Lebanon VA Medical Center

The purpose of these studies was to examine the role of cytokines in the pathogenesis of cisplatin nephrotoxicity. Injection of mice with cisplatin (20 mg/kg) led to severe renal failure. The expression of cytokines, chemokines, and ICAM-1 in kidney was measured by ribonuclease protection assays and RT-PCR. We found significant upregulation of TNF-α, TGF-β, RANTES, MIP-2, MCP-1, TCA3, IL-1β, and ICAM-1 in kidneys from cisplatin-treated animals. In addition, serum, kidney, and urine levels of TNF-α measured by ELISA were increased by cisplatin. Inhibitors of TNF-α production (GM6001, pentoxifylline) and TNF-α Ab’s reduced serum and kidney TNF-α protein levels and also blunted the cisplatin-induced increases in TNF-α, TGF-β, RANTES, MIP-2, MCP-1, and IL-1β, but not ICAM-1, mRNA. In addition, the TNF-α inhibitors also ameliorated cisplatin-induced renal dysfunction and reduced cisplatin-induced structural damage. Likewise, TNF-α–deficient mice were resistant to cisplatin nephrotoxicity. These results indicate cisplatin nephrotoxicity is characterized by activation of proinflammatory cytokines and chemokines. TNF-α appears to play a central role in the activation of this cytokine response and also in the pathogenesis of cisplatin renal injury.

A number of effective, low-cost strategies are available to identify and treat the person at risk for diabetic foot ulcers and lower-extremity amputation. These strategies must be more widely adopted by all diabetic care providers to maintain the integrity and function of the lower limb, and thus improve the quality of life for people with diabetes.

The molecular mechanisms of acute kidney injury (AKI) remain unclear. Toll-like receptors (TLRs), widely expressed on leukocytes and kidney epithelial cells, regulate innate and adaptive immune responses. The present study examined the role of TLR signaling in cisplatin-induced AKI. Cisplatin-treated wild-type mice had significantly more renal dysfunction, histologic damage, and leukocytes infiltrating the kidney than similarly treated mice with a targeted deletion of TLR4 [Tlr4(-/-)]. Levels of cytokines in serum, kidney, and urine were increased significantly in cisplatin-treated wild-type mice compared with saline-treated wild-type mice and cisplatin-treated Tlr4(-/-) mice. Activation of JNK and p38, which was associated with cisplatin-induced renal injury in wild-type mice, was significantly blunted in Tlr4(-/-) mice. Using bone marrow chimeric mice, it was determined that renal parenchymal TLR4, rather than myeloid TLR4, mediated the nephrotoxic effects of cisplatin. Therefore, activation of TLR4 on renal parenchymal cells may activate p38 MAPK pathways, leading to increased production of inflammatory cytokines, such as TNF-alpha and subsequent kidney injury. Targeting the TLR4 signaling pathways may be a feasible therapeutic strategy to prevent cisplatin-induced AKI in humans.

Cisplatin produces acute renal failure in humans and mice. Previous studies have shown that cisplatin upregulates the expression of TNF-alpha in mouse kidney and that inhibition of either the release or action of TNF-alpha protects the kidney from cisplatin-induced nephrotoxicity. In this study, we examined the effect of cisplatin on the expression of TNF receptors TNFR1 and TNFR2 in the kidney and the role of each receptor in mediating cisplatin nephrotoxicity. Injection of cisplatin into C57BL/6 mice led to an upregulation of TNFR1 and TNFR2 mRNA levels in the kidney. The upregulation of TNFR2 but not TNFR1 was blunted in TNF-alpha-deficient mice, indicating ligand-dependent upregulation of TNFR2. To study the roles of each receptor, we administered cisplatin to TNFR1- or TNFR2-deficient mice. TNFR2-deficient mice developed less severe renal dysfunction and showed reduced necrosis and apoptosis and leukocyte infiltration into the kidney compared with either TNFR1-deficient or wild-type mice. Moreover, renal TNF-alpha expression, ICAM-1 expression, and serum TNF-alpha levels were lower in TNFR2-deficient mice compared with wild-type or TNFR1-deficient mice treated with cisplatin. These results indicate that TNFR2 participates in cisplatin-induced renal injury in mice and may play an important role in TNF-alpha-mediated inflammation in the kidney in response to cisplatin.

We tested the hypothesis that differences in sympathetic reflex responses to head-up tilt (HUT) between males (n = 9) and females (n = 8) were associated with decrements in postural vasomotor responses in women. Muscle sympathetic nerve activity (MSNA; microneurography), heart rate, stroke volume (SV; Doppler), and blood pressure (Finapres) were measured during a progressive HUT protocol (5 min at each of supine, 20 degrees, 40 degrees, and 60 degrees ). MSNA and hemodynamic responses were also measured during the cold pressor test (CPT) to examine nonbaroreflex neurovascular control. SV was normalized to body surface area (SV(i)) to calculate the index of cardiac output (Q(i)), and total peripheral resistance (TPR). During HUT, heart rate increased more in females versus males (P < 0.001) and SV(i) and Q(i) decreased similarly in both groups. Mean arterial pressure (MAP) increased to a lesser extent in females versus males in the HUT (P < 0.01) but increases in TPR during HUT were similar. MSNA burst frequency was lower in females versus males in supine (P < 0.03) but increased similarly during HUT. Average amplitude/burst increased in 60 degrees HUT for males but not females. Both males and females demonstrated an increase in MAP as well as MSNA burst frequency, mean burst amplitude, and total MSNA during the CPT. However, compared with females, males demonstrated a greater neural response (DeltaTotal MSNA) due to a larger increase in mean burst amplitude (P < 0.05). Therefore, these data point to gender-specific autonomic responses to cardiovascular stress. The different MSNA response to postural stress between genders may contribute importantly to decrements in blood pressure control during HUT in females.

To identify the prevalence of traumatic brain injury (TBI), posttraumatic stress disorder (PTSD), and pain in Veterans from Operation Iraqi Freedom/Operation Enduring Freedom/Operation New Dawn (OIF/OEF/OND), Veterans who received any inpatient or outpatient care from Veterans Health Administration (VHA) facilities from 2009 to 2011 were studied. A subset of Veterans was identified who were diagnosed with TBI, PTSD, and/or pain (head, neck, or back) as determined by their International Classification of Diseases-9th Revision-Clinical Modification codes. Between fiscal years 2009 and 2011, 613,391 Veterans accessed VHA services at least once (age: 31.9 +/- 9.6 yr). TBI diagnosis in any 1 year was slightly less than 7%. When data from 3 years were pooled, 9.6% were diagnosed with TBI, 29.3% were diagnosed with PTSD, and 40.2% were diagnosed with pain. The full polytrauma triad expression (TBI, PTSD, and pain) was diagnosed in 6.0%. Results show that increasing numbers of Veterans from OIF/OEF/OND accessed VHA over a 3 year period. Among those with a TBI diagnosis, the majority also had a mental health disorder, with approximately half having both PTSD and pain. While the absolute number of Veterans increased by over 40% from 2009 to 2011, the proportion of Veterans diagnosed with TBI and the high rate of comorbid PTSD and pain in this population remained relatively stable.

The medical education community is working-across disciplines and across the continuum-to address the current challenges facing the medical education system and to implement strategies to improve educational outcomes. Educational technology offers the promise of addressing these important challenges in ways not previously possible. The authors propose a role for virtual patients (VPs), which they define as multimedia, screen-based interactive patient scenarios. They believe VPs offer capabilities and benefits particularly well suited to addressing the challenges facing medical education. Well-designed, interactive VP-based learning activities can promote the deep learning that is needed to handle the rapid growth in medical knowledge. Clinically oriented learning from VPs can capture intrinsic motivation and promote mastery learning. VPs can also enhance trainees' application of foundational knowledge to promote the development of clinical reasoning, the foundation of medical practice. Although not the entire solution, VPs can support competency-based education. The data created by the use of VPs can serve as the basis for multi-institutional research that will enable the medical education community both to better understand the effectiveness of educational interventions and to measure progress toward an improved system of medical education.

SUMMARY: Between October 1991 and December 1995, a total of 22 patients (23 knees) underwent meniscal transplantation with nonirradiated, cryopreserved allografts. Implantation was arthroscopically assisted using bone plugs to prevent meniscal extrusion and maintain weight-bearing functional position. Patients were evaluated with an average follow-up of 40 months (range, 13 to 69 months) using the International Knee Documentation Committee, Lysholm, and Tegner scoring systems. The most significant finding was pain reduction after implantation. Lateral and standing anteroposterior radiographs were obtained on all patients at follow-up with an average joint space loss of 0.882 mm (range, 0 to 3 mm). Magnetic resonance imaging was preformed on both knees in 12 of the 22 patients at an average of 24.4 months postoperatively. On average, the allograft meniscus was 63% (range, 31% to 100%) the size of the normal meniscus. Clinical results showed improvement of preoperative pain in all patients. Although patients continue to have good pain relief following their meniscal allograft transplantation, the average shrinkage in the size of the meniscus as shown on magnetic resonance imaging is a concern.

PURPOSE: p95HER2 is an NH(2)-terminally truncated form of HER2 that lacks the trastuzumab binding site and is therefore thought to confer resistance to trastuzumab treatment. In this report, we introduce a new antibody that has enabled the first direct quantitative measurement of p95HER2 in formalin-fixed paraffin-embedded (FFPE) breast cancer tissues. We sought to show that quantitative p95HER2 levels would correlate with outcome in trastuzumab-treated HER2-positive metastatic breast cancer. EXPERIMENTAL DESIGN: The novel p95HER2 antibody used here was characterized for sensitivity, specificity, and selectivity over full-length HER2. Quantitative p95HER2 levels were measured in 93 metastatic breast tumors using a VeraTag FFPE assay to determine the correlation of p95HER2 levels with outcomes. RESULTS: Within a cohort of trastuzumab-treated metastatic breast cancer patients, high levels of p95HER2 were found to correlate with shorter progression-free survival [hazard ratio (HR), 1.9; P = 0.017] and overall survival (HR, 2.2; P = 0.012) in patients with tumors selected to be HER2 positive by the VeraTag HER2 assay. For those with tumors found to be fluorescence in situ hybridization positive, elevated p95HER2 correlated similarly with shorter progression-free survival (HR, 1.8; P = 0.022) and overall survival (HR, 2.2; P = 0.009). CONCLUSIONS: We have successfully generated an antibody that can specifically detect p95HER2, and developed an assay to quantify expression in FFPE tumor specimens. Using this novel assay, we have identified a group of HER2-positive patients expressing p95HER2 that have a worse outcome while on trastuzumab. As p95HER2 retains sensitivity to kinase inhibitors, measurement of p95HER2 in breast tumor sections may be useful in guiding treatment for patients with HER2-positive breast cancer.

Inflammation contributes to the pathogenesis of acute kidney injury. Dendritic cells (DCs) are immune sentinels with the ability to induce immunity or tolerance, but whether they mediate acute kidney injury is unknown. Here, we studied the distribution of DCs within the kidney and the role of DCs in cisplatin-induced acute kidney injury using a mouse model in which DCs express both green fluorescence protein and the diphtheria toxin receptor. DCs were present throughout the tubulointerstitium but not in glomeruli. We used diphtheria toxin to deplete DCs to study their functional significance in cisplatin nephrotoxicity. Mice depleted of DCs before or coincident with cisplatin treatment but not at later stages experienced more severe renal dysfunction, tubular injury, neutrophil infiltration and greater mortality than nondepleted mice. We used bone marrow chimeric mice to confirm that the depletion of CD11c-expressing hematopoietic cells was responsible for the enhanced renal injury. Finally, mixed bone marrow chimeras demonstrated that the worsening of cisplatin nephrotoxicity in DC-depleted mice was not a result of the dying or dead DCs themselves. After cisplatin treatment, expression of MHC class II decreased and expression of inducible co-stimulator ligand increased on renal DCs. These data demonstrate that resident DCs reduce cisplatin nephrotoxicity and its associated inflammation.

We compared reflex responses to static handgrip at 30% maximal voluntary contraction (MVC) in 10 women (mean age 24.1 +/- 1.7 yr) during two phases of their ovarian cycle: the menstrual phase (days 1-4) and the follicular phase (days 10-12). Changes in muscle sympathetic nerve activity (MSNA; microneurography) in response to static exercise were greater during the menstrual compared with follicular phase (phase effect P = 0.01). Levels of estrogen were less during the menstrual phase (75 +/- 5.5 vs. 116 +/- 9.6 pg/ml, days 1-4 vs. days 10-12; P = 0.002). Generated tension did not explain differences in MSNA responses (MVC: 29.3 +/- 1.3 vs. 28.2 +/- 1.5 kg, days 1-4 vs. days 10-12; P = 0.13). In a group of experiments with the use of 31P-NMR spectroscopy, no phase effect was observed for H+ and H2PO-4 concentrations (n = 5). During an ischemic rhythmic handgrip paradigm (20% MVC), a phase effect was not observed for MSNA or H+ or H2PO-4 concentrations, suggesting that blood flow was necessary for the expression of the cycle-related effect. The present studies suggest that, during static handgrip exercise, MSNA is increased during the menstrual compared with the follicular phase of the ovarian cycle.

Medications for treating alcohol dependence primarily have been adjunctive interventions, and only three medications--disulfiram, naltrexone, and acamprosate--are approved for this indication by the U.S. Food and Drug Administration. Disulfiram, an aversive agent that has been used for more than 40 years, has significant adverse effects and compliance difficulties with no clear evidence that it increases abstinence rates, decreases relapse rates, or reduces cravings. In contrast, naltrexone, an anticraving agent, reduces relapse rates and cravings and increases abstinence rates. Acamprosate also reduces relapse rates and increases abstinence rates. Serotonergic and anticonvulsant agents promise to play more of a role in the treatment of alcohol dependence. Although not approved by the U.S. Food and Drug Administration for this indication, the anticonvulsant topiramate and several serotonergic agents (e.g., fluoxetine, ondansetron) have been shown in recent studies to increase abstinence rates and decrease drinking.

We controlled the spread of epidemic methicillin-resistant Staphylococcus aureus (MRSA) infection in an 884-bed veterans' facility by cohorting known active MRSA carriers and MRSA-infected patients on one nursing unit. Simultaneously, all previously-institutionalized transfers into the veterans' facility were screened with swab cultures for MRSA at the time of admission. All MRSA patients were maintained on contact (gown and glove) or strict isolation and treated aggressively with topical and enteral antibiotics with the assistance of the infectious disease consultant. The monthly incidence of new MRSA patients dropped from a maximum of 16 per month to three or less per month within six months of instituting these infection control measures. There were no further MRSA bacteremias after the establishment of the MRSA cohort in a single unit. Aggressive cohort management of known MRSA patients and screening of previously-institutionalized patients on admission for MRSA controlled epidemic MRSA in this large institution.

We examined whether ATP stimulation of P2X purinoceptors would raise blood pressure in decerebrate cats. Femoral arterial injection of the P2X receptor agonist alpha,beta-methylene ATP into the blood supply of the triceps surae muscle induced a dose-dependent increase in arterial blood pressure. The maximal increase in mean arterial pressure (MAP) evoked by 0.1, 0.2, and 0.5 mM alpha,beta-methylene ATP (0.5 ml/min injection rate) was 6.2 +/- 2.5, 22.5 +/- 4.4, and 35.2 +/- 3.9 mmHg, respectively. The P2X receptor antagonist pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (2 mM ia) attenuated the increase in MAP elicited by intra-arterial alpha,beta-methylene ATP (0.5 mM), whereas the P2Y receptor antagonist reactive blue 2 (2 mM ia) did not affect the MAP response to alpha,beta-methylene ATP. In a second group of experiments, we tested the hypothesis that ATP acting through P2X receptors would sensitize muscle afferents and, thereby, augment the blood pressure response to muscle stretch. Two kilograms of muscle stretch evoked a 26.5 +/- 4.3 mmHg increase in MAP. This MAP response was enhanced when 2 mM ATP or 0.1 mM alpha,beta-methylene ATP (0.5 ml/min) was arterially infused 10 min before muscle stretch. Furthermore, this effect of ATP on the pressor response to stretch was attenuated by 2 mM pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (P < 0.05) but not by the P1 purinoceptor antagonist 8-(p-sulfophenyl)-theophylline (2 mM). These data indicate that activation of ATP-sensitive P2X receptors evokes a skeletal muscle afferent-mediated pressor response and that ATP at relatively low doses enhances the muscle pressor response to stretch via engagement of P2X receptors.

Obstructive apnea and voluntary breath holding are associated with transient increases in muscle sympathetic nerve activity (MSNA) and arterial pressure. The contribution of changes in blood flow relative to the contribution of changes in vascular resistance to the apnea-induced transient rise in arterial pressure is unclear. We measured heart rate, mean arterial blood pressure (MAP), MSNA (peroneal microneurography), and femoral artery blood velocity (V(FA), Doppler) in humans during voluntary end-expiratory apnea while they were exposed to room air, hypoxia (10.5% inspiratory fraction of O2), and hyperoxia (100% inspiratory fraction of O2). Changes from baseline of leg blood flow (Q) and vascular resistance (R) were estimated from the following relationships: Q proportional to V(FA), corrected for the heart rate, and R proportional to MAP/Q. During apnea, MSNA rose; this rise in MSNA was followed by a rise in MAP, which peaked a few seconds after resumption of breathing. Responses of MSNA and MAP to apnea were greatest during hypoxia and smallest during hyperoxia (P < 0.05 for both compared with room air breathing). Similarly, apnea was associated with a decrease in Q and an increase in R. The decrease in Q was greatest during hypoxia and smallest during hyperoxia (-25 +/- 3 vs. -6 +/- 4%, P < 0.05), and the increase in R was the greatest during hypoxia and the least during hyperoxia (60 +/- 8 vs. 21 +/- 6%, P < 0.05). Thus voluntary apnea is associated with vasoconstriction, which is in part mediated by the sympathetic nervous system. Because apnea-induced vasoconstriction is most intense during hypoxia and attenuated during hyperoxia, it appears to depend at least in part on stimulation of arterial chemoreceptors.

Importance: Palliative care has the potential to improve care for patients and families undergoing high-risk surgery. Objective: To characterize the use of perioperative palliative care and its association with family-reported end-of-life experiences of patients who died within 90 days of a high-risk surgical operation. Design, Setting, and Participants: This secondary analysis of administrative data from a retrospective cross-sectional patient cohort was conducted in the Department of Veterans Affairs (VA) Healthcare System. Patients who underwent any of 227 high-risk operations between January 1, 2012, and December 31, 2015, were included. Exposures: Palliative-care consultation within 30 days before or 90 days after surgery. Main Outcomes and Measures: The outcomes were family-reported ratings of overall care, communication, and support in the patient's last month of life. The VA surveyed all families of inpatient decedents using the Bereaved Family Survey, a valid and reliable tool that measures patient and family-centered end-of-life outcomes. Results: A total of 95 204 patients underwent high-risk operations in 129 inpatient VA Medical Centers. Most patients were 65 years or older (69 278 [72.8%]), and the most common procedures were cardiothoracic (31 157 [32.7%]) or vascular (23 517 [24.7%]). The 90-day mortality rate was 6.0% (5740 patients) and varied by surgical subspecialty (ranging from 278 of 7226 [3.8%] in urologic surgery to 875 of 6223 patients [14.1%] in neurosurgery). A multivariate mixed model revealed that families of decedents who received palliative care were 47% more likely to rate overall care in the last month of life as excellent than those who did not (odds ratio [OR], 1.47 [95% CI, 1.14-1.88]; P = .007), after adjusting for patient's characteristics, surgical subspecialty of the high-risk operation, and survey nonresponse. Similarly, families of decedents who received palliative care were more likely to rate end-of-life communication (OR, 1.43 [95% CI, 1.09-1.87]; P = .004) and support (OR, 1.31 [95% CI, 1.01-1.71]; P = .05) components of medical care as excellent. Of the entire cohort, 3374 patients (3.75%) had a palliative care consultation, and 770 patients (0.8%) received it before surgery. Of all decedents, 1632 (29.9%) had a palliative care consultation, with 319 (5.6%) receiving it before surgery. Conclusions and Relevance: Receipt of a palliative consultation was associated with better ratings of overall end-of-life care, communication, and support, as reported by families of patients who died within 90 days of high-risk surgery. Yet only one-third of decedents was exposed to palliative care. Expanding integration of perioperative palliative care may benefit patients undergoing high-risk operations and their families.

BACKGROUND: Previous reports based on small patient numbers suggested that changes in serum HER-2/neu levels may predict response or lack of response to trastuzumab-based therapies in metastatic breast cancer (MBC). The objectives of this study were to pool data from 307 patients with MBC from 7 medical institutions to validate that the serum HER-2/neu profile predicts patient resistance to trastuzumab and to establish a clinically relevant cutoff. METHODS: This was an international, multicenter, retrospective analysis of individual pooled data from 307 patients with MBC who were treated with first-line trastuzumab-based therapy. Serum was collected at baseline and 30 to 120 days after the initiation of trastuzumab therapy. A serum HER-2/neu decrease >or=20% (receiver operating curve analysis) was defined as a significant HER-2/neu change. RESULTS: Of the 307 patients with MBC, 191 patients (62%) had a significant decline (>20%) in serum HER-2/neu and 116 patients (38%) did not. The objective response rate was 57% for patients who achieved this decline in serum HER-2/neu (>20%) compared with 28% for patients who did not. Patients who achieved this decline in serum HER-2/neu also had a significantly longer time to disease progression (320 days vs 180 days; P < .0001), longer duration of response (369 days vs 230 days; P = .008), and longer overall survival (898 days vs 593 days; P < .018). CONCLUSIONS: In this pooled analysis of 307 patients with MBC, individuals who did not achieve a significant decline (>or=20%) in serum HER-2/neu levels had decreased benefit from trastuzumab-based therapy, and these patients should be considered for clinical trials evaluating additional HER-2/neu-targeted interventions.

AIM: The treatment of psoriasis remains elusive, underscoring the need for identifying novel disease targets and mechanism-based therapeutic approaches. We recently reported that the PI3K/Akt/mTOR pathway that is frequently deregulated in many malignancies is also clinically relevant for psoriasis. We also provided rationale for developing delphinidin (Del), a dietary antioxidant for the management of psoriasis. This study utilized high-throughput biophysical and biochemical approaches and in vitro and in vivo models to identify molecular targets regulated by Del in psoriasis. RESULTS: A kinome-level screen and Kds analyses against a panel of 102 human kinase targets showed that Del binds to three lipid (PIK3CG, PIK3C2B, and PIK3CA) and six serine/threonine (PIM1, PIM3, mTOR, S6K1, PLK2, and AURKB) kinases, five of which belong to the PI3K/Akt/mTOR pathway. Surface plasmon resonance and in silico molecular modeling corroborated Del's direct interactions with three PI3Ks (α/c2β/γ), mTOR, and p70S6K. Del treatment of interleukin-22 or TPA-stimulated normal human epidermal keratinocytes (NHEKs) significantly inhibited proliferation, activation of PI3K/Akt/mTOR components, and secretion of proinflammatory cytokines and chemokines. To establish the in vivo relevance of these findings, an imiquimod (IMQ)-induced Balb/c mouse psoriasis-like skin model was employed. Topical treatment of Del significantly decreased (i) hyperproliferation and epidermal thickness, (ii) skin infiltration by immune cells, (iii) psoriasis-related cytokines/chemokines, (iv) PI3K/Akt/mTOR pathway activation, and (v) increased differentiation when compared with controls. Innovation and Conclusion: Our observation that Del inhibits key kinases involved in psoriasis pathogenesis and alleviates IMQ-induced murine psoriasis-like disease suggests a novel PI3K/AKT/mTOR pathway modulator that could be developed to treat psoriasis. Antioxid. Redox Signal. 26, 49-69.

The purpose of the present study was to use the microdialysis technique to simultaneously measure the interstitial concentrations of several putative stimulators of the exercise pressor reflex during 5 min of intermittent static quadriceps exercise in humans ( n = 7). Exercise resulted in approximately a threefold ( P &lt; 0.05) increase in muscle sympathetic nerve activity (MSNA) and 13 ± 3 beats/min ( P &lt; 0.05) and 20 ± 2 mmHg ( P &lt; 0.05) increases in heart rate and blood pressure, respectively. During recovery, all reflex responses quickly returned to baseline. Interstitial lactate levels were increased ( P &lt; 0.05) from rest (1.1 ± 0.1 mM) to exercise (1.6 ± 0.2 mM) and were further increased ( P &lt; 0.05) during recovery (2.0 ± 0.2 mM). Dialysate phosphate concentrations were 0.55 ± 0.04, 0.71 ± 0.05, and 0.48 ± 0.03 mM during rest, exercise, and recovery, respectively, and were significantly elevated during exercise. At the onset of exercise, dialysate K + levels rose rapidly above resting values (4.2 ± 0.1 meq/l) and continued to increase during the exercise bout. After 5 min of contractions, dialysate K + levels had peaked with an increase ( P &lt; 0.05) of 0.6 ± 0.1 meq/l and subsequently decreased during recovery, not being different from rest after 3 min. In contrast, H + concentrations rapidly decreased ( P &lt; 0.05) from resting levels (69.4 ± 3.7 nM) during quadriceps exercise and continued to decrease with a mean decline ( P &lt; 0.05) of 16.7 ± 3.8 nM being achieved after 5 min. During recovery, H + concentrations rapidly increased and were not significantly different from baseline after 1 min. This study represents the first time that skeletal muscle interstitial pH, K + , lactate, and phosphate have been measured in conjunction with MSNA, heart rate, and blood pressure during intermittent static quadriceps exercise in humans. These data suggest that interstitial K + and phosphate, but not lactate and H + , may contribute to the stimulation of the exercise pressor reflex.

Objective: To describe neurobehavioural symptoms in Iraq and Afghanistan war veterans evaluated for traumatic brain injury (TBI) through the Veterans Health Administration (VHA) TBI screening and evaluation programme.