A UK Single-Center, Retrospective, Noninterventional Study of Clinical Outcomes and Costs of Two BotulinumtoxinA Treatments for Limb Spasticity.

Service model changes at the North Staffordshire Rehabilitation Centre (UK) included switching spasticity treatment from onabotulinumtoxinA (onaBoNT-A) to abobotulinumtoxinA (aboBoNT-A). This noninterventional, retrospective, longitudinal study (NCT04396704) describes the clinical and economic outcomes in toxin-naive adults with spasticity who received onaBoNT-A (Cohort 1; 2015-2017) or aboBoNT-A (Cohort 2; 2017-2019). Outcomes included Goal Attainment Scale T (GAS-T) score, treatment satisfaction, quality of life (QoL; EQ-5D visual analog scale [VAS] score), and treatment costs.

Testosterone-mediated modulation of HERG blockade by proarrhythmic agents.

Diverse drugs from many therapeutic classes exert cardiotoxic side effects by inducing torsades de pointes (TdP), a life threatening cardiac arrhythmia, which often results from drug interaction with HERG (human ether-a-go-go related gene) encoded K(+) channels, that generate an I(Kr) component of the delayed rectifier cardiac K(+) current. Men are known to be at a lower risk for drug-induced TdP than women suggesting a role of sex steroid hormones, androgens and estrogens, in modulation of drug sensitivity of cardiac K(+) channels, particularly those encoded by HERG. Here by using neuroleptic agents haloperidol, pimozide, and fluspirilene, all of which can induce TdP, and a steroid hormone-sensitive system Xenopus oocytes for HERG channels expression we show that testosterone is able to reduce HERG-blocking potency of neuroleptics.

[Blockade of HERG K+ channels expressed in Xenopus oocytes by antipsychotic agents].

We have investigated the effects of neuroleptic agents, haloperidol, pimozide and fluspirilen, that are used in clinics to treat psychiatric disorders, but reportedly have proarrhythmic side effects, on HERG-encoded K+ channels responsible for the rapid component of cardiac delayed rectifier K+ current, IKr. All three agents blocked HERG-directed IKr in Xenopus oocytes in a voltage-dependent manner. The extent of the blockade increased with depolarization correlating with channels activation consistent with open-channel blocking mechanism.

Syntaxin modulation of slow inactivation of N-type calcium channels.

Syntaxin, a membrane protein vital in triggering vesicle fusion, interacts with voltage-gated N- and P/Q-type Ca(2+) channels. This biochemical association is proposed to colocalize Ca(2+) channels and presynaptic release sites, thus supporting rapid and efficient initiation of neurotransmitter release. The syntaxin channel interaction may also support a novel signaling function, to modulate Ca(2+) channels according to the state of the associated release machinery (Bezprozvanny et al.

[Bone tumors and androgen metabolism].

The paper provides data of comparative assessment of activity of the key enzymes in metabolism of androgens in various morphological variants of sarcomas and benign bone tumors in 46 patients within the age range from 15 to 61, which were under treatment in the ORC named after N. N. Blokhin, RAMS, from 1996 to 1997.

[Metabolism of androgens in various histological variants of bone tumors].

The role of androgens in human normal and neoplastic bone tissues is still unclear. The paper presents data on metabolism of androgens in homogenates of malignant (osteosarcoma, chondrosarcoma, Ewing and giant cell) and benign primary tumors from 46 male and female patients aged 14-58 years. Using two substrates (testosterone and 5 alpha-dihydrotestosterone) for the first time are shown activities of main enzymes of androgen metabolism in all tumor types.

[Reduction of 5alpha-dehydrotestosterone in sex steroid target cells--catabolism or directed biotransformation into hormones?].

Based on analysis of the published experimental data, we propose a hypothetical mechanism of action of two androgens, 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-diol) and 5 alpha-androstane-3 beta,17 beta-diol (3 beta-diol), which are produced when 5 alpha-dihydrotestosterone (DHT) is reduced in sex steroids target cells. The mode of action of these diols as regulatory factors assumes that the androgens possess autocrine, paracrine, and endocrine action that differs from the action of DHT in animals and man and do not merely represent catabolites or metabolites capable of controlling the level of true androgenic hormone DHT. It is proposed that both diols should be classified as parahormones.

Receptors couple to L-type calcium channels via distinct Go proteins in rat neuroendocrine cell lines.

1. The present study examines the hypothesis of G protein subtype selectivity in receptor-induced inhibition of calcium channel currents (ICa) in the insulin-secreting RINm5F and pituitary GH3 rat cell lines. Specificity of receptor coupling to G proteins was studied by infusion of purified G alpha isoforms into cells via a patch pipette.

Calcium channel block by (-)devapamil is affected by the sequence environment and composition of the phenylalkylamine receptor site.

The pore-forming alpha 1 subunit of L-type calcium (Ca2+) channels is the molecular target of Ca2+ channel blockers such as phenylalkylamines (PAAs). Association and dissociation rates of (-)devapamil were compared for a highly PAA-sensitive L-type Ca2+ channel chimera (Lh) and various class A Ca2+ channel mutants. These mutants carry the high-affinity determinants of the PAA receptor site in a class A sequence environment.

Transfer of high sensitivity for benzothiazepines from L-type to class A (BI) calcium channels.

To investigate the molecular basis of the calcium channel block by diltiazem, we transferred amino acids of the highly sensitive and stereoselective L-type (alpha1S or alpha1C) to a weakly sensitive, nonstereoselective class A (alpha1A) calcium channel. Transfer of three amino acids of transmembrane segment IVS6 of L-type alpha1 into the alpha1A subunit (I1804Y, S1808A, and M1811I) was sufficient to support a use-dependent block by diltiazem and by the phenylalkylamine (-)-gallopamil after expression in Xenopus oocytes. An additional mutation F1805M increased the sensitivity for (-)-gallopamil but not for diltiazem.

Transfer of L-type calcium channel IVS6 segment increases phenylalkylamine sensitivity of alpha1A.

Conditioned ("use-dependent") inhibition by phenylalkylamines (PAAs) is a characteristic property of L- type calcium (Ca2+) channels. To determine the structural elements of the PAA binding domain we transferred sequence stretches of the pore-forming regions of repeat III and/or IV from the skeletal muscle alpha1 subunit (alpha1S) to the class A alpha1 subunit (alpha1A and expressed these chimeras together with beta1a and alpha2/delta subunits in Xenopus oocytes. The corresponding barium currents (IBa) were tested for PAA sensitivity during trains of depolarizing test pulses (conditioned block).

A specific G(o) heterotrimer couples somatostatin receptors to voltage-gated calcium channels in RINm5F cells.

The peptide hormone somatostatin inhibits glucose-induced insulin secretion in the rat insulinoma RINm5F cells by inhibition of voltage-gated calcium channels. Here we used micro-injection of antisense oligonucleotides directed against subtypes of G-protein subunits to determine the subunit composition involved in somatostatin-induced inhibition of voltage-gated calcium channels in RINmF5 cells. Injection of antisense oligonucleotides annealing to the respective mRNA of G alpha o2, G beta 1 and G gamma 3 reduced the somatostatin-induced inhibition of calcium channels in these cells.

Ca(2+)-permeable large-conductance nonselective cation channels in rat basophilic leukemia cells.

Spreading of Ca2+ signals in rat basophilic leukemia (RBL) cells occurs by release of ATP. Therefore we studied the effect of ATP on membrane currents. ATP (1-10 microM) activated large-conductance channels.

Subunit composition of G(o) proteins functionally coupling galanin receptors to voltage-gated calcium channels.

The neuropeptide galanin is widely expressed in the central nervous system and other tissues and induces different cellular reactions, e.g. hormone release from pituitary and inhibition of insulin release from pancreatic B cells.

Effects of haloperidol and chlorpromazine on smooth muscle contractility, platelet aggregation and neuronal calcium current.

Effects of chlorpromazine, haloperidol (neuroleptics and calmodulin antagonists), and verapamil on rat platelet aggregation induced by thrombin, on calcium current in snail neurones and on both tonic tension of high potassium contracture and phasic contraction of isolated guinea-pig ureter preparations were studied. Moreover, droperidol, sulpiride and prazosine effects were studied for models of phasic contractility and platelet aggregation. Sulpiride and prazosine were ineffective, verapamil was ineffective on platelet aggregation, while droperidol was the most potent inhibitor of platelet aggregation.

[Protein determination by binding with the dye Coomassie brilliant blue G-250].

Possible applications of the Coomassie brilliant blue G-250 dye method for protein assay are reviewed. The physico-chemical and optical properties of the dye are considered in detail. The data on the protein-binding mechanism are generalized.

The isoquinoline derivative LOE 908 selectively blocks vasopressin-activated nonselective cation currents in A7r5 aortic smooth muscle cells.

The effect of (R,S)-(3,4-dihydro 6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl- N,N-di-[2-(2,3,4-trimethoxyphenyl)ethyl]-acetamide (LOE 908), a cation channel blocker in HL-60 promyeloblasts, was studied in the A7r5 smooth muscle cell line from rat thoracic aorta, using the whole-cell patch-clamp technique. At a holding potential of -60 mV, application of vasopressin induced a nonselective cation conductance in voltage-clamped A7r5 cells. The current-voltage relation was linear, and currents reversed close to 0 mV regardless of the chloride gradient.

[Combined action of gamma and UHF radiation on conditioned reflex behavior of rats].

Dynamics of the conditioned behaviour of rats in a shuttle box was studied after combined exposure to Cs-gamma radiation (1 Gy, 1.32 Gy/min) and microwave radiation (2450 MHz, 1 mW/cm2, 3 h). The number of conditioned and interstimulus responses was found to decrease on day 5 after microwave + gamma irradiation and to increase on day 30 after gamma + microwave irradiation.