Growth hormone suppression and glutamine flux associated with cardiac surgery

Summary. Pharmacological doses of growth hormone (GH) in humans and rats increase plasma and muscle glutamine values. As major surgery results in a physiological rise in serum GH concentration, we investigated whether this physiological increase in GH altered glutamine metabolism. Eighteen patients undergoing coronary artery bypass graft (CABG) surgery were randomly assigned to receive somatostatin, 100 μg subcu-taneously at induction of anaesthesia and 8 hourly for 48 h, or placebo. Somatostatin effectively blocked the physiological surge of GH following injury but did not affect plasma or muscle glutamine concentrations, which fell significantly in both groups. Plasma glutamine decreased by 31% (P<0–01) and 28% (P<0–01) in the control and somatostatin groups respectively. Muscle glutamine was reduced 45% (P<0–001) in the control group and 50% (P<0–001) in the somatostatin group. There was no difference in muscle or circulating glutamate, alanine or branched chain amino acid concentrations or in metabolite values between the somatostatin-treated patients and the control group. There was no relationship between the GH response to surgery and glutamine metabolism following major surgery.     

Perioperative evaluation of regional aortic wall shear stress patterns in patients undergoing aortic valve and/or proximal thoracic aortic replacement

Objectives

To assess in patients with aortopathy perioperative changes in thoracic aortic wall shear stress (WSS), which is known to affect arterial remodeling, and the effects of specific surgical interventions.

Sequential divergence and the multiplicative origin of community diversity

Phenotypic and genetic variation in one species can influence the composition of interacting organisms within communities and across ecosystems. As a result, the divergence of one species may not be an isolated process, as the origin of one taxon could create new niche opportunities for other species to exploit, leading to the genesis of many new taxa in a process termed “sequential divergence.” Here, we test for such a multiplicative effect of sequential divergence in a community of host-specific parasitoid wasps, Diachasma alloeum, Utetes canaliculatus, and Diachasmimorpha mellea (Hymenoptera: Braconidae), that attack Rhagoletis pomonella fruit flies (Diptera: Tephritidae). Flies in the R. pomonella species complex radiated by sympatrically shifting and ecologically adapting to new host plants, the most recent example being the apple-infesting host race of R. pomonella formed via a host plant shift from hawthorn-infesting flies within the last 160 y. Using population genetics, field-based behavioral observations, host fruit odor discrimination assays, and analyses of life history timing, we show that the same host-related ecological selection pressures that differentially adapt and reproductively isolate Rhagoletis to their respective host plants (host-associated differences in the timing of adult eclosion, host fruit odor preference and avoidance behaviors, and mating site fidelity) cascade through the ecosystem and induce host-associated genetic divergence for each of the three members of the parasitoid community. Thus, divergent selection at lower trophic levels can potentially multiplicatively and rapidly amplify biodiversity at higher levels on an ecological time scale, which may sequentially contribute to the rich diversity of life.Population divergence is a fundamental evolutionary process contributing to the diversity of life (1). Studies of how new life forms originate typically focus on how barriers to gene flow evolve in specific lineages, resulting in their divergence into descendent daughter taxa. As a result, evolutionary biologists now have a good understanding of how variation within a population is transformed by selection into differences between taxa (1–3). What is less well understood is whether the divergence of one population has consequences that ripple through the trophic levels of an ecosystem and affect entire communities of interacting organisms. Studies in paleontology (4–6), community ecology (7, 8), systematics (8, 9), and ecosystem genetics (10, 11) suggest that evolutionary change in one lineage can influence entire communities of organisms. For example, when the genotype/phenotype of a “foundation” species influences the relative fitness of other species, evolutionary change(s) in this genotype/phenotype may affect organisms in adjacent trophic levels (10, 11). If these evolutionary changes are linked to ecological adaptation and reproductive isolation (RI), associated organisms may diverge in parallel, potentially creating entire coevolved communities distinct from one another (12–15). Therefore, population divergence may not always be an isolated process, as the differentiation of one taxon could beget the divergence of many others.Such “sequential” or “cascading” divergence events may be particularly relevant to understanding why some groups of organisms, like plants, the insects that feed on them, and the parasitoids that attack the insects, are more diverse and species-rich than other groups (8, 9, 12–15). Specifically, when phytophagous insects diversify by adapting to new host plants, they create a new habitat for their parasitoids to exploit (Fig. 1). If a parasitoid shifts to the new habitat, it can encounter the same divergent ecological selection pressures as its insect host, which could result in the parallel divergence of insect host and parasitoid (12–15) (Fig. 1A). Moreover, sequential divergence may have multiplicative effects in generating biodiversity, as the shift of an insect to a new plant may open a new niche opportunity for not just one but the entire community of parasitoids attacking the insect host (12, 13) (Fig. 1B). However, few convincing examples of sequential divergence exist (12–15), and in no study is there both genetic and ecological evidence for sequential divergence multiplicatively amplifying biodiversity.Open in a separate windowFig. 1.Three scenarios of codivergence in a host−parasitoid system. (A) A single sequential divergence event, (B) sequential divergence with multiplicative amplification of biodiversity, and (C) cospeciation in allopatry. In A, codivergence is driven by the cascade of divergent ecological selection pressures across trophic levels in sympatry. Here, a degree of divergent ecological adaptation must accompany the host shift such that parasitoids are not merely moving between geographically separated hosts. In B, the multiplicative effects of sequential divergence can be seen as several members of the parasitoid community diverge in parallel with their host. In C, codivergence (cospeciation) occurs after host plant, fly, and parasitoid populations become jointly geographically isolated (black bar), resulting in parallel allopatric speciation. Here, little differentiation need accompany the initial host shift of fly or parasitoid. Cospeciation is not necessarily driven by the creation and adaptation to new niches but by the concordant geographic and reproductive separation of hosts and parasitoids.Here, we test for the multiplicative effects of sequential divergence in the community of parasitoid wasps (Hymenoptera: Braconidae) that attack fruit flies in the Rhagoletis pomonella sibling species complex (Diptera: Tephritidae) (Fig. 2). Several features of the biology and biogeography of the Rhagoletis−parasitoid system make it ideal for investigating the multiplicative divergence hypothesis and allow us to directly test multiple criteria supporting sympatric host race formation (16) and sequential divergence (12, 13), summarized in 1–3, 17–19), the hypothesized initial stage of ecological speciation (16, 17). The short time frame and sympatric spatial context of R. pomonella’s shift to apple exclude passive codivergence or speciation (Fig. 1C) as an explanation for differentiation. Specifically, fly and wasp populations could not have diverged in concert, because they became jointly geographically separated in the past (Fig. 1C). Rather, if flies and wasps display concordant adaptations, it is likely due to the direct effects of divergent ecological selection resulting from host shifts cascading from host plants to flies to parasitoids (Fig. 1 A and B).Open in a separate windowFig. 2.The community of host-specific parasitoids that attack members of the (A) Rhagoletis pomonella sibling species complex: (B) D. alloeum, (C) D. mellea, and (D) U. canaliculatus that (E) emerge from the fly pupal case as adults following overwintering. (Scale bar, 1 mm.)

Table 1.

Summary of conditions (criteria) conducive to and supporting hypotheses of sympatric host race formation (modified from ref. 16) and sequential divergence (modified from refs. 12 and 13)

From the Cover: Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth

Mothers with obesity or gestational diabetes mellitus have low circulating levels of adiponectin (ADN) and frequently deliver large babies with increased fat mass, who are susceptible to perinatal complications and to development of metabolic syndrome later in life. It is currently unknown if the inverse correlation between maternal ADN and fetal growth reflects a cause-and-effect relationship. We tested the hypothesis that ADN supplementation in obese pregnant dams improves maternal insulin sensitivity, restores normal placental insulin/mechanistic target of rapamycin complex 1 (mTORC1) signaling and nutrient transport, and prevents fetal overgrowth. Compared with dams on a control diet, female C57BL/6J mice fed an obesogenic diet before mating and throughout gestation had increased fasting serum leptin, insulin, and C-peptide, and reduced high-molecular-weight ADN at embryonic day (E) 18.5. Placental insulin and mTORC1 signaling was activated, peroxisome proliferator-activated receptor-α (PPARα) phosphorylation was reduced, placental transport of glucose and amino acids in vivo was increased, and fetal weights were 29% higher in obese dams. Maternal ADN infusion in obese dams from E14.5 to E18.5 normalized maternal insulin sensitivity, placental insulin/mTORC1 and PPARα signaling, nutrient transport, and fetal growth without affecting maternal fat mass. Using a mouse model with striking similarities to obese pregnant women, we demonstrate that ADN functions as an endocrine link between maternal adipose tissue and fetal growth by regulating placental function. Importantly, maternal ADN supplementation reversed the adverse effects of maternal obesity on placental function and fetal growth. Improving maternal ADN levels may serve as an effective intervention strategy to prevent fetal overgrowth caused by maternal obesity.Obesity and the metabolic syndrome are major risk factors for a wide array of diseases, including type 2 diabetes mellitus, cardiovascular disease, and cancer (1, 2). Compelling evidence shows that metabolic syndrome is caused, in part, by a suboptimal intrauterine environment (3). The strong association between maternal obesity during pregnancy and metabolic syndrome in childhood is of particular concern because almost two-thirds of American women now enter pregnancy either overweight or obese (4). Obesity during pregnancy therefore creates a vicious, detrimental cycle of intrauterine transmission of metabolic disease from the mother to her children (5). Intervention strategies involving lifestyle changes or antiobesity drugs remain largely unsuccessful, and it is therefore urgent to explore the possibility of intervening in utero to prevent the development of obesity and metabolic syndrome.Obesity in pregnant women is associated with activation of placental insulin and mechanistic target of rapamycin complex 1 (mTORC1) signaling, up-regulation of specific placental amino acid transporters, and fetal overgrowth (6, 7). In addition, circulating levels of adiponectin (ADN) are decreased in obese pregnant women (8, 9). The ADN protein is synthesized in adipose tissue and undergoes tightly regulated multimerization involving chaperone proteins, including disulfide-bond A oxidoreductase-like protein (DsbA-L), resulting in the assembly of oligomeric ADN proteins of different molecular weight (10). Multimerization into the high-molecular-weight (HMW) form increases the t_1/2 of ADN (11), and the insulin-sensitizing effect of ADN can largely be attributed to the HMW form (12). Low circulating levels of HMW ADN strongly predict the development of gestational diabetes mellitus (GDM) independent of maternal adiposity (13, 14).We recently reported that ADN, in contrast to its well-known insulin-sensitizing effects in skeletal muscle and liver, inhibits insulin and mTORC1 signaling and amino acid transport in cultured primary human trophoblast (PHT) cells (15) and in pregnant mice in vivo (16). This effect is mediated by activation of trophoblast peroxisome proliferator-activated receptor-α (PPARα) signaling and increased ceramide synthesis, resulting in inhibition of IRS-1 (17). Thus, low circulating ADN in maternal obesity may be causally linked to changes in placental function and increased fetal growth. These findings, together with the recent discovery of an orally active ADN receptor agonist (AdipoRon) (18), provide the rationale for exploring the possibility that maternal ADN supplementation may prevent the adverse fetal outcomes in maternal obesity.We recently established a mouse model of obesity in pregnancy, which shows extensive similarities to the human condition, including low maternal ADN and glucose intolerance, increased placental nutrient transport, and fetal overgrowth (19). In this study, we used this model to test the hypothesis that ADN supplementation in obese pregnant dams improves maternal insulin sensitivity, restores normal placental insulin signaling and nutrient transport, and prevents fetal overgrowth.     

The Mediating Effects of Alexithymia,Intolerance of Uncertainty,and Anxiety on the Relationship Between Sensory Processing Differences and Restricted and Repetitive Behaviours in Autistic Adults

Distress caused by sensory processing differences for autistic individuals may be reduced by repetitive behaviours (RRB), including repetitive motor (RMB) and insistence on sameness (ISB) behaviours. Intolerance of uncertainty (IU) and anxiety mediate the relationship between sensory processing and RRB in autistic children. We replicated this model in autistic adults, extending it to include alexithymia. Serial mediation, using data from 426 autistic adults, identified significant direct effects from sensory processing to RMB and ISB, and indirect effects through alexithymia-IU-anxiety for RMB, and IU alone, and alexithymia-IU for ISB. Different mechanisms may underpin RMB and ISB. Alexithymia alongside, IU and anxiety, should be considered when understanding the relationship between sensory processing and RRB, and when offering interventions to support autistic people.

     

Salvage of locally recurrent breast cancer with repeat breast conservation using 45 Gy hyperfractionated partial breast re-irradiation

Breast Cancer Research and Treatment - Mastectomy has long been the preferred approach for local salvage of recurrent breast cancer following breast-conservation therapy (BCT). Growing interest in...