Aging and aerobic fitness affect the contribution of noradrenergic sympathetic nerves to the rapid cutaneous vasodilator response to local heating

Sedentary aging results in a diminished rapid cutaneous vasodilator response to local heating. We investigated whether this diminished response was due to altered contributions of noradrenergic sympathetic nerves; assessing 1) the age-related decline and, 2) the effect of aerobic fitness. We measured skin blood flow (SkBF)(laser-Doppler flowmetry) in young (24±1 yr) and older (64±1 yr) endurance-trained and sedentary men (n=7 per group) at baseline and during 35 min of local skin heating to 42 °C at three forearm sites: 1) untreated; 2) bretylium tosylate (BT), preventing neurotransmitter release from noradrenergic sympathetic nerves; and 3) yohimbine and propranolol (YP), antagonising α- and β-adrenergic receptors. SkBF was converted to cutaneous vascular conductance (CVC) (SkBF/mean arterial pressure) and normalized to maximal CVC (%CVCmax) achieved by skin heating to 44 °C. Pharmacological agents were administered using microdialysis. In the young trained, the rapid vasodilator response was reduced at the BT and YP sites (P0.05) but treatment with BT did (P>0.05). Neither BT nor YP treatments affected the rapid vasodilator response in the older sedentary group (P>0.05). These data suggest that the age-related reduction in the rapid vasodilator response is due to an impairment of sympathetic-dependent mechanisms, which can be partly attenuated with habitual aerobic exercise. Rapid vasodilation involves noradrenergic neurotransmitters in young trained men, and non-adrenergic sympathetic cotransmitters (e.g., neuropeptide Y) in young sedentary and older trained men, possibly as a compensatory mechanism. Finally, in older sedentary men, the rapid vasodilation appears not to involve the sympathetic system

Determining the Impact of Autobiographical Experience on "Meaning": New Insights from Investigating Sports-related Vocabulary and Knowledge in Two Cases with Semantic Dementia

Snowden, Griffiths, and Neary (1994, 1995) have proposed thatautobiographical experience helps to maintain the integrity of semantic memory in patients with semantic dementia. We investigated this hypothesis by testing knowledge related to golf and bowls in two case studies. If Snowden and colleagues' hypothesis is correct, our two patients should have better semantic knowledge for the sport that they regularly experience, compared with knowledge of other sports. In keeping with Snowden et al's hypothesis, we found that autobiographical experience influenced the ability of the patients to match up a surname with a first name: The names of personally and currently relevant golf bowls partners were more likely to be matched correctly than such personally relevant names from the past, or the names of famous sports celebrities. Unlike Snowden et al., however, we found that knowledge of people, in all categories, was severely impoverished and that any semantic information was produced as part of an autobiographical memory. Likewise, detailed study of each patient's understanding of their favourite sportrevealed no significanteffectof autobiographical experience on true semantic knowledge. We propose that the ability of semantic dementia patients to encode, albeit temporarily, recent autobiographical memories via a spared hippocampal complex supports the production of highly autobiographically constrained semantic-like facts and, to a lesser extent, frequently encountered names. There is, however, no direct effect of autobiographical experience on previously established semantic memory, i.e. knowledge of golf, bowls, and people, presumably stored within the temporal neocortex. These results are discussed with respect to current anatomically based computational models of long-term memory

A questionable semantics: The interaction between semantic knowledge and autobiographical experience in semantic dementia

In our earlier article, we proposed that recent episodic experiences in patients with semantic dementia support the production of nongeneralisable, autobiographically constrained, “semantic-like” facts (Graham, Lambon Ralph, & Hodges, 1997). We argued that this type of “semantic-like” knowledge was distinguishable from true semantic information because our two patients with semantic dementia showed no facilitatory effect of recent autobiographical experiences on their knowledge of golf and bowls; information which was presumably learnt prior to the onset of their disease. In this paper, we discuss the implications of these results for current views relating to the nature and organisation of long-term memory

Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia

Hydroxyurea treatment is recommended for children with sickle cell anemia (SCA) living in high-resource malaria-free regions, but its safety and efficacy in malaria-endemic sub-Saharan Africa, where the greatest sickle-cell burden exists, remain unknown. In vitro studies suggest hydroxyurea could increase malaria severity, and hydroxyurea-associated neutropenia could worsen infections. NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing hydroxyurea to placebo at 20 ± 2.5 mg/kg per day for 12 months. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events (AEs), clinical and laboratory effects, and hematological toxicities. Children received either hydroxyurea (N = 104) or placebo (N = 103). Malaria incidence did not differ between children on hydroxyurea (0.05 episodes per child per year; 95% confidence interval [0.02, 0.13]) vs placebo (0.07 episodes per child per year [0.03, 0.16]); the hydroxyurea/placebo malaria incidence rate ratio was 0.7 ([0.2, 2.7]; P = .61). Time to infection also did not differ significantly between treatment arms. A composite SCA-related clinical outcome (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) was less frequent with hydroxyurea (45%) than placebo (69%; P = .001). Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious AEs, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Three deaths occurred (2 hydroxyurea, 1 placebo, and none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or AEs. Hydroxyurea provides SCA-related laboratory and clinical efficacy, but optimal dosing and monitoring regimens for Africa remain undefined. This trial was registered at www.clinicaltrials.gov as #NCT01976416