Switching Off Vascular MAPK Signaling: A Novel Strategy to Prevent Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage.

Patients who initially survive the rupture and repair of a brain aneurysm often take a devastating turn for the worse some days later and die or suffer permanent neurologic deficits. This catastrophic sequela is attributed to a delayed phase of global cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH), but we lack effective treatment. Here we present our view, based on 20 years of research, that the initial drop in blood flow at the time of rupture triggers genomic responses throughout the brain vasculature that manifest days later as increased vasoconstriction and decreased cerebral blood flow. We propose a novel treatment strategy to prevent DCI by early inhibition of the vascular mitogen-activated protein kinase (MAPK) pathway that triggers expression of vasoconstrictor and inflammatory mediators. We summarize evidence from experimental SAH models showing early treatment with MAPK inhibitors "switches off" these detrimental responses, maintains flow, and improves neurological outcome. This promising therapy is currently being evaluated in clinical trials.

A Survey of the National Comprehensive Cancer Network on Approaches Toward Addressing Patients' Transportation Insecurity.

BACKGROUND: Addressing patients' social determinants of health is a national priority for cancer treatment centers. Transportation insecurity is one major challenge for patients undergoing active cancer treatment, and missing treatments can result in worse cancer treatment outcomes, including worse morbidity and mortality. How cancer treatment centers are addressing transportation insecurity is understudied. METHODS: In January and February 2022, the NCCN Best Practices Committee conducted a survey of NCCN's 31 Member Institutions (currently 32 member institutions as of April 2022) to assess how centers were addressing patient transportation insecurity: how they screen for transportation insecurity, coordinate transportation, and fund transportation initiatives, and their plans to address transportation insecurity in the future. RESULTS: A total of 25 of 31 (81%) NCCN Member Institutions responded to the survey, of which 24 (96%) reported supporting the transportation needs of their patients through screening, coordinating, and/or funding transportation. Patients' transportation needs were most often identified by social workers (96%), clinicians (83%), or patients self-declaring their needs (79%). Few centers (33%) used routine screening approaches (eg, universal screening of social risk factors) to systematically identify transportation needs, and 54% used the support of technology platforms or a vendor to coordinate transportation. Transportation was predominantly funded via some combination of philanthropy (88%), grants (63%), internal dollars (63%), and reimbursement from insurance companies (58%). Over the next 12 months, many centers were either going to continue their current transportation programs in their current state (60%) or expand existing programs (32%). CONCLUSIONS: Many NCCN Member Institutions are addressing the transportation needs of their patients. Current efforts are heterogeneous. Few centers have systematic, routine screening approaches, and funding relies on philanthropy more so than institutional dollars or reimbursement from insurers. Opportunities exist to establish more structured, scalable, and sustainable programs for patients' transportation needs.

Measuring Advanced Practice Provider Productivity at the National Comprehensive Cancer Network's Member Institutions.

Introduction: The utilization of advanced practice providers (APPs) in oncology has been growing over the last decade; however, there is no standard method for assessing an APP's contributions to oncology care. Methods: The NCCN Best Practices Committee (BPC) created an APP Workgroup to develop recommendations to support the roles of APPs at NCCN Member Institutions. The Workgroup conducted surveys to understand how NCCN centers measure productivity. This article will review the survey results and provide recommendations for measuring APP productivity. Results: Although 54% of responding centers indicated they utilize relative value units (RVU) targets for independent APP visits, 88% of APPs are either unsure or do not believe RVUs are an effective measurement of overall productivity. Relative value units do not reflect non-billable hours, and APPs perform a significant number of non-billable tasks that are important to oncology practices. Sixty-six percent of APPs believe that measuring disease-based team productivity is a more reasonable assessment of APP productivity than measuring productivity at the individual level. Conclusion: Our recommendation for cancer centers is to focus on the value that APPs provide to overall care delivery. Advanced practice provider productivity metrics should consider not only the number of patients seen by APPs, but also the high quality and thorough care delivered that contributes to the overall care of the patient and practice. Advanced practice providers can help improve access to care, deliver improved outcomes, and increase patient and provider satisfaction. Reducing the focus on RVUs, accounting for important non-RVU-generating activities, and incorporating quality and team metrics will provide a better overall picture of APP productivity.

COVID-19 and Cancer Center Operations: Lessons Learned From the NCCN Best Practices Committee.

The NCCN Best Practices Committee, which is composed of senior physician, nursing, and administrative leaders from NCCN Member Institutions, evaluated the status of cancer center operations after 1 year of operating during the COVID-19 pandemic. Two major initiatives stood out: the increase in the utilization of network sites, and the gains made in telemedicine operations and reimbursement. Experts from NCCN Member Institutions participated in a webinar series in June 2021 to share their experiences, knowledge, and thoughts on these topics and discuss the impact on the future of cancer care.

Ovariectomy Reduces Vasocontractile Responses of Rat Middle Cerebral Arteries After Focal Cerebral Ischemia.

ABSTRACT: Effects of sex hormones on stroke outcome are not fully understood. A deleterious consequence of cerebral ischemia is upregulation of vasoconstrictor receptors in cerebral arteries that exacerbate stroke injury. Here, we tested the hypothesis that female sex hormones alter vasocontractile responses after experimental stroke in vivo or after organ culture in vitro, a model of vasocontractile receptor upregulation. Female rats with intact ovaries and ovariectomized (OVX) females treated with 17ß-estradiol, progesterone, or placebo were subjected to transient, unilateral middle cerebral artery occlusion followed by reperfusion (I/R). The maximum contractile response, measured my wire myography, in response to the endothelin B receptor agonist sarafotoxin 6c was increased in female arteries after I/R, but the maximum response was significantly lower in arteries from OVX females. Maximum contraction mediated by the serotonin agonist 5-carboxamidotryptamine was diminished after I/R, with arteries from OVX females showing a greater decrease in maximum contractile response. Contraction elicited by angiotensin II was similar in all arteries. Neither estrogen nor progesterone treatment of OVX females affected I/R-induced changes in endothelin B- and 5-carboxamidotryptamine-induced vasocontraction. These findings suggest that sex hormones do not directly influence vasocontractile alterations that occur after ischemic stroke; however, loss of ovarian function does impact this process.

A Study of Advanced Practice Provider Staffing Models and Professional Development Opportunities at National Comprehensive Cancer Network Member Institutions.

INTRODUCTION: The National Comprehensive Cancer Network (NCCN) Best Practices Committee created an Advanced Practice Provider (APP) Workgroup to develop recommendations to support APP roles at NCCN Member Institutions. METHODS: The Workgroup conducted three surveys to understand APP program structure, staffing models, and professional development opportunities at NCCN Member Institutions. RESULTS: The total number of new and follow-up visits a 1.0 APP full-time equivalent conducts per week in shared and independent visits ranged from 11 to 97, with an average of 40 visits per week (n = 39). The type of visits APPs conduct include follow-up shared (47.2%), follow-up independent (46%), new shared (6.5%), and new independent visits (0.5%). Seventy-two percent of respondents utilize a mixed model visit type, with 15% utilizing only independent visits and 13% utilizing only shared visits (n = 39). Of the 95% of centers with APP leads, 100% indicated that leads carry administrative and clinical responsibilities (n = 20); however, results varied with respect to how this time is allocated. Professional development opportunities offered included posters, papers, and presentations (84%), leadership development (57%), research opportunities (52%), writing book chapters (19%), and other professional development activities (12%; n = 422). Twenty percent of APPs indicated that protected time to engage in development opportunities should be offered. CONCLUSION: As evidenced by the variability of the survey results, the field would benefit from developing standards for APPs. There is a lack of information regarding leadership structures to help support APPs, and additional research is needed. Additionally, centers should continuously assess the career-long opportunities needed to maximize the value of oncology APPs.

Hormonal influences in migraine - interactions of oestrogen, oxytocin and CGRP.

Migraine is ranked as the second highest cause of disability worldwide and the first among women aged 15-49 years. Overall, the incidence of migraine is threefold higher among women than men, though the frequency and severity of attacks varies during puberty, the menstrual cycle, pregnancy, the postpartum period and menopause. Reproductive hormones are clearly a key influence in the susceptibility of women to migraine. A fall in plasma oestrogen levels can trigger attacks of migraine without aura, whereas higher oestrogen levels seem to be protective. The basis of these effects is unknown. In this Review, we discuss what is known about sex hormones and their receptors in migraine-related areas in the CNS and the peripheral trigeminovascular pathway. We consider the actions of oestrogen via its multiple receptor subtypes and the involvement of oxytocin, which has been shown to prevent migraine attacks. We also discuss possible interactions of these hormones with the calcitonin gene-related peptide (CGRP) system in light of the success of anti-CGRP treatments. We propose a simple model to explain the hormone withdrawal trigger in menstrual migraine, which could provide a foundation for improved management and therapy for hormone-related migraine in women.

Estrogen receptors α, ß and GPER in the CNS and trigeminal system - molecular and functional aspects.

BACKGROUND: Migraine occurs 2-3 times more often in females than in males and is in many females associated with the onset of menstruation. The steroid hormone, 17ß-estradiol (estrogen, E2), exerts its effects by binding and activating several estrogen receptors (ERs). Calcitonin gene-related peptide (CGRP) has a strong position in migraine pathophysiology, and interaction with CGRP has resulted in several successful drugs for acute and prophylactic treatment of migraine, effective in all age groups and in both sexes. METHODS: Immunohistochemistry was used for detection and localization of proteins, release of CGRP and PACAP investigated by ELISA and myography/perfusion arteriography was performed on rat and human arterial segments. RESULTS: ERα was found throughout the whole brain, and in several migraine related structures. ERß was mainly found in the hippocampus and the cerebellum. In trigeminal ganglion (TG), ERα was found in the nuclei of neurons; these neurons expressed CGRP or the CGRP receptor in the cytoplasm. G-protein ER (GPER) was observed in the cell membrane and cytoplasm in most TG neurons. We compared TG from males and females, and females expressed more ER receptors. For neuropeptide release, the only observable difference was a baseline CGRP release being higher in the pro-estrous state as compared to estrous state. In the middle cerebral artery (MCA), we observed similar dilatory ER-responses between males and females, except for vasodilatory ERß which we observed only in female arteries. CONCLUSION: These data reveal significant differences in ER receptor expression between male and female rats. This contrasts to CGRP and PACAP release where we did not observe discernable difference between the sexes. Together, this points to a hypothesis where estrogen could have a modulatory role on the trigeminal neuron function in general rather than on the acute CGRP release mechanisms and vasomotor responses.

Psychology Staffing at Cancer Centers: Data From National Comprehensive Cancer Network Member Institutions.

PURPOSE: The field of psycho-oncology is relatively undeveloped, with little information existing regarding the use of psychologists at cancer centers. Comprising 30 leading cancer centers across the United States, the National Comprehensive Cancer Network (NCCN) set out to understand the trends in its Member Institutions. METHODS: The NCCN Best Practices Committee surveyed NCCN Member Institutions regarding their use of psychologists. The survey was administered electronically in the spring/summer of 2017. RESULTS: The survey was completed by 18 cancer centers. Across institutions, 94% have psychologists appointed to provide direct care to their cancer center patients. The number of licensed psychologist full-time equivalents (FTEs) on staff who provide direct patient care ranged from < 1.0 FTE (17%) to 17.0-17.9 FTEs (6%). Regarding psychologist appointments, 41% have both faculty and staff appointments, 41% have all faculty appointments, and 18% have all staff appointments. Forty-three percent of institutions indicated that some licensed psychologists at their centers (ranging from 1%-65%) do not provide any direct clinical care, and 57% indicated that all licensed psychologist on staff devote some amount of time to direct clinical care. The percent of clinical care time that is spent on direct clinical care ranged from 15%-90%. CONCLUSION: There is great variability in psychology staffing, academic appointments, and the amount of direct patient care provided by on-staff psychologists at cancer centers.

Current Practices for Screening and Management of Financial Distress at NCCN Member Institutions.

BACKGROUND: Financial distress from medical treatment is an increasing concern. Healthcare organizations may have different levels of organizational commitment, existing programs, and expected outcomes of screening and management of patient financial distress. PATIENTS AND METHODS: In November 2018, representatives from 17 (63%) of the 27 existing NCCN Member Institutions completed an online survey. The survey focused on screening and management practices for patient financial distress, perceived barriers in implementation, and leadership attitudes about such practices. Due to the lack of a validated questionnaire in this area, survey questions were generated after a comprehensive literature search and discussions among the study team, including NCCN Best Practices Committee representatives. RESULTS: Responses showed that 76% of centers routinely screened for financial distress, mostly with social worker assessment (94%), and that 56% screened patients multiple times. All centers offered programs to help with drug costs, meal or gas vouchers, and payment plans. Charity care was provided by 100% of the large centers (≥10,000 unique annual patients) but none of the small centers that responded (<10,000 unique annual patients; P=.008). Metrics to evaluate the impact of financial advocacy services included number of patients assisted, bad debt/charity write-offs, or patient satisfaction surveys. The effectiveness of institutional practices for screening and management of financial distress was reported as poor/very poor by 6% of respondents. Inadequate staffing and resources, limited budget, and lack of reimbursement were potential barriers in the provision of these services. A total of 94% agreed with the need for better integration of financial advocacy into oncology practice. CONCLUSIONS: Three-fourths of NCCN Member Institutions reported screening and management programs for financial distress, although the actual practices and range of services vary. Information from this study can help centers benchmark their performance relative to similar programs and identify best practices in this area.

Oxytocin as a regulatory neuropeptide in the trigeminovascular system: Localization, expression and function of oxytocin and oxytocin receptors.

BACKGROUND: Recent clinical findings suggest that oxytocin could be a novel treatment for migraine. However, little is known about the role of this neuropeptide/hormone and its receptor in the trigeminovascular pathway. Here we determine expression, localization, and function of oxytocin and oxytocin receptors in rat trigeminal ganglia and targets of peripheral (dura mater and cranial arteries) and central (trigeminal nucleus caudalis) afferents. METHODS: The methods include immunohistochemistry, messenger RNA measurements, quantitative PCR, release of calcitonin gene-related peptide and myography of arterial segments. RESULTS: Oxytocin receptor mRNA was expressed in rat trigeminal ganglia and the receptor protein was localized in numerous small to medium-sized neurons and thick axons characteristic of A∂ sensory fibers. Double immunohistochemistry revealed only a small number of neurons expressing both oxytocin receptors and calcitonin gene-related peptide. In contrast, double immunostaining showed expression of the calcitonin gene-related peptide receptor component receptor activity-modifying protein 1 and oxytocin receptors in 23% of the small cells and in 47% of the medium-sized cells. Oxytocin immunofluorescence was observed only in trigeminal ganglia satellite glial cells. Oxytocin mRNA was below detection limit in the trigeminal ganglia. The trigeminal nucleus caudalis expressed mRNA for both oxytocin and its receptor. K+-evoked calcitonin gene-related peptide release from either isolated trigeminal ganglia or dura mater and it was not significantly affected by oxytocin (10 µM). Oxytocin directly constricted cranial arteries ex vivo (pEC50 ∼ 7); however, these effects were inhibited by the vasopressin V1A antagonist SR49059. CONCLUSION: Oxytocin receptors are extensively expressed throughout the rat trigeminovascular system and in particular in trigeminal ganglia A∂ neurons and fibers, but no functional oxytocin receptors were demonstrated in the dura and cranial arteries. Thus, circulating oxytocin may act on oxytocin receptors in the trigeminal ganglia to affect nociception transmission. These effects may help explain hormonal influences in migraine and offer a novel way for treatment.

The distribution of oxytocin and the oxytocin receptor in rat brain: relation to regions active in migraine.

BACKGROUND: Recent work, both clinical and experimental, suggests that the hypothalamic hormone oxytocin (OT) and its receptor (OTR) may be involved in migraine pathophysiology. In order to better understand possible central actions of OT in migraine/headache pathogenesis, we mapped the distribution of OT and OTR in nerve cells and fibers in rat brain with a focus on areas related to migraine attacks and/or shown previously to contain calcitonin gene related peptide (CGRP), another neuropeptide involved in migraine. METHODS: Distribution of OT and OTR in the adult, rat brain was qualitatively examined with immunohistochemistry using a series of well characterized specific antibodies. RESULTS: As expected, OT was extensively localized in the cell somas of two hypothalamic nuclei, the supraoptic (SO or SON) and paraventricular nuclei (Pa or PVN). OT also was found in many other regions of the brain where it was localized mainly in nerve fibers. In contrast, OTR staining in the brain was mainly observed in cell somas with very little expression in fibers. The most distinct OTR expression was found in the hippocampus, the pons and the substantia nigra. In some regions of the brain (e.g. the amygdala and the hypothalamus), both OT and OTR were expressed (match). Mismatch between the peptide and its receptor was primarily observed in the cerebral and cerebellar cortex (OT expression) and hippocampus (OTR expression). CONCLUSIONS: We compared OT/OTR distribution in the CNS with that of CGRP and identified regions related to migraine. In particular, regions suggested as "migraine generators", showed correspondence among the three mappings. These findings suggest central OT pathways may contribute to the role of the hypothalamus in migraine attacks.

C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system.

BACKGROUND: Monoclonal antibodies (mAbs) towards CGRP or the CGRP receptor show good prophylactic antimigraine efficacy. However, their site of action is still elusive. Due to lack of passage of mAbs across the blood-brain barrier the trigeminal system has been suggested a possible site of action because it lacks blood-brain barrier and hence is available to circulating molecules. The trigeminal ganglion (TG) harbors two types of neurons; half of which store CGRP and the rest that express CGRP receptor elements (CLR/RAMP1). METHODS: With specific immunohistochemistry methods, we demonstrated the localization of CGRP, CLR, RAMP1, and their locations related to expression of the paranodal marker contactin-associated protein 1 (CASPR). Furthermore, we studied functional CGRP release separately from the neuron soma and the part with only nerve fibers of the trigeminal ganglion, using an enzyme-linked immunosorbent assay. RESULTS: Antibodies towards CGRP and CLR/RAMP1 bind to two different populations of neurons in the TG and are found in the C- and the myelinated Aδ-fibers, respectively, within the dura mater and in trigeminal ganglion (TG). CASPR staining revealed paranodal areas of the different myelinated fibers inhabiting the TG and dura mater. Double immunostaining with CASPR and RAMP1 or the functional CGRP receptor antibody (AA58) revealed co-localization of the two peptides in the paranodal region which suggests the presence of the CGRP-receptor. Double immunostaining with CGRP and CASPR revealed that thin C-fibers have CGRP-positive boutons which often localize in close proximity to the nodal areas of the CGRP-receptor positive Aδ-fibers. These boutons are pearl-like synaptic structures, and we show CGRP release from fibers dissociated from their neuronal bodies. In addition, we found that adjacent to the CGRP receptor localization in the node of Ranvier there was PKA immunoreactivity (kinase stimulated by cAMP), providing structural possibility to modify conduction activity within the Aδ-fibers. CONCLUSION: We observed a close relationship between the CGRP containing C-fibers and the Aδ-fibers containing the CGRP-receptor elements, suggesting a point of axon-axon interaction for the released CGRP and a site of action for gepants and the novel mAbs to alleviate migraine.

National Comprehensive Cancer Network Infusion Efficiency Workgroup Study: Optimizing Patient Flow in Infusion Centers.

PURPOSE: The National Comprehensive Cancer Network (NCCN) formed an Infusion Efficiency Workgroup to determine best practices for operating efficient and effective infusion centers. METHODS: The Workgroup conducted three surveys that were distributed to NCCN member institutions regarding average patient wait time, chemotherapy premixing practices, infusion chair use, and premedication protocols. To assess chair use, the Workgroup identified and defined five components of chair time. RESULTS: The average patient wait time in infusion centers ranged from 25 to 102 minutes (n = 23; mean, 58 minutes). Five of 26 cancer centers (19%) routinely mix chemotherapy drugs before patient arrival for patients meeting specified criteria. Total planned chair time for subsequent doses of the same drug regimens for the same diseases varied greatly among centers, as follows: Administration of doxorubicin and cyclophosphamide ranged from 85 to 240 minutes (n = 22); of FOLFIRINOX (folinic acid, fluorouracil, irinotecan hydrochloride, and oxaliplation) ranged from 270 to 420 minutes (n = 22); of rituximab ranged from 120 to 350 minutes (n = 21); of paclitaxel plus carboplatin ranged from 255 to 380 minutes (n = 21); and of zoledronic acid ranged from 30 to 150 minutes (n = 22) for planned total chair time. Cancer centers were found to use different premedication regimens with varying administration routes that ranged in administration times from zero to 60 minutes. CONCLUSION: There is a high degree of variation among cancer centers in regard to planned chair time for the same chemotherapy regimens, providing opportunities for improved efficiency, increased revenue, and more standardization across centers. The NCCN Workgroup demonstrates potential revenue impact and provides recommendations for cancer centers to move toward more efficient and more standard practices.

CGRP as the target of new migraine therapies - successful translation from bench to clinic.

Treatment of migraine is on the cusp of a new era with the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are expected to receive approval for use in migraine headache in 2018 and 2019. CGRP-related therapies offer considerable improvements over existing drugs as they are the first to be designed specifically to act on the trigeminal pain system, they are more specific and they seem to have few or no adverse effects. CGRP receptor antagonists such as ubrogepant are effective for acute relief of migraine headache, whereas monoclonal antibodies against CGRP (eptinezumab, fremanezumab and galcanezumab) or the CGRP receptor (erenumab) effectively prevent migraine attacks. As these drugs come into clinical use, we provide an overview of knowledge that has led to successful development of these drugs. We describe the biology of CGRP signalling, summarize key clinical evidence for the role of CGRP in migraine headache, including the efficacy of CGRP-targeted treatment, and synthesize what is known about the role of CGRP in the trigeminovascular system. Finally, we consider how the latest findings provide new insight into the central role of the trigeminal ganglion in the pathophysiology of migraine.

U0126 attenuates cerebral vasoconstriction and improves long-term neurologic outcome after stroke in female rats.

Sex differences are well known in cerebral ischemia and may impact the effect of stroke treatments. In male rats, the MEK1/2 inhibitor U0126 reduces ischemia-induced endothelin type B (ETB) receptor upregulation, infarct size and improves acute neurologic function after experimental stroke. However, responses to this treatment in females and long-term effects on outcome are not known. Initial experiments used in vitro organ culture of cerebral arteries, confirming ERK1/2 activation and increased ETB receptor-mediated vasoconstriction in female cerebral arteries. Transient middle cerebral artery occlusion (tMCAO, 120 minutes) was induced in female Wistar rats, with U0126 (30 mg/kg intraperitoneally) or vehicle administered at 0 and 24 hours of reperfusion, or with no treatment. Infarct volumes were determined and neurologic function was assessed by 6-point and 28-point neuroscores. ETB receptor-mediated contraction was studied with myograph and protein expression with immunohistochemistry. In vitro organ culture and tMCAO resulted in vascular ETB receptor upregulation and activation of ERK1/2 that was prevented by U0126. Although no effect on infarct size, U0126 improved the long-term neurologic function after experimental stroke in female rats. In conclusion, early prevention of the ERK1/2 activation and ETB receptor-mediated vasoconstriction in the cerebral vasculature after ischemic stroke in female rats improves the long-term neurologic outcome.

Genomic and non-genomic regulation of PGC1 isoforms by estrogen to increase cerebral vascular mitochondrial biogenesis and reactive oxygen species protection.

We previously found that estrogen exerts a novel protective effect on mitochondria in brain vasculature. Here we demonstrate in rat cerebral blood vessels that 17ß-estradiol (estrogen), both in vivo and ex vivo, affects key transcriptional coactivators responsible for mitochondrial regulation. Treatment of ovariectomized rats with estrogen in vivo lowered mRNA levels of peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α) but increased levels of the other PGC-1 isoforms: PGC-1ß and PGC-1 related coactivator (PRC). In vessels ex vivo, estrogen decreased protein levels of PGC-1α via activation of phosphatidylinositol 3-kinase (PI3K). Estrogen treatment also increased phosphorylation of forkhead transcription factor, FoxO1, a known pathway for PGC-1α downregulation. In contrast to the decrease in PGC-1α, estrogen increased protein levels of nuclear respiratory factor 1, a known PGC target and mediator of mitochondrial biogenesis. The latter effect of estrogen was independent of PI3K, suggesting a separate mechanism consistent with increased expression of PGC-1ß and PRC. We demonstrated increased mitochondrial biogenesis following estrogen treatment in vivo; cerebrovascular levels of mitochondrial transcription factor A and electron transport chain subunits as well as the mitochondrial/nuclear DNA ratio were increased. We examined a downstream target of PGC-1ß, glutamate-cysteine ligase (GCL), the rate-limiting enzyme for glutathione synthesis. In vivo estrogen increased protein levels of both GCL subunits and total glutathione levels. Together these data show estrogen differentially regulates PGC-1 isoforms in brain vasculature, underscoring the importance of these coactivators in adapting mitochondria in specific tissues. By upregulating PGC-1ß and/or PRC, estrogen appears to enhance mitochondrial biogenesis, function and reactive oxygen species protection.

Male-female differences in upregulation of vasoconstrictor responses in human cerebral arteries.

BACKGROUND AND PURPOSE: Male-female differences may significantly impact stroke prevention and treatment in men and women, however underlying mechanisms for sexual dimorphism in stroke are not understood. We previously found in males that cerebral ischemia upregulates contractile receptors in cerebral arteries, which is associated with lower blood flow. The present study investigates if cerebral arteries from men and women differ in cerebrovascular receptor upregulation. EXPERIMENTAL APPROACH: Freshly obtained human cerebral arteries were placed in organ culture, an established model for studying receptor upregulation. 5-hydroxtryptamine type 1B (5-HT1B), angiotensin II type 1 (AT1) and endothelin-1 type A and B (ETA and ETB) receptors were evaluated using wire myograph for contractile responses, real-time PCR for mRNA and immunohistochemistry for receptor expression. KEY RESULTS: Vascular sensitivity to angiotensin II and endothelin-1 was markedly lower in cultured cerebral arteries from women as compared to men. ETB receptor-mediated contraction occurred in male but not female arteries. Interestingly, there were similar upregulation in mRNA and expression of 5-HT1B, AT1, and ETB receptors and in local expression of Ang II after organ culture. CONCLUSIONS AND IMPLICATIONS: In spite of receptor upregulation after organ culture in both sexes, cerebral arteries from women were significantly less responsive to vasoconstrictors angiotensin II and endothelin-1 as compared to arteries from men. This suggests receptor coupling and/or signal transduction mechanisms involved in cerebrovascular contractility may be suppressed in females. This is the first study to demonstrate sex differences in the vascular function of human brain arteries.

Endogenous ovarian hormones affect mitochondrial efficiency in cerebral endothelium via distinct regulation of PGC-1 isoforms.

Mitochondria support the energy-intensive functions of brain endothelium but also produce damaging-free radicals that lead to disease. Previously, we found that estrogen treatment protects cerebrovascular mitochondria, increasing capacity for ATP production while decreasing reactive oxygen species (ROS). To determine whether these effects occur specifically in endothelium in vivo and also explore underlying transcriptional mechanisms, we studied freshly isolated brain endothelial preparations from intact and ovariectomized female mice. This preparation reflects physiologic influences of circulating hormones, hemodynamic forces, and cell-cell interactions of the neurovascular unit. Loss of ovarian hormones affected endothelial expression of the key mitochondrial regulator family, peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1), but in a unique way. Ovariectomy increased endothelial PGC-1α mRNA but decreased PGC-1ß mRNA. The change in PGC-1ß correlated with decreased mRNA for crucial downstream mitochondrial regulators, nuclear respiratory factor 1 and mitochondrial transcription factor A, as well as for ATP synthase and ROS protection enzymes, glutamate-cysteine ligase and manganese superoxide dismutase. Ovariectomy also decreased mitochondrial biogenesis (mitochondrial/nuclear DNA ratio). These results indicate ovarian hormones normally act through a distinctive regulatory pathway involving PGC-1ß to support cerebral endothelial mitochondrial content and guide mitochondrial function to favor ATP coupling and ROS protection.

Consequences of manipulation in organizations: two studies on its effects on emotions and relationships.

This investigation analyzes the correlates of manipulation in organizations with respect to employees' emotions and interpersonal relationships. In Study 1, twelve tactics were identified as manipulative from a set of 115 tactics. For example: "steer the other person subliminally in a certain direction by using clever arguments," "form covert networks or coalitions," "pretend to build trust and to help the other person with work," "withhold, filter, or falsify information," and "interpret the existing rules in own way, exploit ambiguity." In Study 2, manipulative cases (N = 208) were analyzed. Factor analyses showed three factors of postmanipulation emotions (evaluation, potency, activation). Results showed that the evaluative emotions were significantly more negative and activated emotions were less negative among manipulated employees than among manipulators, whereas the potency emotions in both groups were not significantly different. The deterioration that manipulation caused in relationships was perceived less by manipulators than by the manipulated employees. Conclusions about interpersonal mistrust's resistance to change after manipulation are explained.