bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytokeratin 18 is a specific marker of bovine intestinal M cell
Authors: Hondo Tetsuya , Kanaya Takashi , Takakura Ikuro , Watanabe Hitoshi , Takahashi Yu , Nagasawa Yuya , Terada Shunsuke , Ohwada Shyuichi , Watanabe Kouichi , Kitazawa Haruki , Rose Michael T. , Yamaguchi Takahiro , Aso Hisashi
Published: December 2010

Microfold (M) cells in the follicle-associated epithelium (FAE) of Peyer's patches have an important role in mucosal immune responses. A primary difficulty for investigations of bovine M cells is the lack of a specific molecular marker. To identify such a marker, we investigated the expression of several kinds of intermediate filament proteins using calf Peyer's patches. The expression patterns of cytokeratin (CK) 18 in jejunal and ileal FAE were very similar to the localization pattern of M cells recognized by scanning electron microscopy. Mirror sections revealed that jejunal CK18-positive cells had irregular and sparse microvilli, as well as pocket-like structures containing lymphocytes, typical morphological characteristic of M cells. However, CK18-negative cells had regular and dense microvilli on their surface, typical of the morphology of enterocytes. In contrast, CK20 immunoreactivity was detected in almost all villous epithelial cells and CK18-negative cells in the FAE. CK18-positive proliferating transit-amplifying cells in the crypt exchanged CK18 for CK20 above the mouth of the crypt and after moving to the villi; however, CK18-positive M cells in the crypt continued their expression of CK18 during movement to the FAE region. Terminal deoxynucleotidyl-transferase-mediated deoxyuridine-triphosphate-biotin nick-end labeling-positive apoptotic cells were specifically detected at the apical region of villi and FAE in the jejunum and ileum, and all were also stained for CK20. These data indicate that CK18 may be a molecular marker for bovine M cells in FAE and that M cells may transdifferentiate to CK20-positive enterocytes and die by apoptosis in the apex of the FAE.
Modulation of visceral hypersensitivity by glial cell line-derived neurotrophic factor family receptor α-3 in colorectal afferents
Authors: Tanaka T. , Shinoda M. , Feng B. , Albers K. M. , Gebhart G. F.
Published: December 2010

Irritable bowel syndrome is characterized by colorectal hypersensitivity and contributed to by sensitized mechanosensitive primary afferents and recruitment of mechanoinsensitive (silent) afferents. Neurotrophic factors are well known to orchestrate dynamic changes in the properties of sensory neurons. Although pain modulation by proteins in the glial cell line-derived neurotrophic factor (GDNF) family has been documented in various pathophysiological states, their role in colorectal hypersensitivity remains unexplored. Therefore, we investigated the involvement of the GDNF family receptor α-3 (GFRα3) signaling in visceral hypersensitivity by quantifying visceromotor responses (VMR) to colorectal distension before and after intracolonic treatment with 2,4,6-trinitrobenzene sulfonic acid (TNBS). Baseline responses to colorectal distension did not differ between C57BL/6 and GFRα3 knockout (KO) mice. Relative to intracolonic saline treatment, TNBS significantly enhanced the VMR to colorectal distension in C57BL/6 mice 2, 7, 10, and 14 days posttreatment, whereas TNBS-induced visceral hypersensitivity was significantly suppressed in GFRα3 KO mice. The proportion of GFRα3 immunopositive thoracolumbar and lumbosacral colorectal dorsal root ganglion neurons was significantly elevated 2 days after TNBS treatment. In single fiber recordings, responses to circumferential stretch of colorectal afferent endings in C57BL/6 mice were significantly increased (sensitized) after exposure to an inflammatory soup, whereas responses to stretch did not sensitize in GFRα3 KO mice. These findings suggest that enhanced GFRα3 signaling in visceral afferents may contribute to development of colorectal hypersensitivity.
Interrelationships between tissue iron status and erythropoiesis during postweaning development following neonatal iron deficiency in rats
Authors: Hegde Narasimha V. , Unger Erica L. , Jensen Gordon L. , Hankey Pamela A. , Paulson Robert F.
Published: December 2010

Dietary iron is particularly critical during periods of rapid growth such as in neonatal development. Human and rodent studies have indicated that iron deficiency or excess during this critical stage of development can have significant long- and short-term consequences. Since the requirement for iron changes during development, the availability of adequate iron is critical for the differentiation and maturation of individual organs participating in iron homeostasis. We have examined in rats the effects of dietary iron supplement following neonatal iron deficiency on tissue iron status in relation to erythropoietic ability during 16 wk of postweaning development. This physiological model indicates that postweaning iron-adequate diet following neonatal iron deficiency adversely affects erythroid differentiation in the bone marrow and promotes splenic erythropoiesis leading to splenomegaly and erythrocytosis. This altered physiology of iron homeostasis during postweaning development is also reflected in the inability to maintain liver and spleen iron concentrations and the altered expression of iron regulatory proteins in the liver. These studies provide critical insights into the consequences of neonatal iron deficiency and the dietary iron-induced cellular signals affecting iron homeostasis during early development.
Inhibition of gastric motility by hyperglycemia is mediated by nodose ganglia KATP channels
Authors: Zhou Shi-Yi , Lu Yuanxu , Song Il , Owyang Chung
Published: December 2010

The inhibitory action of hyperglycemia is mediated by vagal afferent fibers innervating the stomach and duodenum. Our in vitro studies showed that a subset of nodose ganglia neurons is excited by rising ambient glucose, involving inactivation of ATP-sensitive K+ (KATP) channels and leading to membrane depolarization and neuronal firing. To investigate whether nodose ganglia KATP channels mediate gastric relaxation induced by hyperglycemia, we performed in vivo gastric motility studies to examine the effects of KATP channel activators and inactivators. Intravenous infusion of 20% dextrose induced gastric relaxation in a dose-dependent manner. This inhibitory effect of hyperglycemia was blocked by diazoxide, a KATP channel activator. Conversely, tolbutamide, a KATP channel inactivator, induced dose-dependent gastric relaxation, an effect similar to hyperglycemia. Vagotomy, perivagal capsaicin treatment, and hexamethonium each prevented the inhibitory action of tolbutamide. Similarly, NG-nitro-l-arginine methyl ester, an inhibitor of nitric oxide synthase, also blocked tolbutamide's inhibitory effect. To show that KATP channel inactivation at the level of the nodose ganglia induces gastric relaxation, we performed electroporation of the nodose ganglia with small interfering RNA of Kir6.2 (a subunit of KATP) and plasmid pEGFP-N1 carrying the green fluorescent protein gene. The gastric responses to hyperglycemia and tolbutamide were not observed in rats with Kir6.2 small interfering RNA-treated nodose ganglia. However, these rats responded to secretin, which acts via the vagal afferent pathway, independently of KATP channels. These studies provide in vivo evidence that hyperglycemia induces gastric relaxation via the vagal afferent pathway. This action is mediated through inactivation of nodose ganglia KATP channels.
Temporal relationships between wall motion, intraluminal pressure, and flow in the isolated rabbit small intestine
Authors: Dinning P. G. , Arkwright J. W. , Costa M. , Wiklendt L. , Hennig G. , Brookes S. J. H. , Spencer N. J.
Published: December 2010

Intraluminal manometry is a tool commonly used to record motility in the human digestive tract. The recorded signal results from a combination of factors, including the hydrodynamic pressure transmitted through the intestinal contents due to contraction of the gut wall and the force of the gut wall acting on the sensors in regions of a luminal occlusion. However, the actual relationships between small bowel wall contraction, the measured intraluminal pressure, and the resultant flow have not been directly addressed. Video recording and high-resolution fiber-optic manometry were used to create spatiotemporal video maps of diameter and intraluminal pressure from isolated segments of rabbit small intestine. In the unstimulated gut, longitudinal muscle contractions were the only detectable motor pattern; circular muscle contractions were elicited by distension or erythromycin (1 μM). Longitudinal muscle contractions were not lumen-occlusive, although they caused measurable low-amplitude changes in pressure. Localized nonpropagating circular muscle contractions caused small localized, nonpropagating peaks of intraluminal pressure. Propagating contractions of circular muscle evoked larger, propagating pressure changes that were associated with outflow. Propagating circular muscle contractions often caused dilation of aboral receiving segments, corresponding to “common cavities”; these were propulsive, despite their low intraluminal pressure. The highest-amplitude pressure events were caused by lumen-occlusive circular muscle contractions that squeezed directly against the catheter. These data allow us to define the complex relationships between wall motion, intraluminal pressure, and flow. A strong correlation between circular and longitudinal muscle contraction and intraluminal pressure was demonstrated. Common-cavity pressure events, caused by propulsion of content by circular muscle contractions into a receptive segment, were often of low amplitude but were highly propulsive. Studies of wall motion in isolated preparations, combined with manometry, can assist in interpretation of pressure recordings in vivo.
Lack of microsomal prostaglandin E synthase-1 reduces cardiac function following angiotensin II infusion
Authors: Harding Pamela , Yang Xiao-Ping , He Quan , LaPointe Margot C.
Published: December 2010

Our laboratory previously reported that inducible PGE2 synthase, mPGES-1, contributes to micromolar production of PGE2 in neonatal ventricular myocytes in vitro, which stimulates their growth. We therefore hypothesized that mPGES-1 contributes to cardiac hypertrophy following angiotensin II (ANG II) infusion. To test this hypothesis, we used 10- to 12-wk-old mPGES-1 knockout mice (mPGES-1 KO) and C57Bl/6 control mice infused for 8 wk with either 1.4 mg·kg−1·day−1 ANG II or vehicle subcutaneously. Blood pressure [systolic blood pressure (SBP)] was measured throughout the study, and cardiac function was assessed by M-mode echocardiography at baseline and at 8 wk of infusion. At the conclusion of the study, immunohistochemistry was used to evaluate collagen fraction, myocyte cross-sectional area (MCSA), and apoptosis. At baseline, there was no difference in SBP between mPGES-1 KO mice and C57BL/6 controls. ANG II infusion increased SBP to similar levels in both strains. In control mice, infusion of ANG II increased MCSA and posterior wall thickness at diastole (PWTd) but had little effect on cardiac function, consistent with compensatory hypertrophy. In contrast, cardiac function was worse in mPGES-1 KO mice after ANG II treatment. Ejection fraction declined from 76.2 ± 2.7 to 63.3 ± 3.4% after ANG II, and left ventricular dimension at systole and diastole increased from 1.29 ± 0.02 to 1.78 ± 0.15 mm and from 2.57 ± 0.03 to 2.90 ± 0.13 mm, respectively. Infusion of ANG II increased both the LV-to-body weight and the mass-to-body weight ratios to a similar extent in both strains. However, PWTd increased by a lesser extent in KO mice, suggesting an impaired hypertrophic response. ANG II infusion increased collagen staining similarly in both strains, but TdT-dUTP nick end labeling staining was greater in mPGES-1 KO mice. Overall, these results are consistent with a beneficial effect for mPGES-1 in the maintenance of cardiac function in ANG II-dependent hypertension.
Differential contribution of mitochondria, NADPH oxidases, and glycolysis to region-specific oxidant stress in the anoxic-reoxygenated embryonic heart
Authors: Raddatz Eric , Thomas Anne-Catherine , Sarre Alexandre , Benathan Messod
Published: December 2010

The ability of the developing myocardium to tolerate oxidative stress during early gestation is an important issue with regard to possible detrimental consequences for the fetus. In the embryonic heart, antioxidant defences are low, whereas glycolytic flux is high. The pro- and antioxidant mechanisms and their dependency on glucose metabolism remain to be explored. Isolated hearts of 4-day-old chick embryos were exposed to normoxia (30 min), anoxia (30 min), and hyperoxic reoxygenation (60 min). The time course of ROS production in the whole heart and in the atria, ventricle, and outflow tract was established using lucigenin-enhanced chemiluminescence. Cardiac rhythm, conduction, and arrhythmias were determined. The activity of superoxide dismutase, catalase, gutathione reductase, and glutathione peroxidase as well as the content of reduced and oxidized glutathione were measured. The relative contribution of the ROS-generating systems was assessed by inhibition of mitochondrial complexes I and III (rotenone and myxothiazol), NADPH oxidases (diphenylene iodonium and apocynine), and nitric oxide synthases ( N-monomethyl-l-arginine and N-iminoethyl-l-ornithine). The effects of glycolysis inhibition (iodoacetate), glucose deprivation, glycogen depletion, and lactate accumulation were also investigated. In untreated hearts, ROS production peaked at 10.8 ± 3.3, 9 ± 0.8, and 4.8 ± 0.4 min (means ± SD; n = 4) of reoxygenation in the atria, ventricle, and outflow tract, respectively, and was associated with arrhythmias. Functional recovery was complete after 30–40 min. At reoxygenation, 1) the respiratory chain and NADPH oxidases were the main sources of ROS in the atria and outflow tract, respectively; 2) glucose deprivation decreased, whereas glycogen depletion increased, oxidative stress; 3) lactate worsened oxidant stress via NADPH oxidase activation; 4) glycolysis blockade enhanced ROS production; 5) no nitrosative stress was detectable; and 6) the glutathione redox cycle appeared to be a major antioxidant system. Thus, the glycolytic pathway plays a predominant role in reoxygenation-induced oxidative stress during early cardiogenesis. The relative contribution of mitochondria and extramitochondrial systems to ROS generation varies from one region to another and throughout reoxygenation.
Regulation of in vivo cardiac contractility by phospholemman: role of Na+/Ca2+exchange
Authors: Wang JuFang , Gao Erhe , Rabinowitz Joseph , Song Jianliang , Zhang Xue-Qian , Koch Walter J. , Tucker Amy L. , Chan Tung O. , Feldman Arthur M. , Cheung Joseph Y.
Published: December 2010

Phospholemman (PLM), when phosphorylated at serine 68, relieves its inhibition on Na+-K+-ATPase but inhibits Na+/Ca2+exchanger 1 (NCX1) in cardiac myocytes. Under stress when catecholamine levels are high, enhanced Na+-K+-ATPase activity by phosphorylated PLM attenuates intracellular Na+concentration ([Na+]i) overload. To evaluate the effects of PLM on NCX1 on in vivo cardiac contractility, we injected recombinant adeno-associated virus (serotype 9) expressing either the phosphomimetic PLM S68E mutant or green fluorescent protein (GFP) directly into left ventricles (LVs) of PLM-knockout (KO) mice. Five weeks after virus injection, ∼40% of isolated LV myocytes exhibited GFP fluorescence. Expression of S68E mutant was confirmed with PLM antibody. There were no differences in protein levels of α1- and α2-subunits of Na+-K+-ATPase, NCX1, and sarco(endo)plasmic reticulum Ca2+-ATPase between KO-GFP and KO-S68E LV homogenates. Compared with KO-GFP myocytes, Na+/Ca2+exchange current was suppressed, but resting [Na+]i, Na+-K+-ATPase current, and action potential amplitudes were similar in KO-S68E myocytes. Resting membrane potential was slightly lower and action potential duration at 90% repolarization (APD90) was shortened in KO-S68E myocytes. Isoproterenol (Iso; 1 μM) increased APD90in both groups of myocytes. After Iso, [Na+]iincreased monotonically in paced (2 Hz) KO-GFP but reached a plateau in KO-S68E myocytes. Both systolic and diastolic [Ca2+]iwere higher in Iso-stimulated KO-S68E myocytes paced at 2 Hz. Echocardiography demonstrated similar resting heart rate, ejection fraction, and LV mass between KO-GFP and KO-S68E mice. In vivo closed-chest catheterization demonstrated enhanced contractility in KO-S68E compared with KO-GFP hearts stimulated with Iso. We conclude that under catecholamine stress when [Na+]iis high, PLM minimizes [Na+]ioverload by relieving its inhibition of Na+-K+-ATPase and preserves inotropy by simultaneously inhibiting Na+/Ca2+exchanger.
IκBα degradation is necessary for skeletal muscle atrophy associated with contractile claudication
Authors: Hain Brian A. , Dodd Stephen L. , Judge Andrew R.
Published: January 2011

The arterial blockage in patients with peripheral arterial disease (PAD) restricts oxygen delivery to skeletal muscles distal to the blockage. In advanced-stage PAD patients, this creates a chronic ischemic condition in the affected muscles. However, in the majority of PAD patients, the muscles distal to the blockage only become ischemic during physical activity when the oxygen demands of these muscles are increased. Therefore, the skeletal muscle of most PAD patients undergoes repeated cycles of low-grade ischemia-reperfusion each time the patient is active and then rests. This has been speculated to contribute to the biochemical and morphological myopathies observed in PAD patients. The current study aimed to determine, using a rodent model, whether repeated hind limb muscle contractions during blood flow restriction to the hind limb muscles increases NF-κB activity. We, subsequently, determined whether an increase in NF-κB activity during this condition is required for the increased transcription of specific atrophy-related genes and muscle fiber atrophy. We found that hind limb muscle contractions during blood flow restriction to the limb increased NF-κB activity, the transcription of specific atrophy-related genes, and caused a 35% decrease in muscle fiber cross-sectional area. We further found that inhibition of NF-κB activity, via gene transfer of a dominant-negative inhibitor of κBα (d.n. IκBα), prevented the increase in atrophy gene expression and muscle fiber atrophy. These findings demonstrate that when blood flow to skeletal muscle is restricted, repeated cycles of muscle contraction can cause muscle fiber atrophy that requires NF-κB-IκBα signaling.
Differential contribution of central command to the cardiovascular responses during static exercise of ankle dorsal and plantar flexion in humans
Authors: Liang Nan , Nakamoto Tomoko , Mochizuki Seina , Matsukawa Kanji
Published: December 2010

To examine whether central command contributes differently to the cardiovascular responses during voluntary static exercise engaged by different muscle groups, we encouraged healthy subjects to perform voluntary and electrically evoked involuntary static exercise of ankle dorsal and plantar flexion. Each exercise was conducted with 25% of the maximum voluntary force of the right ankle dorsal and plantar flexion, respectively, for 2 min. Heart rate (HR) and mean arterial blood pressure (MAP) were recorded, and stroke volume, cardiac output (CO), and total peripheral resistance were calculated. With voluntary exercise, HR, MAP, and CO significantly increased during dorsal flexion (the maximum increase, HR: 12 ± 2.3 beats/min; MAP: 14 ± 2.0 mmHg; CO: 1 ± 0.2 l/min), whereas only MAP increased during plantar flexion (the maximum increase, 6 ± 2.0 mmHg). Stroke volume and total peripheral resistance were unchanged throughout the two kinds of voluntary static exercise. With involuntary exercise, there were no significant changes in all cardiovascular variables, irrespective of dorsal or plantar flexion. Furthermore, before the force onset of voluntary static exercise, HR and MAP started to increase without muscle contraction, whereas they had no significant changes with involuntary exercise at the moment. The present findings indicate that differential contribution of central command is responsible for the different cardiovascular responses to static exercise, depending on the strength of central control of the contracting muscle.
EM Algorithm for Mapping Quantitative Trait Loci in Multivalent Tetraploids
Authors: Li Jiahan , Das Kiranmoy , Fu Guifang , Tong Chunfa , Li Yao , Tobias Christian , Wu Rongling
Published: January 2011

Multivalent tetraploids that include many plant species, such as potato, sugarcane, and rose, are of paramount importance to agricultural production and biological research. Quantitative trait locus (QTL) mapping in multivalent tetraploids is challenged by their unique cytogenetic properties, such as double reduction. We develop a statistical method for mapping multivalent tetraploid QTLs by considering these cytogenetic properties. This method is built in the mixture model-based framework and implemented with the EM algorithm. The method allows the simultaneous estimation of QTL positions, QTL effects, the chromosomal pairing factor, and the degree of double reduction as well as the assessment of the estimation precision of these parameters. We used simulated data to examine the statistical properties of the method and validate its utilization. The new method and its software will provide a useful tool for QTL mapping in multivalent tetraploids that undergo double reduction.
Spatiotemporal Analysis of Multichannel EEG: CARTOOL
Authors: Brunet Denis , Murray Micah M. , Michel Christoph M.
Published: January 2011

This paper describes methods to analyze the brain's electric fields recorded with multichannel Electroencephalogram (EEG) and demonstrates their implementation in the software CARTOOL. It focuses on the analysis of the spatial properties of these fields and on quantitative assessment of changes of field topographies across time, experimental conditions, or populations. Topographic analyses are advantageous because they are reference independents and thus render statistically unambiguous results. Neurophysiologically, differences in topography directly indicate changes in the configuration of the active neuronal sources in the brain. We describe global measures of field strength and field similarities, temporal segmentation based on topographic variations, topographic analysis in the frequency domain, topographic statistical analysis, and source imaging based on distributed inverse solutions. All analysis methods are implemented in a freely available academic software package called CARTOOL. Besides providing these analysis tools, CARTOOL is particularly designed to visualize the data and the analysis results using 3-dimensional display routines that allow rapid manipulation and animation of 3D images. CARTOOL therefore is a helpful tool for researchers as well as for clinicians to interpret multichannel EEG and evoked potentials in a global, comprehensive, and unambiguous way.
Anti-DLL4 Inhibits Growth and Reduces Tumor-Initiating Cell Frequency in Colorectal Tumors with Oncogenic KRAS Mutations
Authors: Fischer Marcus , Yen Wan-Ching , Kapoun Ann M. , Wang Min , O'Young Gilbert , Lewicki John , Gurney Austin , Hoey Timothy
Published: December 2010

KRAS mutations are frequent in colorectal cancer (CRC) and are associated with clinical resistance to treatment with the epidermal growth factor receptor (EGFR)–targeted monoclonal antibodies. Delta-like 4 ligand (DLL4) is an important component of the Notch signaling pathway and mediates stem cell self-renewal and vascular development. DLL4 inhibition in colon tumor cells reduces tumor growth and stem cell frequency. Considering the need for new drugs to treat colon cancers with oncogenic KRAS mutations, we examined in this study the efficacy of anti-DLL4 antibodies in KRAS mutant tumors in a panel of early passage colon tumor xenograft models derived from patients. Consistent with clinical findings, mutant KRAS colorectal xenograft tumors were insensitive to the EGFR therapeutic antibody cetuximab, whereas KRAS wild-type tumors responded to cetuximab. In contrast, anti-DLL4 was efficacious against both wild-type and mutant KRAS colon tumors as a single agent and in combination with irinotecan. Further analysis of mutant KRAS tumors indicated that the anti-DLL4/irinotecan combination produced a significant decrease in colon cancer stem cell frequency while promoting apoptosis in tumor cells. Our findings provide a rationale for targeting DLL4-Notch signaling for improved treatment of CRC patients with activating KRAS mutations. Cancer Res; 71(5); 1520–5. ©2010 AACR.
CXCR4 Promotes Oral Squamous Cell Carcinoma Migration and Invasion through Inducing Expression of MMP-9 and MMP-13 via the ERK Signaling Pathway
Authors: Yu Tao , Wu Yingying , Helman Joseph I. , Wen Yuming , Wang Changmei , Li Longjiang
Published: January 2011

The increased migration and invasion of oral squamous cell carcinoma cells are key events in the development of metastasis to the lymph nodes and distant organs. Although the chemokine receptor CXCR4 and its ligand, stromal cell–derived factor-1α, have been found to play an important role in tumor invasion, its precise role and potential underlying mechanisms remain largely unknown. In this study, we showed that knockdown of CXCR4 significantly decreased Tca8113 cells migration and invasion, accompanied with the reduction of MMP-9 and MMP-13 expression. Inhibition of ligand binding to CXCR4 by a specific antagonist TN14003, also led to reduced cancer cell migration and invasion. Because the degradation of the extracellular matrix and the basement membrane by proteases, such as matrix metalloproteinases (MMP) is critical for migration and invasion of cancer cells, we investigated the expression of several MMPs and found that the expression of functional MMP-9 and MMP-13 was selectively decreased in CXCR4 knockdown cells. More importantly, decreased cell migration and invasion of CXCR4 knockdown cells were completely rescued by exogenous expression of MMP-9 or MMP-13, indicating that the two MMPs are downstream targets of CXCR4-mediated signaling. Furthermore, we found the level of phosphorylated extracellular signal-regulated kinase (ERK) was significantly decreased in CXCR4-silenced cells, suggesting that ERK may be a potential mediator of CXCR4-regulated MMP-9 and MMP-13 expression in Tca8113 cells. Taken together, our results strongly suggest the underlying mechanism of CXCR4 promoting Tca8113 migration and invasion by regulating MMP-9 and MMP-13 expression perhaps via activation of the ERK signaling pathway. Mol Cancer Res; 9(2); 161–72. ©2011 AACR.
Tetanus Immunity in Neonates in a Developed Country
Authors: Prusa Andrea-Romana , Wiedermann Ursula , Kasper David C. , Hayde Michael , Helmer Hanns , Pollak Arnold , Förster-Waldl Elisabeth
Published: January 2011

Objective: In consideration of comprehensive and well-established vaccination programmes in industrialized countries, it is expected that immunity against tetanus among expectant mothers and their offspring is complete. Our study evaluated seroprotection against tetanus among newborns in Austria, who may gain passive immunity by transplacental transfer of maternal tetanus antibody. Methods: Cord blood samples from 99 deliveries were analyzed for antibody concentration against tetanus toxoid by standardized ELISA. Results: 85/99 (85.8%) individuals presented with levels of tetanus immunity having a protective antibody concentration ≧0.1 IU/ml. 9/99 (9.1%) samples showed low seropositivity, while in 5/99 (5.1%) samples no tetanus antibodies could be detected. The median antibody concentration was 0.95 IU/ml. Conclusions: Our data provide evidence for a lack of adequate tetanus immunity in 14.2% of newborns delivered in an Austrian University Hospital. This investigation is emphasizing the importance of stringent regimens concerning prenatal vaccination care, even in countries with generalized immunization programs. If indicated, maternal immunization during pregnancy should be initiated for protection of newborns.
A Long-Term Study of Photodynamic Therapy with Verteporfin for Choroidal Neovascularization at the Edge of Chorioretinal Atrophy in Pathologic Myopia
Authors: Pece Alfredo , Milani Paolo , Isola Vincenzo , Pierro Luisa
Published: January 2011

Purpose: To evaluate the effects of verteporfin photodynamic therapy (PDT) on choroidal neovascularization (CNV) at the edge of chorioretinal atrophy in eyes with pathologic myopia. Procedures: Twenty eyes of 20 consecutive patients were treated according to Verteporfin in Photodynamic Therapy criteria. The patients were divided into 3 groups based on CNV location and were followed up with clinical and fluorescein angiographic examinations to evaluate visual acuity (VA) changes and number of treatments. Results: The mean follow-up was 35 months. In group 1 (n = 8; subfoveal CNV), VA declined from 20/73 (0.56 ± 0.26 logMAR) to 20/115 (0.76 ± 0.30 logMAR; p = 0.192). In group 2 (n = 6; juxtafoveal CNV), VA improved from 20/69 (0.54 ± 0.25 logMAR) to 20/46 (0.36 ± 0.16 logMAR; p = 0.176). In group 3 (n = 6; extrafoveal CNV), VA worsened from 20/50 (0.40 ± 0.21 logMAR) to 20/91 (0.66 ± 0.49 logMAR; p = 0.292). Conclusions: PDT showed inhibitory effects on myopic CNV arising at the edge of chorioretinal atrophy, especially in young adult myopic eyes with juxtafoveal neovascular membranes.
Folic Acid Enhances Early Functional Recovery in a Piglet Model of Pediatric Head Injury
Authors: Naim Maryam Y. , Friess Stuart , Smith Colin , Ralston Jill , Ryall Karen , Helfaer Mark A. , Margulies Susan S.
Published: January 2011

For stroke and spinal cord injury, folic acid supplementation has been shown to enhance neurodevelopment and to provide neuroprotection. We hypothesized that folic acid would reduce brain injury and improve neurological outcome in a neonatal piglet model of traumatic brain injury (TBI), using 4 experimental groups of 3- to 5-day-old female piglets. Two groups were intubated, anesthetized and had moderate brain injury induced by rapid axial head rotation without impact. One group of injured (Inj) animals received folic acid (Fol; 80 µg/kg) by intraperitoneal (IP) injection 15 min following injury, and then daily for 6 days (Inj + Fol; n = 7). The second group of injured animals received an IP injection of saline (Sal) at the same time points (Inj + Sal; n = 8). Two uninjured (Uninj) control groups (Uninj + Fol, n = 8; Uninj + Sal, n = 7) were intubated, anesthetized and received folic acid (80 µg/kg) or saline by IP injection at the same time points as the injured animals following a sham procedure. Animals underwent neurobehavioral and cognitive testing on days 1 and 4 following injury to assess behavior, memory, learning and problem solving. Serum folic acid and homocysteine levels were collected prior to injury and again before euthanasia. The piglets were euthanized 6 days following injury, and their brains were perfusion fixed for histological analysis. Folic acid levels were significantly higher in both Fol groups on day 6. Homocysteine levels were not affected by treatment. On day 1 following injury, the Inj + Fol group showed significantly more exploratory interest, and better motor function, learning and problem solving compared to the Inj + Sal group. Inj + Fol animals had a significantly lower cognitive composite dysfunction score compared to all other groups on day 1. These functional improvements were not seen on day 4 following injury. Axonal injury measured by β-amyloid precursor protein staining 6 days after injury was not affected by treatment. These results suggest that folic acid may enhance early functional recovery in this piglet model of pediatric head injury. This is the first study to describe the application of complex functional testing to assess an intervention outcome in a swine model of TBI.
Delirium Is an Important Predictor of Incident Dementia among Elderly Hip Fracture Patients
Authors: Krogseth Maria , Bruun Wyller Torgeir , Engedal Knut , Juliebø Vibeke
Published: January 2011

Background: Delirium is believed to constitute a risk factor for dementia, but previous research has failed to satisfactorily take account of the patients’ preexisting level of cognitive functioning. Methods: A prospective 6-month follow-up of 106 elderly hip fracture patients free from prefracture dementia. Delirium was assessed by the Confusion Assessment Method. Caregivers described the patients’ prefracture cognition by the Informant Questionnaire on Cognitive Decline in the Elderly, Short Form (IQCODE-SF). Cognition was measured after 6 months, using 5 validated cognitive tests. An expert panel assessed each case as to whether the diagnostic criteria for dementia according to the DSM-IV were fulfilled at baseline and after 6 months. Results: 29/106 patients (27%) developed delirium in the acute phase. In the delirious group, 11/29 (38%) fulfilled the criteria of dementia after 6 months, compared to 5/77 (7%) in the group without delirium (p < 0.001; χ2 test). Delirium was the strongest predictor of dementia after 6 months (adjusted odds ratio: 10.5; 95% CI: 1.6–70.3). IQCODE-SF score was a nonsignificant risk factor for incident dementia. Conclusion: In hip fracture patients free from prefracture dementia, delirium constitutes the main predictor of dementia 6 months later, adjusted for prefracture cognitive decline measured by the IQCODE-SF.
A Randomized Comparison of Target-Controlled Infusion of Remifentanil and Propofol with Desflurane and Fentanyl for Laryngeal Surgery
Authors: Wang Y. , Yan M. , He J.G. , Zhu Y.M. , Hu X.S. , Li X. , Wu W.D.
Published: January 2011

Aims: To compare the clinical profile of target-controlled infusion (TCI) of remifentanil (REM) + propofol (PRO) with fentanyl (FEN) bolus infusion with desflurane (DES) inhalation in direct laryngoscopic surgery. Methods: Sixty patients who were scheduled to undergo laryngoscopic surgery were randomly assigned to two groups (n = 30, respectively). One group of patients received a TCI of REM + PRO anesthetic treatment, while the patients in the other group received a bolus infusion of FEN and DES inhalation treatment. The hemodynamics, recovery profiles and unexpected events that occurred in both groups were recorded. Results: The hemodynamics of the patients in the TCI group was more stable during tracheal intubation, direct laryngoscope insertion and extubation. The mean arterial pressure was also significantly lower in the TCI group compared with the FEN/DES group. The TCI group also showed faster recovery profiles (e.g. a shorter time needed for response to verbal commands, autonomous breathing, tracheal extubation and orientation recovery). The FEN/DES group had lower Stewart recovery scores during the first 15 min determined at the postanesthesia care unit. However, there were no significant differences regarding the occurrence of unexpected events and postoperative complications between the two groups. Conclusions: TCI of REM + PRO anesthesia appears to be a reasonable alternative to FEN bolus infusion combined with DES inhalation during direct laryngoscopic surgery.
Burden of Resistant Hypertension in Hypertensive Patients with Non-Dialysis Chronic Kidney Disease
Authors: De Nicola Luca , Borrelli Silvio , Gabbai Francis B. , Chiodini Paolo , Zamboli Pasquale , Iodice Carmela , Vitiello Santo , Conte Giuseppe , Minutolo Roberto
Published: January 2011

Background/Aims: In chronic kidney disease (CKD), no data on resistant hypertension (RH) are so far available despite the high prevalence of uncontrolled hypertension. We evaluated frequency, correlates and prognosis of RH in 300 consecutive incident hypertensive CKD patients in an academic renal clinic. Methods: RH was defined as office blood pressure (BP) ≧130/80 mm Hg despite ≧3 drugs at full dose including a diuretic, or as BP at goal with ≧4 full-dose drugs. Patients were evaluated at referral and after 6 months of nephrology management; thereafter, they were included in a renal survival analysis lasting 37.6 months. Results: On referral, glomerular filtration rate was 41.3 ± 16.6 ml/min/1.73 m2 and BP 148 ± 23/81 ± 12 mm Hg. After 6 months, BP decreased by 8 ± 23/3 ± 12 mm Hg. From referral to month 6, RH detection increased from 26 to 38% due to the significant increment in full-dose antihypertensive medications (from 2.0, IQR 1.0–3.0 to 2.5, IQR 2.0–3.0). Diabetes and proteinuria predicted the incidence of RH at month 6. Presence of RH at month 6 was associated with greater risk of renal death (HR, 1.85, 95% CI, 1.13–3.03), independent of main clinical features and degree of BP control. Conclusion: In CKD, RH is prevalent and associated with decreased renal survival, independent of BP levels.
Subclinical Hypothyroidism following Hemithyroidectomy: A Simple Risk-Scoring System Using Age and Preoperative Thyrotropin Level
Authors: Tomoda Chisato , Ito Yasuhiro , Kobayashi Kaoru , Miya Akihiro , Miyauchi Akira
Published: January 2011

Hypothyroidism can be a complication after a hemithyroidectomy. The aim of this study was to determine the incidence and risk factors of hypothyroidism after a hemithyroidectomy. We also recommend a risk-scoring system that can predict post-hemithyroidectomy hypothyroidism before surgery. Among 260 patients who underwent hemithyroidectomy from January to June 2005, a total of 233 were euthryoid preoperatively and were followed for more than 3 years. Biochemical subclinical hypothyroidism developed in 57 patients (24.4%). Patients who developed postoperative hypothyroidism showed higher preoperative thyroid stimulation hormone (TSH) levels and older age. A risk-scoring system was calculated by summing the score of these 2 factors (preoperative TSH level and age). The incidences of hypothyroidism were 3, 20, 39, and 70% according to the risk scores of 0, 1, 2 and 3, respectively. Potential risk of postoperative hypothyroidism should be discussed with patients before surgery.
Somatotopic Arrangement of the Corticospinal Tract at the Medullary Pyramid in the Human Brain
Authors: Kwon Hyeok Gyu , Hong Ji Heon , Lee Mi Young , Kwon Yong Hyun , Jang Sung Ho
Published: January 2011

Objectives: Somatotopic arrangements of the corticospinal tract (CST) in the human brain have been generally elucidated; however, very little is known about the somatotopy at the medullary pyramid (MP). Using diffusion tensor tractography (DTT), we investigated the somatotopic arrangement of the CST at the MP in the normal human brain. Methods: We recruited 30 healthy volunteers for this study. Diffusion tensor images were scanned using 1.5 T and the CSTs for hand and leg were obtained using FMRIB software. Normalized DTT was reconstructed using the Montreal Neurological Institute echo-planar imaging template supplied with the SPM software. Results: The hand somatotopy of the CST was located at the medial portion of the MP; in contrast, the leg somatotopy occupied the lateral portion of the MP. Conclusions: We found that the somatotopies for hand and leg were arranged in the mediolateral direction at the MP in the human brain.
Systemic and Targeted Delivery of Semaphorin 3A Inhibits Tumor Angiogenesis and Progression in Mouse Tumor Models
Authors: Casazza Andrea , Fu Xi , Johansson Irja , Capparuccia Lorena , Andersson Fredrik , Giustacchini Alice , Squadrito Mario Leonardo , Venneri Mary Anna , Mazzone Massimiliano , Larsson Erik , Carmeliet Peter , De Palma Michele , Naldini Luigi , Tamagnone Luca , Rolny Charlotte
Published: January 2011

Objective—

The role of semaphorins in tumor progression is still poorly understood. In this study, we aimed at elucidating the regulatory role of semaphorin 3A (SEMA3A) in primary tumor growth and metastatic dissemination.

Methods and Results—

We used 3 different experimental approaches in mouse tumor models: (1) overexpression of SEMA3A in tumor cells, (2) systemic expression of SEMA3A following liver gene transfer in mice, and (3) tumor-targeted release of SEMA3A using gene modified Tie2-expressing monocytes as delivery vehicles. In each of these experimental settings, SEMA3A efficiently inhibited tumor growth by inhibiting vessel function and increasing tumor hypoxia and necrosis, without promoting metastasis. We further show that the expression of the receptor neuropilin-1 in tumor cells is required for SEMA3A-dependent inhibition of tumor cell migration in vitro and metastatic spreading in vivo.

Conclusion—

In sum, both systemic and tumor-targeted delivery of SEMA3A inhibits tumor angiogenesis and tumor growth in multiple mouse models; moreover, SEMA3A inhibits the metastatic spreading from primary tumors. These data support the rationale for further investigation of SEMA3A as an anticancer molecule.
Mast Cells
Authors: Swedenborg Jesper , Mäyränpää Mikko I. , Kovanen Petri T.
Published: January 2011

Mast cells (MCs) regulate inflammation and immunity. Their granular content includes heparin, histamine, and several enzymes (tryptase, chymase, carboxypeptidase, and cathepsin G). In addition, activated MCs synthesize and release eicosanoids and a large number of cytokines and chemokines. Recent findings suggest a role of MCs in abdominal aortic aneurysms (AAAs) in humans, where they are found in the media and adventitia. Experimentally induced AAA in MC-deficient animals and animals treated with MC inhibitors demonstrate that MCs are involved in the pathogenesis of AAA via several different mechanisms. MC-dependent activation of metalloproteinases and the renin–angiotensin system, contribution to smooth muscle cell apoptosis, and release of proteolytic enzymes are some key examples. Human studies indicate that MCs are the main source of cathepsin G in AAAs and contribute to activation of the renin–angiotensin system via chymase and cathepsin G. Activated MCs also contribute to neovascularization, inflammation, and atherosclerosis, all hallmarks of AAA. Thus, we may envision that MC stabilizing agents, as well as leukotriene receptor antagonists and histamine receptor blockers already in clinical use for treatment of other diseases, could also be tested for their efficacy in preventing development and growth of AAA.
Primary Prevention of Sudden Cardiac Death in Silent Cardiac Sarcoidosis
Authors: Mehta Davendra , Mori Neil , Goldbarg Seth H. , Lubitz Steven , Wisnivesky Juan P. , Teirstein Alvin
Published: December 2010

Background—

Cardiac involvement in sarcoidosis is often silent and may lead to sudden death. This study was designed to assess the value of programmed electric stimulation of the ventricle (PES) for risk stratification in patients with sarcoidosis and evidence of preclinical cardiac involvement on imaging studies.

Methods and Results—

Patients with biopsy-proven systemic sarcoidosis but without cardiac symptoms who had evidence of cardiac sarcoidosis on positron emission tomography (PET) or cardiac MRI (CMR) were included. All patients underwent baseline evaluation, echocardiographic assessment of left ventricular function, and programmed electric stimulation of the ventricle. Patients were followed for survival and arrhythmic events. Seventy-six patients underwent PES of the ventricle. Eight (11%) were inducible for sustained ventricular arrhythmias and received an implantable defibrillator. None of the noninducible patients received a defibrillator. Left ventricular ejection fraction was lower in patients with inducible ventricular arrhythmia (36.4±4.2% versus 55.8±1.5%,
P
<0.05). Over a median follow-up of 5 years, 6 of 8 patients in the group with inducible ventricular arrhythmias had ventricular arrhythmia or died, compared with 1 death in the negative group (
P
<0.0001).

Conclusions—

In patients with biopsy-proven sarcoidosis and evidence of cardiac involvement on PET or CMR alone, positive PES may help to identify patients at risk for ventricular arrhythmia. More importantly, patients in this cohort with a negative PES appear to have a benign course within the first several years following diagnosis. PES may help to guide the use of implantable cardioverter defibrillators in this population.
Regional Thicknesses and Thickening of Compacted and Trabeculated Myocardial Layers of the Normal Left Ventricle Studied by Cardiovascular Magnetic Resonance
Authors: Dawson Dana K. , Maceira Alicia M. , Raj Vimal J. , Graham Catriona , Pennell Dudley J. , Kilner Philip J.
Published: December 2010

Background—

We used cardiovascular magnetic resonance (CMR) to study normal left ventricular (LV) trabeculation as a basis for differentiation from pathological noncompaction.

Methods and Results—

The apparent end-diastolic (ED) and end-systolic (ES) thicknesses and thickening of trabeculated and compacted myocardial layers were measured in 120 volunteers using a consistent selection of basal, mid, and apical CMR short-axis slices. All had a visible trabeculated layer in 1 or more segments. The compacted but not the trabeculated layer was thicker in men than in women (
P
<0.01 at ED and ES). When plotted against age, the trabeculated and compacted layer thicknesses demonstrated opposite changes: an increase of the compact layer after the fourth decade at both ED and ES (
P
<0.05) but a decrease of the trabeculated layer. There was age-related preservation of total wall thickness at ED but an increase at ES (
P
<0.05). The compacted layer thickened, whereas the trabeculated layer thinned with systole, but neither change differed between sexes. With age, the most trabeculated LV segments showed significantly greater systolic thinning of trabeculated layers and, conversely, greater thickening of the compact segments (
P
<0.05). Total wall thickening is neither sex nor age dependent. There were no sex differences in the trabeculated/compacted ratio at ES or ED, but the ES trabeculated/compacted ratio was smaller in older (50 to 79 years) versus younger (20 to 49 years) groups (
P
<0.05).

Conclusions—

We demonstrated age- and sex-related morphometric differences in the apparent trabeculated and compacted layer thicknesses and systolic thinning of the visible trabeculated layer that contrasts with compacted myocardial wall thickening.
Evaluation of Polymer-Based Comparator Drug-Eluting Stents Using a Rabbit Model of Iliac Artery Atherosclerosis
Authors: Nakazawa Gaku , Nakano Masataka , Otsuka Fumiyuki , Wilcox Josiah N. , Melder Robert , Pruitt Sean , Kolodgie Frank D. , Virmani Renu
Published: January 2011

Background—

Although atherosclerotic models, especially in the rabbit, have existed for a long time, a comparative study of various drug-eluting stent (DES) implantations in atherosclerotic arteries have not been systematically studied.

Methods and Results—

New Zealand White rabbits (n=44) with induced atheroma received bilateral iliac artery stents: bare metal stent (BMS) (Driver) or a stent eluting zotarolimus (ZES) (Endeavor), sirolimus (SES) (Cypher), or everolimus (EES) (Xience V). After 28 days, tissues were harvested for histomorphometric analyses,
en face
analysis of endothelial coverage, and expression of endothelial nitric oxide synthase (eNOS). Area measurements of external elastic lamina and stent area were similar. Neointimal area was significantly less in all DES versus BMS, which was least in SES and EES; similar trends were noted for cell proliferation. Uncovered struts were greater for SES and EES and least in BMS, whereas ZES were in between and associated with the least fibrin. Macrophages of the neointima were significantly less for all DES relative to BMS. Plaque calcification underneath stents, however, was significantly greater in SES and ZES than in BMS. Although endothelial coverage in between struts was comparable between BMS and DES, there was significantly greater expression of eNOS in BMS and ZES relative to EES and SES.

Conclusions—

The rabbit atherosclerotic model of stenting showed delayed healing and significantly greater reduction of neointima following implantation of SES and EES; however, delayed healing was less in ZES with greater neointima (but less than BMS), endothelial regrowth, and eNOS expression.