Aging, opioid-receptor agonists and antagonists, and the vestibulosympathetic reflex in humans.

Animal studies indicate that opioids inhibit the firing rate of vestibular neurons, which are important in mediating the vestibulosympathetic reflex. Furthermore, this inhibition appears to be greater in more mature rats. In the present study, we tested the hypotheses that opioids inhibit the vestibulosympathetic reflex in humans and that endogenous opioids contribute to the age-related impairment of the vestibulosympathetic reflex. These hypotheses were tested by measuring muscle sympathetic nerve activity (MSNA), arterial blood pressure, and heart rate responses to otolith organ engagement during head-down rotation (HDR) in young (24 +/- 2 yr old) and older (63 +/- 2 yr) subjects before and after administration of either an opioid-receptor antagonist (16 mg naloxone in 9 young and 8 older subjects) or an opioid-receptor agonist (60 mg codeine in 7 young and 7 older subjects). Naloxone did not augment the reflex increase in MSNA during HDR in young (Delta7 +/- 2 vs. Delta4 +/- 2 bursts/min and Delta81 +/- 23 vs. Delta60 +/- 24% change in burst frequency and total MSNA before and after naloxone, respectively) or older subjects (Delta2 +/- 2 vs. Delta1 +/- 2 burst/min and Delta8 +/- 7 vs. Delta8 +/- 9% before and after naloxone). Similarly, codeine did not attenuate the increase in MSNA during HDR in young (Delta8 +/- 1 vs. Delta7 +/- 2 bursts/min and Delta53 +/- 4 vs. Delta64 +/- 16% before and after codeine) or older subjects (Delta6 +/- 4 vs. Delta3 +/- 3 bursts/min and Delta38 +/- 21 vs. Delta33 +/- 20%). Mean arterial blood pressure and heart rate responses to HDR were not altered by either naloxone or codeine. These data do not provide experimental support for the concept that opioids modulate the vestibulosympathetic reflex in humans. Moreover, endogenous opioids do not appear to contribute the age-associated impairment of the vestibulosympathetic reflex.     

Sympathetic vascular transduction is augmented in young normotensive blacks.

The purpose of the present study was to determine sympathetic vascular transduction in young normotensive black and white adults. We hypothesized that blacks would demonstrate augmented transduction of muscle sympathetic nerve activity (MSNA) into vascular resistance. To test this hypothesis, MSNA, forearm blood flow, heart rate, and arterial blood pressure were measured during lower body negative pressure (LBNP). At rest, no differences existed in arterial blood pressure, heart rate, forearm blood flow, and forearm vascular resistance (FVR). Likewise, LBNP elicited comparable responses of these variables for blacks and whites. Baseline MSNA did not differ between blacks and whites, but whites demonstrated greater increases during LBNP (28 +/- 7 vs. 55 +/- 18%, 81 +/- 21 vs. 137 +/- 42%, 174 +/- 81 vs. 556 +/- 98% for -5, -15, and -40 mmHg LBNP, respectively; P < 0.001). Consistent with smaller increases in MSNA but similar FVR responses during LBNP, blacks demonstrated greater sympathetic vascular transduction (%FVR/%MSNA) than whites (0.95 +/- 0.07 vs. 0.82 +/- 0.07 U; 0.82 +/- 0.11 vs. 0.64 +/- 0.09 U; 0.95 +/- 0.37 vs. 0.35 +/- 0.09 U; P < 0.01). In summary, young whites demonstrate greater increases in MSNA during baroreceptor unloading than age-matched normotensive blacks. However, more importantly, for a given increase in MSNA, blacks demonstrate greater forearm vasoconstriction than whites. This finding may contribute to augmented blood pressure reactivity in blacks.     

Molecular Basis of Mucopolysaccharidosis Type IIIB in Emu (Dromaius novaehollandiae): An Avian Model of Sanfilippo Syndrome Type B<

Sanfilippo syndrome type B, or mucopolysaccharidosis (MPS) IIIB, is an autosomal recessive disease caused by a deficiency of lysosomal α-N-acetylglucosaminidase (NAGLU). In Dromaius novaehollandiae (emu), a progressive neurologic disease was recently discovered, which was characterized by NAGLU deficiency and heparan sulfate accumulation. To define the molecular basis, the sequences of the normal emu NAGLU cDNA and gene were determined by PCR-based approaches using primers for highly conserved regions of evolutionarily distant NAGLU homologues. It was observed that the emu NAGLU gene is structurally similar to that of human and mouse, but the introns are considerably shorter. The cDNA had an open reading frame (ORF) of 2259 bp. The deduced amino acid sequence is estimated to share 64% identity with human, 63% with mouse, 41% with Drosophila, 39% with tobacco, and 35% with the Caenorhabditis elegans enzyme. Three normal and two affected emus were studied for nucleotide sequence covering the entire coding region and exon–intron boundaries. Unlike the human gene, emu NAGLU appeared to be highly polymorphic: 19 variations were found in the coding region alone. The two affected emus were found to be homozygous for a 2-bp deletion, 1098-1099delGG, in exon 6. The resulting frameshift predicts a longer ORF of 2370 bp encoding a polypeptide with 37 additional amino acids and 387 altered amino acids. The availability of mutation screening in emus now permits early detection of MPS IIIB in breeding stocks and is an important step in characterizing this unique, naturally occurring avian model for the development of gene transfer studies.     

Influence of the nature of the sterol on the behavior of palmitic acid/sterol mixtures and their derived liposomes

The phase behavior of mixtures formed with palmitic acid (PA) and one of the following sterols (dihydrocholesterol, ergosterol, 7-dehydrocholesterol, stigmasterol and stigmastanol), in a PA/sterol molar ratio of 3/7, has been characterized by IR and ²H NMR spectroscopy at different pH. Our study shows that it is possible to form liquid-ordered (lo) lamellar phases with these binary non-phospholipid mixtures. The characterization of alkyl chain dynamics of PA in these systems revealed the large ordering effect of the sterols. It was possible to extrude these systems, using standard extrusion techniques, to form large unilamellar vesicles (LUVs), except in the case of ergosterol-containing mixture. The resulting LUVs displayed a very limited passive permeability consistent with the high sterol concentration. In addition, the stability of these PA/sterol self-assembled bilayers was also found to be pH-sensitive, therefore, potentially useful as nanovectors. By examining different sterols, we could establish some correlations between the structure of these bilayers and their permeability properties. The structure of the side chain at C17 of the sterol appears to play a prime role in the mixing properties with fatty acid.     

Primary Care Detection of Chronic Kidney Disease in Adults with Type-2 Diabetes: The ADD-CKD Study (Awareness,Detection and Drug Therapy in Type 2 Diabetes and Chronic Kidney Disease)

This US, multicenter, observational study assessed the CKD prevalence in adult patients with type-2 diabetes mellitus (T2DM) and characterized the proportion of detected and undiagnosed CKD in the primary care setting using the following: a clinician survey; a patient physical exam and medical history; a single blood draw for estimated glomerular filtration rate (eGFR) and glycosolated hemoglobin (HbA1c); urine dipstick for protein; urine albumin-creatinine ratio (ACR); two patient quality of life questionnaires; and a 15-month medical record review. The study consisted of 9339 adults with T2DM and 466 investigator sites. Of the 9339 enrolled, 9307 had complete data collection for analysis. The 15-month retrospective review showed urine protein, urine ACR, and eGFR testing were not performed in 51.4%, 52.9% and 15.2% of individuals, respectively. Of the 9307 patients, 5036 (54.1%) had Stage 1–5 CKD based on eGFR and albuminuria; however, only 607 (12.1%) of those patients were identified as having CKD by their clinicians. Clinicians were more successful in diagnosing patients with Stage 3–5 CKD than Stages 1 and 2. There were no differences in clinicians’ likelihood of identification of CKD based on practice setting, number of years in practice, or self-reported patients seen per week. Awareness or patient self-reported CKD was 81.1% with practitioner detection versus 2.6% in the absence of diagnosis. Primary care of T2DM demonstrates recommended urine CKD testing is underutilized, and CKD is significantly under-diagnosed. This is the first study to show CKD detection is associated with awareness.     

Mosquitoes and West Nile virus along a river corridor from prairie to montane habitats in eastern Colorado

We conducted studies on mosquitoes and West Nile virus (WNV) along a riparian corridor following the South Platte River and Big Thompson River in northeastern Colorado and extending from an elevation of 1,215 m in the prairie landscape of the eastern Colorado plains to 1,840 m in low montane areas at the eastern edge of the Rocky Mountains in the central part of the state. Mosquito collection during June‐September 2007 in 20 sites along this riparian corridor yielded a total of 199,833 identifiable mosquitoes of 17 species. The most commonly collected mosquitoes were, in descending order: Aedes vexans, Culex tarsalis, Ae. dorsalis, Ae. trivittatus, Ae. melanimon, Cx. pipiens, and Culiseta inornata. Species richness was higher in the plains than in foothills‐montane areas, and abundances of several individual species, including the WNV vectors Cx. tarsalis and Cx. pipiens and the nuisance‐biter and potential secondary WNV vector Ae. vexans, decreased dramatically from the plains (1,215‐1,487 m) to foothills‐montane areas (1,524‐1,840 m). Ae. vexans and Cx. tarsalis had a striking pattern of uniformly high abundances between 1,200‐1,450 m followed by a gradual decrease in abundance above 1,450 m to reach very low numbers above 1,550 m. Culex species were commonly infected with WNV in the plains portion of the riparian corridor in 2007, with 14 of 16 sites yielding WNV‐infected Cx. tarsalis and infection rates for Cx. tarsalis females exceeding 2.0 per 1,000 individuals in ten of the sites. The Vector Index for abundance of WNV‐infected Cx. tarsalis females during June‐September exceeded 0.5 in six plains sites along the South Platte River but was uniformly low (0–0.1) in plains, foothills and montane sites above 1,500 m along the Big Thompson River. A population genetic analysis of Cx. tarsalis revealed that all collections from the ≈190 km riparian transect in northeastern Colorado were genetically uniform but that these collections were genetically distinct from collections from Delta County on the western slope of the Continental Divide. This suggests that major waterways in the Great Plains serve as important dispersal corridors for Cx. tarsalis but that the Continental Divide is a formidable barrier to this WNV vector.     

Effect of morphine on sympathetic nerve activity in humans.

There are conflicting reports for the role of endogenous opioids on sympathetic and cardiovascular responses to exercise in humans. A number of studies have utilized naloxone (an opioid-receptor antagonist) to investigate the effect of opioids during exercise. In the present study, we examined the effect of morphine (an opioid-receptor agonist) on sympathetic and cardiovascular responses at rest and during isometric handgrip (IHG). Eleven subjects performed 2 min of IHG (30% maximum) followed by 2 min of postexercise muscle ischemia (PEMI) before and after systemic infusion of morphine (0.075 mg/kg loading dose + 1 mg/h maintenance) or placebo (saline) in double-blinded experiments on separate days. Morphine increased resting muscle sympathetic nerve activity (MSNA; 17 +/- 2 to 22 +/- 2 bursts/min; P < 0.01) and increased mean arterial pressure (MAP; 87 +/- 2 to 91 +/- 2 mmHg; P < 0.02), but it decreased heart rate (HR; 61 +/- 4 to 59 +/- 3; P < 0.01). However, IHG elicited similar increases for MSNA, MAP, and HR between the control and morphine trial (drug x exercise interaction = not significant). Moreover, responses to PEMI were not different. Placebo had no effect on resting, IHG, and PEMI responses. We conclude that morphine modulates cardiovascular and sympathetic responses at rest but not during isometric exercise.     

Influence of static magnetic fields on pain perception and sympathetic nerve activity in humans.

Static and pulsed magnetic fields have been reported to have a variety of physiological effects. However, the effect of static magnetic fields on pain perception and sympathetic function is equivocal. To address this question, we measured pain perception during reproducible noxious stimuli during acute exposure to static magnets. Pain perception, muscle sympathetic nerve activity, mean arterial pressure, heart rate, and forearm blood velocity were measured during rest, isometric handgrip, postexercise muscle ischemia, and cold pressor test during magnet and placebo exposure in 15 subjects (25 +/- 1 yr; 8 men and 7 women) following 1 h of exposure. During magnet exposure, subjects were placed on a mattress with 95 evenly spaced 0.06-T magnets imbedded in it. During placebo exposure, subjects were placed on an identical mattress without magnets. The order of the two exposure conditions was randomized. At rest, no significant differences were noted in muscle sympathetic nerve activity (8 +/- 1 and 7 +/- 1 bursts/min for magnet and placebo, respectively), mean arterial pressure (91 +/- 3 and 93 +/- 3 mmHg), heart rate (63 +/- 2 and 62 +/- 2 beats/min), and forearm blood velocity (3.0 +/- 0.3 and 2.6 +/- 0.3 cm/s). Magnets did not alter pain perception during the three stimuli. During all interventions, no significant differences between exposure conditions were found in muscle sympathetic nerve activity and hemodynamic measurements. These results indicate that acute exposure to static magnetic fields does not alter pain perception, sympathetic function, and hemodynamics at rest or during noxious stimuli.