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Abstract Although attempted suicide and non-suicidal self-injury (NSSI) are distinct behaviors differing in intent, form, and function, the behaviors co-occur at a high rate in both adults and adolescents. Researchers have begun to investigate the association between attempted suicide and NSSI among adolescents. The purpose of this paper is to present current research on this association. First, we discuss definitional issues associated with self-injurious behaviors. Next, we present research on the co-occurrence of attempted suicide and NSSI, including prevalence and associations with self-injury characteristics. We then discuss psychosocial variables associated with engaging in both NSSI and attempted suicide or one type of self-injury alone. Finally, we present the research to date on risk factors uniquely associated with either attempted suicide or NSSI. Implications for mental health professionals and future avenues of research are discussed.

While adjacent joint arthritis is a recognized long-term downside of primary tibiotalar arthrodesis (TTA), few studies have identified risk factors for early subtalar arthrodesis (STA) after TTA. This study aims to identify the risk factors for STA within the first few years following TTA. All patients older than 18 years undergoing TTA between 2008 and 2016 were identified retrospectively. Demographic data and comorbidities were collected alongside prior operative procedures, postoperative complications, and subsequent STA. Pre-and postoperative Kellgren-Lawrence osteoarthritis grade of the subtalar joint and postoperative radiographic alignment were obtained. A total of 240 patients who underwent primary TTA were included in this study with median follow up of 13.8 months. Twenty patients (8.3%) underwent STA after TTA due to symptomatic nonunion of TTA in 13 (65%), progression of symptomatic subtalar osteoarthritis (OA) in 4 (20%), and symptomatic nonunion of primary TTA combined progressively symptomatic subtalar OA in 2 (10%). Preoperative radiographic subtalar OA severity and postoperative radiographic alignment were not correlated with subsequent STA. Diabetes mellitus, Charcot arthropathy, neuropathy, alcohol use, substance use disorder, and psychiatric disease were significantly associated with having a subsequent STA. The most common postoperative contributing factor for subsequent STA following primary TTA was the salvage of symptomatic ankle nonunion rather than subtalar joint disease. Patients considering an ankle fusion should be counseled of the risk of subsequent STA, especially if they have risk factors that include diabetes, Charcot arthropathy, neuropathy, alcohol use, substance use disorder, or psychiatric disease., (Copyright © 2022 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Point-of-care hemoglobin testing devices play an important role in intraoperative anesthetic management where significant hemorrhage is anticipated; however, the reliability of these devices has not been examined in the context of pediatric liver transplantation. In this retrospective observational study, we aimed to determine whether 95% of results from two point-of-care hemoglobinometers, the HemoCue and iSTAT, would fall within a difference of ±1 g/dl, our a priori-defined clinically acceptable level of agreement, of the hemoglobin measures on a core laboratory complete blood count., Methods: We retrospectively collected data from 70 patients presenting for a liver transplant at a single center, tertiary care pediatric hospital over a 3.5-year period. We analyzed 92 contemporaneous pairs of hemoglobin values from the HemoCue and complete blood count, and 252 pairs of hemoglobin values from the iSTAT and complete blood count. Agreement between the point-of-care devices and complete blood count was assessed using Bland-Altman analysis, which was the primary outcome. Secondary analyses included an error grid analysis and Cohen's kappa statistic., Results: Both point-of-care devices underestimated complete blood count hemoglobin values and neither device satisfied our a priori-defined clinically acceptable level of agreement that 95% of values would fall within ±1 g/dl of the complete blood count measurement. The mean difference [limits of agreement] of the HemoCue was 0.4 g/dl (p < .001) [-0.9 to 1.6 g/dl] and of the iSTAT was 0.6 g/dl (p < .001) [-1.4 to 2.6 g/dl]. Secondary error grid analysis revealed that neither device performed well enough to replace a complete blood count at critical thresholds of hemoglobin values., Conclusions: While the HemoCue and iSTAT contribute information in a timely manner during dynamic intraoperative situations, there is significant imprecision compared to the gold standard complete blood count. If clinical stability allows, the results of these point-of-care hemoglobinometers should be confirmed with a complete blood count, rather than being used as the sole factor in determining transfusion needs during pediatric liver transplantation., (© 2022 John Wiley & Sons Ltd.)

Background: Surgical management of end-stage ankle arthritis consists of either ankle arthrodesis (AA) or total ankle replacement (TAR). The purpose of this study was to evaluate utilization trends in TAR and AA and compare cost and complications., Methods: Medicare patients with the diagnosis of ankle arthritis were reviewed. Patients undergoing surgical intervention were split into AA and TAR groups, which were evaluated for trends as well as postoperative complications, revision rates, and procedure cost., Results: A total of 673 789 patients were identified with ankle arthritis. A total of 19 120 patients underwent AA and 9059 underwent TAR. While rates of AA remained relatively constant, even decreasing, with 2080 performed in 2005 and 1823 performed in 2014, TAR rates nearly quadrupled. Average cost associated with TAR was $12559.12 compared with $6962.99 for AA ( P < .001). Overall complication rates were 24.9% in the AA group with a 16.5% revision rate compared with 15.1% and 11.0%, respectively, in the TAR group ( P < .001). Patients younger than 65 years had both higher complication and revision rates., Discussion: TAR has become an increasingly popular option for the management of end-stage ankle arthritis. In our study, TAR demonstrated both lower revision and complication rates than AA. However, TAR represents a more expensive treatment option., Levels of Evidence: Level III: Retrospective comparative study.

Purpose: Despite increased utilization of unicompartmental knee arthroplasty (UKA) for unicompartmental knee osteoarthritis, outcomes in Medicare patients are not well-reported. The purpose of this study is to analyze practice patterns and outcome differences between UKA and TKA in the Medicare population. It is hypothesized that UKA utilization will have increased over the course of the study period and that UKA will be associated with reduced opioid use and lower complication rates compared to TKA., Methods: Using PearlDiver, the Humana Claims dataset and the Medicare Standard Analytic File (SAF) were analyzed. Patients who underwent UKA and TKA were identified by CPT codes. Postoperative complications were identified by ICD-9/ICD-10 codes. Opioid use was analyzed by the number of days patients were prescribed opioids postoperatively. Survivorship was defined as conversion to TKA., Results: In the Humana dataset, 7,808 UKA and 150,680 TKA patients were identified. 8-year survivorship was 87.7% (95% CI [0.861,0.894]). Postoperative opioid use was significantly higher after TKA (186.1 days) compared to UKA (144.7 days) (p < 0.01, Δ = 41.1, 95% CI = [30.41, 52.39]). In the SAF dataset, 20,592 UKA patients and 110,562 TKA patients were identified. Survivorship was highest in patients > 80 years old and lowest in patients < 70 years old. In both datasets, postoperative complication rates were higher in TKA patients compared to UKA patients in nearly all categories., Conclusions: UKA represents an increasingly utilized treatment for osteoarthritis in the Medicare population and may be comparatively advantageous to TKA due to reduced opioid use and complication rates after surgery., Level of Evidence: Level III., (© 2021. The Author(s).)

Background: Multiligamentous knee injuries with a posterolateral corner injury represent a devastating insult to the knee., Purpose: To evaluate multiligamentous knee reconstruction rehabilitation programs and recommend a rehabilitation program based on a review of published outcomes studies., Study Design: Systematic review; Level of evidence, 4., Methods: A MEDLINE (PubMed), OVID, and Embase database search was conducted using the terms "posterolateral corner" and "rehabilitation." All articles obtained were examined to confirm their rehabilitation programs for multiligamentous knee injuries. These injuries included a posterolateral corner injury plus an isolated anterior or posterior cruciate ligament injury or a combined cruciate injury., Results: Ten publications representing 245 patients with multiligamentous knee reconstruction were analyzed. Rehabilitation protocols were divided by weightbearing (WB) status: in 2 studies, patients were non-WB until postoperative 4 weeks (delayed WB; n = 61); 5 studies permitted progressive WB until postoperative 6 weeks (progressive WB; n = 123); and 3 studies allowed WB immediately after surgery (immediate WB; n = 61). No significant difference in outcome scores among the 3 WB groups was found. Arthrofibrosis requiring manipulation under anesthesia was the most common complication (11%) in the delayed WB group, followed by the immediate WB group (3%) and the progressive WB group (0%; P < .01). Overall complication rates were highest in the delayed WB group (44%), followed by the immediate and progressive WB groups (25% and 3%, respectively; P < .00001). The delayed WB group was permitted to return to sport at a mean of 10.5 months from the index procedure; the progressive WB group, at 6.0 months; and the immediate WB group, at 9.0 months ( P < .05)., Conclusion: This review revealed no significant difference in outcome scores when comparing immediate, progressive, and delayed WB protocols. Time to permitted return to sport was not significantly different among the groups, but there existed a trend toward earlier return in the progressive WB group. Patients in the delayed and immediate WB groups experienced a higher overall complication rate. Progressive WB postoperative protocols may decrease the risk of complications without compromising outcomes; however, more research is needed to identify the optimal postoperative rehabilitation protocol, given the significant data heterogeneity currently available in the literature., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: B.L.M. has received educational support from Zimmer Biomet. B.B. has received educational support from Titan Surgical. P.S. has received educational support from Arthrex and Titan Surgical and hospitality payments from Arthrex. S.M. has received grant support from DePuy, educational support from Arthrex, and hospitality payments from Stryker and Zimmer Biomet. B.G.V. has received grant support from DePuy and educational support from Smith & Nephew and Titan Surgical. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

Definitive diagnosis and optimal surgical treatment of chronic lateral ankle instability remains controversial. This review distills available biomechanical evidence as it pertains to the clinical assessment, imaging work up, and surgical treatment of lateral ankle instability. Current data suggest that accurate assessment of ligament integrity during physical examination requires the ankle to ideally be held in 16° of plantar flexion when performing the anterior drawer test and 18° of dorsiflexion when performing the talar tilt test, respectively. Stress radiographs are limited by their low sensitivity, and MRI is limited by its static nature. Surgically, both arthroscopic and open repair techniques appear biomechanically equivalent in their ability to restore ankle stability, although sufficient evidence is still lacking for any particular procedure to be considered a superior construct. When performing reconstruction, grafts should be tensioned at 10 N and use of nonabsorbable augmentations lacking viscoelastic creep must factor in the potential for overtensioning. Anatomic lateral ligament surgery provides sufficient biomechanical strength to safely enable immediate postoperative weight bearing if lateral ankle stress is neutralized with a boot. Further research and comparative clinical trials will be necessary to define which of these ever-increasing procedural options actually optimizes patient outcome for chronic lateral ankle instability., (Copyright © 2020 by the American Academy of Orthopaedic Surgeons.)

C-terminal binding proteins (CtBP1/2) are oncogenic transcriptional coregulators and dehydrogenases often overexpressed in multiple solid tumors, including breast, colon, and ovarian cancer, and associated with poor survival. CtBPs act by repressing expression of genes responsible for apoptosis (e.g., PUMA, BIK) and metastasis-associated epithelial-mesenchymal transition (e.g., CDH1), and by activating expression of genes that promote migratory and invasive properties of cancer cells (e.g., TIAM1) and genes responsible for enhanced drug resistance (e.g., MDR1). CtBP's transcriptional functions are also critically dependent on oligomerization and nucleation of transcriptional complexes. Recently, we have developed a family of CtBP dehydrogenase inhibitors, based on the parent 2-hydroxyimino-3-phenylpropanoic acid (HIPP), that specifically disrupt cancer cell viability, abrogate CtBP's transcriptional function, and block polyp formation in a mouse model of intestinal polyposis that depends on CtBP's oncogenic functions. Crystallographic analysis revealed that HIPP interacts with CtBP1/2 at a conserved active site tryptophan (W318/324; CtBP1/2) that is unique among eukaryotic D2-dehydrogenases. To better understand the mechanism of action of HIPP-class inhibitors, we investigated the contribution of W324 to CtBP2's biochemical and physiologic activities utilizing mutational analysis. Indeed, W324 was necessary for CtBP2 self-association, as shown by analytical ultracentrifugation and in vivo cross-linking. Additionally, W324 supported CtBP's association with the transcriptional corepressor CoREST, and was critical for CtBP2 induction of cell motility. Notably, the HIPP derivative 4-chloro-HIPP biochemically and biologically phenocopied mutational inactivation of CtBP2 W324. Our data support further optimization of W318/W324-interacting CtBP dehydrogenase inhibitors that are emerging as a novel class of cancer cell-specific therapeutic., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Metatarsalgia is a common cause of plantar forefoot pain. Causes of metatarsalgia include foot anatomy, gait mechanics, and foot and ankle deformity. One specific cause, mechanical metatarsalgia, occurs because of gastrocnemius muscle contracture, which overloads the forefoot. Muscular imbalance of the gastrocnemius complex alters gait mechanics, which increases recruitment of the toe extensor musculature, thereby altering forefoot pressure. Patients with concomitant metatarsalgia and gastrocnemius contracture demonstrate ankle equinus and a positive Silfverskiold test. Nonoperative therapeutic modalities are mainstays of treatment. In patients in whom these treatments fail to provide metatarsalgia symptomatic relief, gastrocnemius muscle lengthening is a therapeutic option., (Copyright © 2017 Elsevier Inc. All rights reserved.)

C-terminal Binding Proteins (CtBP) 1 and 2 are oncogenic transcriptional co-regulators overexpressed in many cancer types, with their expression level correlating to worse prognostic outcomes and aggressive tumor features. CtBP negatively regulates the expression of many tumor suppressor genes, while coactivating genes that promote proliferation, epithelial-mesenchymal transition, and cancer stem cell self-renewal activity. In light of this evidence, the development of novel inhibitors that mitigate CtBP function may provide clinically actionable therapeutic tools. This review article focuses on the progress made in understanding CtBP structure, role in tumor progression, and discovery and development of CtBP inhibitors that target CtBP's dehydrogenase activity and other functions, with a focus on the theory and rationale behind the designs of current inhibitors. We provide insight into the future development and use of rational combination therapy that may further augment the efficacy of CtBP inhibitors, specifically addressing metastasis and cancer stem cell populations within tumors.

Obstructive apnea during sleep elevates the set point for efferent sympathetic outflow during wakefulness. Such resetting is attributed to hypoxia-induced upregulation of peripheral chemoreceptor and brain stem sympathetic function. Whether recurrent arousal from sleep also influences daytime muscle sympathetic nerve activity is unknown. We therefore tested, in a cohort of 48 primarily nonsleepy, middle-aged, male (30) and female (18) volunteers (age: 59±1 years, mean±SE), the hypothesis that the frequency of arousals from sleep (arousal index) would relate to daytime muscle sympathetic burst incidence, independently of the frequency of apnea or its severity. Polysomnography identified 24 as having either no or mild obstructive sleep apnea (apnea-hypopnea index <15 events/h) and 24 with moderate-to-severe obstructive sleep apnea (apnea-hypopnea index >15 events/h). Burst incidence correlated significantly with arousal index (r=0.53; P<0.001), minimum oxygen saturation (r=-0.43; P=0.002), apnea-hypopnea index (r=0.41; P=0.004), age (r=0.36; P=0.013), and body mass index (r=0.33; P=0.022) but not with oxygen desaturation index (r=0.28; P=0.056). Arousal index was the single strongest predictor of muscle sympathetic nerve activity burst incidence, present in all best subsets regression models. The model with the highest adjusted R 2 (0.456) incorporated arousal index, minimum oxygen saturation, age, body mass index, and oxygen desaturation index but not apnea-hypopnea index. An apnea- and hypoxia-independent effect of sleep fragmentation on sympathetic discharge during wakefulness could contribute to intersubject variability, age-related increases in muscle sympathetic nerve activity, associations between sleep deprivation and insulin resistance or insomnia and future cardiovascular events, and residual adrenergic risk with persistence of hypertension should therapy eliminate obstructive apneas but not arousals., (© 2016 American Heart Association, Inc.)

C-terminal Binding Protein (CtBP) is a transcriptional co-regulator that downregulates the expression of many tumor-suppressor genes. Utilizing a crystal structure of CtBP with its substrate 4-methylthio-2-oxobutyric acid (MTOB) and NAD(+) as a guide, we have designed, synthesized, and tested a series of small molecule inhibitors of CtBP. From our first round of compounds, we identified 2-(hydroxyimino)-3-phenylpropanoic acid as a potent CtBP inhibitor (IC50=0.24μM). A structure-activity relationship study of this compound further identified the 4-chloro- (IC50=0.18μM) and 3-chloro- (IC50=0.17μM) analogues as additional potent CtBP inhibitors. Evaluation of the hydroxyimine analogues in a short-term cell growth/viability assay showed that the 4-chloro- and 3-chloro-analogues are 2-fold and 4-fold more potent, respectively, than the MTOB control. A functional cellular assay using a CtBP-specific transcriptional readout revealed that the 4-chloro- and 3-chloro-hydroxyimine analogues were able to block CtBP transcriptional repression activity. This data suggests that substrate-competitive inhibition of CtBP dehydrogenase activity is a potential mechanism to reactivate tumor-suppressor gene expression as a therapeutic strategy for cancer., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: Delayed heart rate (HR) recovery in the immediate postexercise period has been linked to adverse cardiovascular prognosis. The after effects of an acute bout of exercise on HR modulation in postmenopausal women (PMW) and the influence of estrogen therapy are unknown., Methods: In 13 sedentary PMW (54 ± 2 y, mean ± SEM), we assessed HR variability (HRV)--an index of HR modulation--and the influence of estrogen therapy on HRV. HRV in the frequency domain was quantified during supine rest and again 60 minutes after treadmill exercise for 45 minutes, at 60% VO2peak. PMW were studied before and after 4 weeks of oral estradiol. To obtain reference values for the after effects of exercise on HRV in healthy young women, 14 premenopausal women (PreM) completed the identical exercise protocol., Results: Compared with PreM, PMW demonstrated lower high frequency (vagal modulation) and total HRV (P < 0.05) at rest. In PreM, all HRV values were similar before and after exercise. In contrast, in PMW after exercise, despite having identical HR to PreM, high frequency and total HRV were all lower (all P ≤ 0.01) compared with pre-exercise HRV values. Estrogen therapy had no effect on pre or postexercise values for HRV., Conclusions: When compared with PreM, PMW have identical HR, but lower vagal HR modulation at rest and delayed HRV recovery after exercise. Estrogen does not restore baseline HRV or accelerate HRV recovery postexercise, suggesting aging rather than estrogen deficiency per se may lower HRV in PMW.

This study reported the outcomes of patients treated with the Birmingham Hip Resurfacing System (Smith & Nephew, Memphis, Tennessee) to identify the prevalence of complications and failures. A retrospective review of 202 patients (206 hips) was performed. Outcomes were assessed clinically with Harris Hip Score at 6 and 12 months and then yearly. Subanalysis was performed, with the hips divided according to patient sex and size of the femoral component. Mean patient age was 51±8 years, and mean follow-up was 4±1.6 years. Of the patients, 163 were men (83%) and 35 were women (17%). Postoperative improvement was significant, with preoperative Harris Hip Score of 62.9±10.6 and postoperative Harris Hip Score of 98.6±6.7 (P<.001). There were 9 patients (4%) who had complications. A total of 5 hips (2.4%) underwent revision. At 3 years, mean survival was better for men than for women (99% vs 92%, respectively). Survival was lowest in patients with femoral component diameter of less than 46 mm. According to the authors' results, the Birmingham Hip Resurfacing System resulted in good clinical outcomes at 4 years. Survival and outcomes in women, particularly those with modest bone size, are inferior., (Copyright 2016, SLACK Incorporated.)

The insula (IC) and cingulate are key components of the central autonomic network and central nodes of the salience network (SN), a set of spatially distinct but temporally correlated brain regions identified with resting-state (task free) functional MRI (rsMRI). To examine the SN's involvement in sympathetic outflow, we tested the hypothesis that individual differences in intrinsic connectivity of the SN correlate positively with resting postganglionic muscle sympathetic nerve activity (MSNA) burst incidence (BI) in subjects without and with obstructive sleep apnea (OSA). Overnight polysomnography, 5-min rsMRI, and fibular MSNA recording were performed in 36 subjects (mean age 57 yr; 10 women, 26 men). Independent component analysis (ICA) of the entire cohort identified the SN as including bilateral IC, pregenual anterior cingulate cortex (pgACC), midcingulate cortex (MCC), and the temporoparietal junction (TPJ). There was a positive correlation between BI and the apnea-hypopnea index (AHI) (P < 0.001), but dual-regression analysis identified no differences in SN functional connectivity between subjects with no or mild OSA (n = 17) and moderate or severe (n = 19) OSA. Correlation analysis relating BI to the strength of connectivity within the SN revealed large (i.e., spatial extent) and strong correlations for the left IC (P < 0.001), right pgACC/MCC (P < 0.006), left TPJ (P < 0.004), thalamus (P < 0.035), and cerebellum (P < 0.013). Indexes of sleep apnea were unrelated to BI and the strength of SN connectivity. There were no relationships between BI and default or sensorimotor network connectivity. This study links connectivity within the SN to MSNA, demonstrating several of its nodes to be key sympathoexcitatory regions., (Copyright © 2016 the American Physiological Society.)

Compared with eumenorrhoeic women, exercise-trained women with functional hypothalamic amenorrhoea (ExFHA) exhibit low heart rates (HRs) and absent reflex renin-angiotensin-system activation and augmentation of their muscle sympathetic nerve response to orthostatic stress. To test the hypothesis that their autonomic HR modulation is altered concurrently, three age-matched (pooled mean, 24 ± 1 years; mean ± S.E.M.) groups of women were studied: active with either FHA (ExFHA; n=11) or eumenorrhoeic cycles (ExOv; n=17) and sedentary with eumenorrhoeic cycles (SedOv; n=17). Blood pressure (BP), HR and HR variability (HRV) in the frequency domain were determined during both supine rest and graded lower body negative pressure (LBNP; -10, -20 and -40 mmHg). Very low (VLF), low (LF) and high (HF) frequency power spectra (ms(2)) were determined and, owing to skewness, log10-transformed. LF/HF ratio and total power (VLF + LF + HF) were calculated. At baseline, HR and systolic BP (SBP) were lower (P<0.05) and HF and total power were higher (P<0.05) in ExFHA than in eumenorrhoeic women. In all groups, LBNP decreased (P<0.05) SBP, HF and total power and increased (P<0.05) HR and LF/HF ratio. However, HF and total power remained higher (P<0.05) and HR, SBP and LF/HF ratio remained lower (P<0.05) in ExFHA than in eumenorrhoeic women, in whom measures did not differ (P>0.05). At each stage, HR correlated inversely (P<0.05) with HF. In conclusion, ExFHA women demonstrate augmented vagal yet unchanged sympathetic HR modulation, both at rest and during orthostatic stress. Although the role of oestrogen deficiency is unclear, these findings are in contrast with studies reporting decreased HRV in hypoestrogenic post-menopausal women., (© 2015 Authors; published by Portland Press Limited.)

Our prior observations in normotensive postmenopausal women stimulated the hypotheses that compared with eumenorrheic women, active hypoestrogenic premenopausal women with functional hypothalamic amenorrhea would demonstrate attenuated reflex renin-angiotensin-aldosterone system responses to an orthostatic challenge, whereas to defend blood pressure reflex increases in muscle, sympathetic nerve activity would be augmented. To test these hypotheses, we assessed, in recreationally active women, 12 with amenorrhea (ExFHA; aged 25 ± 1 years; body mass index 20.7 ± 0.7 kg/m(2); mean ± SEM) and 17 with eumenorrhea (ExOv; 24 ± 1 years; 20.9 ± 0.5 kg/m(2)), blood pressure, heart rate, plasma renin, angiotensin II, aldosterone, and muscle sympathetic nerve activity at supine rest and during graded lower body negative pressure (-10, -20, and -40 mm Hg). At baseline, heart rate and systolic blood pressure were lower (P<0.05) in ExFHA (47 ± 2 beats/min and 94 ± 2 mm Hg) compared with ExOv (56 ± 2 beats/min and 105 ± 2 mm Hg), but muscle sympathetic nerve activity and renin-angiotensin-aldosterone system constituents were similar (P>0.05). In response to graded lower body negative pressure, heart rate increased (P<0.05) and systolic blood pressure decreased (P<0.05) in both groups, but these remained consistently lower in ExFHA (P<0.05). Lower body negative pressure elicited increases (P<0.05) in renin, angiotensin II, and aldosterone in ExOv, but not in ExFHA (P>0.05). Muscle sympathetic nerve activity burst incidence increased reflexively in both groups, but more so in ExFHA (P<0.05). Otherwise, healthy hypoestrogenic ExFHA women demonstrate low blood pressure and disruption of the normal circulatory response to an orthostatic challenge: plasma renin, angiotensin II, and aldosterone fail to increase and blood pressure is defended by an augmented sympathetic vasoconstrictor response., (© 2015 American Heart Association, Inc.)

Oncogenic transcriptional coregulators C-terminal Binding Protein (CtBP) 1 and 2 possess regulatory d-isomer specific 2-hydroxyacid dehydrogenase (D2-HDH) domains that provide an attractive target for small molecule intervention. Findings that the CtBP substrate 4-methylthio 2-oxobutyric acid (MTOB) can interfere with CtBP oncogenic activity in cell culture and in mice confirm that such inhibitors could have therapeutic benefit. Recent crystal structures of CtBP 1 and 2 revealed that MTOB binds in an active site containing a dominant tryptophan and a hydrophilic cavity, neither of which are present in other D2-HDH family members. Here, we demonstrate the effectiveness of exploiting these active site features for the design of high affinity inhibitors. Crystal structures of two such compounds, phenylpyruvate (PPy) and 2-hydroxyimino-3-phenylpropanoic acid (HIPP), show binding with favorable ring stacking against the CtBP active site tryptophan and alternate modes of stabilizing the carboxylic acid moiety. Moreover, ITC experiments show that HIPP binds to CtBP with an affinity greater than 1000-fold over that of MTOB, and enzymatic assays confirm that HIPP substantially inhibits CtBP catalysis. These results, thus, provide an important step, and additional insights, for the development of highly selective antineoplastic CtBP inhibitors.

Key Points: People with diminished ventricular contraction who develop heart failure have higher sympathetic nerve firing rates at rest compared with healthy individuals of a similar age and this is associated with less exercise capacity. During handgrip exercise, sympathetic nerve activity to muscle is higher in patients with heart failure but the response to leg exercise is unknown because its recording requires stillness. We measured sympathetic activity from one leg while the other leg cycled at a moderate level and observed a decrease in nerve firing rate in healthy subjects but an increase in subjects with heart failure. Because these nerves release noradrenaline, which can restrict muscle blood flow, this observation helps explain the limited exercise capacity of patients with heart failure. Lower nerve traffic during exercise was associated with greater peak oxygen uptake, suggesting that if exercise training attenuated sympathetic outflow functional capacity in heart failure would improve., Abstract: The reflex fibular muscle sympathetic nerve (MSNA) response to dynamic handgrip exercise is elicited at a lower threshold in heart failure with reduced ejection fraction (HFrEF). The present aim was to test the hypothesis that the contralateral MSNA response to mild to moderate dynamic one-legged exercise is augmented in HFrEF relative to age- and sex-matched controls. Heart rate (HR), blood pressure and MSNA were recorded in 16 patients with HFrEF (left ventricular ejection fraction = 31 ± 2%; age 62 ± 3 years, mean ± SE) and 13 healthy control subjects (56 ± 2 years) before and during 2 min of upright one-legged unloaded cycling followed by 2 min at 50% of peak oxygen uptake (V̇O2,peak). Resting HR and blood pressure were similar between groups whereas MSNA burst frequency was higher (50.0 ± 2.0 vs. 42.3 ± 2.7 bursts min(-1), P = 0.03) and V̇O2,peak lower (18.0 ± 2.0 vs. 32.6 ± 2.8 ml kg(-1) min(-1), P < 0.001) in HFrEF. Exercise increased HR (P < 0.001) with no group difference (P = 0.1). MSNA burst frequency decreased during mild to moderate dynamic exercise in the healthy controls but increased in HFrEF (-5.5 ± 2.0 vs. 6.9 ± 1.8 bursts min(-1), P < 0.001). Exercise capacity correlated inversely with MSNA burst frequency at 50% V̇O2,peak (n = 29; r = -0.64; P < 0.001). At the same relative workload, one-legged dynamic exercise elicited a fall in MSNA burst frequency in healthy subjects but sympathoexcitation in HFrEF, a divergence probably reflecting between-group differences in reflexes engaged by cycling. This finding, coupled with an inverse relationship between MSNA burst frequency during loaded cycling and subjects' V̇O2,peak, is consistent with a neurogenic determinant of exercise capacity in HFrEF., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)

Objective: HIV genotype-resistance testing can help identify more effective antiretroviral treatment (ART) regimens for patients, substantially increasing the likelihood of viral suppression and immune recovery. We sought to evaluate the cost-effectiveness of genotype-resistance testing before first-line ART initiation in Brazil., Design: We used a previously published microsimulation model of HIV disease (CEPAC-International) and data from Brazil to compare the clinical impact, costs, and cost-effectiveness of initial genotype testing (Genotype) with no initial genotype testing (No genotype)., Methods: Model parameters were derived from the HIV Clinical Cohort at the Evandro Chagas Clinical Research Institute and from published data, using Brazilian sources whenever possible. Baseline patient characteristics included 69% male, mean age of 36 years (SD, 10 years), mean CD4 count of 347 per microliter (SD, 300/µL) at ART initiation, annual ART costs from 2012 US $1400 to US $13,400, genotype test cost of US $230, and primary resistance prevalence of 4.4%. Life expectancy and costs were discounted 3% per year. Genotype was defined as "cost-effective" compared with No Genotype if its incremental cost-effectiveness ratio was less than 3 times the 2012 Brazilian per capita GDP of US $12,300., Results: Compared with No genotype, Genotype increased life expectancy from 18.45 to 18.47 years and reduced lifetime cost from US $45,000 to $44,770; thus, in the base case, Genotype was cost saving. Genotype was cost-effective at primary resistance prevalence as low as 1.4% and remained cost-effective when subsequent-line ART costs decreased to 30% of baseline value. Cost-inefficient results were observed only when simultaneously holding multiple parameters to extremes of their plausible ranges., Conclusions: Genotype-resistance testing in ART-naive individuals in Brazil will improve survival and decrease costs and should be incorporated into HIV treatment guidelines in Brazil.

Background: We examined efficacy, toxicity, relapse, cost, and quality-of-life thresholds of hypothetical HIV cure interventions that would make them cost-effective compared to life-long antiretroviral therapy (ART)., Methods: We used a computer simulation model to assess three HIV cure strategies: Gene Therapy, Chemotherapy, and Stem Cell Transplantation (SCT), each compared to ART. Efficacy and cost parameters were varied widely in sensitivity analysis. Outcomes included quality-adjusted life expectancy, lifetime cost, and cost-effectiveness in dollars/quality-adjusted life year ($/QALY) gained. Strategies were deemed cost-effective with incremental cost-effectiveness ratios <$100,000/QALY., Results: For patients on ART, discounted quality-adjusted life expectancy was 16.4 years and lifetime costs were $591,400. Gene Therapy was cost-effective with efficacy of 10%, relapse rate 0.5%/month, and cost $54,000. Chemotherapy was cost-effective with efficacy of 88%, relapse rate 0.5%/month, and cost $12,400/month for 24 months. At $150,000/procedure, SCT was cost-effective with efficacy of 79% and relapse rate 0.5%/month. Moderate efficacy increases and cost reductions made Gene Therapy cost-saving, but substantial efficacy/cost changes were needed to make Chemotherapy or SCT cost-saving., Conclusions: Depending on efficacy, relapse rate, and cost, cure strategies could be cost-effective compared to current ART and potentially cost-saving. These results may help provide performance targets for developing cure strategies for HIV.

End-expiratory breath-holds (BH) and Mueller manoeuvres (MM) elicit large increases in muscle sympathetic nerve activity (MSNA). In 16 healthy humans (9♀, 35 ± 4 years) we used functional magnetic resonance imaging with blood oxygen level-dependent (BOLD) contrast to determine the cortical network associated with such sympathoexcitation. We hypothesized that increases in MSNA evoked by these simulated apneas are accompanied by BOLD contrast changes in the insular cortex, thalamus and limbic cortex. A series of 150 whole-brain images were collected during 3 randomly performed 16-second end-expiratory BHs and MMs (-30 mmHg). The identical protocol was repeated separately with MSNA recorded from the fibular nerve. The time course of the sympathoexcitatory response to both breathing tasks were correlated with whole-brain BOLD signal changes. Brain sites demonstrating both positive (activation) and negative (deactivation) correlations with the MSNA time course were identified. Sympathetic burst incidence increased (p<0.001) from 29 ± 6 (rest) to 49 ± 6 (BH) and 47 ± 6 bursts/100 heartbeats (MM). Increased neural activity (Z-scores) was identified in the right posterior and anterior insular cortices (3.74, 3.64), dorsal anterior cingulate (3.42), fastigial and dentate cerebellar nuclei (3.02, 3.34). Signal intensity decreased in the left posterior insula (3.28) and ventral anterior cingulate (3.01). Apnea both activates and inhibits elements of a cortical network involved in the generation of sympathetic outflow. These findings identify a neuroanatomical substrate to guide future investigations into central mechanisms contributing to disorders characterized by elevated basal MSNA and exaggerated sympathetic responses to simulated apneas such as sleep apnea and heart failure.

Background: Computer simulation models can project long-term patient outcomes and inform health policy. We internally validated and then calibrated a model of HIV disease in children before initiation of antiretroviral therapy to provide a framework against which to compare the impact of pediatric HIV treatment strategies., Methods: We developed a patient-level (Monte Carlo) model of HIV progression among untreated children <5 years of age, using the Cost-Effectiveness of Preventing AIDS Complications model framework: the CEPAC-Pediatric model. We populated the model with data on opportunistic infection and mortality risks from the International Epidemiologic Database to Evaluate AIDS (IeDEA), with mean CD4% at birth (42%) and mean CD4% decline (1.4%/month) from the Women and Infants' Transmission Study (WITS). We internally validated the model by varying WITS-derived CD4% data, comparing the corresponding model-generated survival curves to empirical survival curves from IeDEA, and identifying best-fitting parameter sets as those with a root-mean square error (RMSE) <0.01. We then calibrated the model to other African settings by systematically varying immunologic and HIV mortality-related input parameters. Model-generated survival curves for children aged 0-60 months were compared, again using RMSE, to UNAIDS data from >1,300 untreated, HIV-infected African children., Results: In internal validation analyses, model-generated survival curves fit IeDEA data well; modeled and observed survival at 16 months of age were 91.2% and 91.1%, respectively. RMSE varied widely with variations in CD4% parameters; the best fitting parameter set (RMSE = 0.00423) resulted when CD4% was 45% at birth and declined by 6%/month (ages 0-3 months) and 0.3%/month (ages >3 months). In calibration analyses, increases in IeDEA-derived mortality risks were necessary to fit UNAIDS survival data., Conclusions: The CEPAC-Pediatric model performed well in internal validation analyses. Increases in modeled mortality risks required to match UNAIDS data highlight the importance of pre-enrollment mortality in many pediatric cohort studies.

Atrial mechanoreceptors, stimulated by increased pressure or volume, elicit in healthy humans a net sympathoinhibitory response. The co-existence of an atrial reflex eliciting muscle sympathoexcitation has been postulated but undetected by conventional multi-unit muscle sympathetic nerve activity (MSNA). We hypothesized that in response to a selective increase in atrial pressure, single-unit MSNA would reveal a subpopulation of efferent sympathetic neurons with firing patterns opposite to the integrated multi-unit MSNA envelope. Multi- and single-unit MSNA recordings were acquired in eight healthy middle-aged subjects (age, 57 ± 8 years; body mass index, 25 ± 2 kg/m(2)) submitted to selective decreases or increases in atrial pressure by nonhypotensive lower body negative pressure (LBNP; -10 mmHg) or nonhypertensive lower body positive pressure (LBPP; +10 mmHg), respectively. Single-unit MSNA firing responses were classified as anticipated if spike frequency and incidence increased with LBNP or decreased with LBPP and paradoxical if they decreased with LBNP or increased with LBPP. LBNP decreased (3.2 ± 2.8 to 1.4 ± 3.1 mmHg, P < 0.01) and LBPP increased (3.3 ± 2.7 to 4.9 ± 2.8 mmHg, P < 0.01) estimated central venous pressure without affecting stroke volume, systemic pressure, or resistance. Multi-unit MSNA increased with LBNP (31 ± 17 to 38 ± 19 bursts/min, P < 0.01) and diminished with LBPP (33 ± 15 to 28 ± 15 bursts/min, P < 0.01). Of 21 single-units identified, 76% exhibited firing responses to both LBNP and LBPP concordant with multi-unit MSNA, whereas 24% demonstrated discordant or paradoxical responses. The detection of two subpopulations of single-units within the multi-unit MSNA recording, exhibiting opposite firing characteristics, establishes the first evidence in humans for the existence of an excitatory cardiac-muscle sympathetic reflex activated by increasing atrial pressure.

Objectives: Previous reports, involving hypercholesterolaemic hypertensive subjects, that statins reduce muscle sympathetic nerve activity (MSNA) did not investigate potential neural sites of such sympathoinhibition or determine its consequences for endothelial function or insulin resistance. This study of hypertensive subjects with lower plasma cholesterol tested the hypotheses that lipophilic simvastatin would attenuate resting sympathoexcitation and augment baroreflex modulation of MSNA and heart rate (HR), flow-mediated vasodilation and insulin sensitivity., Design: Prospective, randomised, double-blind, placebo-controlled crossover study., Setting: Academic hospital-based study., Patients: Fourteen non-hyperlipidaemic primary hypertensive subjects (10 men; overall mean±SD age 58±12 years)., Interventions: Four weeks of simvastatin (80 mg/day) or placebo., Main Outcome Measures: Resting blood pressure (BP), HR, MSNA, spontaneous arterial baroreflex MSNA and HR modulation, endothelium-dependent and endothelium-independent vasodilation, and the homoeostatic model assessment of insulin resistance (HOMA-IR)., Results: Simvastatin lowered MSNA burst frequency (from 32±12 to 25±9 bursts/min) and MSNA burst incidence (from 55±23% to 43±17%; all p<0.01) without affecting BP, HR, baroreflex modulation of either MSNA or HR, or HR variability (all p>0.05). Plasma glucose, insulin, HOMA-IR and endothelium-dependent vasodilation (all p>0.05) were unchanged, whereas endothelium-independent vasodilation increased (7.1±3.8% to 9.7±3.9%, n=13; p<0.01). The fall in MSNA was unrelated to the decrease in low-density lipoprotein cholesterol (r=0.41, p=0.14)., Conclusions: These findings are consistent with the concept that, in non-hyperlipidaemic subjects with primary hypertension, simvastatin causes a cholesterol-independent reduction in an elevated central set-point for MSNA, without affecting arterial baroreflex modulation of either MSNA or HR. There may be less neurogenic constraint on endothelium-independent vasodilation as a consequence.

Purpose: Muscle sympathetic nerve activity (MSNA) is increased in older endurance-trained men, yet the reflex sympathetic forearm vasoconstrictor response to graded lower body negative pressure (LBNP) diminishes with age. The aim of this study was to assess the influence of aerobic exercise capacity on this altered neurovascular coupling. We hypothesized that during graded LBNP, the forearm vascular resistance (FVR)-MSNA relationship would be steeper in sedentary versus fit men., Methods: We therefore studied 20 healthy middle-age men (age = 52 ± 2 yr, mean ± SE), 10 physically active (FIT) and 10 sedentary (SED) (129% ± 4% vs 85% ± 3% of predicted peak oxygen uptake) during 4 min each of LBNP at -5, -10, -20, and -40 mm Hg, applied in a random order. We determined HR, plasma norepinephrine, and MSNA (microneurography) and derived FVR from blood pressure and forearm blood flow (plethysmography). The FVR-MSNA relationship was determined by linear regression in each group separately, and groups were compared using multiple linear regression., Results: MSNA burst frequency and FVR at rest and during LBNP (P < 0.003) were similar in the two groups, whereas HR was significantly lower (P < 0.002) both at rest and during LBNP in FIT men (P < 0.05). FVR during LBNP correlated positively with MSNA in the SED group (r = 0.44, P < 0.001) but not in the FIT group (r = 0.19, P = 0.10). Multiple linear regression confirmed that both MSNA (P < 0.001) and fitness level (P = 0.04) contribute to the forearm vascular response., Conclusions: Thus, during simulated orthostasis, middle-age SED men exhibit a significant FVR-MSNA relationship, which is not evident in age-matched FIT men. This alteration in neurovascular coupling may potentially affect cardiovascular risk in middle-age men.

Purpose: Adding an immune-enhancing agent to initial antiretroviral therapy (ART) for HIV is a potential strategy to ensure that patients achieve optimal immune response., Method: Using a mathematical model of HIV disease and treatment, we evaluated the treatment benefits and cost-effectiveness of adding a hypothetical immune-enhancing agent to the initial 6 months of ART. We assumed that the additional agent would result in a higher CD4 increase that would provide clinical benefit. The additional cost ($1,900/month) was based on the cost of a drug currently under investigation for immune enhancement. Outcomes included projected life expectancy and cost-effectiveness in 2009 US dollars/quality-adjusted life year (QALY) with costs and QALYs discounted at 3% annually., Results: Compared to standard ART, immune-enhanced ART resulting in an additional 40 CD4 cell/µL increase at 6 months yields a 2.4 month projected undiscounted life expectancy increase with a cost-effectiveness ratio of $107,600/QALY. Achieving a cost-effectiveness ratio <$100,000/QALY requires a >43 CD4 cell/µL improvement, or >19 cells/µL if immune-enhancing agent costs are halved., Conclusions: In addition to showing clinical efficacy, investigational immune enhancement agents need to increase CD4 counts more than has been previously observed or have a lower cost to be considered cost-effective in the United States.

Background: To determine whether angiotensin II (ANG II) contributes to the reflex skeletal muscle sympathoexcitation elicited by isometric and isotonic exercise, we tested the hypothesis that angiotensin AT(1) receptor blockade (ARB) would attenuate reflex sympathoneural responses to handgrip (HG) and to post-handgrip ischemia (PHGI)., Methods: Seventeen healthy men were studied before and 1 week after random double-blind crossover allocation to oral losartan (100 mg daily) and placebo. Heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were recorded at rest, and during 2 min bouts of isotonic HG at 50% maximum voluntary contraction (MVC) and isometric HG at 30% MVC, performed randomly, each followed by 2 min of PHGI., Results: At rest, losartan doubled plasma renin (P = 0.01) and ANG II (P = 0.03) concentrations, and lowered BP (P < 0.01) yet had no effect on MSNA burst frequency or incidence. HR trended higher (P = 0.060). Losartan's hypotensive effect persisted throughout each exercise bout (P < 0.045). MSNA and HR responses to isotonic exercise and postexercise ischemia were not affected by losartan. Isometric exercise and postexercise ischemia increased MSNA on both sessions (all P < 0.01). Losartan augmented the HR response (P ≤ 0.03), and after losartan MSNA burst frequency (P < 0.01) and incidence (P < 0.04) were significantly higher at all time points, but the magnitude of the MSNA response to isometric exercise and postexercise ischemia was unchanged., Conclusion: In healthy men, short-term ARB does not attenuate reflex sympathoneural responses to HG or PHGI.

Background: Routine HIV screening in emergency department (ED) settings may require dedicated personnel. We evaluated the outcomes, costs and cost-effectiveness of HIV screening when offered by either a member of the ED staff or by an HIV counselor., Methods: We employed a mathematical model to extend data obtained from a randomized clinical trial of provider- vs. counselor-based HIV screening in the ED. We compared the downstream survival, costs, and cost-effectiveness of three HIV screening modalities: 1) no screening program; 2) an ED provider-based program; and 3) an HIV counselor-based program. Trial arm-specific data were used for test offer and acceptance rates (provider offer 36%, acceptance 75%; counselor offer 80%, acceptance 71%). Undiagnosed HIV prevalence (0.4%) and linkage to care rates (80%) were assumed to be equal between the screening modalities. Personnel costs were derived from trial-based resource utilization data. We examined the generalizability of results by conducting sensitivity analyses on offer and acceptance rates, undetected HIV prevalence, and costs., Results: Estimated HIV screening costs in the provider and counselor arms averaged $8.10 and $31.00 per result received. The Provider strategy (compared to no screening) had an incremental cost-effectiveness ratio of $58,700/quality-adjusted life year (QALY) and the Counselor strategy (compared to the Provider strategy) had an incremental cost-effectiveness ratio of $64,500/QALY. Results were sensitive to the relative offer and acceptance rates by strategy and the capacity of providers to target-screen, but were robust to changes in undiagnosed HIV prevalence and programmatic costs., Conclusions: The cost-effectiveness of provider-based HIV screening in an emergency department setting compares favorably to other US screening programs. Despite its additional cost, counselor-based screening delivers just as much return on investment as provider based-screening. Investment in dedicated HIV screening personnel is justified in situations where ED staff resources may be insufficient to provide comprehensive, sustainable screening services.

Background: Although 900,000 HIV-infected South Africans receive antiretroviral therapy, the majority of South Africans with HIV remain undiagnosed., Methods: We use a published simulation model of HIV case detection and treatment to examine 3 HIV screening scenarios, in addition to current practice as follows: (1) one-time; (2) every 5 years; and (3) annually. South African model input data include the following: 16.9% HIV prevalence, 1.3% annual incidence, 49% test acceptance rate, HIV testing costs of $6.49/patient, and a 47% linkage-to-care rate (including 2 sequential antiretroviral therapy regimens) for identified cases. Outcomes include life expectancy, direct medical costs, and incremental cost-effectiveness., Results: HIV screening one-time, every 5 years, and annually increase HIV-infected quality-adjusted life expectancy (mean age 33 years) from 180.6 months (current practice) to 184.9, 187.6, and 197.2 months. The incremental cost-effectiveness of one-time screening is dominated by screening every 5 years. Screening every 5 years and annually each have incremental cost-effectiveness ratios of $1570/quality-adjusted life year and $1720/quality-adjusted life year. Screening annually is very cost-effective even in settings with the lowest incidence/prevalence, with test acceptance and linkage rates both as low as 20%, or when accounting for a stigma impact at least four-fold that of the base case., Conclusions: In South Africa, annual voluntary HIV screening offers substantial clinical benefit and is very cost-effective, even with highly constrained access to care and treatment.

Background: The United States and international agencies have signaled their commitment to containing the human immunodeficiency virus (HIV) epidemic via early case identification and linkage to antiretroviral therapy (ART) immediately at diagnosis. We forecast outcomes of this approach if implemented in Washington DC., Methods: Using a mathematical model of HIV case detection and treatment, we evaluated combinations of HIV screening and ART initiation strategies. We define current practice as no regular screening program and ART at CD4 counts < or = 350 cells/microL, and we define test and treat as annual screening and administration of ART at diagnosis. Outcomes include life expectancy of HIV-infected persons and changes in the population time with transmissible HIV RNA levels. Data, largely from Washington DC, include undiagnosed HIV prevalence of 0.6%, annual incidence of 0.13%, 31% rate of test offer, 60% rate of acceptance, and 50% linkage to care. Input parameters, including optimized ART efficacy, are varied in sensitivity analyses., Results: Projected life expectancies, from an initial mean age of 41 years, are 23.9, 25.0, and 25.6 years for current practice, test and treat, and test and treat with optimized ART, respectively. Compared with current practice, test and treat leads to a 14.7% reduction in time spent with transmissible HIV RNA level in the next 5 years; test and treat with optimized ART results in a 27.3% reduction., Conclusions: An expanded HIV test and treat program in Washington DC will increase life expectancy of HIV-infected patients but will have a modest impact on HIV transmission over the next 5 years and is unlikely to halt the HIV epidemic.

In healthy subjects a standard drink of either red wine (RW) or ethanol (EtOH) has no effect on muscle sympathetic nerve activity or on heart rate (HR), whereas two drinks increase both. Using time- and frequency-domain indexes of HR variability (HRV), we now tested in 12 subjects (24-47 yr, 6 men) the hypotheses that 1) this HR increase reflects concurrent dose-related augmented sympathetic HR modulation and 2) RW with high-polyphenol content differs from EtOH in its acute HRV effects. RW, EtOH, and water were provided on 3 days, 2 wk apart according to a randomized, single-blind design. Eight-minute segments were analyzed. One alcoholic drink increased blood concentrations to 36 + or - 2 mg/dl (mean + or - SE), and 2 drinks to 72 + or - 4 (RW) and 80 + or - 2 mg/dl (EtOH). RW quadrupled plasma resveratrol (P < 0.001). HR fell after both water drinks. When compared with respective baselines, one alcoholic drink had no effect on HR or HRV, whereas two glasses of both increased HR (RW, +5.4 + or - 1.2; and EtOH, +5.7 + or - 1.2 min(-1); P < 0.001), decreased total HRV by 28-33% (P < 0.05) and high-frequency spectral power by 32-42% (vagal HR modulation), and increased low-frequency power by 28-34% and the ratio of low frequency to high frequency by 98-119% (sympathetic HR modulation) (all, P < or = 0.01). In summary, when compared with water, one standard drink lowered time- and frequency-domain markers of vagal HR modulation. When compared with respective baselines, two alcoholic drinks increased HR by diminished vagal and augmented sympathetic HR modulation. Thus alcohol exerts dose-dependent HRV responses, with RW and EtOH having a similar effect.

Many heart failure (HF) patients exhibit paradoxical forearm vasodilation when central blood volume is reduced by lower body negative pressure (LBNP). We tested the hypothesis that this response results from reflex sympathetic withdrawal. We recorded simultaneously forearm blood flow, muscle sympathetic nerve activity (MSNA), and plasma norepinephrine (PNE) during four random applications of LBNP, -5, -10, -20, and -40 mmHg, in 12 men with HF (mean left ventricular ejection fraction = 24 + or - 2%) and 10 healthy, normal, age-matched men (N). Compared with N, MSNA burst frequency (P = 0.001) and PNE (P = 0.005) were significantly higher in the HF group, both at rest and during LBNP. As anticipated in N, LBNP -40 mmHg significantly increased MSNA (+14.2 + or - 2.5 bursts/min; P < 0.05) and PNE (+0.83 + or - 0.22 nmol/l; P < 0.05) and decreased forearm vascular conductance (FVC) (-11.7 + or - 3.2 ml.min(-1).mmHg(-1); P < 0.05). In the HF group, LBNP elicited similar increases in MSNA (+11.5 + or - 2.0; P < 0.05) and PNE (+0.85 + or - 0.12; P < 0.05), without affecting FVC significantly (-4.1 + or - 2.4; P = 0.01 vs. N, interaction P = 0.03). However, within the HF group, responses were bimodal: LBNP -40 mmHg increased MSNA in all subjects (P < 0.001), yet the six patients with nonischemic or dilated cardiomyopathy (DCM) exhibited significant vasoconstriction (decrease in FVC; P = 0.001), whereas the six patients with ischemic cardiomyopathy (ICM) exhibited significant vasodilation (increase in FVC; P < 0.02 vs. DCM and N; interaction P = 0.02). Cold pressor testing increased MSNA and decreased FVC in ICM (n = 4). Thus paradoxical forearm vasodilator responses to LBNP in HF are not mediated by reflex sympathetic withdrawal. ICM and DCM patients differ qualitatively in their vascular responses to hypotensive LBNP.

Objectives: To determine, in patients with pulmonary arterial hypertension (PAH), whether there is a relationship: (1) between sympathetic nerve firing rate and spectral indices of sympathetic neural heart rate modulation; and (2) between heart rate variability (HRV) and right atrial pressure, a stimulus to sinoatrial node stretch., Design: Characterisation of patients and healthy controls., Setting: Teaching hospital-based study., Patients: 9 PAH patients without elevated pulmonary capillary wedge pressure and nine age-matched control subjects., Interventions: Heart rate (HR) and muscle sympathetic nerve activity (MSNA) were recorded during 10 min of supine rest in both PAH patients studied after right heart catheterisation, and healthy volunteers. Coarse-graining spectral analysis determined HR spectral power., Main Outcome Measures: (1) Low-frequency (PL) spectral component of HRV; (2) MSNA burst frequency; and in PAH patients: (3) right atrial pressure., Results: MSNA burst frequency was higher in PAH patients (48 (24) and 29 (11) bursts/min, respectively; mean (SD); p = 0.05), whereas total power (p = 0.01), its fractal (p<0.01) and harmonic (p = 0.04) components, and PL (p = 0.01) were all reduced. PL related inversely to both MSNA burst frequency (r = -0.86, p = 0.005) and right atrial systolic pressure (r = -0.77, p = 0.04)., Conclusions: Thus, in PAH (as in patients with left ventricular systolic dysfunction) loss of PL relates inversely to gain in MSNA burst frequency. Diminished sympathetic neural heart rate modulation and increased right atrial stretch may combine to attenuate HRV, an adverse prognostic marker.

The cardiovascular benefits of light to moderate red wine consumption often have been attributed to its polyphenol constituents. However, the acute dose-related hemodynamic, vasodilator, and sympathetic neural effects of ethanol and red wine have not been characterized and compared in the same individual. We sought to test the hypotheses that responses to one and two alcoholic drinks differ and that red wine with high polyphenol content elicits a greater effect than ethanol alone. Thirteen volunteers (24-47 yr; 7 men, 6 women) drank wine, ethanol, and water in a randomized, single-blind trial on three occasions 2 wk apart. One drink of wine and ethanol increased blood alcohol to 38 +/- 2 and 39 +/- 2 mg/dl, respectively, and two drinks to 72 +/- 4 and 83 +/- 3 mg/dl, respectively. Wine quadrupled plasma resveratrol (P < 0.001) and increased catechin (P < 0.03). No intervention affected blood pressure. One drink had no heart rate effect, but two drinks of wine increased heart rate by 5.7 +/- 1.6 beats/min; P < 0.001). Cardiac output fell 0.8 +/- 0.3 l/min after one drink of ethanol and wine (both P < 0.02) but increased after two drinks of ethanol (+0.8 +/- 0.3 l/min) and wine (+1.2 +/- 0.3 l/min) (P < 0.01). One alcoholic drink did not alter muscle sympathetic nerve activity (MSNA), while two drinks increased MSNA by 9-10 bursts/min (P < 0.001). Brachial artery diameter increased after both one and two alcoholic drinks (P < 0.001). No beverage augmented, and the second wine dose attenuated (P = 0.02), flow-mediated vasodilation. One drink of ethanol dilates the brachial artery without activating sympathetic outflow, whereas two drinks increase MSNA, heart rate, and cardiac output. These acute effects, which exhibit a narrow dose response, are not modified by red wine polyphenols.

Background: The magnitude of sympathetic activation in chronic heart failure is assumed to be independent of its cause. However, because a higher sympathetic component of heart rate variability (HRV) in patients with ischemic cardiomyopathy (ICM) has been reported, we hypothesized that patients with ICM would have a higher resting muscle sympathetic nerve activity (MSNA) than patients with nonischemic dilated cardiomyopathy (DCM)., Methods and Results: Resting MSNA was assessed by microneurography and HRV concurrently by coarse-graining spectral analysis in 30 treated normotensive patients with chronic heart failure (12 with ICM and 18 with DCM), matched for age and left ventricular ejection fraction, and 23 healthy normal control subjects, matched for age and blood pressure. Peak oxygen uptake was determined during graded cycling (17 W/min) to maximum effort. MSNA was significantly different between groups (P < .001; ICM 60 +/- 3; DCM 47 +/- 3; control subjects 35 +/- 3 bursts/min). Compared with control subjects, the total spectral power and the high-frequency component of HRV were lower in both ICM and DCM groups, but fractal and low-frequency power were lower only in the ICM group (P < .05). Peak oxygen uptake (milliliters per kilogram of body weight per minute) was significantly less in the ICM group than in the DCM group (P = .04) and lower in both groups than in the control subjects (P < .001)., Conclusions: These observations suggest an additional ischemic stimulus to sympathetic activation in heart failure, which may impair exercise capacity reflexively.

Background: Sustained hypotension after an acute dynamic exercise bout is due primarily to peripheral vasodilation. We tested the hypothesis that adenosine-mediated vasodilation contributes to hypotension after exercise, by determining the effect of blocking its actions with caffeine., Methods: Fourteen healthy middle-aged subjects (mean age = 51 +/- 3 years), cycled to peak effort on 2 study days, after a randomized double-blind intravenous infusion of caffeine (4 mg/kg) selective for adenosine receptor blockade, or vehicle. Both studies were performed after 72 h of caffeine abstinence., Results: Infusion achieved 52.0 +/- 6.1 mumol/L caffeine in plasma. Significant reductions in mean and diastolic blood pressure (BP) were elicited by prior exercise on the vehicle day (from 93 +/- 2 to 85 +/- 2 mm Hg v from 79 +/- 2 to 73 +/- 3 mm Hg, respectively; both P < .05), but not after caffeine infusion. Systolic and mean BP, 10 min after exercise, were higher on the caffeine than on the vehicle day (by 9 +/- 3 and 6 +/- 2 mm Hg, respectively; P < .05), as was heart rate (HR) (100 +/- 5 v 93 +/- 4 beats/min; P < .05)., Conclusions: These data suggest that endogenous adenosine contributes to early hypotension after exercise in healthy middle-aged subjects and underscore the importance of caffeine abstinence if BP or HR immediately after exercise is used to infer cardiovascular risk.

Sewer and stormwater pipe leakage can lead to the degradation of urban groundwater quality. This groundwater may be subsequently used for public water supply and so the resulting water treatment and public health consequences can be serious. To understand the impact of sewer exfiltration on groundwater quality, suitable indicators need to be sampled and analysed for. This study examined potential sewer-derived inorganic and microbial parameters in the U.K. city of Doncaster. Sulphite reducing clostridia, faecal streptococci and boron were all detected in groundwater with reductions compared with sewer values ranging from 1 to 6 orders of magnitude for the former two, to 1 to 2 orders of magnitude decrease for boron. The correlation between these two different indicator types suggests that groundwater quality is being adversely affected by sewer leakage in the study area. The employment of several and varied indicators can better demonstrate the effect than use of single parameters.

Postmenopausal estrogen replacement therapy (ERT) is reported to increase angiotensin II under resting conditions. To determine the implications of this increase for cardiovascular regulation during simulated orthostasis, blood pressure (BP), heart rate (HR), renin, angiotensinogen, angiotensin II, and aldosterone were measured at rest and during lower body negative pressure (LBNP; -10, -20, and -40 mm Hg). We studied 13 normotensive postmenopausal women (54+/-2 [mean+/-SE] years) before and after 1 month of oral estradiol 2 mg daily, and 14 premenopausal women. LBNP activated the renin-angiotensin system acutely in premenopausal but not postmenopausal women. Resting renin and aldosterone were unaffected by estradiol, whereas angiotensinogen (P<0.001) and angiotensin II (P<0.01) increased. Renin, aldosterone, and HR responses to LBNP (which tended to be less in postmenopausal women [P=0.06]) were not affected by estradiol. Importantly, angiotensin II was higher on estradiol during all stages of LBNP, and increased 70% above resting values at the end of this stimulus (P<0.05), yet BP was significantly lower, both at rest (P<0.05) and during LBNP (P<0.01). In summary, in normotensive postmenopausal women, estradiol increases angiotensin II, but not aldosterone, at rest and during orthostatic stress, yet lowers, rather than raises, BP under both conditions. Downregulation of vascular and adrenal responsiveness to angiotensin II may protect healthy women against this activation. Loss of such protection may elevate BP and have adverse implications for women with conditions that impair their capacity to counteract the pathological actions of angiotensin II. This may contribute to higher cardiovascular event rates reported in recent ERT trials.

Background: Both exercise and postmenopausal estrogen therapy augment endothelial function. We hypothesized that their interaction would be additive. The study objectives were to determine in postmenopausal women (1) the effects of an acute bout of exercise on brachial artery endothelium-dependent flow-mediated vasodilation (FMD), (2) whether these responses to exercise are augmented by concurrent estrogen treatment, and (3) whether these 2 interventions, independently or together, achieve FMD values observed in premenopausal women., Methods: In postmenopausal women (n = 13; age 54 +/- 2 [mean +/- SE] years), FMD was quantified during supine rest and again 60 minutes after treadmill exercise for 45 minutes at 60% V* O2max. Subjects were studied twice: before and after 4 weeks of oral estradiol. To obtain reference normal values, FMD was determined concurrently in 14 premenopausal (28 +/- 1 years) women under identical basal conditions., Results: Flow-mediated vasodilation in postmenopausal women, markedly impaired when compared with premenopausal women (5.3% +/- 0.5% vs 12.1% +/- 1.5%, P < .01), was significantly increased by exercise (to 9.9% +/- 0.6%, P < .01). In contrast, after estrogen, FMD was augmented at rest (P < .01) but was not further enhanced after exercise (11.5% +/- 0.6% vs 9.9% +/- 0.5%, P = .3). Both interventions increased, independently, FMD to values in premenopausal women (P > .05)., Conclusions: In postmenopausal women, both acute exercise and estrogen therapy normalize FMD. However, their effects are not additive, possibly because of redundancy of nitric oxide signaling pathways activated by these 2 interventions. When considered in the context of recent trials with adverse cardiovascular outcomes, these results reinforce the therapeutic potential of exercise as an alternative nonpharmacological intervention to estrogen in postmenopausal women with endothelial dysfunction.

The effects of dietary safflower (control, n = 10), borage (n = 9), and fish oil (n = 10), as sources of linoleic, gamma-linolenic, and eicosapentaenoic acid, respectively, at a dose of 4.5 ml/day for 4 wk, on cardiovascular responses to lower body negative pressure (LBNP) were studied in normotensive humans in a randomized, double-blind design. Pre- and postsupplementation, subjects were exposed to 5 min of -10 and -40 mmHg LBNP. Blood pressure (BP), heart rate (HR), forearm blood flow (FBF), forearm vascular resistance (FVR), and plasma norepinephrine (PNE) were measured at each level. Subjects were then exposed to a cold-pressor test, isometric handgrip, and forearm ischemia. At pretest, LBNP reduced BP and FBF and increased HR and FVR in all groups. After diets, the PNE and vasoconstrictor responses to -40 mmHg LBNP, as well as the reflex vasodilation on its cessation, were significantly augmented by borage oil. No diet differences were observed in the HR responses to LBNP or in the responses to the other tasks, with the exception that fish oil increased FBF after forearm ischemia. These data indicate that borage oil augments the arterial baroreflex control of vascular resistance. The vasodilatory effects of fish oil may be mediated via local mechanisms.

Much attention is given to the development of the clinical nurse specialist role in an institution. This article is written for the seasoned Clinical Nurse Specialist who experiences a change in nursing administration. It describes dilemmas, identifies dynamics, and offers practical suggestions for surviving and thriving during a transition period.

The forearm vasoconstrictor response to lower body negative pressure (LBNP), a reflex stimulus to norepinephrine release, can be augmented by a prior brachial artery infusion of epinephrine. We wished to determine whether this sustained aftereffect of epinephrine could be replicated by systemic infusion and, if so, whether it could be prevented by prior uptake-1 blockade with desipramine. Eight normal men (mean age 30 years) were studied on two separate study days at least 1 week apart, 2.5 hours after taking, at random, either desipramine (125 mg p.o.) or placebo. Forearm vascular resistance was measured at rest and at the end of 6 minutes of LBNP at -40 mm Hg. This was done both before and 30 minutes after a 60-minute infusion of epinephrine (1.5 micrograms/min i.v.). From similar baselines, the forearm vasoconstrictor response to LBNP was significantly augmented 30 minutes after epinephrine on the placebo day (+17 +/- 4 vs. +12 +/- 3 resistance units, mean +/- SEM, p less than 0.01) but not on the desipramine day (+14 +/- 2 vs. +16 +/- 3 resistance units). The heart rate response to LBNP was also greater after epinephrine on the placebo day (+20 +/- 3 vs. +16 +/- 2 beats/min, p less than 0.05). Mean arterial pressure was higher after epinephrine infusion on the placebo (p less than 0.01) but not on the desipramine day.(ABSTRACT TRUNCATED AT 250 WORDS)

The quantity and duration of herpes simplex virus type 1 shedding in the preocular tear film of rabbits were measured before, during, and after administration of acyclovir topically, intravenously, and by these routes. Topical administration reduced shedding significantly, Intravenous administration was without effect and in the combination regimen added nothing to the effectiveness of local application. The effects of acyclovir were temporary because there were significant increase in preocular tear film virus shedding after cessation of treatment.