bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrated effects of multiple modulators on human liver glycogen phosphorylasea
Authors: Ercan-Fang Nacide , Gannon Mary C. , Rath Virginia L. , Treadway Judith L. , Taylor Miriam R. , Nuttall Frank Q.
Published: February 2015

Hepatic glucose production is increased in people with type 2 diabetes. Glucose released from storage in liver glycogen by phosphorylase accounts for ∼50% of the glucose produced after an overnight fast. Therefore, understanding how glycogenolysis in the liver is regulated is of great importance. Toward this goal, we have determined the kinetic characteristics of recombinant human liver glycogen phosphorylase a (HLGP a) (active form) and compared them with those of the purified rat enzyme (RLGP a). The Michaelis-Menten constant ( Km) of HLGP a for Pi, 5 mM, was about fivefold greater than the Kmof RLGP a. Two Pi(substrate) concentrations were used (1 and 5 mM) to cover the physiological range for Pi. Other effectors were added at estimated intracellular concentrations. When added individually, AMP stimulated, whereas ADP, ATP and glucose inhibited, activity. These results were similar to those of the RLGP a. However, glucose inhibition was about twofold more potent with the human enzyme. UDP-glucose, glucose 6-phosphate, and fructose 1-phosphate were only minor inhibitors of both enzymes. We reported previously that when all known effectors were present in combination at physiological concentrations, the net effect was no change in RLGP a activity. However, the same combination reduced HLGP a activity, and the inhibition was glucose dependent. We conclude that a combination of the known effectors of phosphorylase a activity, when present at estimated intracellular concentrations, is inhibitory. Of these effectors, only glucose changes greatly in vivo. Thus it may be the major regulator of HLGP a activity.
Somatostatin-28 regulates GLP-1 secretion via somatostatin receptor subtype 5 in rat intestinal cultures
Authors: Chisholm Connie , Greenberg Gordon R.
Published: February 2015

Five somatostatin receptors (SSTRs) bind somatostatin-14 (S-14) and somatostatin-28 (S-28), but SSTR5 has the highest affinity for S-28. To determine whether S-28 acting through SSTR5 mediates inhibition of glucagon-like peptide-1 (GLP-1), fetal rat intestinal cell cultures were treated with somatostatin analogs with relatively high specificity for SSTRs 2–5. S-28 dose-dependently inhibited GLP-1 secretion stimulated by gastrin-releasing peptide more potently than S-14 (EC500.01 vs. 5.8 nM). GLP-1 secretion was inhibited by an SSTR5 analog, BIM-23268, more potently than S-14 and nearly as effectively as S-28. The SSTR5 analog L-372,588 also suppressed GLP-1 secretion equivalent to S-28, but a structurally similar peptide, L-362,855 (Tyr to Phe at position 7), was ineffective. An SSTR2-selective analog was less effective than S-28, and an SSTR3 analog was inactive. Separate treatment with GLP-1-(7–36)-NH2increased S-28 and S-14 secretion by three- and fivefold; BIM-23268 abolished S-28 without altering S-14, whereas the SSTR2 analog was inactive. The results indicate that somatostatin regulation of GLP-1 secretion occurs via S-28 through activation of SSTR5. GLP-1-stimulated S-28 secretion is also autoregulated by SSTR5 activation, suggesting a feedback loop between GLP-1 and S-28 modulated by SSTR5.
GLUT4-containing vesicles are released from membranes by phospholipase D cleavage of a GPI anchor
Authors: Kristiansen Søren , Richter Erik A.
Published: February 2015

We have previously developed a cell-free assay from rat skeletal muscle that displayed in vitro glucose transporter 4 (GLUT4) transfer from large to small membrane structures by the addition of a cytosolic protein fraction. By combining protein fractionation and the in vitro GLUT4 transfer assay, we have purified a glycosylphosphatidylinositol (GPI) phospholipase D (PLD) that induces transfer of GLUT4 from small to large membranes. The in vitro GLUT4 transfer was activated and inhibited by suramin and 1,10-phenanthroline (an activator and an inhibitor of GPI-PLD activity, respectively). Furthermore, upon purfication of the GLUT4 transporter protein, the protein displayed an elution profile in which the molecular mass was related to the charge, suggesting the presence or absence of phosphate. Second, by photoaffinity labeling of the purified GLUT4 with 3-(trifluoromethyl)-3-(m-[125I]iodopenyl)diazirine, both labeled phosphatidylethanolamine and fatty acids (constituents of a GPI link) were recovered. Third, by using phase transition of Triton X-114, the purified GLUT4 was found to be partly detergent resistant, which is a known characteristic of GPI-linked proteins. Fourth, the purified GLUT4 protein was recognized by an antibody raised specifically against GPI links. In conclusion, GLUT4-containing vesicles may be released from a membrane compartment by action of a GPI-PLD.
Opposing effects of pituitary leukemia inhibitory factor and SOCS-3 on the ACTH axis response to inflammation
Authors: Chesnokova Vera , Kariagina Anastasia , Melmed Shlomo
Published: February 2015

We have shown that leukemia inhibitory factor (LIF) and suppressor of cytokine signaling (SOCS)-3 are expressed in the hypothalamus and pituitary and that LIF induces proopiomelanocortin (POMC) and ACTH, whereas SOCS-3 abrogates corticotroph POMC gene transcription and ACTH secretion. Here, we determined the role of pituitary LIF and SOCS-3 in regulating hypothalamo-pituitary-adrenal (HPA) axis inflammatory responses. Murine pituitary LIF expression was induced up to eightfold after intraperitoneal injection of lipopolysaccharide or tumor necrosis factor-α, concordant with elevated plasma levels of ACTH and corticosterone. In LIF knockout (LIFKO) mice, induction of both ACTH and corticosterone were attenuated. LIF deletion was associated with elevated ( P < 0.05) levels of pituitary TNF-α, interleukin (IL)-1β, and IL-6 mRNA and cytokine-inducible pituitary SOCS-3 expression. Abrogation of the HPA axis stress response and higher pituitary levels of proinflammatory cytokines observed in LIFKO mice resulted in a stronger inflammatory process, as evidenced by elevated erythrocyte sedimentation rate and increased serum amyloid A levels ( P < 0.05). The results indicate that, although LIF induces ACTH, SOCS-3 acts to counterregulate the HPA axis response to inflammation.
Localization and function of group III metabotropic glutamate receptors in rat pancreatic islets
Authors: Tong Qingchun , Ouedraogo Raogo , Kirchgessner Annette L.
Published: February 2015

Pancreatic islets contain ionotropic glutamate receptors that can modulate hormone secretion. The purpose of this study was to determine whether islets express functional group III metabotropic glutamate (mGlu) receptors. RT-PCR analysis showed that rat islets express the mGlu8 receptor subtype. mGlu8 receptor immunoreactivity was primarily displayed by glucagon-secreting α-cells and intrapancreatic neurons. By demonstrating the immunoreactivities of both glutamate and the vesicular glutamate transporter 2 (VGLUT2) in these cells, we established that α-cells express a glutamatergic phenotype. VGLUT2 was concentrated in the secretory granules of islet cells, suggesting that glutamate might play a role in the regulation of glucagon processing. The expression of mGlu8 by glutamatergic cells also suggests that mGlu8 may function as an autoreceptor to regulate glutamate release. Pancreatic group III mGlu receptors are functional because mGlu8 receptor agonists inhibited glucagon release and forskolin-induced accumulation of cAMP in isolated islets, and (R,S)-cyclopropyl-4-phosphonophenylglycine, a group III mGlu receptor antagonist, reduced these effects. Because excess glucagon secretion causes postprandial hyperglycemia in patients with type 2 diabetes, group III mGlu receptor agonists could be of value in the treatment of these patients.
Essential amino acids and muscle protein recovery from resistance exercise
Authors: Børsheim Elisabet , Tipton Kevin D. , Wolf Steven E. , Wolfe Robert R.
Published: February 2015

This study tests the hypothesis that a dose of 6 g of orally administered essential amino acids (EAAs) stimulates net muscle protein balance in healthy volunteers when consumed 1 and 2 h after resistance exercise. Subjects received a primed constant infusion ofl-[2H5]phenylalanine andl-[1-13C]leucine. Samples from femoral artery and vein and biopsies from vastus lateralis were obtained. Arterial EAA concentrations increased severalfold after drinks. Net muscle protein balance (NB) increased proportionally more than arterial AA concentrations in response to drinks, and it returned rapidly to basal values when AA concentrations decreased. Area under the curve for net phenylalanine uptake above basal value was similar for the first hour after each drink (67 ± 17 vs. 77 ± 20 mg/leg, respectively). Because the NB response was double the response to two doses of a mixture of 3 g of EAA + 3 g of nonessential AA (NEAA) (14), we conclude that NEAA are not necessary for stimulation of NB and that there is a dose-dependent effect of EAA ingestion on muscle protein synthesis.
Effects of recurrent hyperinsulinemia with and without hypoglycemia on counterregulation in diabetic rats
Authors: Inouye Karen , Shum Kathy , Chan Owen , Mathoo Julian , Matthews Stephen G. , Vranic Mladen
Published: February 2015

To understand the mechanisms whereby recurrent hypoglycemia increases the risk of subsequent hypoglycemia, it was necessary to differentiate the effects of recurrent hyperinsulinemia from those of hyperinsulinemic hypoglycemia. We examined basal and hypoglycemic endocrine function in normal rats, streptozotocin-diabetic controls, and diabetic rats exposed to 4 days of 2 episodes/day of hyperinsulinemic hypoglycemia (DH) or hyperinsulinemic hyperglycemia (DI). DH and DI rats differentiated the effects of hyperinsulinemia from those of hypoglycemia. In diabetic controls, basal plasma ACTH tended to be increased, and plasma corticosterone, plasma somatostatin, and pancreatic prosomatostatin and proglucagon mRNA were increased ( P < 0.05) vs. normal rats. These parameters were normalized in DH and DI rats. In diabetic controls, glucagon, epinephrine, norepinephrine, corticosterone, and peak glucose production responses to hypoglycemia were reduced ( P < 0.05) vs. normal rats. In DI rats, epinephrine responses were normalized. Conversely, DH rats displayed marked further impairment of epinephrine and glucose production responses and increased peripheral insulin sensitivity ( P < 0.05 vs. diabetic controls). Both insulin regimens partially normalized glucagon and fully normalized norepinephrine and corticosterone responses. In summary, recurrent hyperinsulinemia in diabetic rats normalized most pituitary-adrenal, sympathoadrenal, and pancreatic parameters. However, concurrent hypoglycemia further impaired epinephrine and glucose production responses and increased insulin sensitivity. We conclude that 1) recurrent hypoglycemia may increase the risk of subsequent hypoglycemia by increasing insulin sensitivity, and 2) epinephrine counterregulation is particularly sensitive to impairment by recurrent hypoglycemia.
Stimulation of protein synthesis by both insulin and amino acids is unique to skeletal muscle in neonatal pigs
Authors: Davis Teresa A. , Fiorotto Marta L. , Burrin Douglas G. , Reeds Peter J. , Nguyen Hanh V. , Beckett Philip R. , Vann Rhonda C. , O'Connor Pamela M. J.
Published: February 2015

In neonatal pigs, the feeding-induced stimulation of protein synthesis in skeletal muscle, but not liver, can be reproduced by insulin infusion when essential amino acids and glucose are maintained at fasting levels. In the present study, 7- and 26-day-old pigs were studied during 1) fasting, 2) hyperinsulinemic-euglycemic-euaminoacidemic clamps, 3) euinsulinemic-euglycemic-hyperaminoacidemic clamps, and 4) hyperinsulinemic-euglycemic-hyperaminoacidemic clamps. Amino acids were clamped using a new amino acid mixture enriched in nonessential amino acids. Tissue protein synthesis was measured using a flooding dose ofl-[4-3H]phenylalanine. In 7-day-old pigs, insulin infusion alone increased protein synthesis in various skeletal muscles (from +35 to +64%), with equivalent contribution of myofibrillar and sarcoplasmic proteins, as well as cardiac muscle (+50%), skin (+34%), and spleen (+26%). Amino acid infusion alone increased protein synthesis in skeletal muscles (from +28 to +50%), also with equivalent contribution of myofibrillar and sarcoplasmic proteins, as well as liver (+27%), pancreas (+28%), and kidney (+10%). An elevation of both insulin and amino acids did not have an additive effect. Similar qualitative results were obtained in 26-day-old pigs, but the magnitude of the stimulation of protein synthesis by insulin and/or amino acids was lower. The results suggest that, in the neonate, the stimulation of protein synthesis by feeding is mediated by either amino acids or insulin in most tissues; however, the feeding-induced stimulation of protein synthesis in skeletal muscle is uniquely regulated by both insulin and amino acids.
Atypical β-adrenergic effects on insulin signaling and action in β3-adrenoceptor-deficient brown adipocytes
Authors: Jost Petra , Fasshauer Mathias , Kahn C. Ronald , Benito Manuel , Meyer Marco , Ott Volker , Lowell Bradford B. , Klein H. Harald , Klein Johannes
Published: February 2015

Cross talk between adrenergic and insulin signaling systems may represent a fundamental molecular basis of insulin resistance. We have characterized a newly established β3-adrenoceptor-deficient (β3-KO) brown adipocyte cell line and have used it to selectively investigate the potential role of novel-state and typical β-adrenoceptors (β-AR) on insulin signaling and action. The novel-state β1-AR agonist CGP-12177 strongly induced uncoupling protein-1 in β3-KO brown adipocytes as opposed to the β3-selective agonist CL-316,243. Furthermore, CGP-12177 potently reduced insulin-induced glucose uptake and glycogen synthesis. Neither the selective β1- and β2-antagonists metoprolol and ICI-118,551 nor the nonselective antagonist propranolol blocked these effects. The classical β1-AR agonist dobutamine and the β2-AR agonist clenbuterol also considerably diminished insulin-induced glucose uptake. In contrast to CGP-12177 treatment, these negative effects were completely abrogated by metoprolol and ICI-118,551. Stimulation with CGP-12177 did not impair insulin receptor kinase activity but decreased insulin receptor substrate-1 binding to phosphatidylinositol (PI) 3-kinase and activation of protein kinase B. Thus the present study characterizes a novel cell system to selectively analyze molecular and functional interactions between novel and classical β-adrenoceptor types with insulin action. Furthermore, it indicates insulin receptor-independent, but PI 3-kinase-dependent, potent negative effects of the novel β1-adrenoceptor state on diverse biological end points of insulin action.
Euglycemic hyperinsulinemia augments the cytokine and endocrine responses to endotoxin in humans
Authors: Soop Mattias , Duxbury Helen , Agwunobi Anselm O , Gibson J. Martin , Hopkins Stephen J. , Childs Charmaine , Cooper Robert G. , Maycock Paula , Little Roderick A. , Carlson Gordon L.
Published: February 2015

Type 2 diabetes is associated with biochemical evidence of low-grade inflammation, and experimental studies have suggested that both insulin and glucose affect inflammatory responses. To determine the effect of in vivo changes in glucose availability and plasma insulin concentrations in humans, we administered 20 U/kg Escherichia coli lipopolysaccharide (LPS) or saline (control) to 14 subjects during a euglycemic hyperinsulinemic clamp ( n = 6) or an infusion of sterile saline ( n = 8). Parallel in vitro studies on human whole blood were undertaken to determine whether there was a direct effect of glucose, insulin, and leptin on proinflammatory cytokine production. Infusion of glucose and insulin significantly amplified and/or prolonged the cardiovascular, plasma interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and counterregulatory hormone responses to LPS, whereas the effects on fever, plasma norepinephrine concentrations, and oxygen consumption were unaffected. In vitro studies showed no modulation of LPS-stimulated IL-6 or TNF-α production by glucose, insulin, or leptin at physiologically relevant concentrations. Hyperinsulinemia indirectly enhances key components of the systemic inflammatory and stress responses in this human model of infection.
Brown fat thermogenesis in cold-acclimated rats is not abolished by the suppression of thyroid function
Authors: Zaninovich Angel A. , Raíces Marcela , Rebagliati Inés , Ricci Conrado , Hagmüller Karl
Published: February 2015

The effects of long-term cold exposure on brown adipose tissue (BAT) thermogenesis in hypothyroid rats have been examined. Thyroid ablation was performed in normal rats after 2 mo of exposure to 4°C, when BAT hypertrophy and thermogenic activity were maximal. After ablation, hypothyroid and normal controls remained in the cold for 2 additional months. At the end of the 4-mo cold exposure, all untreated hypothyroid rats were alive, had normal body temperature, and had gained an average 12.8% more weight than normal controls. Long-term cold exposure of hypothyroid rats markedly increased BAT weight, mitochondrial proteins, uncoupling protein (UCP)-1, mRNA for UCP-1, and oxygen consumption to levels similar to those seen in cold-exposed normal rats. The results indicate that thyroid hormones are required for increased thermogenic capacity to occur as an adaptation to long-term cold exposure. However, cold adaptation can be maintained in the absence of thyroid hormone.
Leptin increases FA oxidation in lean but not obese human skeletal muscle: evidence of peripheral leptin resistance
Authors: Steinberg Gregory R. , Parolin Michelle L. , Heigenhauser George J. F. , Dyck David J.
Published: February 2015

The adipocyte-derived hormone leptin has been shown to acutely increase fatty acid (FA) oxidation and decrease esterification in resting rodent skeletal muscle. However, the effects of leptin on human skeletal muscle FA metabolism are completely unknown. In these studies, we have utilized an isolated human skeletal muscle preparation combined with the pulse-chase technique to measure FA metabolism with and without leptin in lean and obese human skeletal muscle. Under basal conditions (in the absence of leptin), muscle from the obese demonstrated significantly elevated levels of total FA uptake (+72%, P = 0.038) and enhanced rates of FA esterification into triacylglycerol (+102%, P = 0.042) compared with lean subjects. In the presence of leptin, lean muscle had elevated rates of endogenous (+103%, P = 0.01) and exogenous (+150%, P = 0.03) palmitate oxidation. When the ratio of esterification to exogenous oxidation was examined, leptin reduced this ratio (−47%, P = 0.032), demonstrating the increased partitioning of FA toward oxidation and away from storage. Contrary to these findings in lean muscle, leptin had no effect on FA metabolism in skeletal muscle of the obese. This study provides the first evidence that leptin increases FA oxidation in skeletal muscle of lean, but not obese humans, thus demonstrating the development of leptin resistance in obese human skeletal muscle.
IGF-I and insulin regulate eIF4F formation by different mechanisms in muscle and liver in the ovine fetus
Authors: Shen Weihua , Mallon Daniel , Boyle David W. , Liechty Edward A.
Published: February 2015

The mechanisms by which insulin-like growth factor I (IGF-I) and insulin regulate eukaryotic initiation factor (eIF)4F formation were examined in the ovine fetus. Insulin infusion increased phosphorylation of eIF4E-binding protein (4E-BP1) in muscle and liver. IGF-I infusion did not alter 4E-BP1 phosphorylation in liver. In muscle, IGF-I increased 4E-BP1 phosphorylation by 27%; the percentage in the γ-form in the IGF-I group was significantly lower than that in the insulin group. In liver, only IGF-I increased eIF4G. Both IGF-I and insulin increased eIF4E · eIF4G binding in muscle, but only insulin decreased the amount of 4E-BP1 associated with eIF4E. In liver, only IGF-I increased eIF4E · eIF4G binding. Insulin increased the phosphorylation of p70 S6 kinase (p70S6k) in both muscle and liver and protein kinase B (PKB/Akt) in muscle, two indicative signal proteins in the phosphatidylinositol (PI) 3-kinase pathway. IGF-I increased PKB/Akt phosphorylation in muscle but had no effect on p70S6kphosphorylation in muscle or liver. We conclude that insulin and IGF-I modulate eIF4F formation; however, the two hormones have different regulatory mechanisms. Insulin increases phosphorylation of 4E-BP1 and eIF4E · eIF4G binding in muscle, whereas IGF-I regulates eIF4F formation by increasing total eIF4G. Insulin, but not IGF-I, decreased 4E-BP1 content associated with eIF4E. Insulin regulates translation initiation via the PI 3-kinase-p70S6kpathway, whereas IGF-I does so mainly via mechanisms independent of the PI 3-kinase-p70S6kpathway.
Suppression of contractile activity in the small intestine by indomethacin and omeprazole
Authors: Lichtenberger Lenard M. , Bhattarai Deepa , Phan Tri M. , Dial Elizabeth J. , Uray Karen
Published: February 2015

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat a number of conditions, and proton pump inhibitors (PPIs) are often used to prevent NSAID-induced gastric mucosal damage; however, the effects of NSAIDs on intestinal motility are poorly understood. The purpose of the present study is to determine the effects of a prototypical NSAID, indomethacin, either alone or in conjunction with the PPI omeprazole, on intestinal motility. Rats were randomly divided into four groups treated with vehicle, omeprazole, indomethacin, or a combination of indomethacin and omeprazole. Intestinal motility and transit were measured along with inflammatory mediators in the intestinal smooth muscle, markers of mucosal damage, and bacterial counts in the intestinal wall. Indomethacin, but not omeprazole, caused mucosal injury indicated by lower gut bleeding; however, both omeprazole and indomethacin suppressed contractile activity and frequency in the distal part of the small intestine. Cotreatment with omeprazole did not reduce indomethacin-induced intestinal bleeding. Furthermore, although indomethacin caused increased inflammation as indicated by increased edema development and inflammatory mediators, cotreatment with omeprazole did not reduce inflammation in the intestinal smooth muscle or prevent the increased bacterial count in the intestinal wall induced by indomethacin. We conclude that both NSAID and PPI treatment suppressed contractile activity in the distal regions of the small intestine. The suppression of intestinal contractility was associated with increased inflammation in both cases; however, indomethacin and omeprazole appear to affect intestinal motility by different mechanisms.
Platelet-derived growth factor-BB enhances MSC-mediated cardioprotection via suppression of miR-320 expression
Authors: Xu Bing , Luo Yong , Liu Yunlong , Li Bai-Yan , Wang Yue
Published: February 2015

Delivery of bone marrow-derived mesenchymal stem cells (MSCs) to myocardium protects ischemic tissue through the paracrine release of beneficial angiogenic and cytoprotective factors. Platelet-derived growth factor (PDGF)-BB, a potent mitogen of MSCs, is involved in the pathophysiology of ischemic heart disease. However, the role(s) of PDGF in MSC-mediated cardioprotection remains unknown. Here, we found that PDGF treatment of MSCs resulted in rapid activation of both Akt and ERK (central intracellular signal mediators), upregulated VEGF, and induced phosphorylation of the activator protein-1 (AP-1) transcription factor c-Jun. Examination of several microRNA genes having predicted promoter c-Jun-binding sites showed that PDGF treatment resulted in upregulation of miR-16-2 and downregulation of miRs-23b, -27b, and -320b. To examine possible PDGF augmentation of therapeutic potential, we evaluated the effects of PDGF using an ex vivo isolated mouse heart ischemia-reperfusion model. Human MSCs, with or without PDGF preconditioning, were infused into the coronary circulation of isolated mouse hearts. The hearts that received PDGF-treated MSCs exhibited a greater functional recovery compared with naïve MSC-infused hearts, following ischemia-reperfusion injury. This enhanced functional recovery was abolished by overexpression of miR-320, a microRNA we found downregulated by PDGF-activated c-Jun. Overexpression of miR-320 also resulted in upregulation of insulin-like growth factor binding protein (IGFBP) family members, suggesting PDGF “cross talk” with the mitogenic IGF signaling pathway. Collectively, we conclude that PDGF enhances MSC-mediated cardioprotection via a c-Jun/miR-320 signaling mechanism and PDGF MSC preconditioning may be an effective therapeutic strategy for cardiac ischemia.
Lifestyle Effects on Hematopoiesis and Atherosclerosis
Authors: Nahrendorf Matthias , Swirski Filip K.
Published: February 2015

Diet, exercise, stress, and sleep are receiving attention as environmental modifiers of chronic inflammatory diseases, including atherosclerosis, the culprit condition of myocardial infarction and stroke. Accumulating data indicate that psychosocial stress and a high-fat, high-cholesterol diet aggravate cardiovascular disease, whereas regular physical activity and healthy sleeping habits help prevent it. Here, we raise the possibility that inflammation-associated leukocyte production plays a causal role in lifestyle effects on atherosclerosis progression. Specifically, we explore whether and how potent real-life disease modifiers influence hematopoiesis’ molecular and cellular machinery. Lifestyle, we hypothesize, may rearrange hematopoietic topography, diverting production from the bone marrow to the periphery, thus propagating a quantitative and qualitative drift of the macrophage supply chain. These changes may involve progenitor-extrinsic and intrinsic communication nodes that connect organ systems along neuroimmune and immunometabolic axes, ultimately leading to an altered number and phenotype of lesional macrophages. We propose that, in conjunction with improved public health policy, future therapeutics could aim to modulate the quantitative and qualitative output, as well as the location, of the hematopoietic tree to decrease the risk of atherosclerosis complications.
Slave or Free? White or Black? The Representation of George Latimer
Authors: Gac Scott
Published: February 2015

When George Latimer fled Southern slavery in 1842, white abolitionists embraced the light-skinned fugitive as essentially white; yet when he died, though he had lived and worked in freedom for half a century, he was memorialized as a black slave. Such differing descriptions expose a radical transformation in the representation of black Americans across the nineteenth century.
Finding Private Suhre: On the Trail of Louisa May Alcott's “Prince of Patients”
Authors: Matteson John
Published: February 2015

John Suhre, whom Louisa May Alcott called the “hero” of her Hospital Sketches, strongly influenced her thinking and writing. However, almost nothing has been known about him. This article identifies Suhre and reconstructs his final months, from his enlistment in the 133rd Pennsylvania Volunteers to his death in an army hospital.
Toadstools, Bartleby, and Badiou
Authors: Saxby Justin
Published: February 2015

This article brings together Herman Melville’s “Bartleby, the Scrivener” with Lives of Jesus authored by David Strauss and Simon Greenleaf and reads them through Alain Badiou’s philosophy of the Event. If we bear in mind the raging debates of the time about how to write an historical account of Jesus, represented here by Strauss and Greenleaf, Melville’s story about a reclusive law-copyist and his frustrated biographer becomes a set of questions about the nature and purpose of biography. When Badiou’s ideas about the Event are taken into account, “Bartleby” intensifies into an anguished consideration of what to do, or what to write, after a life-altering encounter with an elusive subject who leaves no evidentiary trace.
Exploring Interpretation and Misinterpretation of Garden-Path Sentences in Polish
Authors: Solska Agnieszka , Rojczyk Arkadiusz
Published: February 2015

The paper reports on an experiment designed to investigate the interpretation and misinterpretation of Polish sentences such as Gdy Jan pisał list spadł z biurka (e.g. “While John was writing the letter fell off a desk”), paralleling English garden path sentences such as While John hunted the deer ran into the woods. The locally ambiguous NP-V-NP region in sentences of this sort may result in the key noun phrase being incorrectly interpreted as the object in the fronted temporal clause. The experiment was conducted using E-Prime software and involved comparing the participants’ comprehension of garden path sentences in three different conditions with their comprehension of equivalent non-garden path sentences. This was achieved by examining the participants’ performance on comprehension questions probing the interpretation of the subordinate clauses, establishing the times they needed to answer the questions and checking the level of their confidence in their responses. The goals of the experiment were to establish whether the Polish sentences in question force the comprehender to form erroneous interpretations which persist in his mind and to determine to what extent the persistence of the initial incorrect interpretation is influenced by the morphosyntactic properties peculiar to Polish. The results of the experiment indicate that though the Polish sentences under investigation do not trigger a particularly strong garden path effect, the information carried by the case endings and the thematic roles nouns are likely to have in specific contexts affect the way locally ambiguous sentences are analysed.
Intonation Patterns in Pijal Media Lengua
Authors: Stewart Jesse
Published: February 2015

Pijal Media Lengua (pml) is a mixed language described as having Quichua morphosyntactic and phonological systems where nearly every content word (89%), including pronouns and determiners, is replaced by its Spanish-derived counterpart through the process of relexification. pml speakers however, often regard their language as intonationally distinct from both Quichua and Spanish. This paper offers a basic description of the pitch accent and boundary tone configurations found in pml using the autosegmental framework (Pierrehumbert, 1980) in a ToBI transcription system (Silverman, 1984). This paper also explorers the current literature on mixed language phonetics and attempts to promote acoustic analyses of intonation as a useful investigative tool for analyzing the origins of prosodic material. The results suggest that pml predominantly makes use of Quichua-like intonation patterns along with innovative and/or preserved structures.
The Independent Partitive as an Eastern Circum-Baltic isogloss
Authors: Seržant Ilja A.
Published: February 2015

The paper claims that the independent partitive case in Finnic languages and the independent partitive genitive case in Baltic and East Slavic (henceforth: ip(g)) show considerable correlations that cannot be accounted for but by language contact. Given that both the ip(g) in Baltic and East Slavic as well as the ip(g) in Finnic are inherited from the respective proto-languages, the paper also offers a methodological discussion of how inherited categories may also be shown to be subject to language contact. A typologically not infrequent category must be individualized on the basis of a list of properties. Thus, 13 semantic and 5 morphosyntactic properties have been discussed. While the study reveals that in general the ip(g) is or was subject to intensive language contact, there is no common hotbed for all properties analysed and different properties have different hotbeds and are distinct with respect to their geographical distribution and entrenchment. North Russian and Finnic show the greatest degree of correspondence as, e.g., the aspectuality related functions of the ip(g) or the morphological distinction between the possession (sensu lato) and the partitive-related functions are concerned. Here, Finnic is the donor language. However, other properties such as the semantic and syntactic merger of the acc and ip(g) marking must have spread from Russian to Finnic and, to some extent, Baltic. Similarly, the genitive/partitive-under-negation probably developed first in Baltic and Slavic and spread then into Finnic, since preconditions for this rule are already found in the ancient Indo-European languages. Finnic, however, preserves this rule best.
Plague like Cats
Authors: I. Cox Catherine
Published: February 2015

Although many scholars have acknowledged the dark thread interwoven into William Baldwin’s playful narrative Beware the Cat, they have largely ignored the role of plague in heightening the work’s sense of impending danger. Baldwin intensifies our sense of peril by including at every level of his narrative references to plague. In Beware the Cat, contagious disease symbolically melds with other kinds of divine punishment. These include bestial transformations, farcical exposure, and painful afflictions, especially the startling appearances of and painful biting, scratching, strangling, and suffocation by cats. All are ways that God punishes his creatures for their abominations. Baldwin’s emphasis on plague as God’s vengeance for sin becomes one of the cats’ most significant meanings and a key to our understanding of the protagonist Gregory Streamer’s strange quest.
The Dutch Renaissance in a Straightjacket
Authors: Ronnes Hanneke , Witte Arnold
Published: February 2015

During the last decade, research on Renaissance art and architecture in the northern Netherlands has tried to overcome persistent late nineteenth-century concepts connected to the nation-state, and started to adopt more dynamic ideas of culture and the arts in the period between 1450 and 1620. Especially the geographical divide between Flanders and the Northern Netherlands is increasingly contested, and more attention is being paid to the exchange between the Netherlands and Italy. This more international outlook has resulted in publications on artists such as Adriaen de Vries and Abraham Bloemaert, and architects such as De Keyser. Still, this field is overshadowed by the public attention paid to the Dutch Golden Age, and its essentialist interpretation continues to have an impact on the way the preceding period is studied. As a result, there still exists a rather fragmented idea of what ‘Renaissance’ means with respect to the arts in the Netherlands.
A Tornado Watch Scale to Improve Public Response
Authors: Mason Jonathan B. , Senkbeil Jason C.
Published: February 2015

A tornado refuge rubric was revised into a six-level, hierarchical Tornado Watch Scale (TWS) from level 0 to level 5 based on the likelihood of high or low-impact tornadic events. Levels correspond to an estimate of the maximum potential tornado intensity for a given day and include refuge/shelter categories of “adequate,” “questionable,” or “inadequate,” which encompass a range of refuge/shelter locations taken from the Enhanced Fujita scale. Ratings are based on a conservative estimate of damage indicators in high winds and the safety of a person taking refuge inside buildings of varying structural design. Audio recordings similar to those used in current NOAA weather radio communications were developed for each TWS intensity level. Recordings representing an existing tornado watch, existing particularly dangerous situation (PDS) tornado watch, and three proposed levels from the TWS were then used in interviews with Alabama residents to determine how changes to the information contained in the watch statements would affect each participant’s tornado safety actions and risk perception. Participants were also questioned about their knowledge and past experience with tornado hazards and their preference between the existing NWS tornado watches and the TWS. Results indicate a strong preference for the TWS when compared to existing products. The TWS was favored for providing additional information, containing descriptions of expected severity, and being easy to understand. The TWS also elicits more adequate safety decisions and more appropriate risk perception when compared to existing products, and these increases in safety were statistically significant.
Diagnosing Fish Bone and Chicken Bone Impactions in the Emergency Department Setting
Authors: Devarajan Karthik , Voigt Stanley , Shroff Sunil , Weiner Scott G. , Wein Richard O.
Published: February 2015

Objectives:

In the emergency department, fish and chicken bone impactions are typically evaluated with screening x-rays. We sought to determine whether this modality ultimately improves system outcomes, including length of stay (LOS), cost, and radiation dosage.

Methods:

We reviewed patients ≥18 years old presenting to an urban academic emergency department over a 4-year period who received a screening soft-tissue x-ray to determine the presence of a retained fish or chicken bone. We calculated the diagnostic accuracy of x-ray and computed tomography (CT) evaluations, respectively, in addition to system outcomes.

Results:

Twenty-seven of the 78 patients included for analysis were ultimately positive for bone impaction. Initial x-ray interpretations demonstrated a sensitivity of 24.0% (95% CI, 9.4%-45.1%) and a specificity of 90.0% (95% CI, 78.2%-96.7%). However, initial CT interpretation (ie, a preliminary read from on-call residents) demonstrated a sensitivity of 75% (95% CI, 19.4%-99.4%) and a specificity of 100% (95% CI, 59.0%-100%). LOS, cost, and radiation dosage were not significantly different between patients who ultimately had true bone impactions and those who did not ( P > .05).

Conclusions:

X-rays are poor screening tools in determining fish or chicken bone impactions with poor diagnostic and system utility. Further studies should be performed to evaluate the role of a low-radiation CT screen.
Three keys to mission: Kingdom, incarnation and discipleship
Authors: Robinson Gareth
Published: February 2015

Through reflective practice, Glo Church has identified and used three keys to mission: declaring God’s kingdom as part of the missio Dei; incarnating the gospel individually and corporately; and offering support and challenge as the basis for discipleship.
The necessity of social just-ness for a postmodern ecclesi-odicy
Authors: Boursier Helen Taylor
Published: February 2015

Going to “all nations” to share the salvific message of Jesus Christ (Matt 28:19) means that the Christian gospel needs to resonate with the social and existential concerns of the current people of God as well as with changing culture and emerging generations. When the world changes, ecclesial praxis needs to change along with it if the church's missional emphasis is to be consistently relevant. When the church ignores the world, why should (or would) the world pay attention to the church? The church must rethink its ecclesiology through the hermeneutical lens of postmodernity and its interests in acts of (social) justice. 1 This article proposes that a defense or apologetic of the postmodern ecclesia—an “ecclesi-odicy”— is best defended by a renewing of the church's original missional intent and the implementation of the church's (social) ethic. Ecclesi-odicy brings together “ecclesial” and “theodicy” and is an apologetic for the church itself. Ecclesi-odicy is not justification for the church to critique others; rather to critique itself. Deconstructed, ecclesi-odicy becomes a defense of the ecclesia in its interface with the social injustices caused by evil and suffering.
Bodies, selves, and human identity: A Conversation Between Transhumanism and the Apostle Paul
Authors: Kraftchick Steven John
Published: February 2015

In this article I propose the initiation of a conversation between biblical interpreters and proponents of transhumanism. Transhumanists recognize that the rapid expansion of technological innovation is changing our understandings of human behavior, thinking, and physical makeup. The vitality of the post/transhumanism debate about human identity suggests that a “biblical conversation” should be part of a larger conversation not only with theologians, but also the social entities who will hold forth on the values of human/machine transformations. It becomes ever more clear that this debate about human identity will be a real issue in the near future since we will undoubtedly improve our technological capacities and geometrically increase our prosthetic capacities, leading to a possible conclusion that the body itself is best understood as a “prosthesis.” For better or worse, Scripture is and will be adduced on both sides of the debate and often in the form of proof-texting rather than actual consideration of the materials. So, it seems not only reasonable but necessary to reopen the idea of how scriptural materials conceive of the body–self relationship. This is happening in some quarters (e.g. Thweatt-Bates, Cyborg Selves), but the use of biblical materials is not particularly strong. Hence, the viability of this project. This is a first foray into that matter and Paul is a good starting place since the question of the human being as an embodied being occupies a place of importance in many of his letters, especially Romans, 1 and 2 Corinthians, and 1 Thessalonians.
The sense of an ending: Take III
Authors: Janzen J. Gerald
Published: February 2015

Julian Barnes’s novel, The Sense of an Ending, follows his autobiographical meditation on mortality, Nothing to be Frightened Of, in offering a dystopian view of the meaningfulness of existence (“what it all adds up to”) in the face of an ending that amounts to annihilation, for the self and ultimately for the cosmos. In this he follows Frank Kermode’s elegant study in the theory of fiction, The Sense of an Ending, in which Kermode traces the fate of the modern novel in the wake, as he sees it, of the death of the traditional, biblically-grounded sense of existence as arising, continuing and ending under the providential hand of God. The present article provides the author’s own take on these issues, as exemplified in the experience—concurrent with reading Barnes—of a death in the family. The question arises, in this context: How do we assess competing claims to authenticy, and countering claims to mauvais foi, bad faith?
Democracy and critique
Authors: Chambers Simone
Published: February 2015

In this article I challenge Rainer Forst’s model of critical theory from the point of view of democratic theory. I suggest that his approach is too abstract and hypothetical to address the real world challenges facing democratic polities today.
Scientific and Regulatory Policy Committee Points-to-consider Paper*
Authors: Frazier Kendall S. , Engelhardt Jeffery A. , Fant Pierluigi , Guionaud Silvia , Henry Scott P. , Leach Michael W. , Louden Calvert , Scicchitano Marshall S. , Weaver James L. , Zabka Tanja S.
Published: February 2015

Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. Although DIVI in laboratory animal species has been well characterized for vasoactive small molecules, there is little available information regarding DIVI associated with biotherapeutics such as peptides/proteins or antibodies. Because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans and the lack of robust biomarkers of DIVI, preclinical DIVI findings can cause considerable delays in or even halt development of promising new drugs. This review discusses standard terminology, characteristics, and mechanisms of DIVI associated with biotherapeutics. Guidance and points to consider for the toxicologist and pathologist facing preclinical cases of biotherapeutic-related DIVI are outlined, and examples of regulatory feedback for each of the mechanistic types of DIVI are included to provide insight into risk assessment.
Prevalence and disability of headache among Norwegian adolescents: A cross-sectional school-based study
Authors: Krogh Anne-Berit , Larsson Bo , Linde Mattias
Published: February 2015

Background

Headache is common in adolescents and affects schoolwork and relations with friends and family. In most previous epidemiological surveys, only the most bothersome headache has been documented. The aim was to determine headache prevalence not only taking into account the most bothersome headache, but also to compare characteristics of the most bothersome and less bothersome headaches, and to investigate headache-related disability.

Methods

A cross-sectional school-based study was conducted in which 493 representative adolescents aged 12–18 years were recruited by stratified cluster sampling and interviewed. Headache diagnosis was made according to the new classification system of the International Headache Society (ICHD-3 beta), and the Pediatric Migraine Disability Assessment (PedMIDAS) was used to evaluate disability.

Results

The one-year prevalence of any headache type, definite migraine, probable migraine and tension-type headache was 88%, 23%, 13% and 58%, respectively. The point prevalence of any headache was 38%. Nine percent of participants fulfilled criteria for more than one headache diagnosis. The most bothersome headache had a significantly longer duration ( p < 0.001) and higher intensity ( p < 0.001) than the less bothersome headache, but similar frequency ( p = 0.86). Adolescents with headaches lost up to nine days of activity each year, implicating headache as a major health issue.

Conclusions

Headaches are very common and disabling among adolescents. The full extent of this health problem is better appreciated if inquiry is not limited to the most bothersome subtypes.
Height, Weight, and Age Predict Quadriceps Tendon Length and Thickness in Skeletally Immature Patients
Authors: Todd Dane C. , Ghasem Alexander D. , Xerogeanes John W.
Published: February 2015

Background:

Quadriceps tendon autografts have been used with success in adults and are becoming a popular graft option in pediatric patients because of size, decreased donor site morbidity, ease of harvest, and favorable biomechanical characteristics. However, little is known about the length and thickness of the quadriceps tendon in pediatric patients.

Purpose:

This study aimed to determine whether quadriceps tendon length and thickness follow a predictable pattern of development based on height, weight, age, and body mass index in skeletally immature patients.

Study Design:

Cross-sectional study; Level of evidence, 3.

Methods:

The height, weight, age, and sex of 151 children between 4 and 16 years old were recorded. Ultrasound measurements of the length and thickness of bilateral quadriceps tendons were performed by a single technician and recorded for statistical analysis.

Results:

The average quadriceps tendon length and thickness were 6.87 ± 1.49 cm and 0.37 ± 0.12 cm, respectively. Tendon length averaged 3.89 cm at age 4 years and 7.98 cm at 16 years, whereas thickness averaged 0.24 cm at 4 years and 0.40 cm at 16 years of age. There was no significant difference in tendon length or thickness between males and females ( P = .97). Tendon length and thickness increased significantly with age, weight, and height ( P < .01 for all).

Conclusion:

The quadriceps tendon is of sufficient length and thickness to be used as an autograft for pediatric patients. The size of the graft is predictable using the age, height, and weight of the patient. Graft length and thickness can be easily confirmed using ultrasound.