Differences in Lift Quality During the Barbell Back Squat When Using Perceived Recovery Status-Regulated Intrasession Recovery Compared With Standardized Recovery Intervals.

ABSTRACT: Wolfe, AA, Laurent, CM, Tolusso, DV, and Rinehart, AN. Differences in lift quality during the barbell back squat when using perceived recovery status-regulated intrasession recovery compared with standardized recovery intervals. J Strength Cond Res 38(3): 444-449, 2024-The current investigation examined kinetic differences between standardized and perceptually regulated rest internals during power-based resistance training. Recreationally resistance-trained men ( n = 7) and women ( n = 7) completed 3 training sessions. Session 1 consisted of barbell back squat (SQ) 1 repetition maximum (1RM) testing. Two counterbalanced subsequent sessions of perceptually regulated vs. standardized intrasession recovery for 5 sets of 6 repetitions of SQ at 80% 1RM were completed. Lift quality was assessed using a barbell accelerometer that measured concentric and eccentric power and force outputs for each repetition. In each set, subjects reported a rating of perceived exertion (RPE) followed by passive rest for either 2 minutes or a self-selected period using the Perceived Recovery Status (PRS) scale. For the self-selected session, when an individual reported a PRS at level "7," they were instructed to begin the next set. Data were analyzed using a 2 (session) × 5 (set) repeated-measures ANOVA with Bonferroni post hoc analyses performed when appropriate. No significant main effects or interactions were observed for any set quality metrics in the concentric phase or eccentric phase, except peak eccentric power ( p = 0.01). Post hoc analyses revealed a significant increase in peak eccentric power from set 1 to set 2 ( p = 0.003) only. Finally, no significant difference between self-selected vs. standardized work-to-rest strategies on RPE ( p = 0.547) was expressed. These data suggest perceptually regulated intrasession recovery selection yields equivalent lift quality as standardized rest recommendations. Therefore, PRS utilization may provide a more simplified and individualized method of between-set rest prescriptions.

Pathways to water sustainability? A global study assessing the benefits of integrated water resources management.

Integrated water resources management (IWRM) has been central to water governance and management worldwide since the 1990s. Recognizing the significance of an integrated approach to water management as a way to achieve the Sustainable Development Goals (SDGs), IWRM was formally incorporated as part of the SDG global indicator framework, thus committing the UN and its Member States to achieving high IWRM implementation by 2030 and measuring progress through SDG indicator 6.5.1. This paper examines the extent to which the implementation of IWRM improves the sustainable management of water and the health of water-related ecosystems-a first-of-its-kind in terms of quantitative analysis on a global scale. To achieve this objective, we conducted regression analyses between SDG 6.5.1 (both IWRM (total score) and the dimensions of SDG 6.5.1) and key water-related environmental sustainability indicators: SDG 6.2.1a (access to basic sanitation), 6.3.1 (treated wastewater), 6.4.1 (water-use efficiency), 6.4.2 (water stress), 6.6.1 (freshwater ecosystems, although here the trophic state and turbidity variables were used) and 6.3.2 (ambient water quality). Our analysis covers 124 countries for all these SDGs, with the exception of SDG 6.3.1 and SDG 6.3.2, which cover 112 and 85 countries, respectively. Results show that IWRM-to different degrees-is mainly associated with the good status of water-related sustainability indicators, with the exception of water stress, water quality, and turbidity. We observe a strong impact of control variables such as governance arrangements, economic situation and environmental and geographical conditions. Lagged effects and the scope of the framework may also explain some observed variations in the degree of association. Our study highlights the importance of further uncovering the interlinkages between IWRM implementation and the achievement of water-related environmental sustainability. Overall, the results suggest that although IWRM implementation is primarily linked to sustainable water management and the health of water systems, context-specific factors should be taken into account when evaluating its effectiveness, to enable policy- and decision-makers to make the necessary adjustments to optimize its outcomes.

Neurologic manifestations of giant cell arteritis.

Giant cell arteritis, the most frequent form of vasculitis in persons over 50 years of age, is a granulomatous chronic vasculitis involving large and medium-sized vessels, most commonly the temporal and other cranial arteries. This common, treatable condition is associated with various clinical symptoms, including neurological ones, affecting both the central and peripheral nervous systems. In this review, we discuss the cranial and extra cranial neurological complications of giant cell arteritis, to help avoid the many pitfalls in the diagnosis of giant cell arteritis.

Acute health risks to community hand-pumped groundwater supplies following Cyclone Idai flooding.

This longitudinal flood-relief study assessed the impact of the March 2019 Cyclone Idai flood event on E. coli contamination of hand-pumped boreholes in Mulanje District, Malawi. It established the microbiological water-quality safety of 279 community supplies over three phases, each comprising water-quality survey, rehabilitation and treatment verification monitoring. Phase 1 contamination three months after Idai was moderate, but likely underestimated. Increased contamination in Phase 2 at 9 months and even greater in Phase 3, a year after Idai was surprising and concerning, with 40% of supplies then registering E. coli contamination and 20% of supplies deemed 'unsafe'. Without donor support for follow-up interventions, this would have been missed by a typical single-phase flood-relief activity. Contamination rebound at boreholes successfully treated months earlier signifies a systemic problem from persistent sources intensified by groundwater levels likely at a decade high. Problem extent in normal, or drier years is unknown due to absence of routine monitoring of water point E. coli in Malawi. Statistical analysis was not conclusive, but was indicative of damaged borehole infrastructure and increased near-borehole pit-latrine numbers being influential. Spatial analysis including groundwater flow-field definition (an overlooked sector opportunity) revealed 'hit-and-miss' contamination of safe and unsafe boreholes in proximity. Hydrogeological control was shown by increased contamination near flood-affected area and in more recent recharge groundwater otherwise of good quality. Pit latrines are presented as credible e-coli sources in a conceptual model accounting for heterogeneous borehole contamination, wet season influence and rebound behavior. Critical to establish are groundwater level - flow direction, hand-pump plume draw, multiple footprint latrine sources - 'skinny' plumes, borehole short-circuiting and fast natural pathway (e.g. fracture flow) and other source influences. Concerted WASH (Water, Sanitation and Hygiene) sector investment in research and policy driving national water point based E. coli monitoring programs are advocated.

The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload.

Background: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) failure. While current PAH therapies improve patient outlook, they show limited benefit in attenuating RV dysfunction. Recent investigations demonstrated that the thromboxane (TX) A2 receptor (TP) antagonist NTP42 attenuates experimental PAH across key hemodynamic parameters in the lungs and heart. This study aimed to validate the efficacy of NTP42:KVA4, a novel oral formulation of NTP42 in clinical development, in preclinical models of PAH while also, critically, investigating its direct effects on RV dysfunction. Methods: The effects of NTP42:KVA4 were evaluated in the monocrotaline (MCT) and pulmonary artery banding (PAB) models of PAH and RV dysfunction, respectively, and when compared with leading standard-of-care (SOC) PAH drugs. In addition, the expression of the TP, the target for NTP42, was investigated in cardiac tissue from several other related disease models, and from subjects with PAH and dilated cardiomyopathy (DCM). Results: In the MCT-PAH model, NTP42:KVA4 alleviated disease-induced changes in cardiopulmonary hemodynamics, pulmonary vascular remodeling, inflammation, and fibrosis, to a similar or greater extent than the PAH SOCs tested. In the PAB model, NTP42:KVA4 improved RV geometries and contractility, normalized RV stiffness, and significantly increased RV ejection fraction. In both models, NTP42:KVA4 promoted beneficial RV adaptation, decreasing cellular hypertrophy, and increasing vascularization. Notably, elevated expression of the TP target was observed both in RV tissue from these and related disease models, and in clinical RV specimens of PAH and DCM. Conclusion: This study shows that, through antagonism of TP signaling, NTP42:KVA4 attenuates experimental PAH pathophysiology, not only alleviating pulmonary pathologies but also reducing RV remodeling, promoting beneficial hypertrophy, and improving cardiac function. The findings suggest a direct cardioprotective effect for NTP42:KVA4, and its potential to be a disease-modifying therapy in PAH and other cardiac conditions.

Prostanoid receptor subtypes involved in treprostinil-mediated vasodilation of rat pulmonary arteries and in treprostinil-mediated inhibition of collagen gene expression of human lung fibroblasts.

Treprostinil (TRE) is a potent pulmonary vasodilator with effects on other pathological aspects of pulmonary arterial hypertension. In this study, the prostanoid receptors involved in TRE-induced relaxation of isolated rat pulmonary arteries and TRE-induced inhibition of increased gene expression in collagen synthesis and contractility of human lung fibroblasts were determined. TRE (0.01-100 µM) relaxed prostaglandin F2α-precontracted rat pulmonary arteries which was attenuated by denudation of the vascular endothelium. TRE-induced relaxation was predominantly blocked by the IP receptor antagonist RO3244194 (1 µM), with slightly greater inhibition in endothelium-denuded tissue. At higher TRE concentrations (> 1 µM), the DP1 receptor antagonist BW A868C (1 µM) also inhibited relaxation reaching significance above 10 µM. In contrast, the EP3 receptor antagonist L798106 (1 µM) accentuated TRE-induced relaxation of pulmonary arteries with intact endothelium. In human lung fibroblasts, the EP2 receptor antagonist PF-04418948 (1 µM) blocked transforming growth factor ß1 (TGF-ß1)-increased expression of collagen synthesis (COL1A1 and COL1A2) and fibroblast contractility (ACTG2) genes in presence of TRE (0.1 µM). In conclusion, the IP receptor located on rat pulmonary vascular smooth muscle and endothelium is the primary receptor mediating vasorelaxation, while the DP1 receptor present on the rat endothelium is involved only at higher TRE concentrations. In human lung fibroblasts, the EP2 receptor is the dominant receptor subtype involved in suppression of increased collagen synthesis and fibroblast contractility gene expression induced by TGF-ß1 in the presence of TRE.

Inhaled Treprostinil-Prodrug Lipid Nanoparticle Formulations Provide Long-Acting Pulmonary Vasodilation.

Treprostinil (TRE), a prostanoid analogue approved in the USA for the treatment of pulmonary arterial hypertension, requires continuous infusion or multiple dosing sessions per day for inhaled and oral routes of administration due to its short half-life. The inhaled drug is known to induce adverse systemic and local effects including headache, nausea, cough, and throat irritation which may be due at least in part to transiently high drug concentrations in the lungs and plasma immediately following administration [1]. To ameliorate these side effects and reduce dosing frequency we designed an inhaled slow-release TRE formulation. TRE was chemically modified to be an alkyl prodrug (TPD) which was then packaged into a lipid nanoparticle (LNP) carrier. Preclinical screening in a rat model of hypoxia-induced pulmonary vasoconstriction led to selection of a 16-carbon alkyl ester derivative of TRE. The TPD-LNP demonstrated approximately 10-fold lower TRE plasma Cmax compared to inhaled TRE solution while maintaining an extended vasodilatory effect. The favorable PK profile is attributed to gradual dissociation of TPD from the LNP and subsequent conversion to TRE. Together, this sustained presentation of TRE to the lungs and plasma is consistent with a once- or twice-daily dosing schedule in the absence of high Cmax-associated adverse events which could provide patients with an improved treprostinil therapy.

Evaluation of the effects of RP5063, a novel, multimodal, serotonin receptor modulator, as single-agent therapy and co-administrated with sildenafil, bosentan, and treprostinil in a monocrotaline-induced pulmonary arterial hypertension rat model.

Pulmonary arterial hypertension (PAH), a condition that is defined by pulmonary vasculature constriction and remodeling, involves dysfunctional signaling of the serotonin (5-HT) receptors, 5-HT2A/2B/7. In a rat model of monocrotaline (MCT)-induced PAH, the effectiveness of RP5063 (RP), a dopamine and 5-HT receptor modulator, was evaluated as monotherapy and as an adjunct to standard PAH treatments. After a single 60 mg/kg dose of MCT, rats received vehicle (MCT+Veh; gavage twice-daily [b.i.d.]), RP (10 mg/kg; gavage b.i.d.), bosentan (B; 100 mg/kg; gavage BID), sildenafil (S; 50 mg/kg; gavage, BID), treprostinil (T; 100 ng/kg/min over 24 h intravenous), RP+B, RP+S, and RP+T for 28 days. Single-agent RP limited the functional and structural effects of PAH seen in the MCT+Veh group, with significant improvements in pulmonary hemodynamics, right ventricular (RV) hypertrophy, SO2, and pulmonary blood vessel structural changes. These effects appeared comparable with those associated with B, S, and T. Adjunctive RP treatment resulted in significantly lower mean pulmonary arterial pressures, RV systolic pressure. It also improved SO2 measurements, as compared with MCT+Veh (P < 0.05), and diastolic pulmonary artery pressure (P < 0.05), as compared with single-agent B and S therapy (Bonferroni method adjusting for multiplicity). RP+S appeared to show the most consistent and extensive effects on pulmonary hemodynamics, respiratory parameters, and histopathologic changes. These results corroborate earlier preclinical findings supporting the efficacy of single-agent RP in PAH. RP, as mono and adjunctive therapy compared with induced-control, mitigated the functional and structural effects of MCT-induced PAH.

Inhaled hexadecyl-treprostinil provides pulmonary vasodilator activity at significantly lower plasma concentrations than infused treprostinil.

INS1009 is a long acting pulmonary vasodilator prodrug of treprostinil (TRE) that is formulated in a lipid nanoparticle for inhaled delivery by nebulization. This study examined the ability of INS1009 to inhibit vasoconstriction in the pulmonary vasculature of rats and dogs and the extent to which local activity within the lung contributes to its activity. Rats received a single dose of INS1009 by nose-only inhalation or were given a continuous intravenous (i.v.) infusion of TRE, followed by an i.v. challenge of the thromboxane mimetic pulmonary vasoconstrictor U46619 and the increase in pulmonary arterial pressure (PAP) was measured. In beagle dogs, INS1009 was given by inhalation via face mask and TRE was given by continuous i.v. infusion; vasoconstriction was then induced by inhaled hypoxia with reduction of FIO2 to 0.10. Changes in the dog's right ventricular pulse pressure (RVPP) were measured using implanted telemetry probes. Blood samples were collected in rats and dogs immediately after the challenge to measure the plasma TRE concentration. Exposure of rats to inhaled INS1009 (0.5, 3.0 and 20.9 µg/kg) inhibited the U46619-induced increase in PAP at all doses up to 6 h with statistically significant inhibition up to 24 h with the pooled dose-response data. The concentration of TRE in the plasma at which PAP was reduced by 50% was approximately 60-fold lower for INS1009 (EC50 = 0.08 ng/mL) as compared to i.v. TRE (EC50 = 4.9 ng/mL). In dogs, INS1009 (2.7-80.9 µg/kg) inhibited the hypoxia-induced increase in RVPP at all doses up to 6 h with activity once again observed with the pooled dose-response of 10 µg/kg and higher at 24 h. The concentration of TRE in the plasma at which RVPP was reduced by 50% was approximately 550-fold lower for INS1009 (EC50 = 0.0075 ng/mL) as compared to i.v. TRE (EC50 = 4.1 ng/mL). These studies, in two species and by two different pulmonary vasoconstrictor challenges, demonstrate that inhaled INS1009 not only has long-acting vasodilatory effects but also that the local activity within the lung contributes to this response. Therefore, INS1009 may offer the opportunity to effect pulmonary vasodilation for long periods but with substantially lower systemic exposure than infused TRE.

Preclinical Pharmacology and Pharmacokinetics of Inhaled Hexadecyl-Treprostinil (C16TR), a Pulmonary Vasodilator Prodrug.

This article describes the preclinical pharmacology and pharmacokinetics (PK) of hexadecyl-treprostinil (C16TR), a prodrug of treprostinil (TRE), formulated in a lipid nanoparticle (LNP) for inhalation as a pulmonary vasodilator. C16TR showed no activity (>10 µM) in receptor binding and enzyme inhibition assays, including binding to prostaglandin E2 receptor 2, prostaglandin D2 receptor 1, prostaglandin I2 receptor, and prostaglandin E2 receptor 4; TRE potently bound to each of these prostanoid receptors. C16TR had no effect (up to 200 nM) on platelet aggregation induced by ADP in rat blood. In hypoxia-challenged rats, inhaled C16TR-LNP produced dose-dependent (0.06-6 µg/kg), sustained pulmonary vasodilation over 3 hours; inhaled TRE (6 µg/kg) was active at earlier times but lost its effect by 3 hours. Single- and multiple-dose PK studies of inhaled C16TR-LNP in rats showed proportionate dose-dependent increases in TRE Cmax and area under the curve (AUC) for both plasma and lung; similar results were observed for dog plasma levels in single-dose PK studies. In both species, inhaled C16TR-LNP yielded prolonged plasma TRE levels and a lower plasma TRE Cmax compared with inhaled TRE. Inhaled C16TR-LNP was well tolerated in rats and dogs; TRE-related side effects included cough, respiratory tract irritation, and emesis and were seen only after high inhaled doses of C16TR-LNP in dogs. In guinea pigs, inhaled TRE (30 µg/ml) consistently produced cough, but C16TR-LNP (30 µg/ml) elicited no effect. These results demonstrate that C16TR-LNP provides long-acting pulmonary vasodilation, is well tolerated in animal studies, and may necessitate less frequent dosing than inhaled TRE with possibly fewer side effects.

RP5063, a novel, multimodal, serotonin receptor modulator, prevents monocrotaline-induced pulmonary arterial hypertension in rats.

Pulmonary arterial hypertension (PAH), a condition characterized by pulmonary vasculature constriction and remodeling, involves dysregulation of the serotonin (5-HT) receptors 5-HT2A and 5-HT2B. A rat model of monocrotaline (MCT)-induced PAH was used to examine the potential beneficial effects of RP5063, a 5-HT receptor modulator. After a single 60mg/kg dose of MCT, rats were gavaged twice-daily (b.i.d.) with vehicle, RP5063 (1, 3, or 10mg/kg), or sildenafil (50mg/kg) for 28 days. RP5063 at a dose as low as 1mg/kg, b.i.d. reduced pulmonary resistance and increased systemic blood oxygen saturation. The highest dose of RP5063 (10mg/kg, b.i.d.) reduced diastolic, systolic, and mean pulmonary pressure, right systolic ventricular pressure, ventilatory pressure, and Fulton's index (ratio of right to left ventricular weight). Doses as low as 3mg/kg RP5063, b.i.d. also increased weight gain and body temperature, suggesting an improvement in overall health of MCT-treated animals. Similar reductions in pulmonary, right ventricular, and ventilatory pressure, pulmonary resistance, and Fulton's index as well as increased systemic blood oxygen saturation were observed in animals treated with the reference agent sildenafil at a higher dose (50mg/kg, b.i.d.). Histological examination revealed that RP5063 produced dose-dependent reductions in pulmonary blood vessel wall thickness and proportion of muscular vessels, similar to sildenafil. RP5063 completely blocked MCT-induced increases in the plasma cytokines TNFα, IL-1ß, and IL-6 at all doses. In summary, RP5063 improved pulmonary vascular pathology and hemodynamics, right ventricular pressure and hypertrophy, systemic oxygen saturation, and overall health of rats treated with MCT.

RP5063, a novel, multimodal, serotonin receptor modulator, prevents Sugen 5416-hypoxia-induced pulmonary arterial hypertension in rats.

RP5063, a multimodal dopamine (DA) and serotonin (5-HT) modulator with high affinity for DA2/3/4 and 5-HT2A/2B/7 receptors and moderate affinity for SERT, is a novel therapeutic of special interest in the treatment of pulmonary arterial hypertension (PAH). Evidence indicates that therapeutics targeting the 5-HT2A/2B receptors can influence the pathogenesis of PAH. However, the therapeutic effect of RP5063 in humans has yet to be investigated. A Sugen 5416-hypoxia (SuHx)-induced PAH model was used to evaluate twice-daily (b.i.d.) RP5063 at 10mg/kg (RP-10) and 20mg/kg (RP-20), as compared with positive (sildenafil 50mg/kg b.i.d.; Sil-50) and negative controls (SuHx+vehicle; SuHx+veh), in 24 adult male Wistar-Kyoto rats. RP5063 showed significantly lower systolic pulmonary arterial (both doses) and systolic right ventricular (RP-10) pressures, and improvement in oxygen saturation (RP-20). It significantly reduced small-vessel wall thickness (RP-20), lowered the percentage of muscular vessels (both doses). Both doses limited arterial obliteration due to endothelial cell proliferation, prevented plexiform lesion formation, and stemmed the release of leukotriene B4. Sildenafil showed statistically greater effects on vessel structure than that seen in both RP5063 groups and improved oxygen saturation. Additionally, Sildenafil did not demonstrate any significant effect on arterial obliteration, plexiform lesion development, or pulmonary arterial or right ventricular pressure. As PAH gains in severity, the impact of RP5063 inhibition of 5HT2B increases, preventing arterial constriction and improving pulmonary hemodynamics. Due to its functional, structural, and chemokine effects, RP5063 represents a promising candidate for investigation in late-phase PAH.

Dual antiplatelet and anticoagulant APAC prevents experimental ischemia-reperfusion-induced acute kidney injury.

BACKGROUND: Renal ischemia-reperfusion predisposes to acute kidney injury (AKI) and mortality. APAC, mast cell heparin proteoglycan mimetic is a potent dual antiplatelet and anticoagulant inhibiting thrombosis in several vascular models. METHODS: Clinically relevant (0.06 and 0.13 mg/kg) and high (0.32 and 7.3 mg/kg) heparin doses of APAC and unfractionated heparin (UFH) were administered i.v. in pharmacological studies. Antithrombotic action of APAC and UFH was assessed with platelet aggregation to collagen, activated partial thromboplastin (APTT) and prothrombin (PT) times. Pharmacodynamics of [64Cu]-APAC or -UFH were monitored by PET/CT. Next, APAC and UFH doses (0.06 and 0.13 mg/kg) were i.v. administered 10 min prior to renal ischemia-reperfusion injury (IRI) in rats. RESULTS: APAC in contrast to UFH inhibited platelet aggregation. During 0.06 and 0.13 mg/kg dose regimens APTT and PT remained at baseline, but at the high APTT prolonged fourfold to sixfold. Overall bio-distribution and clearance of APAC and UFH were similar. After bilateral 30-min renal artery clamping, creatinine, urea nitrogen and neutrophil gelatinase-associated lipocalin concentrations and histopathology indicated faster renal recovery by APAC (0.13 mg/kg). APAC, unlike UFH, prevented expression of innate immune ligand hyaluronan and tubulointerstitial injury marker Kim-1. Moreover, in severe bilateral 1-h renal artery clamping, APAC (0.13 mg/kg) prevented AKI, as demonstrated both by biomarkers and survival. Compatible with kidney protection APAC reduced the circulating levels of vascular destabilizing and pro-inflammatory angiopoietin-2 and syndecan-1. No tissue bleeding ensued. CONCLUSION: APAC and UFH were similarly eliminated via kidneys and liver. In contrast to UFH, APAC (0.13 mg/kg) was reno-protective in moderate and even severe IRI by attenuating vascular injury and innate immune activation.

Crossmodal session rating of perceived exertion response at low and moderate intensities.

Session rating of perceived exertion (SRPE) permits global effort estimations after an exercise bout and has shown promise for evaluating training load. However, factors mediating SRPE are not well understood. The purpose of this study was to compare SRPE between cycling and treadmill exercise at low and moderate intensities. In a counterbalanced order, male subjects (n = 7) completed a VO2max trial on a cycle ergometer and a motor-driven treadmill. Then, participants completed trials at 50 and 75% mode-specific VO2max on a cycle ergometer (BK75, BK50) and a treadmill (TM75, TM50) to achieve ∼ 400-kcal energy expenditure per trial. Acute RPE (i.e., during exercise) at 5 minutes, midway, and test termination were recorded with SRPE (20-minutes postexercise) expressed as overall (SRPEO), legs (SRPEL), and breathing also recorded were heart rate (HR) and change in rectal temperature (ΔTrec). Significance was accepted at p ≤ 0.05. Repeated-measures analysis of variance revealed significantly greater SRPE for higher intensities within each mode. Crossmodal comparisons also show a higher SRPE at moderate (75% VO2max) intensities [SRPEO] = BK75: 7.6 ± 1.0, TM75: 6.9 ± 1.3) vs. lower (50% VO2max) intensities (BK50: 4.6 ± 1.4, TM50: 4.6 ± 1.1). Within modes, SRPE corresponded well with ΔTrec and HR. Acute RPE was linked with intensity and drifted upward across time. Results indicated that overall and differentiated SRPEs are magnified with exercise intensity with the corresponding disruption in internal environment potentially mediating subjective responses. From a practical application standpoint, SRPE provides a subjective assessment for immediate evaluation of daily training. Results indicate that, when using SRPE to monitor training, consideration should be given to responses across differing exercise modes.

Effective immune restoration after immunosuppressant discontinuation in a lupus patient presenting progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the central nervous system with JC virus. Few cases have been described in lupus patients. We describe biopsy-proven PML in a lupus patient receiving mycophenolate mofetil and corticosteroids. Although the patient received no antiviral treatment, the polymerase chain reaction test for JC virus became negative in cerebrospinal fluid after immunosuppressant discontinuation and the patient survived. We discuss the restoration of immune efficiency after immunosuppressant discontinuation in this case and compare the clinical, radiological and histological features with the inflammatory PML form described in human immunodeficiency virus-infected patients.

Staufen1 regulation of protein synthesis-dependent long-term potentiation and synaptic function in hippocampal pyramidal cells.

Staufen1 (Stau1) is an RNA-binding protein involved in transport, localization, decay, and translational control of mRNA. In neurons, it is present in cell bodies and also in RNA granules which are transported along dendrites. Dendritic mRNA localization might be involved in long-term synaptic plasticity and memory. To determine the role of Stau1 in synaptic function, we examined the effects of Stau1 down-regulation in hippocampal slice cultures using small interfering RNA (siRNA). Biolistic transfection of Stau1 siRNA resulted in selective down-regulation of Stau1 in slice cultures. Consistent with a role of Stau1 in transporting mRNAs required for synaptic plasticity, Stau1 down-regulation impaired the late form of chemically induced long-term potentiation (L-LTP) without affecting early-LTP, mGluR1/5-mediated long-term depression, or basal evoked synaptic transmission. Stau1 down-regulation decreased the amplitude and frequency of miniature excitatory postsynaptic currents, suggesting a role in maintaining efficacy at hippocampal synapses. At the cellular level, Stau1 down-regulation shifted spine shape from regular to elongated spines, without changes in spine density. The change in spine shape could be rescued by an RNA interference-resistant Stau1 isoform. Therefore, Stau1 is important for processing and/or transporting in dendrites mRNAs that are critical in regulation of synaptic strength and maintenance of functional connectivity changes underlying hippocampus-dependent learning and memory.

Session RPE following interval and constant-resistance cycling in hot and cool environments.

PURPOSE: This study examined effects of heat gain, circulatory adjustment to temperature regulation (HR), and [La] consequent to interval (INT) and constant-load (CON) cycling on session RPE (S-RPE). METHODS: Male volunteers (N = 10) completed a cycle ergometer VO2peak test and then, in a randomized, counterbalanced order, four cycling bouts, including constant load (approximately 45% VO2peak) (CON) and interval (8 x 1 min at about 90% VO2peak, 1 min between intervals) (INT), in hot (approximately 32.5 WBGT) (HOT) and cool (approximately 21.0 WBGT) (COOL) environments. Trials included a standardized warm-up and cool-down (10 min each: 0 W, 60 rpm). Total external work was equated among all trials, with blood lactate ([La]), heart rate (HR), rectal temperature (Tre), and acute RPE recorded at 10, 13, 17, 21, 25, and 36 min. S-RPE was recorded 20 min after each session. RESULTS: HOT (CON and INT) resulted in significantly (P < 0.05) greater heat gain (Tre), HR, and RPE-O, whereas INT had significantly elevated [La] versus CON (HOT and COOL). HOT yielded significantly higher S-RPE versus COOL for CON (HOT = 5.6 +/- 2.1, COOL = 4.3 +/- 1.3) and INT (HOT = 7.0 +/- 1.9, COOL = 5.1 +/- 2.0). S-RPE was significantly higher for INT/HOT than CON/HOT. CONCLUSIONS: Heat gain and cardiac strain (Tre, HR) and [La]) were manipulated with environment and exercise type while holding total work constant. The added strain of HOT was reflected in elevated S-RPE for both CON and INT. S-RPE linkage with [La] was limited to HOT trials, indicating only a loose association. These data indicate that under the conditions of this study, S-RPE is similar to acute RPE in that no single mediator seems universally dominant.

Kv4.3-mediated A-type K+ currents underlie rhythmic activity in hippocampal interneurons.

Hippocampal-dependent learning and memory processes are associated with theta frequency rhythmic activity. Interneuron and pyramidal cell network interactions underlie this activity, but contributions of interneuron voltage-gated membrane conductances remain unclear. We show that interneurons at the CA1 lacunosum-moleculare (LM) and radiatum (RAD) junction (LM/RAD) display voltage-dependent subthreshold membrane potential oscillations (MPOs) generated by voltage-gated tetrodotoxin-sensitive Na+ and 4-aminopyridine (4-AP)-sensitive K+ currents. They also exhibit prominent 4-AP-sensitive A-type K+ currents, with gating properties showing activation at subthreshold membrane potentials. We found that LM/RAD cells are part of specific interneuron subpopulations expressing the K+ channel subunit Kv4.3 and their transfection with Kv4.3 small interfering RNA selectively impaired A-type K+ currents and MPOs. Thus, our findings reveal a novel function of Kv4.3-mediated A-type K+ currents in the generation of intrinsic MPOs in specific subpopulations of interneurons that may participate in hippocampal theta-related rhythmic activity.

Insular infarcts and electrocardiographic changes at admission: results of the PRognostic of Insular CErebral infarctS Study (PRINCESS).

BACKGROUND AND PURPOSE: Previous studies showed that insular strokes are associated with electrocardiographic (ECG) changes. However, they did not take into account the 1(st) ECG recorded at admission, but continuous ECG recorded up to 72 hours after onset. Whether these changes are the consequence of the infarct, or are associated with a cardiac source of cerebral ischemia, remains unsettled. If ECG changes are the consequence of insular infarcts, they should not have developed by the time of admission. The aim of this study was to test the hypothesis that ECG changes in patients with insular infarcts are not present at admission. METHODS: We recruited consecutive patients admitted within 48 hours (median 3 hours) after the onset of symptoms of acute hemispheric cerebral ischemia. We compared ECG variables between patients with and without insular infarcts, and with left and right insular infarcts. RESULTS: The study population consisted of 208 patients (94 men; median age: 69 years). Seventy patients had a recent insular infarct (right in 33). ECG variables did not significantly differ between patients with and without insular infarcts, and with left and right insular infarcts. These results were not explained by a lack of statistical power (1-beta >/= 0.90). CONCLUSION: The lack of statistical link between insular infarcts and ECG changes at admission, suggests that ECG changes are not associated with the cause of insular infarcts, but are their consequence.