Biologically Active Amphotericin B-Calix[4]arene Conjugates

In order to provide tools for investigations of amphotericin B ion channels, new conjugates bearing a calix[4]arene scaffold covalently linked to four amphotericin B molecules were synthesized. These macromolecules adopt a cone conformation that mimics the structure of a transmembrane pore. The antifungal activity of the conjugates 3 and 4 was superior or similar to that of native amphotericin B, with minimal inhibitory concentration values of 0.10 and 0.25 microM, respectively. Furthermore, the hemotoxicity of the new conjugates was considerably lower (at least 10 times) than the hemotoxicity of monomeric amphotericin B. Finally, the formation of ion channels in the lipid bilayer by the amphotericin B tetramer was monitored by measuring the K+ efflux from various liposomes

Patient care standards for primary mitochondrial disease in Australia: an Australian adaptation of the Mitochondrial Medicine Society recommendations

This document provides consensus-based recommendations for general physicians and primary care physicians who diagnose and manage patients with mitochondrial diseases (MD). It builds on previous international guidelines, with particular emphasis on clinical management in the Australian setting. This statement was prepared by a working group of medical practitioners, nurses and allied health professionals with clinical expertise and experience in managing Australian patients with MD. As new treatments and management plans emerge, these consensus-based recommendations will continue to evolve, but current standards of care are summarised in this document

Discrimination by SZL49 between contractions evoked by noradrenaline in longitudinal and circular muscle of human vas deferens

1. The effects of irreversible α(1)-adrenoceptor antagonists, SZL-49 (an alkylating analogue of prazosin), dibenamine and benextramine on contractions to noradrenaline (NA) in longitudinal and circular muscle of human epididymal vas deferens were investigated. Competitive α(1)-adrenoceptor antagonists were also used to further characterize the α(1)-adrenoceptor subtype stimulated by NA in longitudinal and circular muscle. 2. NA evoked concentration-dependent contractions of both muscle types (pD(2); 5.4 and 5.2 respectively). The contraction of circular muscle was comparatively more sensitive than that of longitudinal muscle to pretreatment with SZL-49. In contrast, dibenamine or benextramine produced comparable effects in both muscle types. 3. The relationship between receptor occupancy and contraction in either longitudinal or circular muscle was nonlinear, with half-maximal response requiring similar receptor occupancy (longitudinal muscle 14%, circular muscle 16%). Maximal response in both muscle types occurred with little or no receptor reserve (<10%). 4. The competitive α1-adrenoceptor antagonists produced dextral shifts of the dose-response curves to NA in longitudinal and circular muscle. The inhibitory potencies, estimated from the apparent pK(B) values were significantly different in longitudinal and circular muscle respectively for either WB 4101 (pK(B), 8.6 and 9.5) or RS-17053 (pK(B), 7.1 and 9.0) but not for Rec 15/2739 (pK(B), 9.2 and 9.8) or HV 723 (pK(B), 8.3 and 8.4). 5. In conclusion, the potency profile of the competitive α(1)-adrenoceptor antagonists and the lack of different receptor reserves for NA in the muscle types suggest that the discriminatory effects of SZL-49 is primarily due to a predominance of the α(1L)-adrenoceptor subtype in longitudinal muscle and α(1A)-subtype in circular muscle

Epilepsy and Electroencephalographic Abnormalities in SATB2-Associated Syndrome.

Background: Seizures are an under-reported feature of the SATB2-associated syndrome phenotype. We describe the electroencephalographic findings and seizure semiology and treatment in a population of individuals with SATB2-associated syndrome. Methods: We performed a retrospective review of 101 individuals with SATB2-associated syndrome who were reported to have had a previous electroencephalographic study to identify those who had at least one reported abnormal result. For completeness, a supplemental survey was distributed to the caregivers and input from the treating neurologist was obtained whenever possible. Results: Forty-one subjects were identified as having at least one prior abnormal electroencephalography. Thirty-eight individuals (93%) had epileptiform discharges, 28 (74%) with central localization. Sleep stages were included as part of the electroencephalographies performed in 31 individuals (76%), and epileptiform activity was recorded during sleep in all instances (100%). Definite clinical seizures were diagnosed in 17 individuals (42%) with a mean age of onset of 3.2 years (four months to six years), and focal seizures were the most common type of seizure observed (42%). Six subjects with definite clinical seizures needed polytherapy (35%). Delayed myelination and/or abnormal white matter hyperintensities were seen on neuroimaging in 19 individuals (61%). Conclusions: Epileptiform abnormalities are commonly seen in individuals with SATB2-associated syndrome. A baseline electroencephalography that preferably includes sleep stages is recommended during the initial evaluation of all individuals with SATB2-associated syndrome, regardless of clinical suspicion of epilepsy