necessary to optimize the care of cancer patients, whether they are receiving active treatment or are long‐term survivors. Strategies to prevent or mitigate cardiovascular damage from cancer treatment are needed to provide the best cancer care. This review will focus on the common cardiovascular issues that may arise during or after cancer therapy, the detection and monitoring of cardiovascular injury, and the best management principles to protect against or minimize cardiotoxicity during the spectrum of cancer treatment strategies. CA Cancer J Clin 2016;66:309‐325. © 2016 American Cancer Society .     

Cost-Effectiveness Analysis of 12-Versus 4-Weekly Administration of Bone-Targeted Agents in Patients with Bone Metastases from Breast and Castration-Resistant Prostate Cancer

A cost–utility analysis was performed based on the Rethinking Clinical Trials (REaCT) bone-targeted agents (BTA) clinical trial that compared 12-weekly (once every 12 weeks) (n = 130) versus 4-weekly (once every 4 weeks) (n = 133) BTA dosing for metastatic breast and castration-resistant prostate (CRPC) cancer. Using a decision tree model, we calculated treatment and symptomatic skeletal event (SSE) costs as well as quality-adjusted life-years (QALYs) for each treatment option. Deterministic and probabilistic sensitivity analyses were performed to assess the robustness of the study findings. The total cost of BTA treatment in Canadian dollars (C$) and estimated QALYs was C$8965.03 and 0.605 QALY in the 4-weekly group versus C$5669.95 and 0.612 QALY in the 12-weekly group, respectively. De-escalation from 4-weekly to 12-weekly BTA reduces cost (C$3293.75) and improves QALYs by 0.008 unit, suggesting that 12-weekly BTA dominates 4-weekly BTA in breast and CRPC patients with bone metastases. Sensitivity analysis suggests high levels of uncertainty in the cost-effectiveness findings. De-escalation of bone-targeted agents is cost-effective from the Canadian public payer’s perspective.     

Sarcolemmal cardiac K(ATP) channels as a target for the cardioprotective effects of the fluorine-containing pinacidil analogue, flocalin

BACKGROUND AND PURPOSE

A class of drugs known as K_ATP-channel openers induce cardioprotection. This study examined the effects of the novel K_ATP-channel opener, the fluorine-containing pinacidil derivative, flocalin, on cardiac-specific K_ATP-channels, excitability of native cardiac myocytes and on the ischaemic heart.

EXPERIMENTAL APPROACH

The action of flocalin was investigated on: (i) membrane currents through cardiac-specific K_ATP-channels (I_KATP) formed by K_IR6.2/SUR2A heterologously expressed in HEK-293 cells (HEK-293_6.2/2A); (ii) excitability and intracellular Ca²⁺ ([Ca²⁺]_i) transients of cultured rat neonatal cardiac myocytes; and (iii) functional and ultrastructural characteristics of isolated guinea-pig hearts subjected to ischaemia-reperfusion.

KEY RESULTS

Flocalin concentration-dependently activated a glibenclamide-sensitive I_KATP in HEK-293_6.2/2A cells with an EC₅₀ = 8.1 ± 0.4 µM. In cardiac myocytes, flocalin (5 µM) hyperpolarized resting potential by 3–5 mV, markedly shortened action potential duration, reduced the amplitude of [Ca²⁺]_i transients by 2–3-fold and suppressed contraction. The magnitude and extent of reversibility of these effects depended on the type of cardiac myocytes. In isolated hearts, perfusion with 5 µmol·L⁻¹ flocalin, before inducing ischaemia, facilitated restoration of contraction during reperfusion, decreased the number of extrasystoles, prevented the appearance of coronary vasoconstriction and reduced damage to the cardiac tissue at the ultrastructural level (state of myofibrils, membrane integrity, mitochondrial cristae structure).

CONCLUSION AND IMPLICATIONS

Flocalin induced potent cardioprotection by activating cardiac-type K_ATP-channels with all the benefits of the presence of fluorine group in the drug structure: higher lipophilicity, decreased toxicity, resistance to oxidation and thermal degradation, decreased metabolism in the organism and prolonged therapeutic action.