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Non-opioid targets are needed for addressing osteoarthritis pain, which is mechanical in nature and associated with daily activities such as walking and climbing stairs. Piezo2 has been implicated in the development of mechanical pain, but the mechanisms by which this occurs remain poorly understood, including the role of nociceptors. Here we show that nociceptor-specific Piezo2 conditional knock-out mice were protected from mechanical sensitization associated with inflammatory joint pain in female mice, joint pain associated with osteoarthritis in male mice, as well as both knee swelling and joint pain associated with repeated intra-articular injection of nerve growth factor in male mice. Single cell RNA sequencing of mouse lumbar dorsal root ganglia and in situ hybridization of mouse and human lumbar dorsal root ganglia revealed that a subset of nociceptors co-express Piezo2 and Ntrk1 (the gene that encodes the nerve growth factor receptor TrkA). These results suggest that nerve growth factor-mediated sensitization of joint nociceptors, which is critical for osteoarthritic pain, is also dependent on Piezo2, and targeting Piezo2 may represent a therapeutic option for osteoarthritis pain control.

The proposed mission to Mars will expose astronauts to space radiation that is known to adversely affect cognition and tasks that rely on fine sensorimotor function. Space radiation has also been shown to affect the microglial and neurogenic responses in the central nervous system (CNS). We recently reported that a low dose of 5 cGy 600 MeV/n 28Si results in impaired cognition and skilled motor behavior in adult rats. Since these tasks rely at least in part on the proper functioning of the striatum, we examined striatal microglial cells in these same subjects. Using morphometric analysis, we found that 28Si exposure increased activated microglial cells in the striatum. The majority of these striatal Iba1+ microglia were ED1-, indicating that they were in an alternatively activated state, where microglia do not have phagocytic activity but may be releasing cytokines that could negatively impact neuronal function. In the other areas studied, Iba1+ microglial cells were increased in the subventricular zone (SVZ), but not in the dentate gyrus (DG). Additionally, we examined the relationship between the microglial response and neurogenesis. An analysis of new neurons in the DG revealed an increase in doublecortin-positive (DCX+) hilar ectopic granule cells (hEGC) which correlated with Iba1+ cells, suggesting that microglial cells contributed to this aberrant distribution which may adversely affect hippocampal function. Taken together, these results indicate that a single dose of 28Si radiation results in persistent cellular effects in the CNS that may impact astronauts both in the short and long-term following deep space missions.

Sexually dimorphic performance has been observed across humans and rodents in many spatial tasks. In general, these spatial tasks do not dissociate the use of environmental and self-movement cues. Previous work has demonstrated a role for self-movement cue processing in organizing open field behavior; however, these studies have not directly compared female and male movement characteristics. The current study examined the organization of open field behavior under dark conditions in female and male rats. Significant differences between female and male rats were observed in the location of stopping behavior relative to a cue and the topography exhibited during lateral movements. In contrast, no sex differences were observed on measures used to detect self-movement cue processing deficits. These results provide evidence that female and male rats are similar in their use of self-movement cues to organize open field behavior; however, other factors may be contributing to differences in performance.

Lack of blood flow to the brain, i.e., ischemic stroke, results in loss of nerve cells and therefore loss of function in the effected brain regions. There is no effective treatment to improve lost function except restoring blood flow within the first several hours. Rehabilitation strategies are widely used with limited success. The purpose of this study was to examine the effect of electrical stimulation on the impaired upper extremity to improve functional recovery after stroke. We developed a rodent model using an electrode cuff implant onto a single peripheral nerve (median nerve) of the paretic forelimb and applied daily electrical stimulation. The skilled forelimb reaching test was used to evaluate functional outcome after stroke and electrical stimulation. Anterograde axonal tracing from layer V pyramidal neurons with biotinylated dextran amine was done to evaluate the formation of new neuronal connections from the contralesional cortex to the deafferented spinal cord. Rats receiving electrical stimulation on the median nerve showed significant improvement in the skilled forelimb reaching test in comparison with stroke only and stroke with sham stimulation. Rats that received electrical stimulation also exhibited significant improvement in the latency to initiate adhesive removal from the impaired forelimb, indicating better sensory recovery. Furthermore, axonal tracing analysis showed a significant higher midline fiber crossing index in the cervical spinal cord of rats receiving electrical stimulation. Our results indicate that direct peripheral nerve stimulation leads to improved sensorimotor recovery in the stroke-impaired forelimb, and may be a useful approach to improve post-stroke deficits in human patients.

Background: Traumatic brain injury is a significant public health issue that results in serious disability in survivors. Traumatic brain injury patients are often intoxicated with alcohol when admitted to the hospital; however, it is not clear how acute intoxication affects recovery from a traumatic brain injury. Our group has previously shown that binge alcohol prior to traumatic brain injury resulted in long-term impairment in a fine sensorimotor task that was correlated with a decreased proliferative and neuroblast response from the subventricular zone. However, whether binge alcohol prior to traumatic brain injury affects the proliferative response in the hippocampal dentate gyrus is not yet known. Methods: Male rats underwent binge alcohol (3 g/kg/day) by gastric gavage for 3 days prior to traumatic brain injury. Cell proliferation was labeled by BrdU injections following traumatic brain injury. Stereological quantification and immunofluorescence confocal analysis of BrdU+ cells in the hippocampal dorsal dentate gyrus was performed at 24 hours, 1 week and 6 weeks post traumatic brain injury. Results: We found that either traumatic brain injury alone or binge alcohol alone significantly increased dentate gyrus proliferation at 24 hours and 1 week. However, a combined binge alcohol and traumatic brain injury regimen resulted in decreased dentate gyrus proliferation at 24 hours post-traumatic brain injury. At the 6 week time point, binge alcohol overall reduced the number of BrdU+ cells. Furthermore, more BrdU+ cells were found in the dentate hilar region of alcohol traumatic brain injury compared to vehicle traumatic brain injury groups. The location and double-labeling of these mismigrated BrdU+ cells was consistent with hilar ectopic granule cells. Conclusion: The results from this study showed that pre-traumatic brain injury binge alcohol impacts the injury-induced proliferative response in the dentate gyrus in the short-term and may affect the distribution of newly generated cells in the dentate gyrus in the long-term.

Deep space flight missions beyond the Van Allen belt have the potential to expose astronauts to space radiation which may damage the central nervous system and impair function. The proposed mission to Mars will be the longest mission-to-date and identifying mission critical tasks that are sensitive to space radiation is important for developing and evaluating the efficacy of counter measures. Fine motor control has been assessed in humans, rats, and many other species using string-pulling behavior. For example, focal cortical damage has been previously shown to disrupt the topographic (i.e., path circuity) and kinematic (i.e., moment-to-moment speed) organization of rat string-pulling behavior count to compromise task accuracy. In the current study, rats were exposed to a ground-based model of simulated space radiation (5 cGy

Aim:Working at relational depth is considered to be one of the pillars of an effective intervention within person-centred approach. So far, the literature has been mainly focused on the description of the phenomenon. However, there has been little evidence explaining how the therapists can enhance their ability to work at depth. This paper seeks to add to a growing body of literature on the factors that can contribute to the development of the therapist’s ability to work at relational depth.Method and Analysis:The case study is based on a systematic analysis of the therapy sessions’ recordings, the client and supervision notes, and the researcher’s reflective diary. The analysis was aimed to track down the development process of relational depth. This was achieved by identifying critical incidents from the therapy sessions and matching these with the incidents from the therapist’s personal therapy and supervision.Findings:The findings from this case study suggest that the therapist’s ability to work at relational depth can be developed through the expansion of the therapist’s self. The more parts of the self the therapist is able to employ during a therapeutic encounter, the greater the potential they have of being able to work at relational depth with their clients.Discussion:The results point to the crucial role of the therapist’s growing self-awareness (expansion of self) and self-acceptance in the development of their ability to work at relational depth. The theory of configurations of self and accurate symbolisation is used to discuss these findings.

To measure out-of-field doses in a phantom model to better quantify this radiation.The individual contribution of photons and neutrons to the total out-of-field dose for 6 MV and 20 MV photons at open beam were measured in a purpose-designed water phantom. Radiation doses were measured at seven separate points (P1-P7) in the phantom with thermoluminescent detectors (TLD 100, 600, and 700) and GAFchromic™ EBT films.At a prescribed dose of 75Gy to the isocentre, the photon dose level in the close-to-field area (P2) ranged from 2.0-2.5Gy for 6 MV and 1.5-2.0Gy for 20 MV; the total out-of-field doses at P2 and P7, respectively, were estimated to be as follows: for 6 MV: TLD 100 (3.23% and0.14%); radiochromic film (2.52% and0.03%); and for 20 MV: TLD 100 (2.94% and0.78%); TLD 700 (2.02% and0.14%); and radiochromic film (1.73% and0.01%). Although the dose decreased rapidly as the distance from the central beam axis increased, even distant doses could be as high as several centigrays. The neutron dose for 20 MV photons at a distance of 25cm from the isocentre was 4.0mSv/Gy.Our results show that in the close-to-field area, the dose level could be as high as 1.5Gy assuming a prescribed dose of 75Gy to the isocentre. By contrast, the doses delivered to more distant areas from the planning target volume were much lower (centigrays). These findings show that both 6 MV and 20 MV photons could produce dosimetrically important dose levels outside of the field. The data reported here may be of value to study the potential impact of even very low doses of radiation on human tissues.

Purpose During radiotherapy, leakage from the machine head and collimator expose patients to out-of-field irradiation doses, which may cause secondary cancers. To quantify the risks of secondary cancers due to out-of-field doses, it is first necessary to measure these doses. Since most dosimeters are energy-dependent, it is essential to first determine the type of photon energy spectrum in the out-of-field area. The aim of this study was to determine the mean photon energy values for the out-of-field photon energy spectrum for a 6 MV photon beam using the GEANT 4–Monte Carlo method. Material and methods A specially-designed large water phantom was simulated with a static field at gantry 0°. The source-to-surface distance was 92 cm for an open field size of 10 × 10 cm2. The photon energy spectra were calculated at five unique positions (at depths of 0.5, 1.6, 4, 6, 8, and 10 cm) along the central beam axis and at six different off-axis distances. Results Monte Carlo simulations showed that mean radiation energy levels drop rapidly beyond the edge of the 6 MV photon beam field: at a distance of 10 cm, the mean energy level is close to 0.3 MeV versus 1.5 MeV at the central beam axis. In some cases, the energy level actually increased even as the distance from the field edge increased: at a depth of 1.6 cm and 15 cm off-axis, the mean energy level was 0.205 MeV versus 0.252 MeV at 20 cm off-axis. Conclusion The out-of-field energy spectra and dose distribution data obtained in this study with Monte Carlo methods can be used to calibrate dosimeters to measure out-of-field radiation from 6 MV photons.

Background: Physicians' adherence to guideline-recommended therapy is associated with short-term clinical outcomes in heart failure (HF) with reduced ejection fraction (HFrEF). However, its impact on longer-term outcomes is poorly documented. Here, we present results from the 18-month follow-up of the QUALIFY registry. Methods and results: Data at 18 months were available for 6118 ambulatory HFrEF patients from this international prospective observational survey. Adherence was measured as a continuous variable, ranging from 0 to 1, and was assessed for five classes of recommended HF medications and dosages. Most deaths were cardiovascular (CV) (228/394) and HF-related (191/394) and the same was true for unplanned hospitalizations (1175 CV and 861 HF-related hospitalizations, out of a total of 1541). According to univariable analysis, CV and HF deaths were significantly associated with physician adherence to guidelines. In multivariable analysis, HF death was associated with adherence level [subdistribution hazard ratio (SHR) 0.93, 95% confidence interval (CI) 0.87–0.99 per 0.1 unit adherence level increase; P = 0.034] as was composite of HF hospitalization or CV death (SHR 0.97, 95% CI 0.94–0.99 per 0.1 unit adherence level increase; P = 0.043), whereas unplanned all-cause, CV or HF hospitalizations were not (all-cause: SHR 0.99, 95% CI 0.9–1.02; CV: SHR 0.98, 95% CI 0.96–1.01; and HF: SHR 0.99, 95% CI 0.96–1.02 per 0.1 unit change in adherence score; P = 0.52, P = 0.2, and P = 0.4, respectively). Conclusion: These results suggest that physicians' adherence to guideline-recommended HF therapies is associated with improved outcomes in HFrEF. Practical strategies should be established to improve physicians' adherence to guidelines. © 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology

Early pregnancy is associated with morphological and functional changes within the uterus, accompanied by angiogenesis, increased vascular permeability and activation of immune tolerance. Intensive angiogenesis leads to accelerated vascular leakage and accumulation of interstitial fluid in endometrium. To protect the trophoblast from the harmful effect of extracellular fluid, process known as lymphangiogenesis is crucial. These studies are focused on VEGF-C, factor responsible of lymphatic vessels creating, and its receptors: Flk1 (VEGFR2) and Flt4 (VEGFR3) during the time of implantation as well as the effect of trophoblast signals (IFNG and E2) on VEGF-C production. Endometrial samples were collected from mature gilts from days 8, 10, 12, 14 of estrous cycle and pregnancy. Real-Time PCR analysis revealed increased mRNA expression of VEGF-C on days 10, 12, 14 of pregnancy compared to corresponding days of estrous cycle. The highest VEGF-C mRNA expression was observed on 14 day of pregnancy (p 0.05). Increased mRNA expression of Flk1 and Flt4 was noticed on day 14 of pregnancy in comparison to day 10. Enhanced Flk1 mRNA expression during 14 day of pregnancy was observed compared to corresponding day of estrous cycle (p 0.05). No significant difference on the protein level was revealed. VEGF-C and its receptors were localized mainly in luminal and glandular epithelial cells, but their presence were confirmed also in endothelial cells of blood and lymphatic vessels and 14 d trophoblasts. In vitro studies revealed positive effect of IFNG on VEGF-C mRNA expression in stromal cells and protein content in medium after stromal cells culture (p 0.05). Our studies demonstrated the presence of VEGF-C system in porcine endometrium and indicated its possible important role during the time of implantation.

Resume Objectif L’objectif de cette etude a ete d’evaluer l’interet de la saturation veineuse centrale en oxygene (ScvO2) dans la decision transfusionnelle en la confrontant aux criteres de la conference de consensus de la Societe de reanimation de langue francaise (2003). Type d’etude Prospectif, observationnel. Patients et methodes Soixante patients de chirurgie generale, hemodynamiquement stables, pour lesquels une transfusion erythrocytaire (TE) etait discutee dans la periode postoperatoire, ont ete inclus. ScvO2 (%) et le taux d’hemoglobine (g/dl) etaient mesures avant et apres TE. Les patients ont ete retrospectivement divises en deux groupes selon la ScvO2 avant TE ( Resultats Chez 25 patients (47,2 % des patients transfuses), la ScvO2 avant transfusion etait superieure ou egale a 70 %. La ScvO2 augmentait (de 57,8 a 68,5 %) dans le groupe « ScvO2 Conclusion La ScvO2 pourrait etre un parametre biologique pertinent pour completer les criteres transfusionnels des recommandations actuelles chez le patient stable porteur d’un catheter veineux central en periode postoperatoire.

Purpose: We analyzed data collected from worldwide centers active in electron IORT with a focus on the technical variables of the treatment. Particular attention was given to the dominant tumor sites. Methods: 54 Mobetron users from 14 countries in clinical operation prior to December 31, 2014, were invited to participate in this study. 29 centers contributed to this survey in sufficient detail to be included in this report. 6,035 patients were treated since 1997. Parameters were analyzed separately for each treatment site. However, special attention was given to the breast cancer, which turned out to be dominant tumor site. Results: The average number of patients treated per year in each center was 41 and exceeded 100 patients/year in 3 centers. For data received, 70% of patients worldwide were treated for breast cancer (93% in Europe, 14% in the U.S. and 21% in Asia). In 31% of cases electron IORT was the only breast irradiation. In breast patients, 9 MeV was used in 50% cases; 4MeV, 6MeV and 12MeV in 2%, 25% and 23% of cases respectively. 85% of patients were treated with field sizes between 4 and 6 cm and 35% of them were treated with 1/2 cm sized applicators. Beveled applicators (0°, 15° and 30° tips) were used in 51%, 33% and 16% of cases respectively. In 55% cases bolus was required with 5mm bolus used twice as often as 10mm. Chest-wall protectors were used in 53% of treatment procedures. For Non-breast data, main sites were: colorectal tumors (31%), pancreatic cancers (20%), extremity sarcomas (13%) and retroperitoneal sarcomas (5%). Conclusion: A large variety of tumors have been treated with IORT, with breast, colorectal, pancreas and sarcomas being the most frequently treated sites. This survey shows the most common applicators and energies used to treat each tumor site.

Background This study aimed to evaluate whether exposure to sevoflurane at the onset of reperfusion provides protection similar to sevoflurane preconditioning and whether the effect depends on mitochondrial potassium ATP-dependent channel (mitoKATP) in a rat model of focal cerebral ischaemia. Methods Adult Wistar male rats were subjected to focal cerebral ischaemia for 1 h followed by 24 h or 7 days of reperfusion. Preconditioning consisted of 15 min exposure to sevoflurane at 1 minimum alveolar concentration (2.6%) 72 h before ischaemia. Post-conditioning was performed by exposure to sevoflurane immediately at the onset of reperfusion or by a delayed exposure 5 min after the onset of reperfusion. The role of the mitoKATP channel was assessed by i.p. injection of the selective blocker 5-hydroxydecanoate before each sevoflurane administration or by the mitoKATP channel opener, diazoxide (DZX), given in place of sevoflurane. Cerebral infarct size, neurological deficit score, and motor coordination were evaluated 24 h and 7 days after reperfusion. Results Sevoflurane preconditioning and early post-conditioning reduced both cerebral infarct size and neurological defect score at 24 h of reperfusion whereas the sole sevoflurane post-conditioning improved motor coordination. At 7 days, only infarct volume remained lower in pre- and post-conditioned animals. Neuroprotection mediated by sevoflurane was lost when it was given 5 min after the onset of reperfusion and was abolished by inhibition of mitoKATP. DZX alone mimicked sevoflurane-induced pre- and post-conditioning. Conclusions The pretreatment with sevoflurane or its early administration at reperfusion provides neuroprotection via mitoKATP in a rat model of focal cerebral ischaemia.

The aim of this study was to assess the value of central venous oxygen saturation (ScvO(2)) for the decision of blood transfusion in comparison with the criteria of the French guidelines for blood transfusion (2003).Prospective, observational.Sixty patients, haemodynamically stable, for whom a blood transfusion (BT) was discussed in the postoperative course of general surgery, were included. ScvO(2) (%) and haemoglobin (g/dl) were measured before and after BT. Patients were retrospectively divided into two groups according to ScvO(2) measured before BT (oror=70%). Results are expressed as median.The ScvO(2) before transfusion was greater or equal to 70% in 25 (47.2%) patients. Following BT, the ScvO(2) increased significantly (from 57.8 to 68.5%) in the group with initial ScvO(2) less than 70% whereas it was unchanged in patients with initial ScvO(2) greater or equal 70% (from 76.8 to 76.5%). Twenty patients (37.7%) did not meet the French guidelines for BT criteria. Eighteen patients out of 33 that met the criteria had ScvO(2) greater or equal 70% before BT while 13 patients with ScvO(2) less than 70% were not detected by these same criteria.ScvO(2) could be a relevant biological parameter to complete the current guidelines for BT in stable patient with a central venous catheter during the postoperative period.

The feasibility of measuring dose distributions in three‐dimensions using Gafchromic EBT film was studied. A stack of film was used as tomographic dosimeter. The response of film (4×4 cm2) placed between a stack of Gafchromic EBT films and slabs of polystyrene phantom was tested. Differences in film response for two different photon beam qualities, 6 MV and 25 MV, were observed. Measurements with 6 MV beam quality revealed that for different field sizes and depths there were no changes in response of EBT Gafchromic film when placed between polystyrene plates or sandwiched between other films. However, in the case of 25 MV beam quality, a statistically significant over‐response was found for film placed in stack. We conclude that stacked‐film dosimetry is feasible at 6 MV. For 25 MV photon beam quality the stack of films showed different properties than the polystyrene slabs of the same height.

Approximately one-half of women with cervical cancer are premenopausal. Preservation of ovarian function in these women is highly desirable. The safety and efficacy of ovarian retention include risk of ovarian metastasis, risk of surgery, psychological impact of surgical castration, expense of hormone supplementation.This report compares intra- and postoperative surgical complications in 2 groups of women with cancer in stage Ib and IIa treated by radical hysterectomy (Wertheim-Meigs operation).Two groups were compared: 72 patients with ovarian transposition and 55 women without transposition, but after brachy-HDR therapy. The surgery time was mean 30 minute longer in case of ovarian transposition.There was no difference in mean time of hospital stay after the surgery, the frequency of relaparotomy, deep vein thrombosis, urological complications and blood transfusion between the groups. There was confirmed the higher number of lymphatic pseudocysts (p0.0005) and fever (p0.001) in women without transposition, but after brachy-HDR therapy. We linked this with the previously applied radiotherapy.We conclude that ovarian transposition is the procedure which can safe the endogenous ovarian function in young women with cervical cancer without the higher risk of complications.

Purpose: The aim of this study was to carry out a dosimetric verification of statically planned sliding window IMRT for respiratory‐like moving targets using 2D diode array. Methods: Ten 5‐field IMRT plans for mobile lung tumors were created. The target volumes were delineated on the free breathing CT scans. Three tumor motion trajectories have been simulated, with the largest movement amplitude in cranio‐caudal direction of 4 mm, 6 mm and 8 mm, and breathing periods of 4 s. The breathing motion was simulated using the motion kernels derived from the literature data. The moving platform (MotionSim XY/4D‐Sun Nuclear) with the diode array MapCHECK 2 (Sun Nuclear) was used.The evaluation was based on the Gamma analysis (3mm, 3%). The scoring parameter was the percentage of the field area (defined by the jaws plus 1 cm margin) resulting with γ 95% and average gamma < 0.6). For 6 mm amplitude average score was 94.18% (γ=0.468). However when 8 mm movement of target was applied we have observed significant change in analysed parameters: average score and γ of 83.68% and 0.572, respectively. Conclusion: This study showed that statically planned nonuniform dose distribution could cause the tumor under‐dosage due to interplay effect. It is therefore crucial to verify amplitude of individual patient breathing motion trajectory and take it into account by increased margins.For maximal amplitudes of breathing trajectory below 4 mm the disagreement between planned and delivered dose distribution can be neglected. Whereas respiratory motion with amplitude above 6 mm leads to significant changes in delivered dose distribution.

Thirty-one cards of women after radical vulvectomy in Way's mode were analysed. Metastases in inguinal, thigh, iliac and veil lymph nodes were found only in 19.35%. Authors conclude that removal of iliac and veil lymph nodes can be given up after previously negative outcome of intra-operative examination of inguinal and thigh lymph nodes. Mean period of patient's staying in hospital was long--about 40 days. In 51.6% of cases the blood group was "A", with the mean for the whole country 40.5%.