bluuebunny/crossref_metadata_2025 huggingface dataset:
Motion(Less)in Limine
Authors: Scofield Giles
Published: January 2007

“When the two come into conflict, democracy takes priority to philosophy.”

Richard Rorty

“There are some people who use philosophy to lead people astray.”

St. Augustine

As any seasoned litigator knows, occasionally one interposes an evidentiary objection not simply for the sake of preventing this or that from occurring in court, but also for the purpose of alerting a court to and educating it about the likelihood that it will have to rule on what may prove to be a substantial evidentiary dispute. Instead of waiting until a trial has begun and somebody else’s expert witness is ready, willing, able and - most of all - present to testify, it can be useful to file a motionin limine, a pre-trial motion that seeks to bar or set limits to an expert’s testimony.
Dangerous Times for Medicaid
Authors: Jacobi John V.
Published: January 2007

These are indeed dangerous times. In the name of “cost-effectiveness,” we cut back health benefits to the poor, who are more likely to be sick than the nonpoor. We miss our chance to heal. In the setting, we’re told, of “scarce resources,” we imperil the health care safety net. In the name of expedience, we miss our chance to be humane and compassionate.’

Medicaid is again - still - the subject of reform discussions in Washington and in state capitals. The program has been subject to varying, sometimes conflicting pressures since its inception. Its primary purpose has been serving the health care needs of the poor and disabled. It was structured, however, to appeal to (or at least to not alienate) private health care providers. In addition, its mix of state and federal funding and control was intended to draw in the states as partners.
The Confidentiality and Privacy Implications of Functional Magnetic Resonance Imaging
Authors: Tovino Stacey A.
Published: January 2007

Advances in science and technology frequently raise new ethical, legal, and social issues, and developments in neuroscience and neuroimaging technology are no exception. Within the field of neuroethics, leading scientists, ethicists, and humanists are exploring the implications of efforts to image, study, treat, and enhance the human brain.

This article focuses on one aspect of neuroethics: the confidentiality and privacy implications of advances in functional magnetic resonance imaging (“fMRI”). Following a brief orientation to fMRI and an overview of some of its current and proposed uses, this article highlights key confidentiality and privacy issues raised by fMRI in the contexts of health care, research, employment, insurance, criminal justice, litigation, and cognitive privacy.
Incompetent Decisionmakers and Withdrawal of Life-Sustaining Treatment: A Case Study
Authors: Lightfoot Lance
Published: January 2007

One of the most challenging and rewarding roles for in-house hospital attorneys is serving as a member of their hospital’s Bioethics Committee (the “Committee”). As a member of the Committee, an attorney assists in developing institutional ethics policies and guidelines, and also participates in ethics consultations involving disputes about patient care. Institutions such as the Author’s employer, Texas Children’s Hospital, promote open and honest communications between members of a patient’s health care team and the patient’s parents and family; however, when communications break down, the Committee’s goal is to provide an objective forum where disputes can be discussed and hopefully resolved in a professional, ethical manner.
Dietary Supplements: Reports Reviewed by Tia Powell and Barbara A. Noah
Authors: Powell Tia , Noah Barbara A.
Published: January 2007

The Institute of Medicine’s 2005 publication,Dietary Supplements: A Framework for Evaluating Safety, is authoritative and thorough, and thus representative of other reports by the Institute of Medicine (IOM). What makes this report particularly interesting, however, is the rich political subtext that exists in the interstices of the report, popping up here and there in brief comments and barely suppressed yelps of exasperation. To understand this context, it is useful to reflect for a moment on the special nature of the IOM and its relationship to government.

IOM is part of the National Academy of Sciences, and is a private, non-governmental organization that does not receive direct federal funding for its work. Rather, IOM studies are often funded by contract with governmental entities that request reports on particular topics. As a case in point, the dietary supplement study was requested and paid for by the FDA.
Merck and the Vioxx Decision: Playing by the Changing Rules of the Chemical Exposure Game
Authors: Cohen Jacqueline G.
Published: January 2007

For years, legal scholars and environmental activists have maintained that traditional tort proof requirements create insurmountable obstacles to recovery for most plaintiffs in chemical exposure cases, be they pharmaceutical suits or environmental toxic tort cases. Generally, tort law requires a plaintiff to show that the defendant owed a duty, that the defendant breached that duty, and that the breach of that duty caused the injury that is the subject of the suit. In some cases those requirements can be relaxed, as for example, when an injury is of a type that does not occur except as a result of negligence (under the doctrine of res ipsa loquitor).
Exploration or exploitation: life expectancy changes the value of learning in foraging strategies
Authors: Eliassen Sigrunn , Jørgensen Christian , Mangel Marc , Giske Jarl
Published: January 2007

The acquisition of information is a fundamental part of individual foraging behaviour in heterogeneous and changing environments. We examine how foragers may benefit from utilizing a simple learning rule to update estimates of temporal changes in resource levels. In the model, initial expectation of resource conditions and rate of replacing past information by new experiences are genetically inherited traits. Patch‐time allocation differs between learners and foragers that use a fixed patch‐leaving threshold throughout the foraging season. It also deviates from foragers that obtain information about the environment at no cost. At the start of a foraging season, learners sample the environment by frequent movements between patches, sacrificing current resource intake for information acquisition. This is done to obtain more precise and accurate estimates of resource levels, resulting in increased intake rates later in season. Risk of mortality may alter the trade‐off between exploration and exploitation and thus change patch sampling effort. As lifetime expectancy decreases, learners invest less in information acquisition and show lower foraging performance when resource level changes through time.
Extinctions in competitive communities forced by coloured environmental variation
Authors: Ruokolainen Lasse , Fowler Mike S. , Ranta Esa
Published: January 2007

Understanding the relationships between environmental fluctuations, population dynamics and species interactions in natural communities is of vital theoretical and practical importance. This knowledge is essential in assessing extinction risks in communities that are, for example, pressed by changing environmental conditions and increasing exploitation. We developed a model of density dependent population renewal, in a Lotka–Volterra competitive community context, to explore the significance of interspecific interactions, demographic stochasticity, population growth rate and species abundance on extinction risk in populations under various autocorrelation (colour) regimes of environmental forcing. These factors were evaluated in two cases, where either a single species or the whole community was affected by the external forcing. Species’ susceptibility to environmental noise with different autocorrelation structure depended markedly on population dynamics, species’ position in the abundance hierarchy and how similarly community members responded to external forcing. We also found interactions between demographic stochasticity and environmental noise leading to a reversal in extinction probabilities from under‐ to overcompensatory dynamics. We compare our results with studies of single species populations and contrast possible mechanisms leading to extinctions. Our findings indicate that abundance rank, the form of population dynamics, and the colour of environmental variation interact in affecting species extinction risk. These interactions are further modified by interspecific interactions within competitive communities as the interactions filter and modulate the environmental noise.
Alterations of the classic pathway of complement in adipose tissue of obesity and insulin resistance
Authors: Zhang Jinhui , Wright Wendy , Bernlohr David A. , Cushman Samuel W. , Chen Xiaoli
Published: January 2007

Adipose tissue inflammation has recently been linked to the pathogenesis of obesity and insulin resistance. C1 complex comprising three distinct proteins, C1q, C1r, and C1s, involves the key initial activation of the classic pathway of complement and plays an important role in the initiation of inflammatory process. In this study, we investigated adipose expression and regulation of C1 complement subcomponents and C1 activation regulator decorin in obesity and insulin resistance. Expression of C1q in epididymal adipose tissue was increased consistently in ob/ob mice, Zucker obese rats, and high fat-diet-induced obese (HF-DIO) mice. Decorin was found to increase in expression in Zucker obese rats and HF-DIO mice but decrease in ob/ob mice. After TZD administration, C1q and decorin expression was reversed in Zucker obese rats and HF-DIO mice. Increased expression of C1 complement and decorin was observed in both primary adipose and stromal vascular cells isolated from Zucker obese rats. Upregulation of C1r and C1s expression was also perceived in adipose cells from insulin-resistant humans. Furthermore, expression of C1 complement and decorin is dysregulated in TNF-α-induced insulin resistance in 3T3-L1 adipocytes and cultured rat adipose cells as they become insulin resistant after 24-h culture. These data suggests that both adipose and immune cells are the sources for abnormal adipose tissue production of C1 complement and decorin in obesity. Our findings also demonstrate that excessive activation of the classic pathway of complement commonly occurs in obesity, suggesting its possible role in adipose tissue inflammation and insulin resistance.
Microvascular endowment in the developing chicken embryo lung
Authors: Makanya A. N. , Hlushchuk R. , Baum O. , Velinov N. , Ochs M. , Djonov V.
Published: January 2007

In the current study, the contribution of the major angiogenic mechanisms, sprouting and intussusception, to vascular development in the avian lung has been demonstrated. Sprouting guides the emerging vessels to form the primordial vascular plexus, which successively surrounds and encloses the parabronchi. Intussusceptive angiogenesis has an upsurge from embryonic day 15 (E15) and contributes to the remarkably rapid expansion of the capillary plexus. Increased blood flow stimulates formation of pillars (the archetype of intussusception) in rows, their subsequent fusion and concomitant delineation of slender, solitary vascular entities from the disorganized meshwork, thus crafting the organ-specific angioarchitecture. Morphometric investigations revealed that sprouting is preponderant in the early period of development with a peak at E15 but is subsequently supplanted by intussusceptive angiogenesis by the time of hatching. Quantitative RT-PCR revealed that moderate levels of basic FGF (bFGF) and VEGF-A were maintained during the sprouting phase while PDGF-B remained minimal. All three factors were elevated during the intussusceptive phase. Immunohistoreactivity for VEGF was mainly in the epithelial cells, whereas bFGF was confined to the stromal compartment. Temporospatial interplay between sprouting and intussusceptive angiogenesis fabricates a unique vascular angioarchitecture that contributes to the establishment of a highly efficient gas exchange system characteristic of the avian lung.
Physiological significance of hypotonicity-induced regulatory volume decrease: reduction in intracellular Cl−concentration acting as an intracellular signaling
Authors: Miyazaki Hiroaki , Shiozaki Atsushi , Niisato Naomi , Marunaka Yoshinori
Published: January 2007

Regulatory volume decrease (RVD) occurs after hypotonicity-caused cell swelling. RVD is caused by activation of ion channels and transporters, which cause effluxes of K+, Cl−, and H2O, leading to cell shrinkage. Recently, we showed that hypotonicity stimulated transepithelial Na+reabsorption via elevation of epithelial Na+channel (α-ENaC) expression in renal epithelia A6 cells in an RVD-dependent manner and that reduction of intracellular Cl−concentration ([Cl−]i) stimulated the Na+reabsorption. These suggest that RVD would reveal its stimulatory action on the Na+reabsorption by reducing [Cl−]i. However, the reduction of [Cl−]iduring RVD has not been definitely analyzed due to technical difficulties involved in halide-sensitive fluorescent dyes. In the present study, we developed a new method for the measurement of [Cl−]ichange during RVD by using a high-resolution flow cytometer with a halide-specific fluorescent dye, N-(6-methoxyquinolyl) acetoethyl ester. The [Cl−]iin A6 cells in an isotonic medium was 43.6 ± 3.1 mM. After hypotonic shock (268 to 134 mosmol/kgH2O), a rapid increase of cell volume followed by RVD occurred. The RVD caused drastic diminution of [Cl−]ifrom 43.6 to 10.8 mM. Under an RVD-blocked condition with NPPB (Cl−channel blocker) or quinine (K+channel blocker), we did not detect the reduction of [Cl−]i. Based on these observations, we conclude that one of the physiological significances of RVD is the reduction of [Cl−]iand that RVD shows its action via reduction of [Cl−]iacting as an intracellular signal regulating cellular physiological functions.
Effect of ischemic acute renal damage on the expression of COX-2 and oxidative stress-related elements in rat kidney
Authors: Villanueva Sandra , Céspedes Carlos , González Alexis A. , Vio Carlos P. , Velarde Victoria
Published: January 2007

Acute renal failure (ARF) is a clinical syndrome characterized by deterioration of renal function over a period of hours or days. The principal causes of ARF are ischemic and toxic insults that can induce tissue hypoxia. Transcriptional responses to hypoxia can be inflammatory or adaptive with the participation of the hypoxia-inducible factor 1α and the expression of specific genes related to oxidative stress. The production of peroxynitrites and protein nitrotyrosylation are sequelae of oxidative stress. In several clinical and experimental conditions, inflammatory responses have been related to cyclooxygenase (COX)-2, suggesting that its activation might play an important role in the pathogenesis and progression of nephropathies such as ARF. In the kidney, renin and bradykinin participate on the regulation of COX-2 synthesis. With the hypothesis that in ARF there is an increase in the expression of agents involved in adaptive and inflammatory responses, the distribution pattern and abundance of COX-2, its regulators renin, kallikrein, bradykinin B2 receptor, and oxidative stress elements, heme oxygenase-1 (HO-1), erythropoietin (EPO), inducible nitric oxide synthase (iNOS), and nitrotyrosylated residues were studied by immunohistochemistry and immunoblot analysis in rat kidneys after bilateral ischemia. In kidneys with ARF, important initial damage was demonstrated by periodic acid-Schiff staining and by the induction of the damage markers α-smooth muscle actin and ED-1. Coincident with the major damage, an increase in the abundance of EPO, HO-1, and iNOS and an increase in renin and bradykinin B2 receptor were observed. Despite the B2 receptor induction, we observed an important decrease in COX-2 in the ischemic-reperfused kidney. These results suggest that COX-2 does not participate in inflammatory responses induced by hypoxia.
Recovery and maintenance of nephrin expression in cultured podocytes and identification of HGF as a repressor of nephrin
Authors: Takano Yosuke , Yamauchi Kozue , Hiramatsu Nobuhiko , Kasai Ayumi , Hayakawa Kunihiro , Yokouchi Makiko , Yao Jian , Kitamura Masanori
Published: January 2007

Cultured podocytes easily lose expression of nephrin. In this report, we developed optimum media for recovery and maintenance of nephrin gene expression in murine podocytes. Using reporter podocytes, we found that activity of the nephrin gene promoter was enhanced by DMEM/F12 or α-MEM compared with RPMI-1640. In any of these basal media, addition of 1,25-dihydroxyvitamin D3, all- trans-retinoic acid or dexamethasone significantly increased activity of the nephrin promoter. The effects of the supplemental components were synergistic, and the maximum activation was achieved by DMEM/F12 supplemented with three agents. This culture medium was designated as vitamin D3, retinoic acid and dexamethasone-supplemented DMEM/F12 (VRADD). In reporter podocytes that express nephrin, VRADD induced activation of the nephrin gene promoter up to 60-fold. Even in podocytes that have lost nephrin expression during multiple passages, expression of nephrin mRNA was dramatically recovered by VRADD. However, VRADD caused damage of podocytes in prolonged cultures, which was avoided in the absence of dexamethasone (designated as VRAD). VRAD maintained expression of nephrin for extended periods, which was associated with the differentiated phenotype of podocytes. Using the VRAD-primed podocytes, we revealed that expression of nephrin mRNA as well as nephrin promoter activity was suppressed by a putative dedifferentiation factor of podocytes, hepatocyte growth factor.
RANTES mediates TNF-dependent lamina propria mast cell accumulation and barrier dysfunction in neurogenic cystitis
Authors: Chen Michael C. , Keshavan Pavitra , Gregory Greg D. , Klumpp David J.
Published: January 2007

Barrier dysfunction of the urinary bladder is postulated to contribute to patient morbidity in the bladder inflammatory disease interstitial cystitis (IC). IC is often considered a neurogenic cystitis, but the mechanisms underlying barrier dysfunction are unclear. In murine neurogenic cystitis induced by pseudorabies virus (PRV), we previously observed formation of urothelial lesions characterized by urothelial apoptosis and urothelial discontinuities. Lesion formation was preceded by mast cell trafficking to the lamina propria, and trafficking was mediated by tumor necrosis factor-α (TNF). Here, we found that supernatants of TNF-treated urothelial cultures promoted chemotaxis of bone marrow-derived mast cells in vitro that was blocked by anti-RANTES antibodies but unaffected by anti-TNF antibodies. In vivo, PRV infection of wild-type mice induced RANTES expression in the urothelium that was temporally coincident with lamina propria mast cell accumulation (maximum at days 3–4 following infection) and was not induced in TNF−/−mice, TNFR1/2−/−mice, or mice treated with anti-TNF antibodies. Anti-RANTES antibodies blocked PRV-induced lamina propria mast cell accumulation 56% and reduced the prevalence of animals with detectable lesions 42%, relative to isotype control antibodies. Bladder barrier function was quantified by measuring transepithelial resistance (TER). PRV induced a 49% loss of TER in the presence of control antibodies, but mice treated with anti-RANTES antibodies exhibited reduced TER loss (16%, P < 0.01). These data demonstrate that RANTES plays a key role in the pathogenesis of neurogenic cystitis and suggest that chemokines may represent novel therapeutic targets for IC patients with mast cell-associated disease.
Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion ofpara-aminohippurate after ischemic acute renal failure in rats
Authors: Schneider R. , Sauvant C. , Betz B. , Otremba M. , Fischer D. , Holzinger H. , Wanner C. , Galle J. , Gekle M.
Published: January 2007

Ischemic acute renal failure (iARF) was described to reduce renal extraction of the organic anion para-aminohippurate (PAH) in humans. The rate-limiting step of renal organic anion secretion is its basolateral uptake into proximal tubular cells. This process is mediated by the organic anion transporters OAT1 and OAT3, which both have a broad spectrum of substrates including a variety of pharmaceutics and toxins. Using a rat model of iARF, we investigated whether impairing the secretion of the organic anion PAH might be associated with downregulation of OAT1 or OAT3. Inulin and PAH clearance was determined starting from 6 up to 336 h after ischemia-reperfusion (I/R) injury. Net secretion of PAH was calculated and OAT1 as well as OAT3 expression was analyzed by RT-PCR and Western blotting. Inulin and PAH clearance along with PAH net secretion were initially diminished after I/R injury with a gradual recovery during follow-up. This initial impairment after iARF was accompanied by decreased mRNA and protein levels of OAT1 and OAT3 in clamped animals compared with sham-operated controls. In correlation to the improvement of kidney function, both mRNA and protein levels of OAT1 and OAT3 were upregulated during the follow-up. Thus decreased expression of OAT1 and OAT3 is sufficient to explain the decline of PAH secretion after iARF. As a result, this may have substantial impact on excretion kinetics and half-life of organic anions. As a consequence, the biological effects of a variety of organic anions may be affected after iARF.
Alleviation of fatty acid and hypoxia-reoxygenation-induced proximal tubule deenergization by ADP/ATP carrier inhibition and glutamate
Authors: Feldkamp Thorsten , Kribben Andreas , Roeser Nancy F. , Ostrowski Tiffany , Weinberg Joel M.
Published: January 2007

Kidney proximal tubules develop a severe but highly reversible energetic deficit due to nonesterified fatty acid (NEFA)-induced dissipation of mitochondrial membrane potential (ΔΨm) during reoxygenation after severe hypoxia. To assess the mechanism for this behavior, we have compared the efficacies of different NEFA for inducing mitochondrial deenergization in permeabilized tubules measured using safranin O uptake and studied the modification of NEFA-induced deenergization by inhibitors of the ADP/ATP carrier and glutamate using both normoxic tubules treated with exogenous NEFA and tubules deenergized during hypoxia-reoxygenation (H/R). Among the long-chain NEFA that accumulate during H/R of isolated tubules and ischemia-reperfusion of the kidney in vivo, oleate, linoleate, and arachidonate had strong effects to dissipate ΔΨmthat were slightly greater than palmitate, while stearate was inactive at concentrations reached in the cells. This behavior correlates well with the protonophoric effects of each NEFA. Inhibition of the ADP/ATP carrier with either carboxyatractyloside or bongkrekic acid or addition of glutamate to compete for the aspartate/glutamate carrier improved ΔΨmin the presence of exogenous oleate and after H/R. Effects on the two carriers were additive and restored safranin O uptake to as much as 80% of normal under both conditions. The data strongly support NEFA cycling across the inner mitochondrial membrane using anion carriers as the main mechanism for NEFA-induced deenergization in this system and provide the first evidence for a contribution of this process to pathophysiological events that impact importantly on energetics of intact cells.
Vesicular monoamine transporter 1 mediates dopamine secretion in rat proximal tubular cells
Authors: Maurel Agnès , Spreux-Varoquaux Odile , Amenta Francesco , Tayebati Seyed Khosrow , Tomassoni Daniele , Seguelas Marie-Hélène , Parini Angelo , Pizzinat Nathalie
Published: January 2007

Renal dopamine, synthesized by proximal tubules, plays an important role in the regulation of renal sodium excretion. Although the renal dopaminergic system has been extensively investigated in both physiological and pathological situations, the mechanisms whereby dopamine is stored and secreted by proximal tubule cells remain obscure. In the present study we investigated whether vesicular monoamine transporters (VMAT)-1 and -2, which participate in amine storing and secretion, are expressed in rat renal proximal tubules, and we defined their involvement in dopamine secretion. By combining RT-PCR, Western blot, and immunocytochemistry we showed that VMAT-1 is the predominant isoform expressed in isolated proximal tubule cells. These results were confirmed by immunohistochemistry analysis of rat renal cortex showing that VMAT-1 was found in proximal tubules but not in glomeruli. Functional studies showed that, as previously reported for VMAT-dependent amine transporters, dopamine release by cultured proximal tubule cells was partially inhibited by disruption of intracellular H+gradient. In addition, dopamine secretion was prevented by the VMAT-1/VMAT-2 inhibitor reserpine but not by the VMAT-2 inhibitor tetrabenazine. Finally, we demonstrated that tubular VMAT-1 mRNA and protein expression were significantly upregulated during a high-sodium diet. In conclusion, our results show for the first time the expression of a VMAT in the renal proximal tubule and its involvement in regulation of dopamine secretion. These data represent the first step toward the comprehension of the role of this transporter in renal dopamine handling and its involvement in pathological situations.
Exercise training improves the net balance of cardiac Ca2+ handling protein expression in heart failure
Authors: Rolim Natale P. L. , Medeiros Alessandra , Rosa Kaleizu T. , Mattos Katt C. , Irigoyen Maria C. , Krieger Eduardo M. , Krieger Jose E. , Negrão Carlos E. , Brum Patricia C.
Published: January 2007

The molecular basis of the beneficial effects associated with exercise training (ET) on overall ventricular function (VF) in heart failure (HF) remains unclear. We investigated potential Ca2+ handling abnormalities and whether ET would improve VF of mice lacking α2A- and α2C-adrenoceptors (α2A/α2CARKO) that have sympathetic hyperactivity-induced HF. A cohort of male wild-type (WT) and congenic α2A/α2CARKO mice in a C57BL/J genetic background (5–7 mo of age) was randomly assigned into untrained and trained groups. VF was assessed by two-dimensional guided M-mode echocardiography. Cardiac myocyte width and ventricular fibrosis were evaluated with a computer-assisted morphometric system. Sarcoplasmic reticulum Ca2+ ATPase (SERCA2), phospholamban (PLN), phospho-Ser16-PLN, phospho-Thr17-PLN, phosphatase 1 (PP1), and Na+-Ca2+ exchanger (NCX) were analyzed by Western blotting. ET consisted of 8-wk running sessions of 60 min, 5 days/wk. α2A/α2CARKO mice displayed exercise intolerance, systolic dysfunction, increased cardiac myocyte width, and ventricular fibrosis paralleled by decreased SERCA2 and increased NCX expression levels. ET in α2A/α2CARKO mice improved exercise tolerance and systolic function. ET slightly reduced cardiac myocyte width, but unchanged ventricular fibrosis in α2A/α2CARKO mice. ET significantly increased the expression of SERCA2 (20%) and phospho-Ser16-PLN (63%), phospho-Thr17-PLN (211%) in α2A/α2CARKO mice. Furthermore, ET restored NCX and PP1 expression in α2A/α2CARKO to untrained WT mice levels. Thus, we provide evidence that Ca2+ handling is impaired in this HF model and that overall VF improved upon ET, which was associated to changes in the net balance of cardiac Ca2+ handling proteins.
Skeletal Muscle Physiology: Plasticity and Responses to Exercise
Authors: Kraemer William J. , Spiering Barry A.
Published: January 2007

Skeletal muscle displays an impressive capability to adapt to various stimuli. Exercise and physical activity, in their many forms, present specific stresses to muscle. Depending on the exact nature of the stress, muscle may adapt by increasing size, improving neuromuscular performance, or enhancing endurance capabilities. In this article, we provide an overview of the basics of neuromuscular physiology, principles of exercise training, adaptations to exercise, and the role of the endocrine system and intramuscular signalling pathways for mediating these responses and adaptations.
Diet, Exercise and Hormone Interactions on Skeletal Muscle
Authors: Volek Jeff S. , Forsythe Cassandra E.
Published: January 2007

The provision of dietary nutrients is a powerful method by which to alter plasma substrate and hormone concentrations, and to impact cell signalling and protein balance positively in skeletal muscle. Growth hormone, insulin-like growth factor I, testosterone, cortisol and insulin are each uniquely affected by dietary nutrients and exercise. This article summarizes some of the work that has been conducted to assess how diet affects these hormones, in particular the exercise-induced hormone response, with an emphasis on skeletal muscle as a target tissue. Clearly, certain combinations of nutrients, such as carbohydrate combined with protein, can be used to alter nutrient and hormone availability to augment skeletal muscle protein balance. There is a need to link acute diet-induced hormonal responses with chronic muscle adaptations to training, and to determine how chronic manipulations in diet affect training adaptations specific to skeletal muscle.
Effects of Growth Hormone and Insulin-Like Growth Factor I on Muscle in Mouse Models of Human Growth Disorders
Authors: Clark Ryan P. , Schuenke Mark , Keeton Stephanie M. , Staron Robert S. , Kopchick John J.
Published: January 2007

The precise effects of growth hormone (GH) and insulin-like growth factor I (IGF-I) on muscle development and physiology are relatively unknown. Furthermore, there have been conflicting reports on the effects of GH/IGF-I on muscle. Distinguishing the direct effects of GH versus those of IGF-I is problematic, but animal models with altered GH/IGF-I action could help to alleviate some of the conflicting results and help to determine the independent actions of GH and IGF-I. The phenotypes of several mouse models, namely the GH receptor-gene-disrupted (GHR –/–) mouse and a variety of IGF-I –/– mice, are summarized, which ultimately will aid our understanding of this complex area.
Visualizing and Manipulating Growth Hormone (GH) Responses in Muscle and Other GH Target Tissues
Authors: Robinson Iain C.A.F. , Gevers Evelien F.
Published: January 2007

Muscle cells, like almost all other cells in the body, show growth and metabolic responses to growth hormone (GH). Although GH actions are classically thought to be mediated via insulin-like growth factor I (IGF-I), it is now recognized that GH has direct actions via the GH receptor (GHR) expressed in many tissues, including muscle. The aim of this work was to study, at an individual cell and tissue level, those cells that respond directly to GH, and understand how their responsiveness to GH is regulated. We used immunocytochemistry to visualize the cellular expression of components of the major GH signal transduction cascades, GHR, Janus kinase 2 (JAK2), signal transducer and activator of transcription 5b (Stat5b) and suppressor of cytokine signalling 2 (SOCS2), and monitored their activation by detecting GH-induced phosphorylation after a single injection of GH in GH-deficient rodents. GHR, JAK2, Stat5b and SOCS2 proteins were all found to be present in skeletal muscle from normal and GH-deficient mice, and phosphorylated Stat5b increased in heart and skeletal muscle nuclei after a GH injection. In GH-deficient rats, continuous GH infusion increased Stat5b phosphorylation in liver but not in muscle, but blunted the further effects on Stat5b of acute GH injection in both tissues. Extracellular signal-regulated kinase (ERK), SOCS2 and cytokine-inducible SH2 domain-containing protein (CIS) are also activated by GH in different tissues, and other studies have implicated cross-talk with insulin/IGF-I transduction pathways. Activation of several of these pathways could be traced using these methods, which will shed light on the molecular mechanisms that regulate GH responsiveness in individual cells in complex tissues.
Validity of Methods Used for the Assessment of Body Components in Children: Pros and Cons of Modern versus Old Technology
Authors: Wells Jonathan C.K.
Published: January 2007

There is increasing interest in measuring muscle mass in paediatric research and clinical practice. The simplest approach is to measure lean mass and predict muscle mass as a proportion of it, but individuals and groups vary in this ratio. Calculation of arm muscle area from anthropometry has been shown to have poor accuracy in individuals; segmental impedance analysis, however, may perform better as a simple predictive method for limb composition, and merits further development. Biochemical techniques (e.g. urinary creatinine measurement) are cumbersome in children and their data are confounded by variability in maturation, diet and activity level. The best tools are radiographic imaging techniques that attempt direct measurement of muscle mass. The most widely available is dual-energy X-ray absorptiometry, which is capable of detecting the direction of differences or changes, but is less reliable regarding their magnitude because of error that varies with gender, size and fatness. Magnetic resonance imaging is currently the best technique available, as computed tomography has too high a radiation dose to justify its use in younger age groups. Regardless of which technique is used, reference data are required to aid interpretation of results, and are a current research priority.
Interaction between Muscle and Bone
Authors: Schoenau Eckhard , Fricke Oliver
Published: January 2007

Bone densitometric data are often difficult to interpret in children and adolescents because of large inter- and intraindividual variations in bone size. Here, we propose a functional approach to bone densitometry that addresses two questions. Is bone strength normally adapted to the largest physiological loads, that is muscle force? Is muscle force adequate for body size? The theoretical background for this approach is provided by the mechanostat theory, which proposes that bones adapt their strength to keep the strain caused by physiological loads close to a set point. Because the largest physiological loads are caused by muscle contractions, there should be a close relationship between bone strength and muscle force or size. The proposed two-step diagnostic algorithm requires a measure of muscle force or size and a measure of bone mineral content at a corresponding location. The results can be combined into four diagnostic groups. In the first situation, muscle force or size is adequate for height. If the skeleton is adapted normally to the muscle system, the result is interpreted as ‘normal’. If it is lower than expected for muscle force or size, a ‘primary bone defect’ is diagnosed. In the second situation, muscle force or size is too low for height. Even if the skeleton is adapted adequately to the decreased mechanical challenge, this means that bone mass, and presumably strength, are still too low for body height. Therefore, a ‘secondary bone defect’ is diagnosed. Finally, if both muscle force or size and the skeleton are inadequately adapted, a ‘mixed bone defect’ is diagnosed. It is hoped that the more detailed insights thus gained could help to devise targeted strategies for the prevention and treatment of paediatric bone diseases.
Muscle Mass and Insulin Sensitivity in Children and Adolescents
Authors: Dunger David B. , Salgin Burak , Ong Ken
Published: January 2007

Muscle is the major target for insulin-stimulated glucose uptake, the key determinant of total body insulin sensitivity. Muscle-specific insulin resistance with compensatory hyperinsulinaemia is a feature of normal puberty, and contributes to the variation in growth and protein anabolism. Low insulin levels will tend to delay pubertal growth and development, whereas high insulin levels will accelerate the process, reflecting the nutritional regulation of the tempo of development during puberty. Abnormal levels of insulin resistance during childhood, as seen in children born small-for-gestational-age (SGA) who demonstrate rapid post-natal catch-up growth, are associated with excess gains in visceral fat mass and reduced lean body mass. Thus, early developmental changes, as well as genetic variation, may predispose the children to gains in visceral and ectopic fat, which are important determinants of insulin sensitivity and disease risk in children with obesity. The mechanisms that relate fat deposition to risk of diabetes mellitus are still speculative, but insulin sensitization with thiazolidinediones or metformin can reverse nutrient disposal in fat in favour of increases in lean body mass. Such treatment with metformin, which reduces circulating insulin levels, will slow the pubertal tempo of growth and may increase gains in final height in individuals born SGA.
The Effect of Growth Hormone (GH) Treatment on Forearm Muscle in GH-Deficient Children: Evidence Based on Peripheral Quantitative Computed Tomography Measurements
Authors: Schweizer Roland , Martin David D. , Trebar Branko , Binder Gerhard , Schwarze C. Philipp , Ranke Michael B.
Published: January 2007

Conventional analyses of growth hormone (GH) treatment in children focus mainly on height development. We aimed to investigate the complex effects of GH on three components of the body, namely, muscle, fat and bone, by means of peripheral quantitative computed tomography. This method, in which a component of the body is taken to represent the whole, is non-invasive and suitable for children. Our study group comprised 74 pre-pubertal children with GH deficiency (mean age, 7.2 years; height standard deviation score [SDS], –2.9) who received recombinant human GH treatment (30 µg/kg/day [0.03 mg/kg/day]) for 12 months (55 of the children received treatment for up to 24 months). Within 2 years, mean height SDS increased from –2.9 to –1.5, muscle surface area SDS rose from –2.4 to 1.0, while fat surface area SDS decreased from 0.1 to –1.0. Grip strength SDS increased from –1.0 to –0.3, whereas the ratio of strength to muscle area did not change. We thus observed that changes in body compartments (including bone) occur during GH treatment; we also found evidence showing a specific pattern of dynamics over time. In view of the limited literature available on muscle development during GH therapy in children, we explore the potential role and significance of these response variables in the assessment of GH therapy.
Effect on Muscles of Long-Term Treatment with Growth Hormone (GH) in Adults with GH Deficiency: KIMS Data and Review of the Literature
Authors: Feldt-Rasmussen Ulla
Published: January 2007

Growth hormone (GH) deficiency in adulthood, irrespective of aetiology, is associated with decreases in lean body mass (LBM) and muscle strength. Early studies indicated that GH replacement in adults with GH deficiency (GHD) normalized LBM and muscle strength, but these findings were complicated because the GH dose used in these early studies was calculated based on weight (as in children) and was subsequently found to be too high for adults, resulting in insulin-like growth factor I levels as high as those seen in individuals with acromegaly. More recent studies have, however, confirmed that GH replacement has a long-term beneficial effect on muscle mass and function in patients with GHD of all ages, although there appears to be a greater effect in normalizing muscle mass and function in young males and in adults with adult-onset GHD compared with those with childhood-onset GHD. Results also suggest that concomitant exercise training might further improve the outcome of GH replacement therapy.
Amino Acid Supplementation and Skeletal Muscle Metabolism in Ageing Populations
Authors: Sheffield-Moore Melinda , Paddon-Jones Douglas , Urban Randall J.
Published: January 2007

In recent years, considerable scientific interest has been devoted to amino acid supplementation and its role in regulating skeletal muscle metabolism in health, ageing and disease. This interest has, in part, stemmed from clinical evidence that traditional nutritional supplementation in patients is largely ineffective. In particular, this knowledge has prompted extensive research into the mechanisms responsible for amino acid stimulation of muscle protein metabolism in older adults with sarcopenia. It is well established that ageing diminishes muscle strength and size, contributing to a number of serious health problems such as an increased risk of falls and fractures. Although the reasons behind age-related sarcopenia are multifactorial and involve a complex interplay of hormonal and metabolic stimuli, it is clear that inadequate nutrition and inactivity are strong causative factors. Recently, the idea that elderly muscle is perhaps less anabolically sensitive to amino acids has been put forward as an additional causative factor. In light of this recent evidence, and the further suggestion that the effects of essential amino acids on skeletal muscle are independent of changes in insulin, newer studies are focusing on tailoring the optimal amount and proportion of amino acids needed to stimulate muscle protein synthesis most efficiently in ageing populations. Understanding the mechanisms of amino acid stimulation of muscle protein synthesis may also provide insight into the metabolic regulation of anabolism in skeletal muscle by key hormones such as growth hormone. In this article, we summarize current research concerning amino acids and skeletal muscle, particularly with regard to ageing and inactivity.
Supraphysiological Doses of Growth Hormone: Effects on Muscles and Collagen in Healthy Active Young Adults
Authors: Rosén Thord
Published: January 2007

Doping with growth hormone (GH) is a problem among both elite athletes and ordinary young adults who use gyms. However, the role of GH as an effective anabolic muscle doping agent, when taken alone, is questioned, although at lower doses GH may be seen to be effective when taken together with other anabolic androgenic steroids. Furthermore, GH doping does not seem to have any positive effects on cardiac performance, and fluid retention and other acromegalic side-effects reduce its use. A positive effect of supraphysiological doses of GH does seem to be the stimulation of collagen synthesis, though, which could lower the risk of muscle and tendon rupture, allow ruptured muscles and tendons to heal faster, and allow harder training with shorter recovery periods. This may explain its ongoing use as a doping agent. Moreover, it cannot be excluded that in the future this effect on collagen synthesis could become useful in clinical practice for the treatment of muscle and tendon ruptures.
The Effects of Breath-Holds and Muller Manoeuvres on Upper Airway Carbon Dioxide Concentration in Humans
Authors: Raza A. , Farrell T. , O’Halloran K.D. , Bradford A.
Published: January 2007

Background: Obstructive sleep apnoea is caused by collapse of the upper airway. The presence of CO2 in the upper airway lumen evokes a number of reflexes which favour upper airway re-opening, and we have proposed previously that CO2 would build up in the upper airway following airway collapse and that this would contribute to reflex airway re-opening. However, it is not known if CO2 can transfer from the alveoli to the anatomical dead space of the upper airway during apnoea. Objectives: To determine if alveolar CO2 can enter the upper airway during breath-holds and Muller manoeuvres. Material and Methods: With local ethics committee approval, 6 male volunteers (aged 22–48 years), following a quiet inspiration, carried out breath-holds and Muller manoeuvres until breaking point. CO2 was measured continuously in samples obtained from the hypopharynx using an infrared analyser with a sample rate of 50 ml/min. Muller manoeuvres (forced inspirations against a closed upper airway) mimic the respiratory efforts which occur during obstructive apnoeas. Results: In all cases, CO2 increased progressively during apnoeas. There was a much larger increase in Muller manoeuvres (3.78 ± 0.51%, mean ± SEM at breaking point) compared to breath-holds. Discussion: These results show that upper airway CO2 concentration rises substantially during apnoeas and suggest that transfer of CO2 from the lungs to the upper airway may evoke a number of reflex effects which could affect breathing and upper airway re-opening during obstructive apnoeas.
Prenatal Management and Postnatal Separation of Omphalopagus and Craniopagus Conjoined Twins
Authors: Athanasiadis A. , Mikos T. , Zafrakas M. , Diamanti V. , Papouli M. , Assimakopoulos E. , Pados G. , Tzevelekis F. , Bontis J.
Published: January 2007

Two cases of prenatally diagnosed conjoined twins are presented: a set of omphalopagus twins sharing a common liver, and a set of craniopagus with involvement limited to the skull. In both cases, prenatal diagnosis allowed accurate planning of pre- and postnatal management. Prenatal management involved serial imaging and counseling with participation of different specialists according to imaging findings. In the rare case of conjoined twins, an interdisciplinary approach is required, with feto-maternal specialists playing a pivotal role in co-ordinating teamwork and planning successive stages of management.
Alpha-Lipoic Acid Protects against Hepatic Ischemia-Reperfusion Injury in Rats
Authors: Dulundu Ender , Ozel Yahya , Topaloglu Umit , Sehirli Özer , Ercan Feriha , Gedik Nursal , Şener Goksel
Published: January 2007

Background and Aim: To evaluate the protective effect of alpha-lipoic acid in reducing oxidative damage after severe hepatic ischemia/reperfusion (IR) injury. Methods: Wistar albino rats were subjected to 45 min of hepatic ischemia, followed by 60 min reperfusion period. Lipoic acid (100 mg/kg i.p.) was administered 15 min prior to ischemia and immediately before reperfusion period. At the end of the reperfusion period aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) activity, and cytokine, TNF-α and IL-1β levels were determined in serum samples. Malondialdehyde (MDA), and glutathione (GSH) levels and myeloperoxidase (MPO) activity were determined in the liver tissue samples while formation of reactive oxygen species was monitored by using chemiluminescence (CL) technique with luminol and lucigenin probes. Tissues were also analyzed histologically. Results: Serum ALT, AST, and LDH activities and TNF-α and IL-1β levels were elevated in the I/R group, while this increase was significantly lower in the group of animals treated concomitantly with lipoic acid. Hepatic GSH levels, significantly depressed by I/R, were elevated back to control levels in lipoic acid-treated I/R group. Furthermore, increases in tissue luminol and lucigenin CL, MDA levels and MPO activity due to I/R injury were reduced back to control levels with lipoic acid treatment. Conclusion: Since lipoic acid administration alleviated the I/R-induced liver injury and improved the hepatic structure and function, it seems likely that lipoic acid with its antioxidant and oxidant-scavenging properties may be of potential therapeutic value in protecting the liver against oxidative injury due to ischemia-reperfusion.