UV-C radiation induced conformational relaxation of pMTa4 DNA in Escherichia coli may be the cause of single strand breaks

Purpose: The biological consequences of initial physicochemical events following exposure of DNA to germicidal (254 nm) ultraviolet C (UV-C) radiation are not fully understood despite progress that has been made. In particular the cause of UV-C induced single strand breaks is not known. This question has been addressed in the present investigation.

Materials and methods: A plasmid construct, pMTa4, was exposed to UV-C in vitro as well as in vivo after transforming the plasmid into a repair proficient wild type and repair deficient, recF, mutant of E. coli. Following UV exposure in vivo, the plasmid was isolated under repair non-permissive and permissive conditions. The plasmid isolate and the pure super-coiled closed circular (CC) topological form of the plasmid were analyzed by agarose gel electrophoresis. The dependence of UV-C induced damage and conformational changes on the dose of radiation as well as on the duration of post-irradiation repair incubations was observed. The influence of UV-C on hyperchromic change and intercalation of ethidium bromide into plasmid DNA were also recorded.

Results: UV-C exposure of pMTa4 DNA in vitro and in vivo induced dose dependent, but sparsely placed, single strand breaks (SSB). While the wild type (AB1157) E. coli was able to repair SSB nearly completely under repair permissive condition, the recF (JC9239) mutant failed to do so. A dose-dependent relaxation of super-structure of CC form of pMTa4 DNA concomitant with enhanced ethidium bromide intercalation into the plasmid DNA was observed.

Conclusion: It is proposed that the conformational relaxation generated negative super-coiling strain on the DNA backbone of CC form of plasmid as well as exposed chemical bonds for hydrolytic cleavage. This might be the cause of the production of sparsely placed single strand breaks in pMTa4 upon exposure to low doses of UV-C.     

Bioactivation to an aldehyde metabolite—Possible role in the onset of toxicity induced by the anti-HIV drug abacavir

Aldehydes are highly reactive molecules, which can be generated during numerous physiological processes, including the biotransformation of drugs. Several non-P450 enzymes participate in their metabolism albeit alcohol dehydrogenase and aldehyde dehydrogenase are the ones most frequently involved in this process. Endogenous and exogenous aldehydes have been strongly implicated in multiple human pathologies. Their ability to react with biomacromolecules (e.g. proteins) yielding covalent adducts is suggested to be the common primary mechanism underlying the toxicity of these reactive species.     

Effect of progressive muscular relaxation exercises versus transcutaneous electrical nerve stimulation on tension headache: A comparative study

Tension-type headache (TTH) is most frequent among all types of headaches. According to the International Headache Classification Subcommittee of the International Headache Society (2004), TTH occurs in 30–78% of the population. Progressive muscular relaxation exercises have been shown to reduce TTH, and home-based relaxation programmes can result in significant improvement in headaches. Transcutaneous electrical nerve stimulation (TENS) is a method of electrical stimulation that primarily aims to provide a degree of symptomatic pain relief by exciting sensory nerves and stimulating either the pain gate mechanisms or the opioid systems. The objective of this study was to compare between the effects of progressive muscular relaxation exercises and TENS on pain intensity and stress in people with TTH. Thirty patients with TTH were allocated to either Group A or Group B. Group A practised progressive muscular relaxation exercise, whereas Group B received TENS. In the latter group, TENS electrodes were placed bilaterally either on the head at the site of pain or on the occiput. The treatment was carried out for 15 minutes a day, for 7 days. Patients were assessed for pain intensity (Visual Analogue Scale) and level of stress (Lakaev Academic Stress Response Scale) before and after the intervention period. The results showed that progressive muscular relaxation exercises were effective in reducing pain as well as stress (p < 0.001). TENS, by contrast, reduced stress significantly (p < 0.001), but not pain (p = 0.233). Between-group analysis revealed that there was no statistically significant difference in reduction of pain between the two groups (p = 0.595), but the amount of stress reduction in Group A (p = 0.002) was significantly more than that in Group B. In conclusion, progressive muscular relaxation exercises were more effective in reducing stress level than TENS in patients with TTH. The effect on pain reduction was similar between the two treatment methods.     

Fatal metabolic stroke in a child with propionic acidemia 11 years post liver transplant

Propionic acidemia is a rare autosomal recessive inborn error of metabolism caused by a deficiency of propionyl CoA carboxylase which often manifests with frequent metabolic decompensations and risk of neurological injury. Outcomes with medical therapy remain suboptimal. Liver transplantation has been shown to be a therapeutic option for patients and results in a milder phenotype of the disease and partial correction of the enzyme defect. Liver transplantation has been increasingly reported over the last decade and experience in managing these patients is improving. Long-term outcomes are generally good; however, the risk of complications still exists despite transplantation. We report a child who presented with a fatal metabolic stroke 11 years post liver transplant without any biochemical evidence of decompensation. We highlight the need to closely monitor these patients lifelong despite liver transplantation and maintain multidisciplinary working between hepatology and metabolic clinicians.     

Empagliflozin restores chronic kidney disease–induced impairment of endothelial regulation of cardiomyocyte relaxation and contraction

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High-conductance calcium-activated potassium channels

High-conductance, calcium-activated potassium (Maxi-K) channels represent a group of proteins with diverse physiologic functions. Although the role of Maxi-K channels in the CNS is complex and still an area of active academic research, there appears to be better agreement concerning the contribution of these channels to the regulation of smooth muscle tone and, thus the expectations remain high for Maxi-K channel openers having use in the treatment of hypertension, overactive bladder, asthma or erectile dysfunction. Despite this consensus view, at the present time, there is only one compound that targets Maxi-K channels in clinical development for overactive bladder conditions. In the present review, the latest developments in the identification of potent and selective Maxi-K channel openers and their utility in the treatment of smooth muscle disorders will be discussed.     

A comprehensive review of intake estimates of di-isononyl phthalate (DINP) based on indirect exposure models and urinary biomonitoring data

Di-isononyl phthalate (DINP) is a high molecular weight general purpose plasticizer used principally in the manufacture of flexible polyvinyl chloride (PVC) articles. DINP metabolites can be measured in biological media such as blood and urine. However, measurement of a substance in the blood or urine does not by itself mean that the chemical causes or is associated with adverse health outcomes. This is particularly pertinent given the advances in modern analytical techniques whereby ever diminishing trace amounts of substances can be detected. Therefore, it is a scientific necessity that risk assessors understand the relationship of biomonitoring data to estimation of exposure so that appropriate comparisons can be made to the no observed adverse effects levels (NOAELs) or other points of departure from toxicological studies in animals. In this paper, estimates of daily DINP intake are calculated for various population segments based on urinary biomonitoring data and are compared to estimates of exposure based on indirect methods and to health-based exposure guidance values. In general, intake estimates converge on a mean of 1–2 μg/kg/day regardless of source of exposure or population cluster; a value 2-orders of magnitude lower than health-based exposure guidance values, ranging from 120 to 290 μg/kg/day, which have been established by regulatory authorities and other authoritative bodies as representing acceptable levels.