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The etiology of localized provoked vulvodynia (LPV) remains unknown, but observations suggest the involvement of the vaginal microbiota. We examined the vaginal microbiota of women with LPV and healthy controls, upon after a low-oxalate diet (LOD).A total of 9 women diagnosed with secondary LPV and 21 healthy controls were recruited from the Galilee Medical Center in Israel and subjected to prospective evaluations of their vaginal microbiota. Total DNA was extracted from vaginal discharge samples provided before and after following LOD for 3 weeks and was then subjected to 16S sequencing. Data obtained were then used to evaluate α and β diversity, identify differentially abundant bacterial taxa in LPV, and determine their impact on the metabolism.These evaluations revealed decreased diversity in the vaginal microbiota of women with LPV and identified the Ochrobactrum genus and Pseudomonadaceae family as indicators for LPV. In addition, we identified 23 differentially expressed bacterial metabolic pathways between the LPV and control samples and revealed that LOD could induce changes in the β diversity of LPV vaginal microbiomes, which was further supported by some degree of pain reduction in patients.Localized provoked vulvodynia and LOD were associated with shifts in the vaginal microbiota. However, the impact of these changes on the development of LPV requires additional studies with a larger cohort.

The effects of MgSO

Epidemiological and experimental evidence demonstrates that maternal exposure to infection during gestation increases the offspring's risk of developing schizophrenia and other neurodevelopmental disorders. In addition, the NRG-ErbB4 signaling pathway is involved in brain development and neuropsychiatric disorders. Specifically, this pathway modulates the dopaminergic and GABAergic systems and is expressed in the early stages of prenatal development. We recently demonstrated that maternal immune activation (MIA) at late gestation altered the expression of NRG1, its receptor ErbB4, and the dopamine D2 receptor four hours post-injection of viral or LPS in the fetal brain. We also reported that blocking the ErbB pathway during adolescence resulted in increased striatal DA content and reduced preference for sweetness and alcohol that persists into adulthood. However, the combined effects of MIA, re-activation of the immune system, and disruption of the ErbB signaling during adolescence would affect young adult mice's behavioral phenotype is unknown. Here, we report that the expression levels of the NRG1, ErbB4, GAD

The physiological pattern of hormonal and signaling molecules associated with labor induction is not fully clear. We conducted a preliminary study in order to investigate hormonal changes during labor induction in women with previous cesarean section. Eighty-seven women at term, with previous cesarean section, were randomized to undergo induction of labor by breast stimulation or intracervical balloon and compared with spontaneous labor (controls). Maternal serum levels of oxytocin, prostaglandin F2α, prostaglandin E2, prolactin, estradiol, and cortisol were analyzed at 0, 3, and 6 h post-induction initiation. Fetal umbilical cord hormones were measured. No significant difference was found in the induction-to-delivery time or mode of delivery between the induction groups. Maternal serum oxytocin levels decreased to a lesser extent in the breast stimulation group vs. the control group (p=0.003, p

The classic bone tissue engineering model for bone regeneration combines three elements: scaffolds, biomaterials, and mesenchymal stem cells (MSCs). Incorporation of MSCs and growth factors into a scaffold implanted into the area of bone injury is a proven strategy to achieve successful bone regeneration as demonstrated in the literature. However, a major limitation of using bone grafts or scaffolds is oxygen (O

Yaseen Awad-Igbaria,1,2 Shilo Dadon,1,2 Alon Shamir,3,4 Alejandro Livoff,5 Mark Shlapobersky,5 Jacob Bornstein,1,2,* Eilam Palzur2,* 1Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel; 2The Research Institute of Galilee Medical Center, Nahariya, Israel; 3Psychobiology Research Laboratory, Mazor Mental Health Center, Akko, Israel; 4The Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel; 5Pathology Department, Barzilai University Medical Center, Ashkelon, Israel*These authors contributed equally to this workCorrespondence: Yaseen Awad-Igbaria, The Research Institute of Galilee Medical Center, PO Box 21, Nahariya, 22100, Israel, Tel +972 50-4500101, Email Yaseenawad123@gmail.comBackground: Provoked vulvodynia (PV) is the main cause of vulvar pain and dyspareunia. The etiology of PV has not yet been elucidated. However, PV is associated with a history of recurrent inflammation, and its often accompanied by increases in the numbers of mast cells (MCs) and sensory hyperinnervation in the vulva. Therefore, this study aimed to examine the role of MCs and the early inflammatory events in the development of chronic vulvar pain in a rat model of PV.Methods: Mechanical and thermal vulvar sensitivity was measured for 5 months following zymosan vulvar challenges. Vulvar changes in glutamate and nerve growth factor (NGF) were analyzed using ELISA. Immunofluorescence (IF) staining of the vulvar section after 20, 81, and 160 days of the zymosan challenge were performed to test MCs accumulation, hyperinnervation, and expression of pain channels (transient receptor potential vanilloid/ankyrin-1-TRPV1 & TRPA1) in vulvar neurons. Changes in the development of vulvar pain were evaluated following the administration of the MCs stabilizer ketotifen fumarate (KF) during zymosan vulvar challenges.Results: Zymosan-challenged rats developed significant mechanical and thermal vulvar sensitivity that persisted for over 160 days after the zymosan challenge. During inflammation, increased local concentrations of NGF and glutamate and a robust increase in MCs degranulation were observed in zymosan-challenged rats. In addition, zymosan-challenged rats displayed sensory hyperinnervation and an increase in the expression of TRPV1 and TRPA1. Treatment with KF attenuated the upregulated level of NGF during inflammation, modulated the neuronal modifications, reduced MCs accumulation, and enhanced mechanical hypersensitivity after repeated inflammation challenges.Conclusion: The present findings suggest that vulvar hypersensitivity is mediated by MCs accumulation, nerve growth, and neuromodulation of TRPV1 and TRPA1. Hence, KF treatment during the critical period of inflammation contributes to preventing chronic vulvar pain development.Keywords: provoked vulvodynia, inflammation, mast cell, nerve growth factor, glutamate, hyperinnervation

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/., This short opinion aimed to present the evidence to support our hypothesis that vulvodynia is a neuroinflammatory pain syndrome originating in the pelvic visceral nerve plexuses caused by the failure of weakened uterosacral ligaments (USLs) to support the pelvic visceral nerve plexuses, i.e., T11-L2 sympathetic and S2-4 parasympathetic plexuses. These are supported by the USLs, 2 cm from their insertion to the cervix. They innervate the pelvic organs, glands, and muscles. If the USLs are weak or lax, gravitational force or even the muscles may distort and stimulate the unsupported plexuses. Inappropriate afferent signals could then be interpreted as originating from an end-organ site. Activation of sensory visceral nerves causes a neuro-inflammatory response in the affected tissues, leading to neuroproliferation of small peripheral sensory nerve fibers, which may cause hyperalgesia and allodynia in the territory of the damaged innervation. Repair of the primary abnormality of USL laxity, responsible for mechanical stimulation of the pelvic sensory plexus, may lead to resolution of the pain syndrome.

The opening of the mitochondrial permeability transition pore (mPTP) has emerged as a pivotal event following traumatic brain injury (TBI). Evidence showing the impact of the translocator protein (TSPO) over mPTP activity has prompted several studies exploring the effect of TSPO ligands, including etifoxine, on the outcome of traumatic brain injury (TBI). Mitochondrial respiration was assessed by respirometry in isolated rat brain mitochondria (RBM) by measurements of oxidative phosphorylation capacity (OXPHOS). The addition of calcium to RBM was used to induce mitochondrial injury and resulted in significant OXPHOS reduction that could be reversed by preincubation of RBM with etifoxine. Sensorimotor and cognitive functions were assessed following controlled cortical impact and compared in vehicle and etifoxine-treated animals. There was no difference between the vehicle and etifoxine groups for sensorimotor functions as assessed by rotarod. In contrast, etifoxine resulted in a significant improvement of cognitive functions expressed by faster recovery in Morris water maze testing. The present findings show a significant neuroprotective effect of etifoxine in TBI through restoration of oxidative phosphorylation capacity associated with improved behavioral and cognitive outcomes. Since etifoxine is a registered drug used in common clinical practice, implementation in a phase II study may represent a reasonable step forward.

Experimental studies have shown that ligands of the 18 kDa translocator protein can reduce neuronal damage induced by traumatic brain injury by protecting mitochondria and preventing metabolic crisis. Etifoxine, an anxiolytic drug and 18 kDa translocator protein ligand, has shown beneficial effects in the models of peripheral nerve neuropathy. The present study investigates the potential effect of etifoxine as a neuroprotective agent in traumatic brain injury (TBI). For this purpose, the effect of etifoxine on lesion volume and modified neurological severity score at 4 weeks was tested in Sprague&ndash, Dawley adult male rats submitted to cortical impact contusion. Effects of etifoxine treatment on neuronal survival and apoptosis were also assessed by immune stains in the perilesional area. Etifoxine induced a significant reduction in the lesion volume compared to nontreated animals in a dose-dependent fashion with a similar effect on neurological outcome at four weeks that correlated with enhanced neuron survival and reduced apoptotic activity. These results are consistent with the neuroprotective effect of etifoxine in TBI that may justify further translational research.

Cerebral edema represents a major threat following traumatic brain injury. However, therapeutic measures for control of intracranial pressure alone have failed to restore cerebral metabolism and improve neurological outcome. Since mitochondrial damage results in ATP depletion and deactivation of membrane ionic pumps, we hypothesized that modulation of ATP bioavailability may directly affect cytotoxic edema. Intracranial pressure measurements were performed in Sprague-Dawley rats treated by intraperitoneal injection of dimethylsulfoxide (vehicle), cyclosporine A (CsA), or Oligomycin B (OligB) following cortical contusion and further correlated with water content, mitochondrial damage, and electron microscopic assessment of neuronal and axonal edema. As hypothesized, ultra-structural figures of edema closely correlated with intracranial pressure elevation, increased water content and mitochondrial membrane permeabilization expressed by loss of transmembrane mitochondrial potential. Further, mitochondrial damage evidenced ultra-structurally by figures of swollen mitochondria with severely distorted cristae correlated with both cytotoxic edema and mitochondrial dysfunction. Importantly, cerebral edema and mitochondrial impairment were significantly worsened by treatment with OligB, whereas a noticeable improvement could be observed in animals that received injections of CsA. Since OligB and CsA are responsible for symmetrical and opposite effects on oxidative metabolism, these findings support the hypothesis of a causative relationship between edema and mitochondrial function.

Traumatic brain injuries (TBI) are a major cause of mortality and disability among young adults. TBI are characterized by primary injury, the result of a mechanical impact to the cranium and a secondary injury, a series of molecular mechanism processes developing thereafter. Cerebral cells modify their gene and protein expression as a result of the injury. Epigenetic modifications have a key role as regulators of gene transcription and may simultaneously be involved in the regulation of the molecular pathways following TBI. However, the mechanisms are unknown.To clarify whether modification in the expression of Histone Acetyl Transferase1 (HAT1) and Histone deacetylase2 (HDAC 2) occurs during secondary brain damage.Rat diffused head injury model was used; 72 hours post injury animals were sacrificed and the brains were removed for immunohistochemistry staining with Caspase 3, HAT1 and HDAC2 antibodies. We compared these stains in the perilesional versus the contralateral cortex.An increase of Caspase 3 stained cells were observed in the perilesional cortex. HAT1 expression was elevated and HDAC2 expression reduced in the injured cortex.TBI induced modifications in the expression of epigenetic factors were concomitant with increases in apoptotic cell death. The mitochondria involved in the apoptotic processes is a target for epigenetic regulation and also influences it at the same time.This study contributes to the understanding of epigenetic modification following TBI. Further study on the relationship between mitochondrial activity and epigenetic regulation has to be performed in order to develop novel drugs and therapies for TBI.

Traumatic brain injuries represent the leading cause of death and morbidity in young adults in western countries, and are responsible for a major social and economical burden. For decades, the mainstay of neurotrauma management has been represented by control of post-traumatic edema. With the emergence of a better understanding of the underlying cellular mechanisms responsible for the generation of secondary brain damage, the hope for the "magic bullet" has prompted the development of novel drugs that have repeatedly failed to significantly improve outcome of head-injured patients. During the past decade, mitochondrial functional and structural impairment has emerged as a pivotal event in the pathway of cell to secondary death. Extensive research has identified a vast range of deleterious signals that are generated and integrated at the mitochondrial level resulting in impairment of major mitochondrial functions such as calcium homeostasis, free radicals generation and detoxification, energy production and neurosteroidogenesis. Mitochondria have therefore emerged as a potential therapeutic target. Within the spectrum of major mitochondrial structural components, the 18 kDa translocator protein (TSPO) has shown important and relevant functions such as steroid synthesis and modulation of the mitochondrial permeability transition that may substantially affect the fate of injured cells. This review summarizes the potential therapeutic implications of TSPO modulation in traumatic brain injury in the view of the current knowledge on this intriguing mitochondrial complex.

Recent experimental data have shown that hyperbaric oxygen therapy (HBOT) was associated increased Bcl-2 expression at the injury site that correlated with reduced apoptosis. We hypothesized that HBOT mediated enhancement of Bcl-2 expression and increased intracellular oxygen bio-availability may both contribute to preserve mitochondrial integrity and reduce the activation of the mitochondrial pathway of apoptosis. For this purpose, a cortical lesion was created in the parietal cortex of Sprague-Dawley rats by dynamic cortical deformation (DCD) and outcome measures in non-treated animals were compared with that of HBOT treated rats. Morphological analysis showed a profound reduction in neuronal counts in the perilesional area and a marked rarefaction of the density of the axonal-dendritic network. In treated animals, however, there was a significant attenuation of the impact of DCD over perilesional neurons, characterized by significantly higher cell counts and denser axonal network. In mitochondria isolated from injured brain tissue, there was a profound loss of mitochondrial transmembrane potential (Deltapsi(M)) that proved to be substantially reversed by HBOT. This finding correlated with a significant reduction of caspases 3 and 9 activation in HBOT treated animals but not of caspase 8, indicating a selective effect over the intrinsic pathway of apoptosis. All together, our results indicate that the neuroprotective effect of HBOT may represent the consequence of preserved mitochondrial integrity and subsequent inhibition of the mPTP and reduction of the mitochondrial pathway of apoptosis.

Increasing evidence has established the involvement of the 18-kDa translocator protein (TSPO) in the process of mitochondrial membrane permeabilization and subsequent apoptosis through modulation of the mitochondrial permeability transition pore. Recent studies have shown that treatment with Ro5-4864, a TSPO ligand, resulted in a neuroprotective effect in traumatic brain injury. Yet, the nature of this effect remained uncertain as mature neurons are considered to be lacking the TSPO protein. In order to investigate the mechanism of Ro5-4864-mediated neuroprotection, the neuro-inflammatory and neurosteroid response to cortical injury was tested in sham-operated, vehicle, cyclosporine A (CsA) and Ro5-4864-treated rats. As anticipated, the levels of interleukin 1β and tumor necrosis factor α, as well as the astrocyte and microglia cellular density in the injured area were all decreased by CsA in comparison with the vehicle group. By contrast, no visible effect could be observed in Ro5-4864-treated animals. None of the groups showed any significant difference with any other in respect with the expression of brain-derived neurotrophic factor. Double immunofluorescence staining with NeuN and TSPO confirmed the absence of TSPO in native neurons though showed clear evidence of co-localization of TSPO in the cytoplasm of NeuN-stained injured neurons. Altogether, this study shows that the neuronal protection mediated by Ro5-4864 in brain injury cannot be solely attributed to an indirect effect of the ligand on glial TSPO but may also represent the consequence of the modulation of upregulated TSPO in injured neurons. This observation may be of importance for future pharmacological research in neurotrauma.

The acute inflammatory response plays an important role in secondary brain damage after traumatic brain injury (TBI). Neutrophils provide the main source of matrix metalloproteinases (MMPs) which also play a deleterious role in TBI. Numerous preclinical studies have suggested that hyperbaric oxygen therapy (HBOT) may by beneficial in various noncerebral and cerebral inflammatory diseases. The goal of this study was to evaluate the effects of HBOT on inflammatory infiltration and the expression of MMPs in correlation with secondary cell death in the rat model of dynamic cortical deformation (DCD). Twenty animals underwent DCD with subsequent HBOT (2.8 ATA, two sessions of 45 min each); 10 animals: DCD and normobaric oxygenation (1 ATA), 10 animals: not treated after DCD. Cell death was evaluated by TUNEL. Neutrophils were revealed by myeloperoxidase staining. Immunohistochemical staining for MMP-2 and -9 and tissue inhibitors of MMP-1 (TIMP-1) and -2 was also performed and the results were quantitatively evaluated by image analysis. In the animals treated by HBOT, a significant decrease in the number of TUNEL-positive cells and neutrophilic inflammatory infiltration was seen in comparison with nontreated animals and those treated by normobaric oxygen. The expression of MMP-9 was also significantly lower in the treated group. Staining for MMP-2 and TIMP-2 did not change significantly. Our results demonstrate that HBOT decreased the extent of secondary cell death and reactive neuroinflammation in the TBI model. The decline of MMP-9 expression after HBOT may also contribute to protection of brain tissue in the perilesional area. Further research should be centred on the evaluation of long-term functional and morphological results of HBOT.

The growth and progression of traumatic brain injury (TBI) lesions depend significantly on developments in the traumatic penumbra area, perilesional region, where delayed neuronal death occurs. Recent data supports the important role of apoptosis in delayed cell death in TBI. Previously we demonstrated a significant reduction of apoptosis in traumatic penumbra in animals treated by hyperbaric oxygen (HBO). In this study we evaluate the expression of apoptosis-related proteins of the Bcl-2 family (Bcl-2, Bax and Bcl-xL) in the traumatic penumbra area in correlation with the extent of apoptosis in the rat model of focal cerebral contusion, treated by HBO. Sprague-Dawley rats underwent cortical dynamic deformation, some with subsequent hypoxemia. A group of both hypoxemic and non-hypoxemic animals was treated by HBO. The pathological study was based on immunohistochemical staining of the brain sections for Bcl-2, Bax and Bcl-xL with quantitative evaluation of staining by image analysis. The expression of Bcl-2 in hypoxemic animals was lower than in non-hypoxemic animals, but a significant increase in Bcl-2 expression was seen in both groups after HBO treatment. Bcl-xL also demonstrated an increase after HBO treatment but less significant. Staining for Bax protein did not demonstrate significant change after treatment. These data correlate well with the reduction of TUNEL-positive cells in traumatic penumbra after HBO treatment. We concluded that the apoptotic mechanisms are important in delayed cell death in TBI and that post-traumatic hypoxemia increases the intensity of apoptosis, probably through a decrease in Bcl-2 and Bcl-xL expression which normally repress apoptosis. The beneficial effect of HBO treatment in our model of brain contusion correlates well with the increased expression of anti-apoptotic proteins (Bcl-2 and Bcl-xL) following treatment and the appropriate decrease in the extent of apoptosis. In light of these results, the usage of HBO is justified as neuroprotective treatment in TBI.

AIMS Hyperbaric hyperoxia has been shown to reduce apoptosis in brain injury. As the 18-kDa translocator protein (TSPO), also known as peripheral-type benzodiazepine receptor, is closely associated with the mitochondrial transition pore and because of its role in mitochondrial respiration and apoptosis, we hypothesized that reduction of apoptosis by hyperoxia may involve the TSPO. METHODS TSPO and transferase-mediated dUTP nick end labelling (TUNEL) immunopositivity was first assessed in cortical contusion, created by dynamic cortical deformation, by immunohistochemistry in rats exposed to normoxia [(dynamic cortical deformation (DCD)], normobaric hyperoxia or hyperbaric hyperoxia [hyperbaric oxygen therapy (HBO)]. In a second step, transmembrane mitochondrial potential (Deltapsi(M)) and caspase 9 activity were assessed in the injured area in comparison with the noninjured hemisphere. Measurements were performed in DCD and HBO groups. A third group receiving both HBO and the TSPO ligand PK11195 was investigated as well. RESULTS TSPO correlated quantitatively and regionally with TUNEL immunopositivity in the perilesional area. Hyperoxia reduced both the number of TSPO expressing and TUNEL positive cells in the perilesional area, and this effect proved to be pressure dependent. After contusion, we demonstrated a dissipation of Deltapsi(M) in isolated mitochondria and an elevation of caspase 9 activity in tissue homogenates from the contused area, both of which could be substantially reversed by hyperbaric hyperoxia. This protective effect of hyperoxia was reversed by PK11195. CONCLUSIONS The present findings suggest that the protective effect of hyperoxia may be due to a negative regulation of the proapoptotic function of mitochondrial TSPO, including conservation of the mitochondrial membrane potential.

Traumatic brain injury (TBI) is a leading cause of death and functional disability in western countries, affecting mostly young patients. Despite intense and sustained efforts deployed for the development of new therapeutic strategies, no clinical benefit has been shown by any of the investigated compounds. Increasing attention has been drawn during the past two decades to the neuroprotective effects of estrogens, although most of the available data relate to ischemic brain injury. The purpose of the present study was to investigate the potential neuroprotective value of estrogens in TBI as a therapeutic modality. For this purpose, a contusion was created in the parietal cortex by dynamic cortical deformation in two groups of 10 Sprague-Dawley male rats. Following the injury, treated animals received conjugated estrogens for 3 days, using a subcutaneously implanted osmotic pump. Animals were then sacrificed, and TUNEL, anti-active Caspase 3, bcl-2, and bax labeling were performed in paraffin-embedded brain sections, allowing for comparative and quantitative analysis. In estrogen-treated animals, there was a marked and significant reduction of apoptosis in comparison with non-treated animals. The reduction in TUNEL and active Caspase 3 staining was similar and close to 50%. Optical analysis of histological slides prepared by bcl-2 labeling showed a significant increase in bcl-2 expression in estrogen-treated animals compared to non-treated animals. On the contrary, bax expression was not influenced by hormonal treatment, and no difference could be noticed between the two groups. These results support the potential therapeutic value of estrogens in TBI and further clarify their mode of action.

Cerebral contusions are one the most frequent traumatic lesions and the most common indication for secondary surgical decompression. The purpose of this study was to investigate the physiology of perilesional secondary brain damage and evaluate the value of hyperbaric oxygen therapy (HBOT) in the treatment of these lesions. Five groups of five Sprague-Dawley rats each were submitted to dynamic cortical deformation (DCD) induced by negative pressure applied to the cortex. Cerebral lesions produced by DCD at the vacuum site proved to be reproducible. The study protocol entailed the following: (1) DCD alone, (2) DCD and HBOT, (3) DCD and post-operative hypoxia and HBOT, (4) DCD, post-operative hypoxia and HBOT, and (5) DCD and normobaric hyperoxia. Animals were sacrificed after 4 days. Histological sections showed localized gross tissue loss in the cortex at injury site, along with hemorrhage. In all cases, the severity of secondary brain damage was assessed by counting the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and caspase 3-positive cells in successive perilesional layers, each 0.5 mm thick. Perilesional TUNEL positive cells suggested the involvement of apoptosis in group 1 (12.24% of positive cells in layer 1). These findings were significantly enhanced by post-operative hypoxia (31.75%, p < 0.001). HBOT significantly reduced the severity and extent of secondary brain damage expressed by the number of TUNEL positive cells in each layer and the volume of the lesion (4.7% and 9% of TUNEL positive cells in layer 1 in groups 2 and 4 respectively, p < 0.0001 and p < 0.003). Normobaric hyperoxia also proved to be beneficial although in a lesser extent. This study demonstrates that the vacuum model of brain injury is a reproducible model of cerebral contusion. The current findings also suggest that HBOT may limit the growth of cerebral contusions and justify further experimental studies.