bluuebunny/crossref_metadata_2025 huggingface dataset:
IDENTIFYING HUMAN VARIANCES AND FUTURE PALLIATIVE CARE TRAINING NEEDS FOR NON-SPECIALIST HEALTHCARE PROFESSIONALS
Authors: Stewart C , Archer S , Bali A , Hay D
Published: February 2015

Introduction

The General Medical Council and UK Department of Health both emphasise the importance of palliative care education and training for all healthcare professionals (HCPs), yet there are large variances in the implementation and provision of this training across the UK. Consequently, many junior doctors report feeling unprepared and unsupported with very little 'real life' experience of providing end of life care.

Aim(s) and method(s)

This study investigated the experiences of gynaecology HCPs when caring for patients with advanced disease, and aimed to identify educational variances and other barriers to the provision of palliative care in non­specialist settings. Individual semi­structured interviews were completed with 12 HCPs from the Gynaecology department of a large tertiary hospital. Interviews were audio­recorded, transcribed verbatim and analysed using Interpretative Phenomenological Analysis (IPA).

Results

Four superordinate themes were identified: (1) Discrepant Discourses (2) Relationships and Roles (3) Duties and Expectations (4) Healthcare Professionals as Emotional Beings. Key gaps in training were evident, with little focus on the psychosocial and human aspects of palliative care provision.

Conclusions

When providing palliative care, staff may experience significant emotional trauma and long term psychological effects associated with feelings of failure, yet these issues are not commonly discussed or addressed in current practice. Increasing demands for palliative care mean that general physicians and surgeons will be increasingly involved in the care of patients at the end of life, and therefore compulsory, specifically tailored palliative care training needs to be introduced for all HCPs to prevent ongoing inequalities in care for patients managed in non-specialist settings.
CANCER CARERS MEDICINES MANAGEMENT: A FEASIBILITY TRIAL OF AN EDUCATIONAL INTERVENTION FOR MANAGING END OF LIFE PAIN MEDICATION
Authors: Latter S , Hopkinson J , Lowson E , Richardson A , Hughes J , Duke S , Anstey S , Bennett M , May C , Smith P , Hughes J
Published: February 2015

Introduction

Family carers need support with managing end-of-life pain medicines, yet no UK research has developed and tested interventions to help with this.

We have recently completed a Phase I-II feasibility study, funded by Dimbleby Marie Curie, to test a new intervention: Cancer Carer Medicines Management (CCMM).

Aim(s) and method(s)

To test the feasibility, acceptability and efficacy of CCMM to improve carers' knowledge, beliefs, and self-efficacy for pain medicines management.

Phase I

We used an incremental, multi-method approach to develop CCMM including a systematic review of interventions for carer end-of-life medicines management, interviews and action research workshops. Phase II: A two arm, cluster randomised feasibility trial of CCMM with outcomes at baseline, 1 and 4 weeks post-intervention and a qualitative sub-study of CCMM acceptability and trial methods, with carer interviews conducted 1 and 4 weeks post-intervention, and with nurses on study completion.

Results

Phase I enabled us to develop an evidence-based, clinically applicable intervention. In Phase II we recruited, randomised and trained nurses to use CCMM at two sites. 16 patient-carer dyads were recruited to the study; 8 dyads completed the study protocol. 10 of 12 study nurses took part in an interview. We will present results on study feasibility and acceptability including: the randomisation process; recruitment and attrition rates; key factors that promoted or inhibited routine utilization of CCMM by nurses and carers; and obstacles to the trial process.

Conclusions

A newly developed intervention for carers was tested in a feasibility trial. Important lessons were learned to inform the design and evaluation of future research in this area.
Different conformational dynamics of PDZ1 and PDZ2 in full-length EBP50 analyzed by hydrogen/deuterium exchange mass spectrometry
Authors: Park Ji Young , Duc Nguyen Minh , Kim Dong Kyun , Lee Su Youn , Li Sheng , Seo Min-Duk , Woods Virgil L. , Chung Ka Young
Published: February 2015

Ezrin-radixin-moesin-binding protein 50 (EBP50) is a scaffolding protein expressed in polarized epithelial cells in various organs, including the liver, kidney, and small intestine, in which it regulates the trafficking and targeting cellular proteins. EBP50 contains two postsynaptic density-95/disk-large/ZO-1 homology (PDZ) domains (e.g., PDZ1 and PDZ2) and an ezrin/radixin/moesin-binding (EB) domain. PDZ domains are one of the major scaffolding domains regulating protein–protein interactions with critical biological roles in cell polarity, migration, proliferation, recognition, and cell–cell interaction. PDZ1 and PDZ2 in EBP50 have different ligand selectivity, although several high-resolution structural studies of isolated PDZ1 and PDZ2 showed similar structures. We studied the conformations of full-length EBP50 and isolated PDZ1 and PDZ2 using hydrogen/deuterium exchange mass spectrometry (HDX-MS). The deuterium uptake profiles of isolated PDZ1 and PDZ2 were similar to those of full-length EBP50. Interestingly, PDZ1 was more dynamic than PDZ2, and these PDZ domains underwent different conformational changes upon ligand binding. These results might explain the differences in ligand-selectivity between PDZ1 and PDZ2.
The ameliorative effect of thymol against hydrocortisone-induced hepatic oxidative stress injury in adult male rats
Authors: Aboelwafa Hanaa R. , Yousef Hany N.
Published: February 2015

The aim of the present study was to investigate whether hydrocortisone induces oxidative stress in hepatocytes and to evaluate the possible ameliorative effect of thymol against such hepatic injury. Twenty-four adult male rats were divided into control, thymol, hydrocortisone, and hydrocortisone+thymol groups. The 4 groups were treated daily for 15 days. Hydrocortisone significantly induced oxidative stress in the liver tissues, marked by increased serum levels of alanine transaminase (ALT), aspartate transaminase (AST), total oxidative capacity (TOC), and tumor necrosis factor-alpha (TNF-α) accompanied by marked decline of serum levels of total protein, albumin, and total antioxidant capacity (TAC). Also, marked elevation in the levels of the thiobarbituric acid reactive substances (TBARS) and TNF-α, beside significant decrease in the level of glutathione (GSH) in hepatic tissues were recorded. These biochemical alterations were accompanied by histopathological changes marked by destruction of the normal hepatic architecture, in addition to ultrastructural alterations represented by degenerative features covering almost all the cytoplasmic organelles of the hepatocytes. Supplementation of hydrocortisone-treated rats with thymol reversed most of the biochemical, histological, and ultrastructural alterations. The results of our study confirm that thymol has strong ameliorative effect against hydrocortisone-induced oxidative stress injury in hepatic tissues.
Mechanisms of cardiac radiation injury and potential preventive approaches
Authors: Slezak Jan , Kura Branislav , Ravingerová Táňa , Tribulova Narcisa , Okruhlicova Ludmila , Barancik Miroslav
Published: February 2015

In addition to cytostatic treatment and surgery, the most common cancer treatment is gamma radiation. Despite sophisticated radiological techniques however, in addition to irradiation of the tumor, irradiation of the surrounding healthy tissue also takes place, which results in various side-effects, depending on the absorbed dose of radiation. Radiation either damages the cell DNA directly, or indirectly via the formation of oxygen radicals that in addition to the DNA damage, react with all cell organelles and interfere with their molecular mechanisms. The main features of radiation injury besides DNA damage is inflammation and increased expression of pro-inflammatory genes and cytokines. Endothelial damage and dysfunction of capillaries and small blood vessels plays a particularly important role in radiation injury. This review is focused on summarizing the currently available data concerning the mechanisms of radiation injury, as well as the effectiveness of various antioxidants, anti-inflammatory cytokines, and cytoprotective substances that may be utilized in preventing, mitigating, or treating the toxic effects of ionizing radiation on the heart.
Influence of microbial framework on Cryogenian microbial facies, Rasthof Formation, Namibia
Authors: Le Ber E. , Le Heron D. P. , Oxtoby N. H.
Published: February 2015

The Rasthof Formation is a mid-Cryogenian cap carbonate succession deposited in Namibia following the Sturtian glaciation. It includes a microbial member, typically >100 m thick. This member exhibits contorted intervals, and is divisible into two informally defined units. The lower unit (microbial member 1: MM1) comprises thickly laminated microbialites (1–6 mm); the upper unit (MM2) is characterized by thinly laminated microbialites (sub-millimetre layering). Contortion of the microbialite deposits – a recurrent feature of this succession – is interpreted to result from soft-sediment deformation. Deformed intervals and styles range from metre- to decimetre-scale chaotic folds in MM1 to a few centimetre-scale, localized roll-up structures in MM2. Study of the microfacies of MM1 and MM2 reveals two essentially different architectures. In MM1 the microfacies is dominated by an alternation of thin micritic laminae with thicker cemented intervals; this probably gave less rigidity to the sediments than in MM2 where the laminated fabric is also present but connected vertically as well, forming a continuous framework. We suggest that the continuity of this framework limited the frequency and scale of soft-sediment deformation. In the Rasthof Formation, the microarchitecture is thus suggested to translate into different degrees of rigidity of the macrofacies.
Microbial carbonates: a sampling and measurement challenge for petrophysics addressed by capturing the bioarchitectural components
Authors: Corbett Patrick , Hayashi Felipe Yuji , Alves Michael Saad , Jiang Zeyun , Wang Haitao , Demyanov Vasily , Machado Alessandra , Borghi Leonardo , Srivastava Narendra
Published: February 2015

Ancient and modern stromatolites are potentially a challenge for petrophysicists when characterizing biosediments of microbial origin. Because of the heterogeneity, sometimes very cemented and lacking porosity, sometimes highly porous, these widely differing states can be used to develop techniques that can have wider application to addressing the representative elementary volume (REV – single or multiple REVs) challenge in microbial carbonates. Effective media properties – like porosity – need to be defined on REV scales and the challenge is that this scale is often close to or significantly larger than the traditional core plugs on which properties are traditionally measured. A combination of outcrop images, image analysis techniques, micro-computed tomography (CT) and modelling have been used to capture the porosity (or in some cases, precursor porosity) architecture and provide a framework for estimating petrophysical property sensitivities in a range of situations that can be subjected to further calibration by measurements in relevant microbial reservoir rocks. This work will help guide the sampling approach along with the interpretation and use of petrophysical measurements from microbial carbonates. The bioarchitectural component, when controlling porosity in microbial carbonates, presents a significant challenge as the REV scale is often much larger than core plugs, requiring careful screening of existing data and measurement and additional geostatistical model-based approaches (with further calibration).
The effectiveness of web-based, multimedia tutorials for teaching methods of human body composition analysis
Authors: Buzzell Paul R. , Chamberlain Valerie M. , Pintauro Stephen J.
Published: February 2015

This study examined the effectiveness of a series of Web-based, multimedia tutorials on methods of human body composition analysis. Tutorials were developed around four body composition topics: hydrodensitometry (underwater weighing), dual-energy X-ray absorptiometry, bioelectrical impedance analysis, and total body electrical conductivity. Thirty-two students enrolled in the course were randomly assigned to learn the material through either the Web-based tutorials only (“Computer”), a traditional lecture format (“Lecture”), or lectures supplemented with Web-based tutorials (“Both”). All students were administered a validated pretest before randomization and an identical posttest at the completion of the course. The reliability of the test was 0.84. The mean score changes from pretest to posttest were not significantly different among the groups (65.4 ± 17.31, 78.82 ± 21.50, and 76 ± 21.22 for the Computer, Both, and Lecture groups, respectively). Additionally, a Likert-type assessment found equally positive attitudes toward all three formats. The results indicate that Web-based tutorials are as effective as the traditional lecture format for teaching these topics.
Cardiovascular interactions: an interactive tutorial and mathematical model
Authors: Rothe Carl F. , Gersting John M.
Published: February 2015

The maintenance of an adequate cardiac output and systemic arterial blood pressure is a complex process with intricacies that are often difficult to understand. Cardiovascular Interactions is an active learning tool that demonstrates the interactions between the functions of the heart and peripheral circulation. This learning package consists of a Lab Book, a Model, and an Information file. The Lab Book is an interactive tutorial for exploring the relative influences of parameter changes on the cardiovascular system under normal, stressful, or pathophysiological conditions. The learners are guided to predict the direction and relative magnitude of changes of key variables in the cardiovascular system, evaluate the accuracy of their predictions, and describe the cause-and-effect mechanisms involved. Consequences of heart failure, hemorrhage, exercise, and changes in intrathoracic pressure can be explored. The results obtained in the Lab Book are based on a five-compartment mathematical Model, which reflects our current understanding of the basic control of the cardiovascular system. The Model was designed to be complex enough to be realistic, yet not so complex as to be overwhelming. An Information File contains definitions and descriptions of classical physiology about key concepts, including figures, and a detailed description of the Model. Hypertext tags embedded in the Lab Book are used to access the Information File. The Cardiovascular Interactions learning package was designed to run from its CD and so does not need to be installed.
RECENT ADVANCES IN PATHOPHYSIOLOGY AND TREATMENT OF SPINAL CORD INJURY
Authors: Hulsebosch Claire E.
Published: February 2015

Thirty years ago, patients with spinal cord injury (SCI) and their families were told “nothing can be done” to improve function. Since the SCI patient population is reaching normal life expectancy through better health care, it has become an obviously worthwhile enterprise to devote considerable research effort to SCI. Targets for intervention in SCI toward improved function have been identified using basic research approaches and can be simplified into a list: 1) reduction of edema and free-radical production, 2) rescue of neural tissue at risk of dying in secondary processes such as abnormally high extracellular glutamate concentrations, 3) control of inflammation, 4) rescue of neuronal/glial populations at risk of continued apoptosis, 5) repair of demyelination and conduction deficits, 6) promotion of neurite growth through improved extracellular environment, 7) cell replacement therapies, 8) efforts to bridge the gap with transplantation approaches, 9) efforts to retrain and relearn motor tasks, 10) restoration of lost function by electrical stimulation, and 11) relief of chronic pain syndromes. Currently, over 70 clinical trials are in progress worldwide. Consequently, in this millennium, unlike in the last, no SCI patient will have to hear “nothing can be done.”
PROBLEM-BASED WRITING WITH PEER REVIEW IMPROVES ACADEMIC PERFORMANCE IN PHYSIOLOGY
Authors: Pelaez Nancy J.
Published: February 2015

The aim of this study was to determine whether problem-based writing with peer review (PW-PR) improves undergraduate student performance on physiology exams. Didactic lectures were replaced with assignments to give students practice explaining their reasoning while solving qualitative problems, thus transferring the responsibility for abstraction and generalization to the students. Performance on exam items about concepts taught using PW-PR was compared with performance on concepts taught using didactic lectures followed by group work. Calibrated Peer Review™, a Web-delivered program, was used to collect student essays and to manage anonymous peer review after students “passed” three calibration peer reviews. Results show that the students had difficulty relating concepts. Relationship errors were categorized as 1) problems recognizing levels of organization, 2) problems with cause/effect, and 3) overgeneralizations. For example, some described cells as molecules; others thought that vesicles transport materials through the extracellular fluid. With PW-PR, class discussion was used to confront and resolve such difficulties. Both multiple-choice and essay exam results were better with PW-PR instead of lecture.
Regulation of IGF-I mRNA by GH: putative functions for class 1 and 2 message
Authors: O'Sullivan D. C. , Szestak T. A. M. , Pell J. M.
Published: February 2015

This study investigated mechanisms regulating hepatic insulin-like growth factor (IGF)-I class 1 and 2 mRNA levels. Lambs were treated with growth hormone (GH) either as an acute, single dose or over a longer term. Total hepatic unspliced, pre-mRNA levels increased after the single dose of GH but were attenuated after 8 days of GH, with exon 1- and 2-derived pre-mRNA levels displaying coordinate responses. Surprisingly, changes in total spliced, mature mRNA levels did not reflect those for pre-mRNA, instead being augmented after 8 days of GH. GH also induced a differential increase in the ratio of mature class 2-to-class 1 IGF-I mRNA; therefore, this must be predominantly via posttranscriptional mechanisms. Increases in the ratio of class 2-to-class 1 mRNA were observed in polysomal vs. total RNA preparations derived from GH-treated but not control lambs, indicating an increased proportion of class 2 transcripts engaged in translation. Our findings indicate that GH may stabilize mature class 2 transcripts or destabilize mature class 1 transcripts and that class 2 mRNA may have a greater translational potential. The following two main functions of hepatic class 2 IGF-I mRNA are suggested: an efficient “monitor” of GH status via providing a rapid negative feedback mechanism and a coordinator of endocrine-regulated tissue growth.
Thyroid hormone and cardiac function in mice deficient in thyroid hormone receptor-α or -β: an echocardiograph study
Authors: Weiss Roy E. , Korcarz Claudia , Chassande Olivier , Cua Kevin , Sadow Peter M. , Koo Eugene , Samarut Jacques , Lang Roberto
Published: February 2015

We investigated the effect of thyroid hormone (TH) receptor (TR)α and -β isoforms in TH action in the heart. Noninvasive echocardiographic measurements were made in mice homozygous for disruption of TRα (TRα0/0) or TRβ (TRβ−/−). Mice were studied at baseline, 4 wk after TH deprivation (using a low-iodine diet containing propylthiouracil), and after 4-wk treatment with TH. Baseline heart rates (HR) were similar in wild-type (WT) and TRα0/0mice but were greater in TRβ−/−mice. With TH deprivation, HR decreased 49% in WT and 37% in TRβ−/−mice and decreased only 5% in TRα0/0mice from baseline, whereas HR increased in all genotypes with TH treatment. Cardiac output (CO) and cardiac index (CI) in WT mice decreased (−31 and −32%, respectively) with TH deprivation and increased (+69 and +35%, respectively) with TH treatment. The effects of CO and CI were blunted with TH withdrawal in both TRα0/0(+8 and −2%, respectively) and TRβ−/−mice (−17 and −18%, respectively). Treatment with TH resulted in a 64% increase in LV mass in WT and a 44% increase in TRα0/0mice but only a 6% increase in TRβ−/−mice (ANOVA P < 0.05). Taken together, these data suggest that TRα and TRβ play different roles in the physiology of TH action on the heart.
ADRP stimulates lipid accumulation and lipid droplet formation in murine fibroblasts
Authors: Imamura Minako , Inoguchi Toyoshi , Ikuyama Shoichiro , Taniguchi Susumu , Kobayashi Kunihisa , Nakashima Naoki , Nawata Hajime
Published: February 2015

Adipose differentiation-related protein (ADRP) is a lipid droplet-associated protein that is expressed early during adipose differentiation. The present study was undertaken to reveal the role of ADRP in adipose differentiation. In murine fibroblasts infected with green fluorescent protein (GFP)-ADRP fusion protein expression adenovirus vector, confocal microscopic analysis showed the number and size of lipid droplets apparently increased comparing with those of control cells. Overexpressed GFP-ADRP were mainly located at the surface of lipid droplets and appeared to be “ring-shaped.” Triacylglycerol content was also significantly ( P < 0.001) increased in GFP-ADRP-overexpressed cells compared with control cells. ADRP-induced lipid accumulation did not depend on adipocyte-specific gene induction, such as peroxisome proliferator-activated receptor-γ, lipoprotein lipase, or other lipogenic genes, including acyl-CoA synthetase, fatty acid-binding protein, and fatty acid transporter. In conclusion, ADRP stimulated lipid accumulation and lipid droplet formation without induction of other adipocyte-specific genes or other lipogenic genes in murine fibroblasts. The detailed molecular mechanisms of ADRP on lipid accumulation remain to be elucidated.
Rapid effects of glucose on the insulin signaling of endothelial NO generation and epithelial Na transport
Authors: Schnyder Bruno , Pittet Martine , Durand Jacques , Schnyder-Candrian Silvia
Published: February 2015

Insulin resistance is associated with deficits in glucose metabolism. We tested whether the vascular and renal responses to insulin might contribute to insulin resistance. Generation of endothelial-derived vasodilator nitric oxide (NO), estimated after a 2-h period of insulin stimulation, was inhibited in the presence of high glucose. Immunoprecipitations indicated that insulin-induced endothelial signal transduction was mediated through an immediate complex formation of insulin receptor substrate (IRS) with phosphatidylinositol 3-kinase, which caused serine phosphorylation of a protein complex that was comprised of Akt kinase and endothelial NO synthase. The enzymatic complexes did not form when the endothelial insulin stimulation occurred in the presence of high glucose concentrations. By contrast, neither epithelial signal transduction nor sodium transport in renal epithelial cells was affected by high glucose. Hence, glucose does not appear to modulate either the epithelial IRS cascade or renal sodium retention. Dysfunction of the endothelial IRS cascade and NO generation, which suppresses efficient delivery of nutrients, may further exacerbate the metabolic syndrome of insulin resistance.
Altered corticosteroid metabolism differentially affects pituitary corticotropin response
Authors: Hanafusa Junko , Mune Tomoatsu , Tanahashi Tetsuya , Isomura Yukinori , Suwa Tetsuya , Isaji Mako , Daido Hisashi , Morita Hiroyuki , Murayama Masanori , Yasuda Keigo
Published: February 2015

To evaluate the effects of altered corticosteroid metabolism on the hypothalamic-pituitary-adrenal axis, we examined rats treated with glycyrrhizic acid (G rats) or rifampicin (R rats) for 7 days. The half-life of exogenously administered hydrocortisone as a substitute for corticosterone was longer in G rats and shorter in R rats, with no differences in basal plasma levels of ACTH or corticosterone. The ACTH responses to human corticotropin-releasing factor (CRF) or insulin-induced hypoglycemia were greater in G rats and tended to be smaller in R rats compared with those in the control rats, whereas the corticosterone response was similar. No difference was observed in the content and mRNA level of hypothalamic CRF among the groups. The number and mRNA level of CRF receptor and type 1 11β-hydroxysteroid dehydrogenase (11-HSD1) mRNA level in the pituitary were increased in G rats but not changed in R rats, suggesting that chronically increased intrapituitary corticosterone upregulates pituitary CRF receptor expression. In contrast, CRF mRNA levels in the pituitary were increased in R rats. Our data indicate novel mechanisms of corticosteroid metabolic modulation and the involvement of pituitary 11-HSD1 and CRF in glucocorticoid feedback physiology.
Increased muscle fatigability in GLUT-4-deficient mice
Authors: Gorselink M. , Drost M. R. , de Brouwer K. F. J. , Schaart G. , van Kranenburg G. P. J. , Roemen T. H. M. , van Bilsen M. , Charron M. J. , van der Vusse G. J.
Published: February 2015

GLUT-4 plays a predominant role in glucose uptake during muscle contraction. In the present study, we have investigated in mice whether disruption of the GLUT-4 gene affects isometric and shortening contractile performance of the dorsal flexor muscle complex in situ. Moreover, we have explored the hypothesis that lack of GLUT-4 enhances muscle fatigability. Isometric performance normalized to muscle mass during a single tetanic contraction did not differ between wild-type (WT) and GLUT-4-deficient [GLUT-4(−/−)] mice. Shortening contractions, however, revealed a significant 1.4-fold decrease in peak power per unit mass, most likely caused by the fiber-type transition from fast-glycolytic fibers (IIB) to fast-oxidative fibers (IIA) in GLUT-4(−/−) dorsal flexors. In addition, the resting glycogen content was significantly lower (34%) in the dorsal flexor complex of GLUT-4(−/−) mice than in WT mice. Moreover, the muscle complex of GLUT-4(−/−) mice showed enhanced susceptibility to fatigue, which may be related to the decline in the muscle carbohydrate store. The significant decrease in relative work output during the steady-state phase of the fatigue protocol suggests that energy supply via alternative routes is not capable to compensate fully for the lack of GLUT-4.
C2C12myocytes lack an insulin-responsive vesicular compartment despite dexamethasone-induced GLUT4 expression
Authors: Tortorella Lori L. , Pilch Paul F.
Published: February 2015

Insulin regulates the uptake of glucose into skeletal muscle and adipocytes by redistributing the tissue-specific glucose transporter GLUT4 from intracellular vesicles to the cell surface. To date, GLUT4 is the only protein involved in insulin-regulated vesicular traffic that has this tissue distribution, thus raising the possibility that its expression alone may allow formation of an insulin-responsive vesicular compartment. We show here that treatment of differentiating C2C12myoblasts with dexamethasone, acting via the glucocorticoid receptor, causes a ≥10-fold increase in GLUT4 expression but results in no significant change in insulin-stimulated glucose transport. Signaling from the insulin receptor to its target, Akt2, and expression of the soluble N-ethylmaleimide-sensitive factor-attachment protein receptor, or SNARE, proteins syntaxin 4 and vesicle-associated membrane protein are normal in dexamethasone-treated C2C12cells. However, these cells show no insulin-dependent trafficking of the insulin-responsive aminopeptidase or the transferrin receptor, respective markers for intracellular GLUT4-rich compartments and endosomes that are insulin responsive in mature muscle and adipose cells. Therefore, these data support the hypothesis that GLUT4 expression by itself is insufficient to establish an insulin-sensitive vesicular compartment.
Intracranial administration of transforming growth factor-β3 increases fat oxidation in rats
Authors: Yamazaki Hanae , Arai Masanao , Matsumura Shigenobu , Inoue Kazuo , Fushiki Tohru
Published: February 2015

The effects of intracranial transforming growth factor (TGF)-β3 on spontaneous motor activity and energy metabolism were examined in rats. After injection of TGF-β3 into the cisterna magna of the rat, spontaneous motor activity decreased significantly for 1 h. The intracranial injection of TGF-β3 produced an immediate decrease in respiratory exchange ratio (RER). No significant changes were observed in energy expenditure. TGF-β3 induced a significant increase in total fat oxidation and a decrease in total carbohydrate oxidation. Furthermore, the serum substrates associated with fat metabolism were significantly altered in rats injected with TGF-β3. Both lipoprotein lipase activity in skeletal muscle and the concentration of serum ketone bodies increased, suggesting that the increase in fat oxidation caused by TGF-β3 may have occurred in the liver and muscle. Intracranial injection of TGF-β3 appeared to evoke a switch in the energy substrates accessed in energy expenditure. These results suggest that the release of TGF-β3 in the brain by exercise is a signal for regulating energy consumption.
Messenger RNA for progesterone receptor isoforms in the late-gestation rat uterus
Authors: Fang X. , Wong S. , Mitchell B. F.
Published: February 2015

The progesterone receptor (PR) has three isoforms, PR-A, PR-B, and PR-C, which have different physiological effects. PR-A may inhibit PR-B-mediated transcription. Parturition requires withdrawal of progesterone (P4). This could occur through decreased P4concentrations and/or a change in PR isoforms to diminish the effect of P4. We measured mRNA for PR isoforms in rat uterine tissues through late gestation and investigated the effects of antagonists to estrogen (tamoxifen) and P4(RU-486). Two specific probes were used for ribonuclease protection assays; one (PR-total) measured PR-A, PR-B, and PR-C, and the other recognized only PR-B. PR-total mRNA increased significantly through late gestation, whereas PR-B was unchanged. The ratio of PR-total to PR-B peaked on the day before parturition. Tamoxifen delayed parturition and inhibited the increase in PR-total without affecting PR-B mRNA. RU-486 caused early parturition associated with increased PR-total mRNA, with no change in PR-B. We conclude that there are significant changes in PR isoforms in late-gestation rat uterus. These changes may be regulated by estrogen and P4and may influence the timing of parturition.
Normal insulin sensitivity and IMCL content in overweight humans are associated with higher fasting lipid oxidation
Authors: Perseghin Gianluca , Scifo Paola , Danna Massimo , Battezzati Alberto , Benedini Stefano , Meneghini Elena , Del Maschio Alessandro , Luzi Livio
Published: February 2015

Intramyocellular lipid (IMCL) storage is considered a local marker of whole body insulin resistance; because increments of body weight are supposed to impair insulin sensitivity, this study was designed to assess IMCL content, lipid oxidation, and insulin action in individuals with a moderate increment of body fat mass and no family history of diabetes. We studied 14 young, nonobese women with body fat <30% ( n = 7) or >30% ( n = 7) and 14 young, nonobese men with body fat <25% ( n = 7) or >25% ( n = 7) by means of the euglycemic-insulin clamp to assess whole body glucose metabolism, with indirect calorimetry to assess lipid oxidation, by localized1H NMR spectroscopy of the calf muscles to assess IMCL content, and with dual-energy X-ray absorptiometry to assess body composition. Subjects with higher body fat had normal insulin-stimulated glucose disposal ( P = 0.80), IMCL content in both soleus ( P = 0.22) and tibialis anterior ( P = 0.75) muscles, and plasma free fatty acid levels ( P = 0.075) compared with leaner subjects in association with increased lipid oxidation ( P < 0.05), resting energy expenditure ( P = 0.046), resting oxygen consumption ( P = 0.049), and plasma leptin levels ( P < 0.01) in the postabsorptive condition. In conclusion, in overweight subjects, preservation of insulin sensitivity was combined with increased lipid oxidation and maintenance of normal IMCL content, suggesting that abnormalities of these factors may mutually determine the development of insulin resistance associated with weight gain.
Type 2 diabetic patients may have a mild form of an injury response: a clinical research center study
Authors: Richardson Arthur P. , Tayek John A.
Published: February 2015

Patients with type 2 diabetes (DM) demonstrate inadequate insulin release, elevated gluconeogenesis, and diminished nonoxidative glucose disposal. Similar metabolic changes occur during systemic injury caused by infection, trauma, or cancer. Described here are metabolic changes occurring in 16 DM and 11 lung cancer patients (CA) and 13 normal volunteers (NV). After a 10-h overnight fast, all subjects had fasting hormone and substrate concentrations determined, along with rates of glucose production, leucine appearance (LA), and leucine oxidation (LO). Fasting insulin (data not shown) and C-peptide concentrations were elevated in DM and CA compared with weight-matched NV (0.72 ± 0.09 and 0.64 ± 0.08 vs. 0.51 ± 0.03 mg/l, P < 0.05). C-reactive protein concentration was elevated in CA compared with DM and NV (23.3 ± 6.0 vs. 4.2 ± 1.4 and 2.1 ± 0.5 mg/l, P < 0.01). All counterregulatory hormones were normal except for serum cortisol (11.4 ± 1.0 and 12.1 ± 1.0 vs. 8.9 ± 0.7 μg/dl, DM and CA vs. NL, respectively, P < 0.05). Glucose production was increased in DM and CA compared with NV (4.22 ± 0.6 and 3.53 ± 0.3 vs. 2.76 ± 0.2 mg · kg lean body wt−1 · min−1, P < 0.01). LO and LA were increased in DM and CA compared with NV (LO: 27.3 ± 1.5 and 19.7 ± 1.5 vs. 12.5 ± 1.1 mmol · kg lean body wt−1 · min−1, P < 0.05; LA: 91.9 ± 6.6 and 90.7 ± 7.0 vs. 79.1 ± 6.0 mmol · kg lean body wt−1 · min−1, P < 0.01). DM share similar metabolic derangements with CA. The increase in LA may be secondary to an increased glucose production where amino acids are mobilized to provide the liver with adequate substrate to make glucose. The increase in glucose production may also be part of the injury response, or it may represent a form of insulin resistance that exists in both the DM and (non-DM) CA patients.
Adrenomedullin improves cardiac function and prevents renal damage in streptozotocin-induced diabetic rats
Authors: Dobrzynski Eric , Montanari David , Agata Jun , Zhu Juhong , Chao Julie , Chao Lee
Published: February 2015

Adrenomedullin (AM) is a potent vasodilating peptide and is involved in cardiovascular and renal disease. In the present study, we investigated the role of AM in cardiac and renal function in streptozotocin (STZ)-induced diabetic rats. A single tail-vein injection of adenoviral vectors harboring the human AM gene (Ad.CMV-AM) was administered to the rats 1-wk post-STZ treatment (65 mg/kg iv). Immunoreactive human AM was detected in the plasma and urine of STZ-diabetic rats treated with Ad.CMV-AM. Morphological and chemical examination showed that AM gene delivery significantly reduced glycogen accumulation within the hearts of STZ-diabetic rats. AM gene delivery improved cardiac function compared with STZ-diabetic rats injected with control virus, as observed by decreased left ventricular end-diastolic pressure, increased cardiac output, cardiac index, and heart rate. AM gene transfer significantly increased left ventricular long axis (11.69 ± 0.46 vs. 10.31 ± 0.70 mm, n = 10, P < 0.05) and rate of pressure rise and fall (+6,090.1 ± 597.3 vs. +4,648.5 ± 807.1 mmHg/s), (−4,902.6 ± 644.2 vs. −3,915.5 ± 805.8 mmHg/s, n = 11, P < 0.05). AM also significantly attenuated renal glycogen accumulation and tubular damage in STZ-diabetic rats as well as increased urinary cAMP and cGMP levels, along with increased cardiac cAMP and Akt phosphorylation. We also observed that delivery of the AM gene caused an increase in body weight along with phospho-Akt and membrane-bound GLUT4 levels in skeletal muscle. These results suggest that AM plays a protective role in hyperglycemia-induced glycogen accumulation and cardiac and renal dysfunction via Akt signal transduction pathways.
Adiponectin is not altered with exercise training despite enhanced insulin action
Authors: Hulver Matthew W. , Zheng Donghai , Tanner Charles J. , Houmard Joseph A. , Kraus William E. , Slentz Cris A. , Sinha Madhur K. , Pories Walter J. , MacDonald Kenneth G. , Dohm G. Lynis
Published: February 2015

Adiponectin is an adipocytokine that is hypothesized to be involved in the regulation of insulin action. The purpose of the present investigation was to determine whether plasma adiponectin is altered in conjunction with enhanced insulin action with exercise training. An insulin sensitivity index (SI) and fasting levels of glucose, insulin, and adiponectin were assessed before and after 6 mo of exercise training (4 days/wk for ∼45 min at 65–80% peak O2 consumption) with no loss of body mass (PRE, 91.9 ± 3.8 kg vs. POST, 91.6 ± 3.9 kg) or fat mass (PRE, 26.5 ± 1.8 kg vs. POST, 26.7 ± 2.2 kg). Insulin action significantly ( P < 0.05) improved with exercise training (SI +98%); however, plasma adiponectin concentration did not change (PRE, 6.3 ± 1.5 μg/ml vs. POST, 6.6 ± 1.8 μg/ml). In contrast, in a separate group of subjects examined before and after weight loss, there was a substantial increase in adiponectin (+281%), which was accompanied by enhanced insulin action (SI, +432%). These data suggest that adiponectin is not a contributory factor to the exercise-related improvements in insulin sensitivity.
Sick euthyroid syndrome is associated with decreased TR expression and DNA binding in mouse liver
Authors: Beigneux Anne P. , Moser Arthur H. , Shigenaga Judy K. , Grunfeld Carl , Feingold Kenneth R.
Published: February 2015

Infection is associated with low serum thyroid hormones and thyrotropin levels. Here we demonstrate that infection also reduces thyroid hormone receptor (TR) expression. In gel shift experiments, retinoid X receptor (RXR)/TR DNA binding was reduced in mouse liver by 60 and 77%, respectively, 4 and 16 h after lipopolysaccharide (LPS) administration. Surprisingly, LPS did not decrease either TR-α or TR-β protein levels at 4 h, but by 16 h TR-α1, TR-α2, and TR-β levels were reduced by 55, 87, and 41%, respectively. We previously reported that LPS rapidly decreases RXR protein levels in liver. Therefore, we added RXR-β to hepatic nuclear extracts prepared 4 h after LPS treatment, which restored RXR/TR DNA binding to a level comparable to that of controls. A similar experiment conducted on extracts prepared 16 h after LPS administration did not restore RXR/TR DNA binding. We propose that decreased RXR expression is limiting for RXR/TR DNA binding at 4 h, whereas the reduction in both TR and RXR levels results in further decreased binding at 16 h.
Melanin-concentrating hormone activates signaling pathways in 3T3-L1 adipocytes
Authors: Bradley Richard L. , Mansfield Julia P. R. , Maratos-Flier Eleftheria , Cheatham Bentley
Published: February 2015

Energy homeostasis is regulated by peripheral signals, such as leptin, and by several orexigenic and anorectic neuropeptides. Recently, we reported that the orexigenic neuropeptide melanin-concentrating hormone (MCH) stimulates leptin production by rat adipocytes and that the MCH receptor (MCH-R1) is present on these cells. Here, we show that MCH-R1 is present on murine 3T3-L1 adipocytes. Treatment of 3T3-L1 adipocytes with 1 μM MCH for up to 2 h acutely downregulated MCH-R1, indicating a mechanism of ligand-induced receptor downregulation. Potential signaling pathways mediating MCH-R1 action in adipocytes were investigated. Treatment of 3T3-L1 adipocytes with 1 μM MCH rapidly induced a threefold and a fivefold increase in p44/42 MAPK and pp70 S6 kinase activities, respectively. In addition, 3T3-L1 adipocytes transiently transfected with a murine leptin-luciferase promoter construct showed a fourfold and a sixfold increase in leptin promoter-reporter gene expression at 1 h and 4 h, respectively, in response to MCH. Activity decreased to basal levels at 8 h. Furthermore, MCH-stimulated leptin promoter-driven luciferase activity was diminished in the presence of the MAP/ERK kinase inhibitor PD-98059 and in the presence of rapamycin, an inhibitor of pp70 S6 kinase activation. These results provide further evidence for a functional MCH signaling pathway in adipocytes.
Diabetes and insulin secretion: whither KATP?
Authors: Nichols C. G. , Koster J. C.
Published: February 2015

The critical involvement of ATP-sensitive potassium (KATP) channels in insulin secretion is confirmed both by the demonstration that mutations that reduce KATPchannel activity underlie many if not most cases of persistent hyperinsulinemia, and by the ability of sulfonylureas, which inhibit KATPchannels, to enhance insulin secretion in type II diabetics. By extrapolation, we contend that mutations that increase β-cell KATPchannel activity should inhibit glucose-dependent insulin secretion and underlie, or at least predispose to, a diabetic phenotype. In transgenic animal models, this prediction seems to be borne out. Although earlier genetic studies failed to demonstrate a linkage between KATPmutations and diabetes in humans, recent studies indicate significant association of KATPchannel gene mutations or polymorphisms and type II diabetes. We suggest that further efforts to understand the involvement of KATPchannels in diabetes are warranted.
Impaired fatty acid oxidation in muscle of aging rats perfused under basal conditions
Authors: Tucker Michelle Z. , Turcotte Lorraine P.
Published: February 2015

The purpose of the present study was to examine the utilization of fatty acids (FA) and muscle substrates by skeletal muscle in young, middle-aged, and old adult rats under conditions of euglycemia with low insulin levels. Male Fischer 344 × Brown Norway rats aged 5, 15, or 24 mo underwent hindlimb perfusion with a medium of 8 mM glucose, 1 mM palmitate, 25 μU/ml insulin, [1-14C]palmitate, and [3-3H]glucose. Glucose and palmitate uptake were similar among age groups. The percent and total palmitate oxidized (nmol · min−1· g−1) were 30–36 and 41–49% lower ( P < 0.05) in 15-mo- and 24-mo-old than in 5-mo-old animals. Compared with 5-mo- and 15-mo-old animals, pre- and postperfusion muscle triglyceride (TG) levels were significantly ( P < 0.05) elevated 91–305% in red and 118–219% in white muscles of 24-mo-old animals. Fatty acid-binding protein content was 40–64% higher ( P < 0.05) in 24-mo- than in 5-mo- or 15-mo-old animals. In red muscle, hormone-sensitive lipase (HSL) content was 28% lower ( P < 0.05) in 24-mo- than in 5-mo-old animals. These results indicate that, under euglycemic conditions in the presence of low insulin levels, the reduction in FA disposal to oxidation and the decrease in HSL content may contribute to the accumulation of TG in muscle of old animals.
Estrogen effects on osmotic regulation of AVP and fluid balance
Authors: Stachenfeld Nina S. , Keefe David L.
Published: February 2015

To determine estrogen effects on osmotic regulation of arginine vasopressin (AVP) and body fluids, we suppressed endogenous estrogen and progesterone using the gonadotropin-releasing hormone (GnRH) analog leuprolide acetate (GnRHa). Subjects were assigned to one of two groups: 1) GnRHa alone, then GnRHa + estrogen (E, n = 9, 25 ± 1 yr); 2) GnRHa alone, then GnRHa + estrogen with progesterone (E/P, n = 6, 26 ± 3). During GnRHa alone and with hormone treatment, we compared AVP and body fluid regulatory responses to 3% NaCl infusion (HSI, 120 min, 0.1 ml · min−1 · kg body wt−1), drinking (30 min, 15 ml/kg body wt), and recovery (60 min of seated rest). Plasma [E2] increased from 23.9 to 275.3 pg/ml with hormone treatments. Plasma [P4] increased from 0.6 to 5.7 ng/ml during E/P and was unchanged (0.4 to 0.6 ng/ml) during E. Compared with GnRHa alone, E reduced osmotic AVP release threshold (275 ± 4 to 271 ± 4 mosmol/kg, P < 0.05), and E/P reduced the AVP increase in response during HSI (6.0 ± 1.3 to 4.2 ± 0.6 pg/ml at the end of HSI), but free water clearance was unaffected in either group. Relative to GnRHa, pre-HSI plasma renin activity (PRA) was greater during E (0.8 ± 0.1 vs. 1.2 ± 0.2 ng ANG I · ml−1 · h−1) but not after HSI or recovery. PRA was greater than GnRHa during E/P at baseline (1.1 ± 0.2 vs. 2.5 ± 0.6) and after HSI (0.6 ± 0.1 vs. 1.1 ± 1.1) and recovery (0.5 ± 0.1 vs. 1.3 ± 0.2 ng ANG I · ml−1 · h−1). Baseline fractional excretion of sodium was unaffected by E or E/P but was attenuated by the end of recovery for both E (3.3 ± 0.6 vs. 2.4 ± 0.4%) and E/P (2.8 ± 0.4 vs 1.7 ± 0.4%, GnRHa alone and with hormone treatment, respectively). Fluid retention increased with both hormone treatments. Renal sensitivity to AVP may be lower during E due to intrarenal effects on water and sodium excretion. E/P increased sodium retention and renin-angiotensin-aldosterone stimulation.
No effect of menstrual cycle phase on glucose kinetics and fuel oxidation during moderate-intensity exercise
Authors: Horton Tracy J. , Miller Emily K. , Glueck Deborah , Tench Kathleen
Published: February 2015

Resting and exercise fuel metabolism was assessed in three different phases of the menstrual cycle, characterized by different levels of estrogen relative to progesterone: early follicular (EF, low estrogen and progesterone), midfollicular (MF, elevated estrogen, low progesterone), and midluteal (ML, elevated estrogen and progesterone). It was hypothesized that exercise glucose utilization and whole body carbohydrate oxidation would decrease sequentially from the EF to the MF to the ML phase. Normal-weight healthy females, experiencing a regular menstrual cycle, were recruited. Subjects were moderately active but not highly trained. Testing occurred after 3 days of diet control and after an overnight fast (12–13 h). Resting (2 h) and exercise (50% maximal O2 uptake, 90 min) measurements of whole body substrate oxidation, tracer-determined glucose flux, and substrate and hormone concentrations were made. No significant difference was observed in whole body fuel oxidation during exercise in the three phases (nonprotein respiratory exchange ratio: EF 0.84 ± 0.01, MF 0.85 ± 0.01, ML 0.85 ± 0.01) or in rates of glucose appearance or disappearance. There were, however, significantly higher glucose ( P < 0.05) and insulin ( P < 0.001) concentrations during the first 45 min of exercise in the ML phase vs. EF and MF phases. In conclusion, whole body substrate oxidation and glucose utilization did not vary significantly across the menstrual cycle in moderately active women, either at rest or during 90 min of moderate-intensity exercise. During the ML phase, however, this similar pattern of substrate utilization was associated with greater glucose and insulin concentrations. Both estrogen and progesterone are elevated during the ML phase of the menstrual cycle, suggesting that one or both of these sex steroids may play a role in this response.