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New Cu(II), Ni(II), Co(II), Fe(II), and Mn(II) metal complexes of buparvaquone {3-trans(4-tert.-butylcyclohexyl)methyl-2-hydroxy-1,4-naphthoquione) (L1H) have been synthesized and characterized using IR, electron paramagnetic resonance (EPR) spectroscopy, microanalytical methods and single crystal X-ray diffraction methods. The single crystal structures were determined for ligand L1H [space group P-1 with a=6.2072(14) A˚, b=10.379 (2) A˚, c=13.840 (3) A˚, V=878.7(3) A˚3, Z=2, Dcalcd.=1.234 mg/m3] and copper complex [Cu(L1)2(C2H5OH)2] C1 [space group I2/a with a=17.149(14) A˚, b=9.4492(8) A˚, c=26.946(3) A˚, V=4335.3(7)A˚3, Z=4, Dcalcd.=1.233 mg/m3]. All the metal complexes along with the parent ligand have been studied for their electrochemical properties using cyclic voltammetric techniques. The compounds were tested for their in vitro antimalarial activity against Plasmodium falciparum strains. A correlation between the antimalarial activity and the redox property of these complexes is presented. The ocpper complex C1 exhibits significantly higher growth inhibitory activity both in vitro and in vivo than the parent ligand. [Copyright &y& Elsevier]

Two novel hypolipidaemic agents, both members of the aminopyrimidine series, with a mode of action of inhibition of oxidosqualene cyclase (OSC), were administered orally to dogs and mice for 14 and 28 days. Both compounds produced a similar spectrum of pathologic changes. In dogs, the agents produced equatorial single cell necrosis and cataract in the lens (also observed clinically); atrophy, ulceration, and inflammation of the cornea; hyperkeratosis, acanthosis, hair papillary atrophy, and inflammation of the skin; and epithelial degeneration and sperm granuloma in the epididymides. One female dog showed signs of liver toxicity. In mice, severe cataract formation was seen with both compounds, and liver toxicity was produced by one of the compounds. The severity and speed of onset of the cataract formation were very marked. The changes seen were dissimilar to those reported with the most commonly used class of hypolipidaemic agents in the clinic, the hydroxymethyl glutaryl coenzyme A (HMGCoA) reductase inhibitors but were reminiscent of those reported for the hypolipidaemic agent Triparanol, which was predictive of toxicity seen in man. [ABSTRACT FROM AUTHOR]

Objective: The primary objectives of this study are to (1) compare the inter- and intra-observer reliability of thoracic limb circumference measurement methods in sound dogs, and (2) determine the most reliable thoracic limb positioning and location on the thoracic limb for performing circumferential measurements., Methods: Thoracic limbs of 10 apparently sound dogs (20 limbs) were blindly and independently measured by 3 observers. Triplicate measurements were performed with dogs in lateral recumbency at 50 and 70% brachial (Br) length (length between the greater tubercle and lateral humoral epicondyle) and 25% ABr length (length between the lateral humeral epicondyle and ulnar styloid process), both with the elbow extended and at an approximate weight-bearing (WB) angle. Intra-class correlation coefficients (ICC) with a 95% confidence interval (CI) were used for data analysis with a p  < 0.05 being significant., Results: All measures had significantly good to excellent intra- (ICC 0.836-0.994, p  < 0.001) and inter-observer reliability (ICC 0.834-0.996, p  < 0.001). Inter-observer reliability was excellent at 25% ABr extended and WB positions, and at 50% Br WB position, with a wider confidence interval at the latter location. Intra-observer reliability was excellent across all observers for 25% ABr extended and WB, and 50% Br WB positions, also with a wider confidence interval at the latter location., Conclusion: Circumferential measurement of the canine thoracic limb was most reliable at 25% ABr length with the elbow either in an extended or WB position., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Deabold, Harriz, Madeiros, Davies, Shmalberg and Miscioscia.)

Pain demands attention, yet pain can be reduced by focusing attention elsewhere. The neural processes involved in this robust psychophysical phenomenon, attentional analgesia, are still being defined. Our previous fMRI study linked activity in the brainstem triad of locus coeruleus (LC), rostral ventromedial medulla (RVM) and periaqueductal grey (PAG) with attentional analgesia. Here we identify and model the functional interactions between these regions and the cortex in healthy human subjects (n = 57), who received painful thermal stimuli whilst simultaneously performing a visual attention task. RVM activity encoded pain intensity while contralateral LC activity correlated with attentional analgesia. Psycho-Physiological Interaction analysis and Dynamic Causal Modelling identified two parallel paths between forebrain and brainstem. These connections are modulated by attentional demand: a bidirectional anterior cingulate cortex (ACC) - right-LC loop, and a top-down influence of task on ACC-PAG-RVM. By recruiting discrete brainstem circuits, the ACC is able to modulate nociceptive input to reduce pain in situations of conflicting attentional demand., (Copyright © 2020. Published by Elsevier Inc.)

Previous human imaging studies manipulating attention or expectancy have identified the periaqueductal gray (PAG) as a key brainstem structure implicated in endogenous analgesia. However, animal studies indicate that PAG analgesia is mediated largely via caudal brainstem structures, such as the rostral ventromedial medulla (RVM) and locus coeruleus (LC). To identify their involvement in endogenous analgesia, we used brainstem optimized, whole-brain imaging to record responses to concurrent thermal stimulation (left forearm) and visual attention tasks of titrated difficulty in 20 healthy subjects. The PAG, LC, and RVM were anatomically discriminated using a probabilistic atlas. Pain ratings disclosed the anticipated analgesic interaction between task difficulty and pain intensity ( p < 0.001). Main effects of noxious thermal stimulation were observed across several brain regions, including operculoinsular, primary somatosensory, and cingulate cortices, whereas hard task difficulty was represented in anterior insular, parietal, and prefrontal cortices. Permutation testing within the brainstem nuclei revealed the following: main effects of task in dorsal PAG and right LC; and main effect of temperature in RVM and a task × temperature interaction in right LC. Intrasubject regression revealed a distributed network of supratentorial brain regions and the RVM whose activity was linearly related to pain intensity. Intersubject analgesia scores correlated to activity within a distinct region of the RVM alone. These results identify distinct roles for a brainstem triumvirate in attentional analgesia: with the PAG activated by attentional load; specific RVM regions showing pronociceptive and antinociceptive processes (in line with previous animal studies); and the LC showing lateralized activity during conflicting attentional demands. SIGNIFICANCE STATEMENT Attention modulates pain intensity, and human studies have identified roles for a network of forebrain structures plus the periaqueductal gray (PAG). Animal data indicate that the PAG acts via caudal brainstem structures to control nociception. We investigated this issue within an attentional analgesia paradigm with brainstem-optimized fMRI and analysis using a probabilistic brainstem atlas. We find pain intensity encoding in several forebrain structures, including the insula and attentional activation of the PAG. Discrete regions of the rostral ventromedial medulla bidirectionally influence pain perception, and locus coeruleus activity mirrors the interaction between attention and nociception. This approach has enabled the resolution of contributions from a hub of key brainstem structures to endogenous analgesia., (Copyright © 2017 Brooks, Davies et al.)