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The Mitochondrial Permeability Transition Pore and ATP Synthase. - Handbook of experimental pharmacology
Mitochondrial ATP generation by oxidative phosphorylation combines the stepwise oxidation by the electron transport chain (ETC) of the reducing equivalents NADH and FADH2 with the generation of ATP by the ATP synthase. Recent studies show that the ATP synthase is not only essential for the generation of ATP but may also contribute to the formation of the mitochondrial permeability transition pore (PTP). We present a model, in which the PTP is located within the c-subunit ring in the Fo subunit of the ATP synthase. Opening of the PTP was long associated with uncoupling of the ETC and the initiation of programmed cell death. More recently, it was shown that PTP opening may serve a physiologic role: it can transiently open to regulate mitochondrial signaling in mature cells, and it is open in the embryonic mouse heart. This review will discuss how the ATP synthase paradoxically lies at the center of both ATP generation and cell death.
An early diagnostic tool for diabetic peripheral neuropathy in rats. - PloS one
The skin's rewarming rate of diabetic patients is used as a diagnostic tool for early diagnosis of diabetic neuropathy. At present, the relationship between microvascular changes in the skin and diabetic neuropathy is unclear in streptozotocin (STZ) diabetic rats. The aim of this study was to investigate whether the skin rewarming rate in diabetic rats is related to microvascular changes and whether this is accompanied by changes observed in classical diagnostic methods for diabetic peripheral neuropathy. Computer-assisted infrared thermography was used to assess the rewarming rate after cold exposure on the plantar skin of STZ diabetic rats' hind paws. Peripheral neuropathy was determined by the density of intra-epidermal nerve fibers (IENFs), mechanical sensitivity, and electrophysiological recordings. Data were obtained in diabetic rats at four, six, and eight weeks after the induction of diabetes and in controls. Four weeks after the induction of diabetes, a delayed rewarming rate, decreased skin blood flow and decreased density of IENFs were observed. However, the mechanical hyposensitivity and decreased motor nerve conduction velocity (MNCV) developed 6 and 8 weeks after the induction of diabetes. Our study shows that the skin rewarming rate is related to microvascular changes in diabetic rats. Moreover, the skin rewarming rate is a non-invasive method that provides more information for an earlier diagnosis of peripheral neuropathy than the classical monofilament test and MNCV in STZ induced diabetic rats.
Mirror-image pain after nerve reconstruction in rats is related to enhanced density of epidermal peptidergic nerve fibers. - Experimental neurology
Mirror-image pain is a phenomenon in which unprovoked pain is detected on the uninjured contralateral side after unilateral nerve injury. Although it has been implicated that enhanced production of nerve growth factor (NGF) in the contralateral dorsal root ganglion is important in the development of mirror-image pain, it is not known if this is related to enhanced expression of nociceptive fibers in the contralateral skin. Mechanical and thermal sensitivity in the contralateral hind paw was measured at four different time points (5, 10, 20 and 30weeks) after transection and immediate end-to-end reconstruction of the sciatic nerve in rats. These findings were compared to the density of epidermal (peptidergic and non-peptidergic) nerve fibers on the contralateral hind paw. Mechanical hypersensitivity of the contralateral hind paw was observed at 10weeks PO, a time point in which both subgroups of epidermal nerve fibers reached control values. Thermal hypersensitivity was observed with simultaneous increase in the density of epidermal peptidergic nerve fibers of the contralateral hind paw at 20weeks PO. Both thermal sensitivity and the density of epidermal nerve fibers returned to control values 30weeks PO. We conclude that changes in skin innervation and sensitivity are present on the uninjured corresponding side in a transient pain model. Therefore, the contralateral side cannot serve as control. Moreover, the current study confirms the involvement of the peripheral nervous system in the development of mirror-image pain.Copyright Â© 2015 Elsevier Inc. All rights reserved.
Long-term follow-up of peptidergic and nonpeptidergic reinnervation of the epidermis following sciatic nerve reconstruction in rats. - Journal of neurosurgery
Peripheral nerve injuries are a commonly encountered clinical problem and often result in long-term functional deficits. The current gold standard for transected nerves is an end-to-end reconstruction, which results in the intermittent appearance of neuropathic pain.To improve our understanding of the relation between this type of reconstruction and neuropathic pain, the authors transected and immediately end-to-end reconstructed the sciatic nerve in rats. The effect of this procedure on neuropathic pain, as measured by thermal and mechanical hypersensitivity at 4 different time points (5, 10, 20, and 30 weeks), was related to the density of peptidergic and nonpeptidergic fiber innervation in the glabrous skin of rats' hind paws.Thermal hypersensitivity occurring 20 weeks after reconstruction was accompanied by a significant increase in peptidergic epidermal fibers. However, the lesion-induced reduction in the density of nonpeptidergic epidermal fibers remained decreased at all experimental time points. Moreover, temporal collateral sprouting by undamaged saphenous nerve was visualized using the recently revised Evans blue extravasation technique. Strikingly, as the sciatic nerve repopulated rats' hind paw, the saphenous nerve withdrew to its original territory.The authors conclude that the transient thermal hypersensitivity is related to increased density of epidermal peptidergic fibers, which mainly originate from regenerating fibers. Furthermore, a changed composition in the peptidergic and nonpeptidergic epidermal fibers is demonstrated following end-to-end reconstruction of the sciatic nerve.
Human Papillomavirus Deoxyribonucleic Acid may not be Detected in Non-genital Benign Papillomatous Skin Lesions by Polymerase Chain Reaction. - Indian journal of dermatology
Papillomatosis is a known histopathologic pattern usually seen in human papillomavirus (HPV) infection and verruca vulgaris is the typical example. This pattern is also detected in some other benign cutaneous lesions such as nevus sebaceous (NS), seborrheic keratosis (SK), trichilemmoma (TL) and inverted follicular keratosis (IFK). The association between papillomatous lesions and HPV infection is questionable.The objective of this study was to investigate the presence of HPV deoxyribonucleic acid (DNA) in non-genital benign papillomatous skin lesions (NS, SK, TL and IFK) by polymerase chain reaction (PCR).A total of 100 specimens of non-genital NS, SK, TL and IFK were retrieved from archives of Dermatopathology Department of Razi Hospital, between 2003 and 2010. The conventional PCR using consensus GP5+/GP6+ primer and hydroxymethylbilane synthase gene as inner control was performed.PCR for HPV DNA revealed no positive results in any of 28 seborrheic keratosis (SK), 28 nevus sebaceous (NS), 28 inverted follicular keratosis (IFK) and 13 trichilemmoma (TL) studied specimens.Papillomatosis is usually a characteristic pattern of HPV infection. However, we found no association between HPV infection and non-genital benign papillomatous lesions.
Innervation mapping of the hind paw of the rat using Evans Blue extravasation, Optical Surface Mapping and CASAM. - Journal of neuroscience methods
Although numerous studies investigate sensory regeneration and reinnervation of the hind paw of the rat after nerve damage, no comprehensive overview of its normal innervation is present in literature. The Evans Blue extravasation technique is a well-known technique to study patterns of skin innervation. This technique has been performed differently by various groups but was never used to study the entire skin innervation in rats' hind paw including all three branches of the sciatic nerve and the saphenous nerve in detail.In this paper, we have used the Evans Blue extravasation technique to chart the skin areas innervated by the sural, peroneal, tibial and/or saphenous nerves, which together innervate the entire hind paw of the rat, and use a new technique to analyze the distribution, overlap and variability of the results. The technique is based on analysis of whole hind paws using Optical Surface Mapping (OSM) in combination with the Computer Assisted Surgical Anatomy Mapping (CASAM) technology.While the plantar hind paw is mainly innervated by the tibial nerve, the dorsal hind paw is supplied by the sural, peroneal and the saphenous nerve.Although our results basically concur with the general nerve-specific innervation of the rat hind paw, they show considerable detail in their areas of overlap as well as in the amount of variability between animals.These results will be invaluable to study and evaluate patterns of innervation and reinnervation of intact and damaged nerve fibers.Copyright Â© 2014 Elsevier B.V. All rights reserved.
Thermo-sensitive TRP channels in peripheral nerve injury: a review of their role in cold intolerance. - Journal of plastic, reconstructive & aesthetic surgery : JPRAS
One of the sensory complications of traumatic peripheral nerve injury is thermal intolerance, which manifests in humans mainly as cold intolerance. It has a major effect on the quality of life, and adequate therapy is not yet available. In order to better understand the pathophysiological background of thermal intolerance, we focus first on the various transient receptor potential (TRP) channels that are involved in temperature sensation, including their presence in peripheral nerves and in keratinocytes. Second, the role of thermo-sensitive TRP channels in cold and heat intolerance is described showing three different mechanisms that contribute to thermal intolerance in the skin: (a) an increased expression of TRP channels on nerve fibres and on keratinocytes, (b) a lower activation threshold of TRP channels and (c) the sprouting of non-injured nerve fibres. Finally, the data that are available on the effects of TRP channel agonists and antagonists and their clinical use are discussed. In conclusion, TRP channels play a major role in temperature sensation and in cold and heat intolerance. Unfortunately, the available pharmaceutical agents that successfully target TRP channels and counteract thermal intolerance are still very limited. Yet, our focus should remain on TRP channels since it is difficult to imagine a reliable treatment for thermal intolerance that will not involve TRP channels.Copyright Â© 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Comparing experiential acceptance and cognitive reappraisal as predictors of functional outcome in individuals with serious mental illness. - Behaviour research and therapy
Two psychological regulation strategies to cope with psychotic symptoms proposed by the cognitive behavioral tradition were examined in this study: cognitive reappraisal and experiential acceptance. Although cognitive behavior therapy for psychosis has increasing empirical support, little is known about the role of these two strategies using methods of known ecological validity.Intensive longitudinal data was gathered from 25 individuals diagnosed with a psychiatric disorder with psychotic features. During the course of six days we measured contextual factors, psychotic and stressful events, psychological regulation strategies and functional outcome.Positive psychotic symptoms and stressful events had negative associations with quality of life and affect, whereas experiential acceptance had positive associations with them. Cognitive reappraisal had inconsistent associations with quality of life and no association with affect. Social interactions and engagement in activities had a positive association with quality of life. Results were supported by additional and exploratory analyses.Across measures of functional outcome, experiential acceptance appears to be an effective coping strategy for individuals facing psychotic and stressful experiences, whereas cognitive reappraisal does not. In order to inform treatment development efforts, results suggest the need to further investigate the role of these psychological regulation strategies using ecologically valid methods.Copyright Â© 2013 Elsevier Ltd. All rights reserved.
Spatiotemporal dynamics of re-innervation and hyperinnervation patterns by uninjured CGRP fibers in the rat foot sole epidermis after nerve injury. - Molecular pain
The epidermis is innervated by fine nerve endings that are important in mediating nociceptive stimuli. However, their precise role in neuropathic pain is still controversial. Here, we have studied the role of epidermal peptidergic nociceptive fibers that are located adjacent to injured fibers in a rat model of neuropathic pain. Using the Spared Nerve Injury (SNI) model, which involves complete transections of the tibial and common peroneal nerve while sparing the sural and saphenous branches, mechanical hypersensitivity was induced of the uninjured lateral (sural) and medial (saphenous) area of the foot sole. At different time points, a complete foot sole biopsy was taken from the injured paw and processed for Calcitonin Gene-Related Peptide (CGRP) immunohistochemistry. Subsequently, a novel 2D-reconstruction model depicting the density of CGRP fibers was made to evaluate the course of denervation and re-innervation by uninjured CGRP fibers. The results show an increased density of uninjured CGRP-IR epidermal fibers on the lateral and medial side after a SNI procedure at 5 and 10 weeks. Furthermore, although in control animals the density of epidermal CGRP-IR fibers in the footpads was lower compared to the surrounding skin of the foot, 10 weeks after the SNI procedure, the initially denervated footpads displayed a hyper-innervation. These data support the idea that uninjured fibers may play a considerable role in development and maintenance of neuropathic pain and that it is important to take larger biopsies to test the relationship between innervation of injured and uninjured nerve areas.
The efficacy of a 1-week triple therapy for eradication of Helicobacter pylori infection in children. - Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology
Poor compliance to therapy and antibiotic resistance are the main causes for failure of anti-Helicobacter pylori (H. pylori) therapy. The purpose of this study was to assess the effectiveness of omeprazole-based triple therapy in Iranian children.Fifty-seven children with H. pylori-related gastroduodenal disease received 1-week triple therapy with a combination of omeprazole, amoxicillin and clarithromycin (according to the susceptibility test). Success of eradication was assessed by (13)C-urea breath test and endoscopy.Sixty-four patients (mean age 11.3years; range 2.7-16years) were included. Eradication was successful in 84.2% (95% confidence interval, 72.8% intention to treat).One-week triple therapy was effective for the eradication of H. pylori infection in children.Copyright Â© 2011 Arab Journal of Gastroenterology. Published by Elsevier Ltd. All rights reserved.
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