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Common understanding of human sex-linked behaviors is that proximal mechanisms of genetic and hormonal sex, ultimately shaped by the differential reproductive challenges of ancestral males and females, act on the brain to transfer sex-linked predispositions across generations. Here, we extend the debate on the role of nature and nurture in the development of traits in the lifetime of an individual, to their role in the cross-generation transfer of traits. Advances in evolutionary theory that posit the environment as a source of trans-generational stability, and new understanding of sex effects on the brain, suggest that the cross-generation stability of sex-linked patterns of behavior are sometimes better explained in terms of inherited socioenvironmental conditions, with biological sex fostering intrageneration variability., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Differences in breastfeeding, other milk feeding and complementary feeding patterns were evaluated in infants at increased genetic risk with and without maternal type 1 diabetes (T1D). The Trial to Reduce IDDM in the Genetically at Risk is an international nutritional primary prevention double-blinded randomized trial to test whether weaning to extensively hydrolyzed vs. intact cow's milk protein formula will decrease the development of T1D-associated autoantibodies and T1D. Infant diet was prospectively assessed at two visits and seven telephone interviews between birth and 8 months. Countries were grouped into seven regions: Australia, Canada, Northern Europe, Southern Europe, Central Europe I, Central Europe II and the United States. Newborn infants with a first-degree relative with T1D and increased human leukocyte antigen-conferred susceptibility to T1D were recruited. A lower proportion of infants born to mothers with than without T1D were breastfed until 6 months of age in all regions (range, 51% to 60% vs. 70% to 80%). Complementary feeding patterns differed more by region than by maternal T1D. In Northern Europe, a higher proportion of infants consumed vegetables and fruits daily compared with other regions. Consumption of meat was more frequent in all European regions, whereas cereal consumption was most frequent in Southern Europe, Canada and the United States. Maternal T1D status was associated with breastfeeding and other milk feeding patterns similarly across regions but was unrelated to the introduction of complementary foods. Infant feeding patterns differed significantly among regions and were largely inconsistent with current recommended guidelines., (© 2016 John Wiley & Sons Ltd.)

Frustrated Lewis pair (FLP)-catalyzed reduction of Michael acceptors is a challenging reaction that proceeds with specific FLP structures. Kinetics and equilibrium of the reactions of two phosphines (Ar 3 P), namely tri(1-naphthyl)phosphine and tri(o-tolyl)phosphine, are reported with reference electrophiles. The reason for the failure of the FLPs (Ar 3 P/B(C 6 F 5 ) 3 ) to reduce activated alkenes under H 2 pressure is shown to be a hydrophosphination process that inhibits the reduction reaction. Kinetic and thermodynamic factors controlling both pathways are discussed in light of Mayr's free linear energy relationships.

The view that life is composed of distinct entities with well-defined boundaries has been undermined in recent years by the realisation of the near omnipresence of symbiosis. What had seemed to be intrinsically stable entities have turned out to be systems stabilised only by the interactions between a complex set of underlying processes (Dupré, 2012). This has not only presented severe problems for our traditional understanding of biological individuality but has also led some to claim that we need to switch to a process ontology to be able adequately to understand biological systems. A large group of biological entities, however, has been excluded from these discussions, namely viruses. Viruses are usually portrayed as stable and distinct individuals that do not fit the more integrated and collaborative picture of nature implied by symbiosis. In this paper we will contest this view. We will first discuss recent findings in virology that show that viruses can be 'nice' and collaborate with their hosts, meaning that they form part of integrated biological systems and processes. We further offer various reasons why viruses should be seen as processes rather than things, or substances. Based on these two claims we will argue that, far from serving as a counterexample to it, viruses actually enable a deeper understanding of the fundamentally interconnected and collaborative nature of nature. We conclude with some reflections on the debate as to whether viruses should be seen as living, and argue that there are good reasons for an affirmative answer to this question., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Viruses have been virtually absent from philosophy of biology. In this editorial introduction, we explain why we think viruses are philosophically important. We focus on six issues (the definition of viruses, the individuality and diachronic identity of a virus, the possibility to classify viruses into species, the question of whether viruses are living, the question of whether viruses are organisms, and finally the biological roles of viruses in ecology and evolution), and we show how they relate to classic questions of philosophy of biology and even general philosophy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This article documents how biomedical researchers in the United Kingdom understand and enact the idea of "openness." This is of particular interest to researchers and science policy worldwide in view of the recent adoption of pioneering policies on Open Science and Open Access by the U.K. government-policies whose impact on and implications for research practice are in need of urgent evaluation, so as to decide on their eventual implementation elsewhere. This study is based on 22 in-depth interviews with U.K. researchers in systems biology, synthetic biology, and bioinformatics, which were conducted between September 2013 and February 2014. Through an analysis of the interview transcripts, we identify seven core themes that characterize researchers' understanding of openness in science and nine factors that shape the practice of openness in research. Our findings highlight the implications that Open Science policies can have for research processes and outcomes and provide recommendations for enhancing their content, effectiveness, and implementation., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Kyphoplasty has been shown as a well-established technique for spinal injuries. This technique allows a vertebral bone augmentation with a reduction of morbidity and does not involve any adjacent segment immobilisation. There is a lack of biomechanical information resulting in major gaps of knowledge such as: the evaluation of the "quality" of stabilisation provided by kyphoplasty as a standalone procedure in case of unstable fracture. Our objective is to analyse biomechanical response of spine segments stabilised by Kyphoplasty and PMMA cement after experiencing burst fractures. Six fresh-frozen cadaveric spine specimens constituted by five vertebra (T11-L3) and four disks were tested. A specific loading setup has been developed to impose pure moments corresponding to loadings of flexion-extension, lateral bending and axial rotation. Tests were performed on each specimen in an intact state and post kyphoplasty following a burst fracture. Strain measurements and motion variations of spinal unit are measured by a 3D optical method. Strain measurements on vertebral bodies after kyphoplasty shows a great primary stabilisation. Comparisons of mobility and angles variations between the intact and post kyphoplasty states do not highlight significant difference. Percutaneous kyphoplasty offers a good primary stability in case of burst fracture. Kinematics analysis during physiological movements shows that this stabilisation solution preserve disk mobility in each adjacent spinal unit., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The purpose of the present study was to test the behavior of two different generations of cochlear implant systems subjected to a clinical radiotherapy scheme and to determine the maximal acceptable cumulative radiation levels at which the devices show out-of-specification behaviors. Using stereotactic irradiation (Cyberknife, 6 MV photon beam), three Digisonic SP and three Neuro devices were submitted to 5 Gy doses that cumulated to 60 Gy (12 sessions) and 80 Gy (16 sessions), respectively. A follow-up series of irradiation was then applied, in which Digisonic SP devices received two additional fractions of 50 Gy each, cumulating to 160 Gy, and Neuro devices three additional fractions of 20, 40, and 150 Gy, cumulating to 290 Gy. Output current values were monitored during the treatment. At clinical doses, with 60 or 80 Gy cumulative radiation exposure, no single measurement showed more than 10% divergence from the reference measure. The cochlear implants tested in this study showed high resistance to clinically relevant cumulative radiation doses and showed no out-of-bounds behavior up to cumulative doses of 140 or 160 Gy. These observations suggest that cochlear implant users can undergo radiotherapy up to cumulative doses well above those currently used in clinical situations without risk of failure.

Standard microbial evolutionary ontology is organized according to a nested hierarchy of entities at various levels of biological organization. It typically detects and defines these entities in relation to the most stable aspects of evolutionary processes, by identifying lineages evolving by a process of vertical inheritance from an ancestral entity. However, recent advances in microbiology indicate that such an ontology has important limitations. The various dynamics detected within microbiological systems reveal that a focus on the most stable entities (or features of entities) over time inevitably underestimates the extent and nature of microbial diversity. These dynamics are not the outcome of the process of vertical descent alone. Other processes, often involving causal interactions between entities from distinct levels of biological organisation, or operating at different time scales, are responsible not only for the destabilisation of pre-existing entities, but also for the emergence and stabilisation of novel entities in the microbial world. In this article we consider microbial entities as more or less stabilised functional wholes, and sketch a network-based ontology that can represent a diverse set of processes including, for example, as well as phylogenetic relations, interactions that stabilise or destabilise the interacting entities, spatial relations, ecological connections, and genetic exchanges. We use this pluralistic framework for evaluating (i) the existing ontological assumptions in evolution (e.g. whether currently recognized entities are adequate for understanding the causes of change and stabilisation in the microbial world), and (ii) for identifying hidden ontological kinds, essentially invisible from within a more limited perspective. We propose to recognize additional classes of entities that provide new insights into the structure of the microbial world, namely "processually equivalent" entities, "processually versatile" entities, and "stabilized" entities.

Short-term breastfeeding and early exposure to complex dietary proteins, such as cow milk proteins and cereals, or to fruit, berries, and roots have been implicated as risk factors for β cell autoimmunity, clinical type 1 diabetes, or both. The Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR) is an international, randomized, double-blind, controlled intervention trial designed to answer the question of whether weaning to an extensively hydrolyzed formula in infancy will decrease the risk of type 1 diabetes later in childhood. In our pilot study, weaning to a highly hydrolyzed formula decreased by ≈ 50% the cumulative incidence of one or more diabetes-associated autoantibodies by a mean age of 4.7 y. This finding was confirmed in a recent follow-up analysis to 10 y of age. Currently, the full-scale TRIGR takes place in 77 centers in 15 countries. The TRIGR initially recruited 5606 newborn infants with a family member affected by type 1 diabetes and enrolled 2159 eligible subjects who carried a risk-conferring HLA genotype. All recruited mothers were encouraged to breastfeed. The intervention lasted for 6-8 mo with a minimum study formula exposure time of 2 mo, and hydrolyzed casein and standard cow milk-based weaning formulas were compared. Eighty percent of the participants were exposed to the study formula. The overall retention rate over the first 5 y was 87%, and protocol compliance was 94%. The randomization code will be opened when the last recruited child turns 10 y of age (ie, in 2017).

Aims/hypothesis: The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study was designed to establish whether weaning to a highly hydrolysed formula in infancy subsequently reduces the risk of type 1 diabetes., Methods: The study population comprises newborn infants who have first-degree relatives with type 1 diabetes and meet the increased risk HLA inclusion, but not exclusion criteria. The study is being performed in 15 countries in three continents. First-degree relatives of patients with type 1 diabetes were identified from diabetes clinics, diabetes registries, and from other endocrinology or obstetrics offices and websites. HLA typing was performed at birth from cord or heel stick blood, and the results sent to the study's Data Management Unit within 2 weeks for communication of eligibility to the clinical study centre. All mothers recruited were encouraged to breastfeed. The intervention lasted for 6 to 8 months, and weaning formulas based on hydrolysed casein and standard cow's milk were compared., Results: TRIGR recruited 5,606 infants, of whom 2,160 were enrolled as eligible participants, 6% more than the target of 2,032. Of those enrolled, 80% were exposed to the study formula. The overall retention rate over the first 5 years is 87%, with protocol compliance at 94%. The randomisation code will be opened when the last recruited child turns 10 years of age, i.e. in 2017., Conclusions/interpretation: The TRIGR experience demonstrates the feasibility and successful implementation of an international dietary intervention study. TRIGR is the first ever primary prevention trial for type 1 diabetes and, if completed successfully, will provide a definite answer to the research question., Trial Registration: ClinicalTrials.gov NCT00179777, Funding: The study was funded by the National Institute of Child Health and Development (NICHD) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) (grant numbers HD040364, HD042444 and HD051997), Canadian Institutes of Health Research, the Juvenile Diabetes Research Foundation International and the Commission of the European Communities (specific RTD programme 'Quality of Life and Management of Living Resources', contract number QLK1-2002-00372 'Diabetes Prevention'. Other funding came from the EFSD/JDRF/Novo Nordisk Focused Research Grant, Academy of Finland, Dutch Diabetes Research Foundation and Finnish Diabetes Research Foundation).

Background: Both the initiation and maintenance of breastfeeding have been reported to be negatively affected by maternal type 1 diabetes (T1D). The aim of this study was to prospectively examine the breastfeeding patterns among mothers with and without T1D participating in a large international randomized infant feeding trial (TRIGR)., Methods: Families with a member affected by T1D and with a newborn infant were invited into the study. Those who had HLA-conferred genetic susceptibility for T1D tested at birth with gestation > 35 weeks and were healthy were eligible to continue in the trial. Among the 2160 participating children, 1096 were born to women with T1D and 1064 to unaffected women. Information on infant feeding was acquired from the family by frequent prospective dietary interviews., Results: Most (>90%) of the infants of mothers with and without T1D were initially breastfed. Breastfeeding rates declined more steeply among mothers with than without T1D being 50 and 72% at 6 months, respectively. Mothers with T1D were younger, less educated and delivered earlier and more often by caesarean section than other mothers (p < 0.01). After adjusting for all these factors associated with the termination of breastfeeding, there was no difference in the duration of breastfeeding among mothers with and without T1D., Conclusions: Maternal diabetes status per se was not associated with shorter breastfeeding. The lower duration of breastfeeding in mothers with T1D is largely explained by their more frequent caesarean sections, earlier delivery and lower age and education., (Copyright 2010 John Wiley & Sons, Ltd.)

Background: The concept of a tree of life is prevalent in the evolutionary literature. It stems from attempting to obtain a grand unified natural system that reflects a recurrent process of species and lineage splittings for all forms of life. Traditionally, the discipline of systematics operates in a similar hierarchy of bifurcating (sometimes multifurcating) categories. The assumption of a universal tree of life hinges upon the process of evolution being tree-like throughout all forms of life and all of biological time. In multicellular eukaryotes, the molecular mechanisms and species-level population genetics of variation do indeed mainly cause a tree-like structure over time. In prokaryotes, they do not. Prokaryotic evolution and the tree of life are two different things, and we need to treat them as such, rather than extrapolating from macroscopic life to prokaryotes. In the following we will consider this circumstance from philosophical, scientific, and epistemological perspectives, surmising that phylogeny opted for a single model as a holdover from the Modern Synthesis of evolution., Results: It was far easier to envision and defend the concept of a universal tree of life before we had data from genomes. But the belief that prokaryotes are related by such a tree has now become stronger than the data to support it. The monistic concept of a single universal tree of life appears, in the face of genome data, increasingly obsolete. This traditional model to describe evolution is no longer the most scientifically productive position to hold, because of the plurality of evolutionary patterns and mechanisms involved. Forcing a single bifurcating scheme onto prokaryotic evolution disregards the non-tree-like nature of natural variation among prokaryotes and accounts for only a minority of observations from genomes., Conclusion: Prokaryotic evolution and the tree of life are two different things. Hence we will briefly set out alternative models to the tree of life to study their evolution. Ultimately, the plurality of evolutionary patterns and mechanisms involved, such as the discontinuity of the process of evolution across the prokaryote-eukaryote divide, summons forth a pluralistic approach to studying evolution., Reviewers: This article was reviewed by Ford Doolittle, John Logsdon and Nicolas Galtier.

Although molecular biology has meant different things at different times, the term is often associated with a tendency to view cellular causation as conforming to simple linear schemas in which macro-scale effects are specified by micro-scale structures. The early achievements of molecular biologists were important for the formation of such an outlook, one to which the discovery of recombinant DNA techniques, and a number of other findings, gave new life even after the complexity of genotype-phenotype relations had become apparent. Against this background we outline how a range of scientific developments and conceptual considerations can be regarded as enabling and perhaps necessitating contemporary systems approaches. We suggest that philosophical ideas have a valuable part to play in making sense of complex scientific and disciplinary issues.

Metagenomics is an emerging microbial systems science that is based on the large-scale analysis of the DNA of microbial communities in their natural environments. Studies of metagenomes are revealing the vast scope of biodiversity in a wide range of environments, as well as new functional capacities of individual cells and communities, and the complex evolutionary relationships between them. Our examination of this science focuses on the ontological implications of these studies of metagenomes and metaorganisms, and what they mean for common sense and philosophical understandings of multicellularity, individuality and organism. We show how metagenomics requires us to think in different ways about what human beings are and what their relation to the microbial world is. Metagenomics could also transform the way in which evolutionary processes are understood, with the most basic relationship between cells from both similar and different organisms being far more cooperative and less antagonistic than is widely assumed. In addition to raising fundamental questions about biological ontology, metagenomics generates possibilities for powerful technologies addressed to issues of climate, health and conservation. We conclude with reflections about process-oriented versus entity-oriented analysis in light of current trends towards systems approaches.

Systems biology is the rapidly growing and heavily funded successor science to genomics. Its mission is to integrate extensive bodies of molecular data into a detailed mathematical understanding of all life processes, with an ultimate view to their prediction and control. Despite its high profile and widespread practice, there has so far been almost no bioethical attention paid to systems biology and its potential social consequences. We outline some of systems biology's most important socioethical issues by contrasting the concept of systems as dynamic processes against the common static interpretation of genomes. New issues arise around systems biology's capacities for in silico testing, changing cultural understandings of life, synthetic biology, and commercialization. We advocate an interdisciplinary and interactive approach that integrates social and philosophical analysis and engages closely with the science. Overall, we argue that systems biology socioethics could stimulate new ways of thinking about socioethical studies of life sciences.

Understanding how scientific activities use naming stories to achieve disciplinary status is important not only for insight into the past, but for evaluating current claims that new disciplines are emerging. In order to gain a historical understanding of how new disciplines develop in relation to these baptismal narratives, we compare two recently formed disciplines, systems biology and genomics, with two earlier related life sciences, genetics and molecular biology. These four disciplines span the twentieth century, a period in which the processes of disciplinary demarcation fundamentally changed from those characteristic of the nineteenth century. We outline how the establishment of each discipline relies upon an interplay of factors that include paradigmatic achievements, technological innovation, and social formations. Our focus, however, is the baptism stories that give the new discipline a founding narrative and articulate core problems, general approaches and constitutive methods. The highly plastic process of achieving disciplinary identity is further marked by the openness of disciplinary definition, tension between technological possibilities and the ways in which scientific issues are conceived and approached, synthesis of reductive and integrative strategies, and complex social interactions. The importance--albeit highly variable--of naming stories in these four cases indicates the scope for future studies that focus on failed disciplines or competing names. Further attention to disciplinary histories could, we suggest, give us richer insight into scientific development.

Polyanionic microgels containing negatively charged tetrazole binding sites show supramolecular binding of various protonated amines (e.g. dibucaine and spermine) in a competitive aqueous medium at millimolar concentration.

In the context of scientists' reflections on genomics, we examine some fundamental issues in the emerging postgenomic discipline of systems biology. Systems biology is best understood as consisting of two streams. One, which we shall call 'pragmatic systems biology', emphasises large-scale molecular interactions; the other, which we shall refer to as 'systems-theoretic biology', emphasises system principles. Both are committed to mathematical modelling, and both lack a clear account of what biological systems are. We discuss the underlying issues in identifying systems and how causality operates at different levels of organisation. We suggest that resolving such basic problems is a key task for successful systems biology, and that philosophers could contribute to its realisation. We conclude with an argument for more sociologically informed collaboration between scientists and philosophers., ((c) 2005 Wiley Periodicals, Inc.)

Exendin-4 is a reptilian peptide that activates the mammalian receptor for truncated glucagon-like peptide 1 (tGLP-1) with relatively prolonged actions. Exendin-4 and tGLP-1 can reduce blood glucose levels by stimulating insulin secretion, inhibiting glucagon secretion, and delaying gastric emptying. We tested a range of doses of exendin-4 on postcibal glycemic excursions in nine volunteers with type 1 diabetes, all with negligible endogenous insulin secretion, in paired comparisons with vehicle in at least six volunteers with each of six doses. We established a side effect-free dose and an appropriate antecibal time for sc administration of exendin-4. Subsequently, exendin-4 was administered 15 min before breakfast, with usual insulin, to eight of the volunteers. Acetaminophen was ingested with the meal as an indicator of gastric emptying. The mean plasma glucose excursion was reduced by 90%, falling into the normal range, after breakfast, whereas plasma pancreatic polypeptide, glucagon, and acetaminophen levels were reduced, and insulin levels were not affected. Thus, normalization of postcibal glycemia was associated with delayed gastric emptying and suppression of glucagon secretion, without increased secretion or blood levels of insulin. We suggest that tGLP-1 agonists have therapeutic potential as congeners with insulin in C-peptide-negative type 1 diabetes.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) and its agonists are under assessment in treatment of type 2 diabetes, by virtue of their antidiabetic actions, which include stimulation of insulin secretion, inhibition of glucagon release, and delay of gastric emptying. We examined the potential of GLP-1 to improve glycemic control in type 1 diabetes with no endogenous insulin secretion. METHODS: Dose-finding studies were carried out to establish mid range doses for delay of gastric emptying indicated by postponement of pancreatic polypeptide responses after meals. The selected dose of 0.63 micrograms/kg GLP-1 was administered before breakfast and lunch in 8-hour studies in hospital to establish the efficacy and safety of GLP-1. In outside-hospital studies, GLP-1 or vehicle was self-administered double-blind before meals with usual insulin for five consecutive days by five males and three females with well-controlled C-peptide-negative type 1 diabetes. Capillary blood glucose values were self-monitored before meals, at 30 and 60 min after breakfast and supper, and at bedtime. Breakfast tests with GLP-1 were conducted on the day before and on the day after 5-day studies. Paired t-tests and ANOVA were used for statistical analysis. RESULTS: In 8-hour studies time-averaged incremental (delta) areas under the curves(AUC) for plasma glucose through 8 hours were decreased by GLP-1 compared to vehicle (3.2 PlusMinus; 0.9, mean PlusMinus; se, vs 5.4 PlusMinus; 0.8 mmol/l, p <.05), and for pancreatic polypeptide, an indicator of gastric emptying, through 30 min after meals (4.0 PlusMinus; 3.1 vs 37 PlusMinus; 9.6 pmol/l, p <.05) with no adverse effects. Incremental glucagon levels through 60 min after meals were depressed by GLP-1 compared to vehicle (-3.7 PlusMinus; 2.5 vs 3.1 PlusMinus; 1.9 ng/l, p <.04). In 5-day studies, AUC for capillary blood glucose levels were lower with GLP-1 than with vehicle (-0.64 PlusMinus; 0.33 vs 0.34 PlusMinus; 0.26 mmol/l, p <.05). No assisted episode of hypoglycaemia or change in insulin dosage occurred. Breakfast tests on the days immediately before and after 5-day trials showed no change in the effects of GLP-1. CONCLUSION: We have demonstrated that subcutaneous GLP-1 can improve glucose control in type 1 diabetes without adverse effects when self-administered before meals with usual insulin during established intensive insulin treatment programs.

To study the metabolic effects of insulin derived from islet grafts, oral glucose tolerance (OGT) and glucose turnover were examined in streptozotocin-induced diabetic Lewis rats rendered normoglycemic by syngeneic islet grafts in the renal subcapsular space (REN), in REN with renal vein-to-mesenteric vein anastomosis (REN-RMA), in the liver (intrahepatic [IH]), or in a parahepatic omental pouch (POP) and compared with normal rats. Normal OGT was found at 1 month posttransplant in all animals receiving approximately 3,000 islets, with hyperinsulinemic responses in the REN group compared with the other groups, and with higher C-peptide responses in the IH group than in the other groups (P < 0.05 by one-way analysis of variance). Glucose turnover studies in the insulin-stimulated steady state (INS-SS; infusion of insulin at 10 pmol x kg(-1) x min(-1)) at 2 months posttransplant showed that whole body glucose disappearance rates (Rd) were similar in all groups, but the REN group had higher steady-state insulin levels than the other groups. Glucose infusion rates (GIRs) were lower in the REN and IH groups than in the other groups. Apparent endogenous glucose production (EGP) was not completely inhibited in the REN and IH groups, while complete inhibition was observed in the other groups. When INS-SS insulin levels were matched to the level in REN rats by increasing the insulin infusion rate to 20 pmol x kg(-1) x min(-1) in REN-RMA, IH, and normal rats, GIR and Rd were elevated, exceeding those values in REN rats, but GIR in IH rats was still lower than in REN-RMA and normal rats. Thus, 1) in the REN group, impairment of inhibition of EGP and of stimulation of Rd by exogenous insulin contribute to insulin resistance; 2) in the IH group, incomplete inhibition of EGP is the major determinant of insulin resistance; and 3) with portal delivery of insulin in the REN-RMA and POP groups, normal insulin sensitivity is preserved. The present study confirms that hepatic portal delivery of islet secretions is necessary for physiological regulation of glucose metabolism. The study also suggests the IH grafts do not provide physiological regulation of glucose metabolism, raising the question of whether the liver is an appropriate site for insulin-secreting tissue replacement therapy in diabetes.

We determined the metabolic effects of insulin derived from renal subcapsular islet grafts, either with systemic delivery of insulin through renal venous drainage (REN) or with portal delivery of insulin after renal vein-to-superior mesenteric vein anastomosis (RMA), in streptozotocin-induced diabetic Lewis rats, in comparison with normal rats. After gavage glucose, the plasma glucose responses were similar to normal in REN and RMA rats; however, hyperinsulinemia occurred in REN rats (area under the concentration curves [AUCs] of insulin, 27 +/- 3 nmol x 1(-l) min) in comparison with RMA (14 +/- 2) and normal rats (19 +/- 2), P < 0.003, with no difference in C-peptide responses. The ratio of AUC C-peptide to AUC insulin was lower in REN (2.0 +/- 0.2) than in RMA (3.4 +/- 0.3) and normal animals (3.2 +/- 0.3), P < 0.0005. In euglycemic-hyperinsulinemic clamp studies using the same insulin infusion rate (10 pmol x kg(-1) x min(-1), insulin resistance was found in REN animals (mean glucose infusion rate [GIR], REN: 7.5 +/- 1.2; RMA: 12.0 +/- 1.2; normal: 12.7 +/- 1.0 mg x kg(-1) x min(-1); P < 0.008), with higher steady-state insulin levels in REN (554 +/- 63 pmol/l) than in RMA (291 +/- 26) and normal rats (269 +/- 60), P < 0.0001. With matching steady-state insulin levels in RMA and REN rats during infusion of insulin at 20 pmol x kg(-1) x min(-1) in RMA rats (steady-state insulin 623 +/- 64 pmol/l), GIR was 15.7 +/- 0.7 mg x kg(-1) x min(-1). Thus, systemic delivery of insulin from islet grafts is associated with hyperinsulinemia, insulin resistance, and decreased metabolic clearance of insulin. These abnormalities are prevented by portal delivery of insulin from islet grafts in the same site. The findings are consistent with the hypothesis that portal delivery of insulin is important in maintenance of normal whole-body insulin sensitivity.

The aim of this study was to analyse the Raman and infrared spectra of eight common mammalian bile acids in order to identify intermolecular interactions between hydroxyl and carbonyl groups. The results are considered in the light of the new hydrophilic/hydrophobic classification of bile acids. The alcohol OH group of the hydrophobic bile acids forms different intermolecular bonds. The most hydrophobic bile acid, lithocholic acid forms polymers, and this may explain its very low water solubility. The hydrophilic bile acids have some of their alcohol OH groups free of any intermolecular interaction. The strongly hydrophilic murideoxycholic acid also forms dimers, again consistent with a very low water solubility. The proposed structural arrangements are in agreement with published crystallographic studies.

To compare the metabolic effects of portal and systemic delivery of insulin, we used portal-caval transposition (PCT) in rats to provide total systemic diversion of splanchnic venous blood. PCT rats exhibited normal weight gain, liver histology, liver-function tests, glycosylated hemoglobin, arterial blood pressure, and hepatic blood flow. Mean liver weight relative to body weight was 12% lower in PCT rats than in sham-operated control (CTR) rats 30 days following transposition. Indwelling venous catheters were established to facilitate metabolic studies in conscious, minimally restrained animals. Postabsorptive plasma glucose and C-peptide (CPEP) levels were similar in PCT and CTR rats; however, postabsorptive immunoreactive insulin (IRI) levels were elevated in PCT rats (67 +/- 3.1 v 49 +/- 3.5 pmol.L-1, P < .002, n = 11 v 11), as were postabsorptive plasma glucagon levels (570 +/- 67 v 240 +/- 11 ng.L-1, P < .001, n = 11 v 16) at similar body weights. The postabsorptive CPEP/IRI concentration ratio was lower in PCT than in CTR rats (4.0 +/- 0.3 v 6.0 +/- 0.6, P < .02), suggesting reduced hepatic extraction of insulin. Insulin sensitivity (IS), determined by minimal model analysis of frequently sampled intravenous glucose tolerance tests yielding the sensitivity index (SI), was reduced in PCT compared with CTR (61 +/- 5.6 v 86 +/- 9.0 (mumol.L-1)-1.min-1, P < .04, n = 9 v 10). During euglycemic-hyperinsulinemic clamps, glucose infusion rates (GIRs) from 60 to 120 minutes were lower in PCT than in CTR rats (6.0 +/- 0.3 v 8.0 +/- 0.4 g.kg-1.min-1, P < .002, n = 9 v 7) with matching plasma IRI levels, confirming the reduced IS in PCT rats. Areas under the concentration curves ([AUCs] 0 to 150 minutes) for glucose tolerance tests (gavage) indicated that plasma glucose excursion was similar in PCT and CTR rats whereas AUC IRI was significantly higher in PCT than in CTR rats (23 +/- 1.3 v 18 +/- 0.6 nmol.L-1.min, P < .009, n = 11 v 11). However, AUC CPEP for oral glucose tolerance tests was lower in PCT than in CTR rats (55 +/- 3.4 v 68 +/- 4.8 nmol.L-1.min, P < .05), indicating decreased insulin secretion. Thus, the mean ratio AUC CPEP/AUC IRI was significantly lower in PCT rats (2.5 +/- 0.2 v 3.8 +/- 0.3, P < .002), again suggesting reduced hepatic extraction of insulin. Thus, euglycemia after PCT was accompanied by elevated postabsorptive and glucose-stimulated levels of IRI in systemic blood, postabsorptive hyperglucagonemia, and decreased insulin secretion in response to glucose challenge (gavage), with diminished hepatic extraction of insulin and decreased IS. The PCT model illustrates the insulin-resistant adaptive state that results from systemic delivery of insulin, and indicates the importance of hepatic portal delivery of insulin and possibly of other gastroenteropancreatic hormones in the maintenance of IS and physiological metabolic control.

Diabetes mellitus had traditionally been considered disqualifying for flying duties. Increasingly, our understanding of both Type I and Type II diabetes permits identification of subgroups of diabetics with an acceptable aeromedical risk. A case is presented of a Canadian Forces pilot with Type I diabetes who continues on restricted flying duties. The pathophysiology of Type I and Type II diabetes is discussed, as well as aeromedical considerations for returning a diabetic to flying status. Within an envelope of defined geographic and operational flying limitations, diabetic aircrew may be safely and usefully returned to restricted flying duties.

Previous studies demonstrated that porcine galanin is a potent inhibitor of insulin secretion in many species but fails to alter human insulin secretion. To resolve whether this discrepancy was due to the use of a heterologous peptide or to a true species response difference, we studied the effect of a synthetic replicate of human galanin on glucose-stimulated insulin secretion in rats, dogs, and humans. On administration into rats, human and rat galanin significantly inhibited glucose-induced insulin responses to a similar degree. Similarly, porcine and human galanin significantly elevated canine plasma glucose and inhibited canine plasma insulin responses. In contrast, plasma glucose and insulin responses to glucose administration in humans were unaltered by the addition of human galanin at or above the maximum effective dose employed in dogs. Possible effects of galanin administration were seen on human glucagon and pancreatic polypeptide responses to glucose at the highest dose of human galanin infused. We conclude that galanin probably does not play a major role in modulating human beta-cell function.

To determine whether hepatic extraction of insulin differs when glucose is administered by parenteral and physiological routes, we studied responses to oral glucose and to intravenous (IV) infusion of glucose or glucose plus arginine in normal volunteers. As in earlier studies, when IV glucose infusions were empirically programmed to to produce isoglycemic responses with 50 or 75 g oral glucose, ratios of integrated areas under concentration curves for immunoreactive C-peptide (CP) to insulin in the plasma were higher with IV than with oral glucose. Mean values +/- standard errors for these ratios in paired experiments with 50 g oral glucose were 5.6 +/- 0.66 compared with 8.3 +/- 1.4 with IV glucose (P < .03). With 75 g oral glucose, the corresponding values were 4.3 +/- 0.38 and 7.8 +/- 0.50 (P < .001). These results suggest that hepatic extraction of insulin is diminished when insulin secretion is potentiated by enteroinsular mechanisms after oral glucose administration. To determine whether this phenomenon is related to the route of administration of glucose or to the enhancement of insulin secretion with oral glucose, programmed IV infusions of glucose were used to elicit excursions of plasma CP similar to those obtained after 50 g oral glucose, and programmed infusions of glucose plus arginine were used to elicit excursions of plasma CP similar to those obtained after 75 g oral glucose. Plasma levels of immunoreactive gastric inhibitory polypeptide (GIP) increased substantially after ingestion of 75 g glucose, but did not change during isoglycemic IV glucose infusions or during IV infusions of glucose plus arginine.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Corticotropin-independent nodular adrenal hyperplasia is a rare cause of Cushing's syndrome, and the factors responsible for the adrenal hyperplasia are not known., Methods: We studied a 48-year-old woman with Cushing's syndrome, nodular adrenal hyperplasia, and undetectable plasma corticotropin concentrations in whom food stimulated cortisol secretion., Results: Cortisol secretion had an inverse diurnal rhythm in this patient, with low-to-normal fasting plasma cortisol concentrations and elevated postprandial cortisol concentrations that could not be suppressed with dexamethasone. The cortisol concentrations increased in response to oral glucose (4-fold increase) and a lipid-rich meal (4.8-fold increase) or a protein-rich meal (2.6-fold increase), but not intravenous glucose. The infusion of somatostatin blunted the plasma cortisol response to oral glucose. Intravenous infusion of gastric inhibitory polypeptide (GIP) for one hour increased the plasma cortisol concentration in the patient but not in four normal subjects. Fasting plasma GIP concentrations in the patient were similar to those in the normal subjects; feeding the patient test meals induced increases in plasma GIP concentrations that paralleled those in plasma cortisol concentrations. Cell suspensions of adrenal tissue from the patient produced more cortisol when stimulated by GIP than when stimulated by corticotropin. In contrast, adrenal cells from normal adults and fetuses or patients with cortisol-producting or aldosterone-producing adenomas responded to corticotropin but not to GIP., Conclusions: Nodular adrenal hyperplasia and Cushing's syndrome may be food-dependent as a result of abnormal responsiveness of adrenal cells to physiologic secretion of GIP. "Illicit" (ectopic) expression of GIP receptors on adrenal cells presumably underlies this disorder.

In the Canadian/European randomized controlled study on cyclosporin A (CsA) in recent onset Type 1 (insulin-dependent) diabetes, treatment with the immunosuppressive drug had increased and maintained Beta-cell function and clinical remission during the first 12 months. Following discontinuation of the study drug and double-blinding after a mean of 13.8 months former CsA patients doubled the daily insulin dose within 6 months reaching the level of former placebo patients. The difference in Beta-cell function between the two groups was also lost. Metabolic control (HbA1c) was transiently worse in the former CsA group. Adverse effects of cyclosporin A on systolic blood pressure, haemoglobin levels, serum potassium and creatinine levels also remitted during that time. We conclude that treatment with cyclosporin A for a mean of 13.8 months had no long-lasting effect on the course of Type 1 diabetes persisting beyond drug discontinuation.

Allogeneic islets obtained from Lewis rats were transplanted into diabetic BB/W rats with or without cyclosporine. In addition, these islets were encapsulated in alginate-poly L-lysine membranes and then transplanted into diabetic BB/W rats with or without immunosuppressive and/or antiinflammatory agents. The agents used were cyclosporine, dexamethasone, indomethacin (Ind), or a combination of these. Our results show that islets alone survived for 7 days, with or without CsA therapy. Encapsulated islets survived for 14.2 days, and this was extended by CsA, Dex, or CsA + Ind. Loss of encapsulated graft functions was associated with formation of a dense pericapsular infiltrate, which was inhibited by CsA, Dex, CsA + Ind, or CsA + Dex. In addition, the infiltrate was reduced in animals that had diabetes for long periods of time (greater than 5 months versus less than 1 month). Empty capsules also provoked this cellular response. Thus, encapsulation of islets resulted in slightly prolonged islet survival, which was further enhanced by immunosuppression.

The structure of rat galanin, recently elucidated using recombinant DNA technology, differs from porcine galanin by three amino acid residue substitutions at positions located in the C-terminal region. A synthetic replicate of the proposed structure of rat galanin was prepared and its potency to inhibit insulin responses to glucose in anesthetized rats was compared with that of porcine galanin. Within experimental error, the dose-response curves of porcine and rat galanin to inhibit glucose-stimulated rat insulin responses were indistinguishable. The ED50 dose of porcine galanin was 0.6 micrograms/100 g body weight and for rat galanin 0.8 micrograms/100 g body weight. These results suggest that the C-terminal region of the molecule is not essential for galanin's potent inhibitory action on insulin responses to glucose administration.

Approaches to better control of diabetes with more sophisticated insulin therapy are being tested in the hope that they will prevent the sequelae that incapacitate and kill. Some of the regimens and techniques are relatively simple and practicable; others are less easily implemented; still others are speculative. Collectively, they add up to an encouraging outlook for effective treatment.

Gastric inhibitory polypeptide (GIP) is insulinotropic and is released after ingestion of glucose in normal man. Changes in plasma immunoreactive gastric inhibitory polypeptide (IRGIP) were therefore studied during a 50-gm. oral glucose tolerance test in 10 normal subjects and 20 subjects with maturity-onset diabetes mellitus. The diabetics were nonobese and treated by diet alone; they exhibited exaggerated increments of plasma IRGIP in association with delayed and diminished peak increases in plasma immunoreactive insulin, suggesting relative failure of the beta-cell response to GIP. The diabetic subjects also showed a paradoxic rise in mean plasma immunoreactive glucagon, with a peak coinciding with that of plasma IRGIP. It is suggested that the defective beta-cell response may lead to diminished feedback inhibition of GIP secretion by insulin in diabetes mellitus and that the glucagonotropic action of GIP may be expressed under these conditions.

The results of uncontrolled trials in immunomodulation of insulin-dependent diabetes mellitus (IDDM) led to randomized controlled trials in Canada and Europe. In the Canadian open study, the rate of clinical remissions (target control of glycemia maintained with less than or equal to 0.15 U.kg-1.day-1 insulin) was unexpectedly high among 81 subjects who had been treated with cyclosporin for at least 3 mo (mean serum trough levels approximately 125 ng/ml by radioimmunoassay). Subjects entered the study within 14 wk of onset of symptoms and received 6 wk of insulin therapy. The clinical remission rate at 1 yr was 46%; of these patients, 84% were not receiving insulin. An effect on beta-cell function was suggested by recovery of plasma glucagon-stimulated C-peptide levels into the normal range in many patients, with maintenance of levels through 1 yr in patients in remission. On the basis of these findings, the French and Canadian-European study groups conducted randomized double-blind controlled trials of cyclosporin, which confirmed the results of the open studies in terms of clinical remission. The Canadian-European study also demonstrated enhancement of beta-cell function by cyclosporin by 3 mo, which was maintained for 1 yr. In the Canadian open study, most patients relapsed within a few weeks after discontinuation of cyclosporin, indicating the need for longer-term immunomodulatory therapy for maintenance of remission. The nature and degree of structural change in kidney biopsies from patients in these studies are under assessment. The results strongly support the hypothesis that autoimmune mechanisms mediate beta-cell damage in many patients with IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of morphine (0.1 mg/kg) on insulin secretion stimulated by oral, intraduodenal, or intravenous administration of glucose was studied in seven healthy volunteers. When glucose was given intravenously, morphine had no effect on plasma glucose, insulin, glucose-dependent insulinotropic polypeptide (GIP), or pancreatic glucagon. Following oral glucose, morphine slowed gastric emptying and reduced plasma concentrations of glucose, insulin, and GIP. During intraduodenal infusion of glucose, insulin concentrations in plasma were also decreased by morphine, an effect best explained by decreased small intestinal transit with delayed absorption of glucose and delayed release of GIP. We conclude that clinically relevant doses of morphine have no direct effect on insulin secretion and that the changes observed were secondary to slowed gastric emptying and small intestinal transit.