Pressure In Humans Research Articles

Lower Limb Venous Distension Reflex and Orthostatic Tolerance in Young Healthy Humans

We and others showed that venous distension induced by saline infusion into veins of an arterially occluded arm evokes reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in humans (i.e. venous distension reflex). Our recent report also shows that suction of arterially occluded limb (forearm or lower leg) evokes significant increases in MSNA and BP, which are induced by the vascular distension in the limbs. We postulate that venous distension reflex will be activated when humans stand. We speculate that the individual differences in the venous distension reflex may contribute to the individual differences in the orthostatic tolerance. Thus, we hypothesized that the orthostatic tolerance would be related with the MSNA response to the lower limb suction. Fifteen healthy subjects (8M, 7F, 26 ± 1 yrs, 172 ± 3 cm, 69 ± 4 kg) were tested in supine position. One of the subject's lower legs was inserted into an airtight pressure tank. An arterial occlusion cuff was put on the mid thigh (~10–15 cm above the level of the suction tank). MSNA (in the opposite limb), ECG, and BP (Finometer) were recorded throughout the study. After the arterial occlusion cuff on the mid thigh was inflated (250 mmHg), limb suction (‐100 mmHg) is applied for 2 min. Limb occlusion without suction was used as a control trial. In a separate visit, the individual's orthostatic tolerance was assessed using a graded lower body negative pressure (LBNP) tolerance test (from 20 up to 70 mmHg, no MSNA). Mean arterial BP (MAP, 78.9 ± 1.1 to 86.9 ± 1.7 mmHg) and MSNA (18.5 ± 1.9 to 23.6 ± 2.0 bursts/min) significantly (both P < 0.05) increased during the suction of a leg, while heart rate was not significantly different from the baseline. Occlusion alone did not significantly alter MSNA. The magnitude of the MSNA response to single leg suction at 100 mmHg was then compared to the orthostatic tolerance index for that subject. The orthostatic tolerance index positively correlated (R = 0.636, P = 0.011) with the MSNA response seen with suction during occlusion. The presented data suggest that the venous distension reflex strength correlates with the level of orthostatic tolerance. Thus, we speculate that lower limb venous distension reflex engagement increases the sympathetic responses during orthostatic challenge and serves to maintain BP with postural stress.Support or Funding InformationSupported by American Heart Association Grant 15GRNT24480051 (Cui), National Institutes of Health Grants P01 HL096570 (Sinoway) and UL1 TR000127 (Sinoway).

Echocardiographic Pulmonary Artery Systolic Pressure in the Coronary Artery Risk Development in Young Adults (CARDIA) Study: Associations With Race and Metabolic Dysregulation.

BackgroundThe determinants of pulmonary artery systolic pressure (PASP) are not fully understood. It is unknown whether racial differences in PASP exist or if other population characteristics are associated with pulmonary pressure in humans. We examined echocardiographically estimated PASP in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a middle‐aged, biracial community‐based cohort.Methods and ResultsAt the CARDIA year‐25 examination, 3469 participants underwent echocardiography, including measurement of tricuspid regurgitant jet velocity to estimate PASP. Clinical features, laboratory values, pulmonary function tests, and measurement of adipose depot volume were analyzed for association with PASP. PASP was estimated in 1311 individuals (61% female, 51% white). Older age, higher blood pressure, and higher body mass index were associated with higher PASP. Black race was associated with higher PASP after adjustment for demographics and left and right ventricular function (β 0.94, 95% CI 0.24‐1.64; P=0.009), but this association was no longer significant after further adjustment for lung volume (β 0.42, 95% CI −0.68 to 0.96; P=0.74). Insulin resistance, inflammation (C‐reactive protein and interleukin‐6), and visceral adipose volume were independently associated with higher PASP after adjustment for relevant covariates. PASP rose with worsening diastolic function (ratio of early transmitral Doppler velocity to average mitral annular tissue Doppler velocity [E/e′] and left atrial volume index).ConclusionsIn a large biracial cohort of middle‐aged adults, we identified associations among black race, insulin resistance, and diastolic dysfunction with higher echocardiographically estimated PASP. Further studies are needed to examine racial differences in PASP and whether insulin resistance directly contributes to pulmonary vascular disease in humans.

Uncovering Adiponectin Replenishing Property of Sujiaonori Algal Biomaterial in Humans.

The replenishment of adiponectin—an adipocyte-derived hormone with salutary health effects—has recently been proposed as a new approach to treat hypertension, also ameliorate cardiovascular and metabolic risks. We conducted a prospective placebo-controlled, non-randomized and investigator-blinded dietary intervention study to evaluate the health effects of dietary intake of Sujiaonori (Ulva/Enteromorpha prolifera Müller) algal biomaterial (SBM), especially on adiponectin production, blood pressure (BP), and body mass index (BMI) in human subjects. Participants (N = 32) were divided into two equally sized groups (n = 16 for each group): SBM group (subjects supplemented with 3 g SBM powder twice a day during meal) and the control group (subjects who took 3 g of a supplement made of 70% corn starch powder and 30% spinach twice a day) for four weeks. Two health survey questionnaires (dietary and current health questionnaires) were completed anonymously, saliva sampling was done for adiponectin measurement by ELISA, and blood pressure (BP) and anthropometric parameters were measured at baseline and four weeks later. Student paired t-test was performed to compare baseline and post-intervention data on outcome variables between the two study groups. Results showed a 2.24-fold increase in adiponectin level in SBM group (2.81 and 6.26 ng/mL at baseline and at the end of study, respectively) (p < 0.01); whereas no significant change was observed in controls (3.58 and 3.51 ng/mL, respectively) (p > 0.05). In SBM subjects, an improvement of BP profile was noted with a significant decrease in systolic BP (p < 0.01). A positive correlation was found between SBM supplementation and adiponectin level, whereas an inverse correlation was noted between SBM supplementation and blood pressure, and also BMI. These findings suggest that SBM-increased adiponectin level and improved BP in a sample of Japanese young adults, and has the potential to improve blood pressure in humans.

Correction to: Inorganic Nitrate Supplementation Lowers Blood Pressure in Humans: Role for Nitrite-Derived NO.

Correction to: Inorganic Nitrate Supplementation Lowers Blood Pressure in Humans: Role for Nitrite-Derived NO In the article by Kapil et al, “Inorganic Nitrate Supplementation Lowers Blood Pressure in Humans: Role …

Chlorogenic acid from coffee beans: evaluating the evidence for a blood pressure-regulating health claim.

The consumption of coffee has been associated with a number of health benefits, including a reduced risk of cardiovascular disease. Hypertension is an important risk factor for adverse cardiovascular events. Coffee may help reduce blood pressure (BP) in humans, which might be attributable to its polyphenolic compound, chlorogenic acid. The high incidence of hypertension among Canadians underscores the need for new and effective strategies to reduce BP. Dietary interventions may constitute such a strategy, but consumers need to be informed about which foods are most effective for regulating BP. To guide healthy eating, Health Canada permits the use of health claims on the labels of foods that confer health benefits. Currently, there is only one health claim for BP regulation. Additional health claims for foods that assist in BP regulation are therefore warranted. This review provides background information on chlorogenic acid and examines the evidence regarding the use of chlorogenic acid for BP regulation in the context of Health Canada's health claims framework.

Cannabinoids in the Cardiovascular System.

Cannabinoids are known to modulate cardiovascular functions including heart rate, vascular tone, and blood pressure in humans and animal models. Essential components of the endocannabinoid system, namely, the production, degradation, and signaling pathways of endocannabinoids have been described not only in the central and peripheral nervous system but also in myocardium, vasculature, platelets, and immune cells. The mechanisms of cardiovascular responses to endocannabinoids are often complex and may involve cannabinoid CB1 and CB2 receptors or non-CB1/2 receptor targets. Preclinical and some clinical studies have suggested that targeting the endocannabinoid system can improve cardiovascular functions in a number of pathophysiological conditions, including hypertension, metabolic syndrome, sepsis, and atherosclerosis. In this chapter, we summarize the local and systemic cardiovascular effects of cannabinoids and highlight our current knowledge regarding the therapeutic potential of endocannabinoid signaling and modulation.

Does leptin cause an increase in blood pressure in animals and humans?

Cardiovascular diseases (CVDs) are the number one cause of death globally. The risk for the development of CVDs is significantly increased in obesity. Leptin, the product of white adipose tissue, appears to contribute to the development of CVDs in obesity. Here, we discuss the premise that leptin engages the sympathetic nervous system and contributes to elevated blood pressure (BP) developing in obesity. The long-term regulation of BP is dependent on the activity of the autonomic nervous system and specifically the sympathetic nervous system. Sympathetic nerve activity is significantly increased in obese rodents and humans. Leptin increases sympathetic nerve activity in rodents and humans; however, leptin only consistently increases BP chronically in rodents. The ability of leptin to increase BP in rodents is via both hypothalamic and extrahypothalamic regions. In leptin-deficient and leptin receptor-deficient humans, leptin appears to be the key reason for decreased systolic BP. However, in other research conducted in humans, chronic administration of leptin does not elevate BP. Further research into the role of leptin in the development of CVDs, especially in humans, needs to be conducted.

An Integrative Approach to Hypertension: A Comprehensive Review of Antihypertensive Nutrients and Botanicals

Functional medicine doctors can learn more about herbs for hypertension in the new restorativemedicine.org/herbal/ program. This review article shows botanical and nutrient supplements which effectively lower blood pressure in humans with good tolerability.

Enhanced and Extended Anti-Hypertensive Effect of VP5 Nanoparticles.

Hypertension has become a significant global public health concern and is also one of the most common risk factors of cardiovascular disease. Recent studies have shown the promising result of peptides inhibiting angiotensin converting enzyme (ACE) in lowering the blood pressure in both animal models and humans. However, the oral bioavailability and continuous antihypertensive effectiveness require further optimization. Novel nanoparticle-based drug delivery systems are helpful to overcome these barriers. Therefore, a poly-(lactic-co-glycolic) acid nanoparticle (PLGANPs) oral delivery system, of the antihypertensive small peptides Val-Leu-Pro-Val-Pro (VLPVP, VP5) model, was developed in this study and its antihypertensive effect was investigated in spontaneously hypertensive rats (SHRs) for the first time. The obtained VP5 nanoparticles (VP5-NPs) showed a small particle size of 223.7 ± 2.3 nm and high entrapment efficiency (EE%) of 87.37% ± 0.92%. Transmission electronic microscopy (TEM) analysis showed that the nanoparticles were spherical and homogeneous. The optimal preparation of VP5-NPs exhibited sustained release of VP5 in vitro and a 96 h long-term antihypertensive effect with enhanced efficacy in vivo. This study illustrated that PLGANPs might be an optimal formulation for oral delivery of antihypertensive small peptides and VP5-NPs might be worthy of further development and use as a potential therapeutic strategy for hypertension in the future.

White blood cell concentrations during lower body negative pressure and blood loss in humans.

What is the central question of this study? Is lower body negative pressure a useful surrogate to study white blood cell responses to haemorrhage in humans? What is the main finding and its importance? We found that lower body negative pressure appears to be a useful surrogate to study the early white blood cell mobilization response during blood loss. Hypovolaemia has been associated with an immune response that might be secondary to sympathoexcitation. We tested the hypothesis that simulated hypovolaemia using lower body negative pressure (LBNP) and real hypovolaemia induced via experimental blood loss (BL) cause similar increases in the white blood cell concentration ([WBC]). We measured [WBC] and catecholamine concentrations in 12 men who underwent an LBNP and a BL protocol in a randomized order. We compared 45mmHg of LBNP with 1000ml of BL; therefore, [WBC] and catecholamine concentrations were plotted against central venous pressure to obtain stimulus-response relationships using the linear regression line slopes for both protocols. Mean regression line slopes were similar for total [WBC] (LBNP 183±4μl-1 mmHg-1 versus BL 155±109μl-1 mmHg-1 , P=0.15), neutrophils (LBNP 110±2μl-1 mmHg-1 versus BL 96±72μl-1 mmHg-1 , P=0.15) and lymphocytes (LBNP 65±21μl-1 mmHg-1 versus BL 59±38μl-1 mmHg-1 , P=0.90). Mean regression line slopes for adrenaline were similar (LBNP 15±5pgml-1 mmHg-1 versus BL 16±4 pgml-1 mmHg-1 , P=0.84) and were steeper during LBNP for noradrenaline (LBNP 28±6pgml-1 mmHg-1 versus BL 9±6pgml-1 mmHg-1 , P=0.01). These data indicate that central hypovolaemia elicits a relative leucocytosis with a predominantly neutrophil-based response. Additionally, our results indicate that LBNP models the stimulus-response relationship between central venous pressure and [WBC] observed during BL.

Abstract P194: A New Role of Sox6 in Blood Pressure Through Renin Regulation

Hypertension afflicts 33% of the U.S. adult population. Despite current treatments, approximately 50% of people are unresponsive to treatment. There is a critical need to develop new therapies to treat this disease and its complications. The Renin Angiotensin Aldosterone System plays a key role in regulating blood pressure in humans. Renin controls the rate-limiting step in the conversion of angiotensinogen to angiotensin I. In adults, renin is produced and stored by Juxtaglomerular (JG) cells in the kidney. However, the transcriptional mechanisms that govern formation of renin expressing cells under normal or pathophysiological conditions remain poorly understood. During blood pressure changes the number of adult renal cells expressing renin increase through a process known as JG cell expansion. We found that this process involves differentiation of mesenchymal stromal-like cells (MSC) to renin expressing cells among others. We aim to determine new regulators of renin expression and blood pressure control. Renin expression in vitro was induced by treatment of MSCs with 3-isobutyl-1-methylxanthine (IBMX) and Forskolin. MSCs were transduced with lentivirus carrying vectors Sox6 shRNA or control shRNA. A new transgenic mouse, in which Sox6 is deleted specifically in renin expressing cells (Ren1dCre/Sox6 fl/fl ), was used to study the impact of Sox6 in renin expression in vivo . Gene array comparing renal MSC and JG cells identified potential genes that control MSC differentiation, including Sox6. In vitro silencing of Sox6 by shRNA decreased differentiation of renal MSCs into renin producing cells (3.5 fold, n=4, P= 0.01). Preliminary IHC data showed that the transcription factor Sox6 is expressed by renin producing cells in the adult kidney during JG cell expansion. Plasma renin concentration (PRC) increased during JG cell expansion (induced with low sodium diet and furosemide) in wild type mice (27-fold), whereas in mice lacking Sox6 in JG cells PRC was as low as non-treated mice. We conclude that Sox6 has a novel role in modulating renin expression and thereby can contribute to renal physiology, opening new possibilities of addressing questions regarding physiological regulation of renin and hypertension.

PP.30.18] EFFECTS OF A COMBINED BLOOD PRESSURE AND LIPID-LOWERING NUTRACEUTICAL ON MILDLY HYPERTENSIVE HYPERCHOLESTEROLEMIC SUBJECTS

Objective: A number of nutraceuticals have demonstrated to significantly lower blood pressure or lipid levels in humans. Our aim was to evaluate the effect of a combination of both blood pressure and lipid lowering nutraceuticals in mildly hypertensive hypercholesterolemic subjects.Design and method: This is a pilot, double-blind, randomized, placebo-controlled, clinical trial carried out on 30 mildly hypertensive hypercholesterolemic subjects in primary prevention for cardiovascular disease, randomized to active treatment or placebo for 2 months. Active treatment contained red yeast rice extract (with 10 mg monacolin per dose), an NO-donor, magnesium, and vitamins. Results: The tested product was well-tolerated by all patients. Subjects in active treatment experienced a significant improvement in morning SBP, DBP, MAP, evening SBP, LDL-C and estimated CV risk vs. placebo (see table). Conclusions Conclusion: A combined blood pressure and lipid lowering nutraceutical improved morning SBP, DBP, MAP, evening SBP, LDL-C and estimated CV risk vs. placebo in mildly hypertensive hypercholesterolemic subjects.

OP.1C.01] HIGH SALT DIET INCREASES AORTIC STIFFNESS AND PRESSURE PULSE AMPLIFICATION IN RAT

Objective: High salt consumption is associated with increased blood pressure and vascular changes in humans. This association is confounded by other lifestyle factors that could equally influence cardiovascular function. This study examines effects of high salt diet on aortic function in a controlled animal study. Design and method: Sprague-Dawley rats were fed either high salt (8% sodium chloride, n = 6) or normal chow (0.26% sodium chloride, n = 5) from weaning. Body weight (BW), nose-to-rump length, tail-cuff systolic blood pressure (SBP), water and food intake, and urine output were measured. At 14 to 17 weeks, rats were anaesthetised and thoracic and abdominal aortic pressure (invasive solid-state catheters) recorded over a physiological mean arterial pressure (MAP) range (60 to 150 mmHg, induced via intra-venous infusion of phenylephrine and sodium nitroprusside, 30 μg/kg/min). Aortic pulse wave velocity (aPWV) and thoracic to abdominal aortic pulse pressure amplification (PPA) were calculated. Left ventricular (LV) and kidney mass were recorded post-mortem. Results Results: High salt diet rats had lower BW (average across all age: 451 ± 57 g, control 498 ± 68 g, p = 0.03), body mass index (0.79 ± 0.08 g/cm2, control 0.82 ± 0.10 g/cm2, p < 0.001) and kidney mass (kidney/BW 0.50 ± 0.09%, control 0.39 ± 0.05%, p = 0.01) without LV hypertrophy (LV/BW 0.24 ± 0.04%, control 0.22 ± 0.03%, p = 0.16). Food intake was similar (high salt 20 ± 3 g/day, control 19 ± 5 g/day, p = 0.36). High salt diet rats drank more (65 ± 10 ml/day, control 22 ± 6 ml/day, p < 0.001) with correspondingly higher urine output (55 ± 9 ml/day, control 15 ± 6 ml/day p < 0.001); conscious SBP was greater (125 ± 12 mmHg, control 117 ± 13 mmHg, p < 0.05). High salt diet resulted in higher aPWV (high salt aPWV across MAP range 60 to 150 mmHg, 4.3 ± 0.2 to 5.4 ± 0.2 m/s, control 3.6 ± 0.3 to 3.9 ± 1.1 m/s, p < 0.001 at each 5 mmHg MAP interval). PPA was greater in high salt diet rats (high salt PPA across MAP range 60 to 150 mmHg, 0.78 ± 0.04 to 1.53 ± 0.27, control 0.62 ± 0.14 to 1.25 ± 0.17, p < 0.001 at each 5 mmHg MAP interval). Conclusions: A high salt diet induced moderately higher arterial blood pressure, greater aortic stiffness and higher PPA, indicating marked changes in transmission characteristics of the aorta, including altered stiffness gradient across the aorta and changed peripheral wave reflection characteristics.

The Effect of High Dose Cholecalciferol on Arterial Stiffness and Peripheral and Central Blood Pressure in Healthy Humans: A Randomized Controlled Trial.

BackgroundLow levels of serum 25-hydroxy vitamin D are associated with increased arterial stiffness and hypertension. Supplementation with vitamin D precursors has been proposed as a treatment option for these conditions. We examined the effect of oral cholecalciferol on arterial stiffness and blood pressure in healthy normotensive adults.Methods40 healthy adults were randomised in this double-blinded study to either oral cholecalciferol 3000 IU/day or matching placebo and were followed for 16 weeks to examine any effects on pulse wave velocity (PWV), augmentation index (AIx), peripheral and central blood pressure and 24-hour ambulatory blood pressure.Results22 subjects in the cholecalciferol arm and 18 subjects in the placebo arm completed the 16 weeks of follow-up. There was no difference in changes in PWV, AIx corrected for heart rate or central or peripheral blood pressure between the two groups. There was no correlation between serum 25-hydroxy vitamin D and any of these parameters.ConclusionsOral cholecalciferol 3000 IU/day does not affect arterial stiffness or blood pressure after 16 weeks of treatment in healthy normotensive adults.Trial RegistrationClinicalTrials.gov NCT00952562

Novel MicroRNA Regulators of Atrial Natriuretic Peptide Production.

Atrial natriuretic peptide (ANP) has a central role in regulating blood pressure in humans. Recently, microRNA 425 (miR-425) was found to regulate ANP production by binding to the mRNA of NPPA, the gene encoding ANP. mRNAs typically contain multiple predicted microRNA (miRNA)-binding sites, and binding of different miRNAs may independently or coordinately regulate the expression of any given mRNA. We used a multifaceted screening strategy that integrates bioinformatics, next-generation sequencing data, human genetic association data, and cellular models to identify additional functional NPPA-targeting miRNAs. Two novel miRNAs, miR-155 and miR-105, were found to modulate ANP production in human cardiomyocytes and target genetic variants whose minor alleles are associated with higher human plasma ANP levels. Both miR-155 and miR-105 repressed NPPA mRNA in an allele-specific manner, with the minor allele of each respective variant conferring resistance to the miRNA either by disruption of miRNA base pairing or by creation of wobble base pairing. Moreover, miR-155 enhanced the repressive effects of miR-425 on ANP production in human cardiomyocytes. Our study combines computational, genomic, and cellular tools to identify novel miRNA regulators of ANP production that could be targeted to raise ANP levels, which may have applications for the treatment of hypertension or heart failure.

Passive heat therapy improves endothelial function, arterial stiffness and blood pressure in sedentary humans

A recent 30year prospective study showed that lifelong sauna use reduces cardiovascular-related and all-cause mortality; however, the specific cardiovascular adaptations that cause this chronic protection are currently unknown. We investigated the effects of 8weeks of repeated hot water immersion ('heat therapy') on various biomarkers of cardiovascular health in young, sedentary humans. We showed that, relative to a sham group which participated in thermoneutral water immersion, heat therapy increased flow-mediated dilatation, reduced arterial stiffness, reduced mean arterial and diastolic blood pressure, and reduced carotid intima media thickness, with changes all on par or greater than what is typically observed in sedentary subjects with exercise training. Our results show for the first time that heat therapy has widespread and robust effects on vascular function, and as such, could be a viable treatment option for improving cardiovascular health in a variety of patient populations, particularly those with limited exercise tolerance and/or capabilities. The majority of cardiovascular diseases are characterized by disorders of the arteries, predominantly caused by endothelial dysfunction and arterial stiffening. Intermittent hot water immersion ('heat therapy') results in elevations in core temperature and changes in cardiovascular haemodynamics, such as cardiac output and vascular shear stress, that are similar to exercise, and thus may provide an alternative means of improving health which could be utilized by patients with low exercise tolerance and/or capabilities. We sought to comprehensively assess the effects of 8weeks of heat therapy on biomarkers of vascular function in young, sedentary subjects. Twenty young, sedentary subjects were assigned to participate in 8weeks (4-5 times per week) of heat therapy (n=10; immersion in a 40.5°C bath sufficient to maintain rectal temperature ≥38.5°C for 60min per session) or thermoneutral water immersion (n=10; sham). Eight weeks of heat therapy increased flow-mediated dilatation from 5.6±0.3 to 10.9±1.0% (P<0.01) and superficial femoral dynamic arterial compliance from 0.06±0.01 to 0.09±0.01mm(2) mmHg(-1) (P=0.03), and reduced (i.e. improved) aortic pulse wave velocity from 7.1±0.3 to 6.1±0.3ms(-1) (P=0.03), carotid intima media thickness from 0.43±0.01 to 0.37±0.01mm (P<0.001), and mean arterial blood pressure from 83±1 to 78±2mmHg (P=0.02). No changes were observed in the sham group or for carotid arterial compliance, superficial femoral intima media thickness or endothelium-independent dilatation. Heat therapy improved endothelium-dependent dilatation, arterial stiffness, intima media thickness and blood pressure, indicating improved cardiovascular health. These data suggest heat therapy may provide a simple and effective tool for improving cardiovascular health in various populations.

Blood Pressure Monitoring for the Anesthesiologist: A Practical Review.

Periodic, quantitative measurement of blood pressure (BP) in humans, predating the era of evidence-based medicine by over a century, is a component of the American Society of Anesthesiologists standards for basic anesthetic monitoring and is a staple of anesthetic management worldwide. Adherence to traditional BP parameters complicates the ability of investigators to determine whether particular BP ranges confer any clinical benefits. The BP waveform is a complex amalgamation of both antegrade and retrograde (reflected) pressure waves and is affected by vascular compliance, distance from the left ventricle, and the 3D structure of the vascular tree. Although oscillometry is the standard method of measuring BP semicontinuously in anesthetized patients and is the primary form of measurement in >80% of general anesthetics, major shortcomings of oscillometry are its poor performance at the extremes and its lack of information concerning BP waveform. Although arterial catheterization remains the gold standard for accurate BP measurement, 2 classes of devices have been developed to noninvasively measure the BP waveform continuously, including tonometric and volume clamp devices. Described in terms of a feedback loop, control of BP requires measurement, an algorithm (usually human), and an intervention. This narrative review article discusses the details of BP measurement and the advantages and disadvantages of both noninvasive and invasive monitoring, as well as the principles and algorithms associated with each technique.

White Blood Cell Counts during Lower Body Negative Pressure vs. Blood Loss in Humans

Hypovolemia‐induced sympathoexcitation might initiate an immune response through an increase in circulating epinephrine and splenic demargination. We tested the hypothesis that lower body negative pressure (LBNP) and blood loss (BL) result in comparable increases in white blood cell counts (WBCs). We determined WBCs and epinephrine levels in 12 men who performed a LBNP and BL protocol in a randomized order. LBNP consisted of 5‐minute stages at 0, ‐15, ‐30, and ‐45 mmHg of suction. BL included 5 minutes at baseline and following three stages of 333 mL of blood removal (up to 1000 mL total). Blood draws were performed at baseline and after the last stage of each protocol. LBNP to −45mmHg was a greater central hypovolemic stimulus vs. BL, therefore WBCs and epinephrine concentrations were plotted against central venous pressure (CVP) to obtain stimulus‐response relationships using the linear regression line slopes for both protocols. Paired tests were used to determine if the slopes of these regression lines fell on similar trajectories for each protocol. Mean regression line slopes fell on similar trajectories for total WBC (LBNP 183±46 vs. BL 155±109 mcL−1 *mmHg−1, p=0.15), neutrophils (LBNP 110±29 vs. BL 96±72 mcL−1 *mmHg−1, p=0.15) and lymphocytes (LBNP 65±21 vs. BL 59±38 mcL−1 *mmHg−1, p=0.90). Mean regression line slopes for epinephrine were similar as well (LBNP 15±5 vs. BL 16±4 pg *mL−1 *mmHg−1, p=0.84). Our results indicate that LBNP models the stimulus‐response relationship between CVP and WBCs observed during BL. Central hypovolemia, induced by LBNP or BL, elicits a relative leukocytosis with a predominantly neutrophil‐based response.Support or Funding InformationUS Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11‐1‐0823

Dihydrofolate-Reductase Mutations in Plasmodium knowlesi Appear Unrelated to Selective Drug Pressure from Putative Human-To-Human Transmission in Sabah, Malaysia.

BackgroundMalaria caused by zoonotic Plasmodium knowlesi is an emerging threat in Eastern Malaysia. Despite demonstrated vector competency, it is unknown whether human-to-human (H-H) transmission is occurring naturally. We sought evidence of drug selection pressure from the antimalarial sulfadoxine-pyrimethamine (SP) as a potential marker of H-H transmission.MethodsThe P. knowlesi dihdyrofolate-reductase (pkdhfr) gene was sequenced from 449 P. knowlesi malaria cases from Sabah (Malaysian Borneo) and genotypes evaluated for association with clinical and epidemiological factors. Homology modelling using the pvdhfr template was used to assess the effect of pkdhfr mutations on the pyrimethamine binding pocket.ResultsFourteen non-synonymous mutations were detected, with the most common being at codon T91P (10.2%) and R34L (10.0%), resulting in 21 different genotypes, including the wild-type, 14 single mutants, and six double mutants. One third of the P. knowlesi infections were with pkdhfr mutants; 145 (32%) patients had single mutants and 14 (3%) had double-mutants. In contrast, among the 47 P. falciparum isolates sequenced, three pfdhfr genotypes were found, with the double mutant 108N+59R being fixed and the triple mutants 108N+59R+51I and 108N+59R+164L occurring with frequencies of 4% and 8%, respectively. Two non-random spatio-temporal clusters were identified with pkdhfr genotypes. There was no association between pkdhfr mutations and hyperparasitaemia or malaria severity, both hypothesized to be indicators of H-H transmission. The orthologous loci associated with resistance in P. falciparum were not mutated in pkdhfr. Subsequent homology modelling of pkdhfr revealed gene loci 13, 53, 120, and 173 as being critical for pyrimethamine binding, however, there were no mutations at these sites among the 449 P. knowlesi isolates.ConclusionAlthough moderate diversity was observed in pkdhfr in Sabah, there was no evidence this reflected selective antifolate drug pressure in humans.

Angiotensin Converting Enzyme (ACE) Inhibitor Extends Caenorhabditis elegans Life Span.

Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabdtitis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new therapeutic strategies for addressing age-related degenerative changes.