Development, Validation, and Field-Testing of an Instrument for Clinical Assessment of HIV-Associated Neuropathy and Neuropathic Pain in Resource-Restricted and Large Population Study Settings.

HIV-associated sensory peripheral neuropathy (HIV-SN) afflicts approximately 50% of patients on antiretroviral therapy, and is associated with significant neuropathic pain. Simple accurate diagnostic instruments are required for clinical research and daily practice in both high- and low-resource setting. A 4-item clinical tool (CHANT: Clinical HIV-associated Neuropathy Tool) assessing symptoms (pain and numbness) and signs (ankle reflexes and vibration sense) was developed by selecting and combining the most accurate measurands from a deep phenotyping study of HIV positive people (Pain In Neuropathy Study-HIV-PINS). CHANT was alpha-tested in silico against the HIV-PINS dataset and then clinically validated and field-tested in HIV-positive cohorts in London, UK and Johannesburg, South Africa. The Utah Early Neuropathy Score (UENS) was used as the reference standard in both settings. In a second step, neuropathic pain in the presence of HIV-SN was assessed using the Douleur Neuropathique en 4 Questions (DN4)-interview and a body map. CHANT achieved high accuracy on alpha-testing with sensitivity and specificity of 82% and 90%, respectively. In 30 patients in London, CHANT diagnosed 43.3% (13/30) HIV-SN (66.7% with neuropathic pain); sensitivity = 100%, specificity = 85%, and likelihood ratio = 6.7 versus UENS, internal consistency = 0.88 (Cronbach alpha), average item-total correlation = 0.73 (Spearman's Rho), and inter-tester concordance > 0.93 (Spearman's Rho). In 50 patients in Johannesburg, CHANT diagnosed 66% (33/50) HIV-SN (78.8% neuropathic pain); sensitivity = 74.4%, specificity = 85.7%, and likelihood ratio = 5.29 versus UENS. A positive CHANT score markedly increased of pre- to post-test clinical certainty of HIV-SN from 43% to 83% in London, and from 66% to 92% in Johannesburg. In conclusion, a combination of four easily and quickly assessed clinical items can be used to accurately diagnose HIV-SN. DN4-interview used in the context of bilateral feet pain can be used to identify those with neuropathic pain.

The Interrater Reliability of Subjective Assessments of the Babinski Reflex.

The Babinski reflex is a clinical diagnostic tool; however, the interrater reliability of this tool is currently greatly contested. A comparison between rater groups with objective measurements of the Babinski reflex was therefore conducted. Fifteen recorded Babinski reflexes were assessed by 12 neurologists and 12 medical students as being either pathological or nonpathological. Kinematic and electromyographic variables were collected and used to assess which aspects of the Babinski reflex predict classification. Substantial interrater agreement within the neurologist and student groups (κ = .72 and .67, respectively) was shown; however, there were some differing aspects between what neurologists and students used to assess the reflex as determined by objective kinematic measurements.

The accuracy of subjective clinical assessments of the patellar reflex.

INTRODUCTION: Measurement precision and accuracy of spinal reflexes plays an essential role in the clinical neurological examination. Reflexes are conventionally assessed either electromyographically or with rating scales. In this study we compared objective kinematic T-reflex and subjective assessments of patellar reflexes in 15 normal healthy subjects. METHODS: Randomized recordings of objectively quantified reflexes were rated by 24 medical students, 16 general practitioners, and 12 neurologists, using a visual analog scale and the NINDS and Mayo clinical reflex scales. RESULTS: For all groups of raters, Spearman rank correlations showed that subjective ratings significantly correlated with change of knee angle (R2 = 0.72-0.79, P < 0.001) and maximum T-reflex amplitude (R2 = 0.84-0.94, P < 0.001). Stepwise multiple regression analysis showed that all subjective rater groups relied most on the change of knee angle to assess the reflex. CONCLUSIONS: These findings show that subjective assessments of reflexes using reflex rating scales correlate strongly with biomechanical and electromyographic measures.

Aldosterone-to-renin ratio and the relationship between urinary salt excretion and blood pressure in a community of African ancestry.

BACKGROUND: Although aldosterone influences the effect of salt intake on blood pressure (BP), the extent to which this occurs at a population level is uncertain. We therefore aimed to determine, at a community level in a group of African descent, whether in the absence of primary aldosteronism, the relationship between salt intake and BP is modified by circulating aldosterone, and the extent to which this occurs. METHODS: In 575 participants of African ancestry (age >16 years), we assessed whether aldosterone-to-renin ratio (ARR) is associated with the relationship between urinary sodium (Na(+))-to-potassium (K(+)) ratio (urinary Na(+)/K(+)) (from 24-h urine samples), an index of salt intake, and BP. RESULTS: With adjustments for confounders, interactions between ARR and urinary Na(+)/K(+) were independently associated with systolic BP (SBP) (P < 0.0001), an effect that was accounted for by interactions between serum aldosterone concentrations and urinary Na(+)/K(+) (P < 0.0001), but not between plasma renin concentrations and urinary Na(+)/K(+) (P = 0.52). The interaction between ARR and urinary Na(+)/K(+) translated into a marked difference in the relationship between urinary Na(+)/K(+) and SBP in participants above compared to below the median for ARR (effect of 1 s.d. increase in urinary Na(+)/K(+) on SBP: ARR > median = 4.2 ± 0.6 mm Hg; ARR < median = 1.2 ± 0.4 mm Hg, P < 0.0001). In addition, participants with urinary Na(+)/K(+) above the median had higher multivariate-adjusted SBP (P < 0.001) only if ARR was also above the median. CONCLUSIONS: In groups of African descent, in the absence of primary aldosteronism, an increased aldosterone concentration relative to renin modifies a substantial proportion of the relationship between urinary Na(+)/K(+) and BP at a community level.

Impact of aldosterone receptor blockade on the deleterious cardiac effects of adrenergic activation in hypertensive rats.

Although in hypertension beta-adrenoreceptor activation promotes the transition from cardiac hypertrophy to pump dysfunction, the use of beta-blockers is controversial. As adrenergic activation may mediate adverse effects on the heart through the renin-angiotensin-aldosterone system, we evaluated the effects of the aldosterone receptor blocker, spironolactone (SPIRO), on isoproterenol (ISO)-induced changes in left ventricular cavity size and pump function and the determinants thereof in spontaneously hypertensive rats (SHR). ISO administered for 4.5 months resulted in increases in left ventricular dimensions and a decrease in pump function in SHR but not in normotensive rats, changes that, without affecting blood pressure, were abolished by SPIRO. In SHR, 4-5 days of ISO increased myocardial matrix metalloproteinase-2 activity, which was associated with matrix metalloproteinase-2 but not tissue inhibitor of MMP expression; persisted at 4.5 months; and was prevented by SPIRO. Moreover, after 4.5 months, ISO increased non-cross-linked myocardial collagen concentrations in SHR, which was abolished by SPIRO. Although after 4.5 months, ISO was not associated with increased cardiomyocyte apoptosis, an early (4-5 days) ISO-induced apoptotic effect was noted, which was prevented by SPIRO. Hence, aldosterone receptor blockade may be sufficient to prevent those adverse effects of beta-adrenoreceptor activation responsible for the transition from concentric cardiac hypertrophy to pump dysfunction in hypertension.

Hyperalgesia induced by oral stavudine administration to rats does not depend on spinal neuronal cell death, or on spinal or systemic inflammatory cytokine secretion, or metabolic dysregulation.

To investigate possible mechanisms of the hyperalgesia induced by the nucleoside reverse transcriptase inhibitor (NRTI) stavudine in rats, we examined neuronal death and inflammatory cytokine secretion in the spinal cord, and cytokine and lactate secretion in the plasma. Stavudine (50 mg kg(-1)) or placebo was administered orally to Sprague-Dawley rats once daily for three or six weeks. In one group, rats' responses to a blunt noxious mechanical stimulus applied to their tails were recorded before and at the end of the period of stavudine or placebo administration. Spinal cords excised from these rats after three and six weeks of stavudine or placebo administration were examined for neuronal necrosis and apoptosis. In a second group of rats, plasma and spinal cord samples collected after three and six weeks of placebo or stavudine administration were examined for changes in CINC-1, IL-6, adiponectin (plasma only) and lactate (plasma only) concentration. Daily stavudine administration induced mechanical hyperalgesia within three weeks, which was sustained until week six, but the hyperalgesia was not associated with neuronal apoptosis or necrosis, or elevated IL-6 concentrations in the spinal cord. The spinal cord concentration of CINC-1 increased, but only after six weeks of stavudine administration, when the hyperalgesia had been established for over three weeks. Stavudine administration did not affect the plasma concentration of IL-6, CINC-1, adiponectin or lactate. Thus, neither peripheral nor central inflammatory cytokine secretion, or neuronal death, or metabolic dysregulation contributed to the development of hyperalgesia in our model of stavudine-induced hyperalgesia in rats.

Susceptibility to systolic dysfunction in the myocardium from chronically infarcted spontaneously hypertensive rats.

We explored whether the hypertensive heart is susceptible to myocardial dysfunction in viable noninfarcted tissue post-myocardial infarction (MI), the potential mechanisms thereof, and the impact of these changes on pump function. Six to seven months after the ligation of the left anterior descending coronary artery, left ventricular (LV) myocardial systolic function, as assessed from the percent shortening of the noninfarcted lateral wall segmental length determined over a range of filling pressures (ultrasonic transducers placed in the lateral wall in anaesthetized, open-chest, ventilated rats) and the percent thickening of the posterior wall (echocardiography), was reduced in infarcted spontaneous hypertensive rats (SHR-MI) (P < 0.05) but not in normotensive Wistar-Kyoto (WKY-MI) animals compared with corresponding controls [SHR-sham operations (Sham) and WKY-Sham]. This change in the regional myocardial function in SHR-MI, but not in WKY-MI, occurred despite a similar degree of LV dilatation (increased LV end-diastolic dimensions and volume intercept of the LV end-diastolic pressure-volume relation) in SHR-MI and WKY-MI rats and a lack of difference in LV relative wall thinning, LV wall stress, apoptosis [terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling (TUNEL)], or necrosis (pathological score) between SHR-MI and WKY-MI rats. Although the change in regional myocardial function in the SHR-MI group was not associated with a greater reduction in baseline global LV chamber systolic function [end-systolic elastance (LV E(es)) and endocardial fractional shortening determined in the absence of an adrenergic stimulus], in the presence of an isoproterenol challenge, noninfarct-zone LV systolic myocardial dysfunction manifested in a significant reduction in LV E(es) in SHR-MI compared with WKY-MI and SHR and WKY-Sham rats (P < 0.04). In conclusion, these data suggest that with chronic MI, the hypertensive heart is susceptible to the development of myocardial dysfunction, a change that cannot be attributed to excessive chamber dilatation, apoptosis, or necrosis, but which in turn contributes toward a reduced cardiac adrenergic inotropic reserve.

Phosphodiesterase inhibition promotes the transition from compensated hypertrophy to cardiac dilatation in rats.

The cellular signaling pathways responsible for the transition from compensated left ventricular hypertrophy (LVH) to LV dilatation (remodeling) and heart failure are unclear. As chronic administration of a beta-adrenoreceptor (beta-AR) agonist mediates the premature onset of cardiac remodeling without myocyte necrosis or myocardial dysfunction in LVH, we suggest that beta-AR activation is critical in promoting the transition from compensated LVH to cardiac dilatation. However, beta-AR mediated effects in the heart can occur via either the cyclic adenosine monophosphate (cAMP) system or via cAMP independent signaling pathways. To determine the role of cAMP in promoting adverse cardiac chamber remodeling, we evaluated whether phosphodiesterase inhibition (PDEI) promotes LV dilatation in rats with compensated LVH. The impact of chronic administration of the PDEI, pentoxifylline, on LV remodeling and function was assessed in spontaneously hypertensive rats (SHR) with compensated LVH. The PDEI mediated inotropic effects and increased cAMP concentrations in SHR. This dose of the PDEI administered for 4 months to SHR did not modify LV weight or influence intrinsic myocardial systolic function (as assessed in the absence of the PDEI) in SHR. However, the PDEI mediated the development of a right shift in LV end diastolic (LVED) pressure-internal dimension and LVED pressure-volume relations, LV wall thinning, and increments in myocardial soluble (non-cross-linked) collagen concentrations. In conclusion, chronic PDEI administration induces adverse geometric and interstitial cardiac remodeling in SHR, a finding that supports the notion that the beta-AR-cAMP system is important in mediating the progression to heart failure by promoting interstitial remodeling and LV dilatation in LVH.

Aldosterone receptor blockade prevents the transition to cardiac pump dysfunction induced by beta-adrenoreceptor activation.

The transition from compensated to decompensated left ventricular hypertrophy (LVH) in hypertension involves excessive beta-adrenoreceptor (beta-AR) stimulation. To explore whether aldosterone receptor activation contributes toward beta-AR-induced left ventricular (LV) decompensation in hypertensive LVH, the effect of spironolactone (SPIRO; 80 mg x kg(-1) x day(-1)) on LV cavity dimensions, function, and chamber remodeling mechanisms was evaluated in spontaneously hypertensive rats (SHR) receiving a low dose of the beta-AR agonist isoproterenol (ISO) at 0.02 to 0.04 mg x kg(-1) . day for 4.5 months. ISO administered to SHR resulted in an increased 24-hour urinary aldosterone excretion and LV cavity dimensions, a right shift in LV diastolic pressure-volume relations, a decreased LV relative wall thickness, and increased total, noncross-linked, type I and type III myocardial collagen concentrations without further enhancing increased myocardial norepinephrine (NE) release. ISO reduced pump function without modifying intrinsic myocardial systolic function or inducing further myocyte necrosis or apoptosis. ISO only increased LV cavity volumes after prolonged periods of administration. SPIRO abolished ISO-induced chamber dilatation, wall thinning, and pump dysfunction and reduced total, noncross-linked, type I and type III myocardial collagen concentrations but failed to modify blood pressure, volume preloads, intrinsic myocardial systolic function, myocardial NE release, or the degree of necrosis or apoptosis. In conclusion, these results suggest that aldosterone receptor blockade, through load-independent effects, may be useful in preventing the transition from compensated LVH to dilatation and pump dysfunction mediated by chronic beta-AR activation.

Chronic beta-adrenoreceptor activation increases cardiac cavity size through chamber remodeling and not via modifications in myocardial material properties.

Chronic beta-adrenoreceptor (beta-AR) activation increases left ventricular (LV) cavity size by promoting a rightward shift in LV diastolic pressure-volume (P-V) relations in association with increases in low-tensile strength myocardial (non-cross-linked) collagen concentrations. Because diastolic P-V relations are determined by chamber remodeling as well as by myocardial material properties (indexed by myocardial stiffness), both of which are associated with modifications in myocardial collagen cross-linking, we evaluated whether chamber remodeling or alterations in myocardial material properties govern beta-AR-mediated modifications in diastolic P-V relations. The effects of chronic administration of isoproterenol (Iso; 0.04 mg.kg(-1).day(-1) from 12 to 19 mo of age) to spontaneously hypertensive rats (SHRs) on LV cavity dimensions, LV diastolic P-V relations, myocardial collagen characteristics, myocardial stiffness constants [e.g., the slope of the LV diastolic stress-strain relation (k)], and LV chamber and myocardial systolic function were assessed. SHRs at 19 mo of age had normal LV diastolic P-V relations, marked myocardial fibrosis (using a pathological score), increased myocardial cross-linked (insoluble to cyanogen bromide digestion) type I and type III collagen concentrations, and enhanced myocardial k values. Iso administration to SHRs resulted in enlarged LV cavity dimensions mediated by a rightward shift in LV diastolic P-V relations, increased volume intercept of the LV diastolic P-V relation, decreased LV relative wall thickness despite a tendency to augment LV hypertrophy, and increased non-cross-linked type I and type III myocardial collagen concentrations. Iso administration resulted in reduced pump function without modification of intrinsic myocardial systolic function. However, despite increasing myocardial non-cross-linked concentrations, Iso failed to alter myocardial k in SHRs. These results suggest that beta-AR-mediated rightward shifts in LV diastolic P-V relations, which induce decreased pump function, are mediated by chamber remodeling but not by modifications in myocardial material properties.

The agreement between reaction-board measurements and kinematic estimation of adult male human whole body centre of mass location during running.

The segmental method for estimating the centre of mass (COM) location of the human body has been widely used since 1889. How closely this method agrees with direct measurements of the location and movement of COM during activity however, remains unclear. To test this, a novel reaction-board utilizing life sized projections of human subjects is designed for measuring COM location. Agreement between the segmental method and the more direct reaction-board measurement method is then assessed. Our data demonstrate that the reaction-board system has a physical maximum error of 1.28 cm and 1.95 cm for locating COM along the vertical (board length) and horizontal (board width) axes respectively, and show that the reaction-board and segmental methods agree to within limits of 6.0 cm for the location of COM and to within 5.6 cm for the movement of COM between two points, in recumbent individuals. Applied to running, the segmental method agrees to within limits of 4.8 cm for oscillation of COM and 5.3 cm for stride median COM height. The segmental method agrees with a more direct technique of known accuracy, the reaction-board method, most closely when measuring averaged oscillation over repeated strides, where it displays a measurement error range of 5.1 cm to 0.1 cm in runners.

Beta-adrenergic activation initiates chamber dilatation in concentric hypertrophy.

It is uncertain whether chronic beta-adrenoreceptor (beta-AR)-activation in hypertension could initiate the progression from compensated left ventricular (LV) hypertrophy to pump dysfunction. It is also uncertain if this effect is through adverse LV remodeling (chamber dilatation with wall thinning and pump dysfunction) or intrinsic myocardial contractile dysfunction. We evaluated the effect of 5 months of isoprenaline (0.02 mg x kg(-1) x d(-1)) on hemodynamics, LV wall thickness, cavity size, and interstitial characteristics in spontaneously hypertensive rats (SHR) with compensated LV hypertrophy. In the absence of myocyte necrosis, changes in volume preload, pressure afterload, and heart rate or decreases in baseline systolic myocardial elastance (load independent measure of intrinsic myocardial contractility), ISO produced a right shift in LV diastolic pressure-volume (P-V) relations (chamber dilatation), a decrease in LV wall thickness despite a further increase in LV weight in SHR, LV pump dysfunction (right shift in LV systolic P-V relations), and deleterious interstitial remodeling (increments in total and noncrosslinked myocardial collagen concentrations). The isoprenaline-induced LV geometric, chamber performance, and interstitial changes were similar to alterations noted during decompensation in older SHR. In summary, in the absence of tissue necrosis and baseline intrinsic myocardial contractile dysfunction, chronic beta-AR activation induces interstitial and chamber remodeling and, hence, pump dysfunction. These data suggest that chronic sympathetic activation initiates the progression from compensated concentric LV hypertrophy in hypertension to cardiac dysfunction primarily through deleterious cardiac remodeling rather than intrinsic myocardial contractile dysfunction.