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Adult body size is determined by the quality and quantity of nutrients available to animals. In insects, nutrition affects adult size primarily during the nymphal or larval stages. However, measures of adult size like body weight are likely to also change with adult nutrition. In this study, we sought to explore the roles of nutrition throughout the life cycle on adult body weight and the size of two appendages, the wing and the femur, in the fruit fly Drosophila melanogaster. We manipulated nutrition in two ways: by varying the protein to carbohydrate content of the diet, called macronutrient restriction, and by changing the caloric density of the diet, termed caloric restriction. We employed a fully factorial design to manipulate both the larval and adult diets for both diet types. We found that manipulating the larval diet had greater impacts on all measures of adult size. Further, macronutrient restriction was more detrimental to adult size than caloric restriction. For adult body weight, a rich adult diet mitigated the negative effects of poor larval nutrition for both types of diets. In contrast, small wing and femur size caused by poor larval diet could not be increased with the adult diet. Taken together, these results suggest that appendage size is fixed by the larval diet, while those related to body composition remain sensitive to adult diet. Further, our studies provide a foundation for understanding how the nutritional environment of juveniles affects how adults respond to diet., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We investigated a possible relationship between pre-operative platelet count and reduced sensitivity to heparin in 87 patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Sensitivity to heparin was determined by measuring the slope of the heparin dose response (HDR) before surgery. Pre-operative platelet counts were measured as part of routine analysis of the patients' coagulation status. Patients with an HDR slope of <80 s u. ml(-1), were considered to have a reduced sensitivity to heparin and activated clotting time data were collected from these patients before and after heparin administration before CPB. A significant correlation was determined between pre-operative platelet levels and HDR slope (P<0.001). Platelet counts were significantly greater in heparin-resistant patients compared with those who had the expected response to the anticoagulant (P<0.05). This could be caused by an increased capacity to produce platelet factor 4, which neutralizes heparin.

Background: Immediately available blood substitutes could transform medicine. In coronary artery surgery, vasoconstriction induced by some of these agents could have serious implications. We have examined some of the vasoactive effects of one of these blood substitute, diaspirin cross-linked haemoglobin (DCLHb), on isolated rings of human arterial conduits., Methods: Sections of human left internal mammary artery (LIMA) and radial artery (RA) were cut into 3-mm rings, mounted in individual organ baths containing aerated (95% O(2)/5% CO(2)) Krebs-Heinseleit solution at 37 degrees C and attached to isometric strain gauge for measurements of tension. All rings were tested for the presence of endothelium by addition of carbachol to rings pre-contracted with phenylephrine. The relative importance of nitric oxide (NO) in contraction mediated by the addition of DCLHb was studied., Results: Carbachol relaxed phenylephrine precontracted LIMA by 72.3+/-1.7% and RA by 97+/-0.7% confirming the presence of a functional endothelium. Sodium nitroprusside (SNP) caused complete relaxation of LIMA with an EC(50) value of 2.0+/-0.1x10(-8) M and RA with an EC(50) value of 1. 9+/-0.1x10(8) M. In the presence of DCLHb (10(-7) M), carbachol-induced relaxation was significantly reduced to 46.3+/-0. 7% (P<0.01) and the BC(50) value for SNP relaxation increased to 1. 2+/-0.1x10(-7) M (P<0.01). DCLHb caused rings to contract in the absence of phenylephrine with EC(50) values of 1.6+/-0.1x10(-7) M (LIMA) and 1.8+/-0.1x10(-7) M (RA). Presence of L-NAME (300 microM) caused no alteration in DCLHb-induced contraction., Conclusion: In this study of isolated rings of human vessels, DCLHb causes a significant reduction in relaxation mediated by carbachol and SNP, which is likely to be due to its ability to bind NO. However, it is possible that other mechanisms might contribute to the vasoconstrictor effects of DCLHb and these might be amenable to anti-vasospastic strategies.

Glibenclamide has been shown to inhibit prostanoid-induced contraction in a number of blood vessel types. In this study, the effects of glibenclamide on the contraction of human peripheral arteries in response to both prostanoid and non-prostanoid agonists were compared and possible mechanisms of action were investigated. Segments of left internal mammary artery (LIMA) and radial artery, taken from patients undergoing coronary artery bypass graft (CABG) surgery, were mounted in organ baths containing physiological saline solution aerated with 95% O2/5% CO2 at 37 degrees C. Contractions were obtained by either the use of a thromboxane analogue (U46619), L-phenylephrine, KCl or CaCl2. The effects of glibenclamide on these contractions were observed and pEC50 values were determined after manipulation of a logistic curve-fitting equation. Concentration-dependent relaxation of U46619-contracted LIMA and radial artery was observed in the presence of glibenclamide, with calculated pEC50 values of 4.2+/-0.17 (n = 7) for LIMA and 3.26+/-0.48 (n = 5) for radial artery. Incubation of both LIMA and radial artery with glibenclamide (50 microM) caused the concentration-response curves for U46619 and L-phenylephrine to shift significantly to the right. Similarly the KCl tension relationship was caused to shift to the right. Finally, glibenclamide (100 microM) also had an inhibitory effect on Ca2+-induced tension in radial artery. These results show that the inhibitory effects of glibenclamide on human peripheral blood vessels are not restricted to prostanoid-induced contractions. Furthermore, evidence has been provided to suggest that these effects might be mediated through an interaction with voltage-sensitive Ca2+ channels.

Unlabelled: Brain dysfunction after cardiopulmonary bypass (CPB) is common, and it has been hypothesized that this injury might be due partly to activation of inflammatory processes in the brain. We measured juguloarterial gradients for interleukin-1beta, interleukin-6, and interleukin-8 (IL-8) as indices of local proinflammatory cytokine production in the brain and studied the effect of temperature during CPB on these changes. Twelve patients undergoing coronary artery bypass graft surgery (normothermic CPB n = 6, hypothermic CPB n = 6) were studied. Cytokine levels were measured in paired arterial and jugular bulb samples obtained before, during, and after CPB. Although systemic levels of all three cytokines increased during and after CPB, increases in juguloarterial cytokine gradients were observed only for IL-8. Juguloarterial IL-8 gradients started to increase 1 h post-CPB and were significantly elevated 6 h post-CPB (P < 0.05). At this time point, the median (interquartile range) juguloarterial IL-8 gradients were significantly larger in the normothermic CPB group (25.81 [24.49-39.51] pg/mL) compared with the hypothermic CPB group (6.69 [-0.04 to 15.47] pg/mL; P < 0.05). These data imply specific and significant IL-8 production in the cerebrovascular bed during CPB and suggest that these changes may be suppressed by hypothermia during CPB., Implications: Using juguloarterial gradients to measure cerebrovascular cytokine production is novel in the setting of cardiopulmonary bypass and implicates the cerebral activation of inflammatory processes, which may contribute to brain dysfunction. Hypothermia during cardiopulmonary bypass may significantly attenuate this response.

In Edinburgh, we have compared presymptomatic testing by linkage and by direct mutation analysis by investigating the demand for testing and characteristics of test applicants. Annual new requests for the direct test (DT) are now double the peak with the linkage test (LT) but only 6% individuals have requested re-testing. DT applicants were older with a smaller proportion having lived with an affected relative that LT applicants. This was because many were relatives of newly diagnosed first known cases in their family. This may also explain why DT applicants were less likely to expect a negative result and more likely to be uncertain about their risk. A greater proportion of DT applicants first heard about the test from relatives or their GP than LT applicants who were more likely to hear from Genetic Centre. The demand for follow-up by the Geneticist/Genetic Nurse was much less for DT than for LT applicants largely due to the support offered by the HD Advisors.

The widespread distribution of enzymes classed as semicarbazide-sensitive amine oxidases (SSAO enzymes) throughout a very wide range of eukaryotic as well as prokaryotic organisms encourages the aspirations of those who wish to demonstrate physiological, pathological or pharmacological importance. Such enzymes are found in several tissues of mammals, both freely soluble, as in blood plasma, and membrane-bound, for example, in smooth muscle and adipose tissue. While they are capable of deaminating many amines with the production of an aldehyde and hydrogen peroxide, doubt still surrounds the identity of the most important endogenous substrates for these enzymes. At present, methylamine and aminoacetone appear to head the list of candidates. The possibility that SSAO enzymes can convert amine substrates to highly toxic metabolites is illustrated by the production of acrolein from the xenobiotic amine, allylamine and formaldehyde and methylglyoxal from methylamine and aminoacetone, respectively. Activities of SSAO enzymes may be influenced by physiological changes, such as pregnancy or pathologically by disease states, including diabetes, tumours and burns. Increased deamination of aminoacetone by tissue and plasma SSAO enzymes as a result of its increased production from L-threonine in conditions such as exhaustion, starvation and diabetes mellitus may be harmful. Such dangers could be mitigated either physiologically by a compensatory reduction in SSAO activity or pharmacologically by treatment with inhibitors of SSAO.

The present study has examined the affinities of sheep plasma semicarbazide-sensitive amine oxidase (SSAO) enzymes for a range of aliphatic amines and also the effects of two inhibitory compounds, beta-aminopropionitrile (BAPN) and mexiletine. Two kinetically separable enzyme activities appeared to be responsible for the metabolism of amines containing 2-5 carbon atoms while the deamination of higher amines and methylamine and allylamine produced kinetic plots characteristic of only one enzyme activity. When benzylamine metabolism was used as an indication of enzyme activity, the two inhibitors had different effects. BAPN exhibited predominantly a mixed pattern of inhibition while the effects of low concentrations of mexiletine were largely competitive. These results present evidence confirming the presence of two kinetically separable SSAO activities in sheep plasma, although we must await the development of highly selective inhibitors before these two activities can be fully resolved.