bluuebunny/crossref_metadata_2025 huggingface dataset:
Knowledge and attitude of final - year medical students in Germany towards palliative care - an interinstitutional questionnaire-based study
Authors: Weber Martin , Schmiedel Sven , Nauck Friedemann , Alt-Epping Bernd
Published: November 2011

Background

To care for terminally ill and dying patients requires a thorough medical education, encompassing skills, knowledge, and attitudes in the field of palliative care. Undergraduate medical students in Germany will receive mandatory teaching in palliative care in the near future driven by recent changes in the Medical Licensure Act. Before new curricula can be implemented, the knowledge of medical students with respect to palliative care, their confidence to handle palliative care situations correctly, their therapeutic attitude, and their subjective assessment about previous teaching practices have to be better understood.

Method

We designed a composite, three-step questionnaire (self estimation of confidence, knowledge questions, and opinion on the actual and future medical curriculum) conducted online of final - year medical students at two universities in Germany.

Results

From a total of 318 enrolled students, 101 responded and described limited confidence in dealing with specific palliative care issues, except for pain therapy. With regard to questions examining their knowledge base in palliative care, only one third of the students (33%) answered more than half of the questions correctly. Only a small percentage of students stated they had gained sufficient knowledge and experience in palliative care during their studies, and the vast majority supported the introduction of palliative care as a mandatory part of the undergraduate curriculum.

Conclusion

This study identifies medical students' limited confidence and knowledge base in palliative care in 2 German universities, and underlines the importance of providing a mandatory palliative care curriculum.
Common fixed-point results for nonlinear contractions in ordered partial metric spaces
Authors: Samet Bessem , Rajović Miloje , Lazović Rade , Stojiljković Rade
Published: November 2011

In this paper, a new class of a pair of generalized nonlinear contractions on partially ordered partial metric spaces is introduced, and some coincidence and common fixed-point theorems for these contractions are proved. Presented theorems are twofold generalizations of very recent fixed-point theorems of Altun and Erduran (Fixed Point Theory Appl 2011(Article ID 508730):10, 2011), Altun et al. (Topol Appl 157(18):2778-2785, 2010), Matthews (Proceedings of the 8th summer conference on general topology and applications, New York Academy of Sciences, New York, pp. 183-197, 1994) and many other known corresponding theorems.

2000 Mathematics Subject Classifications: 54H25; 47H10.
Hyperalgesic Activity of Kisspeptin in Mice
Authors: Spampinato Simona , Trabucco Angela , Biasiotta Antonella , Biagioni Francesca , Cruccu Giorgio , Copani Agata , Colledge William H , Sortino Maria Angela , Nicoletti Ferdinando , Chiechio Santina
Published: November 2011

Background:

Kisspeptin is a neuropeptide known for its role in the hypothalamic regulation of the reproductive axis. Following the recent description of kisspeptin and its 7-TM receptor, GPR54, in the dorsal root ganglia and dorsal horns of the spinal cord, we examined the role of kisspeptin in the regulation of pain sensitivity in mice.

Results:

Immunofluorescent staining in the mouse skin showed the presence of GPR54 receptors in PGP9.5-positive sensory fibers. Intraplantar injection of kisspeptin (1 or 3 nmol/5 μl) induced a small nocifensive response in naive mice, and lowered thermal pain threshold in the hot plate test. Both intraplantar and intrathecal (0.5 or 1 nmol/3 μl) injection of kisspeptin caused hyperalgesia in the first and second phases of the formalin test, whereas the GPR54 antagonist, p234 (0.1 or 1 nmol), caused a robust analgesia. Intraplantar injection of kisspeptin combined with formalin enhanced TRPV1 phosphorylation at Ser800 at the injection site, and increased ERK1/2 phosphorylation in the ipsilateral dorsal horn as compared to naive mice and mice treated with formalin alone.

Conclusion:

These data demonstrate for the first time that kisspeptin regulates pain sensitivity in rodents and suggest that peripheral GPR54 receptors could be targeted by novel drugs in the treatment of inflammatory pain.
Coming from behind to win - A Qualitative research about psychological conditions of adolescents who have undergone open-heart surgery for single ventricle between the ages 0-5
Authors: Zahmacioglu Oguzhan , Yildiz Cenk Eray , Koca Bulent , Ugurlucan Murat , Gokalp Selman , Cetin Gurkan , Guler Eroglu Ayse , Oztunc Funda
Published: November 2011

Early recognition of congenital cardiac pathologies and their treatment by means of palliative or corrective surgery at birth or infancy has vital importance. Successful repair of congenital cardiac defects by surgical methods has gained importance especially during the last twenty years. As the scope of the surveillance increased so did the interest in the outcomes of these treatments when the patients had reached puberty and adulthood. The purpose of our research was to study the psychological framework of the adolescents who had experienced these surgeries by listening both the children and the parents talk about their feelings and experiences. Our data was accumulated through interviews with 17 adolescents and their families, using qualitative methods. The main theme at the end of the analysis was "to be strong and resistive". We reached the conclusion that this condition was not a pathological build up but an attitude of coping, as it did not cause loss of functionality. The defensive psychological mechanisms used by these adolescents consisted of repression, compensation and reaction formation. We believe that this information is important to understand the real meaning of the manners displayed when these adolescents and their families pursue their daily lives, communicate and make relationships with their environment and especially professionals in the health services.
Risk Factors For Recurrent Stroke After Coronary Artery Bypass Grafting
Authors: Cao Li , Li Qin , Bi Qi , Yu Qin-Jun
Published: November 2011

Objectives

Preventing stroke after coronary artery bypass grafting (CABG) remains a therapeutic goal, due in part to the lack of identifiable risk factors. The aim of this study, accordingly, was to identify risk factors in CABG patients with a previous history of stroke.

Methods

Patients with a history of stroke who underwent CABG at Beijing An Zhen hospital from January 2007 to July 2010 were selected (n = 430), and divided into two groups according to the occurrence of postoperative stroke. Pre-operative and post-operative data were retrospectively collected and analyzed by univariate and multivariate logistic regression analyses.

Results

Thirty-two patients (7.4%) suffered post-operative stroke. Univariate analysis identified several statistically significant risk factors in the post-operative stroke group, including pre-surgical left ventricular ejection fractions (LVEF) ≤50%, on-pump surgery, post-operative atrial fibrillation (AF), and hypotension. Multivariable analysis identified 4 independent risk factors for recurrent stroke: unstable angina (odds ratio (OR) = 2.95, 95% CI: 1.05-8.28), LVEF ≤50% (OR = 2.77, 95% CI: 1.23-6.27), AF (OR = 4.69, 95% CI: 1.89-11.63), and hypotension (OR = 2.55, 95% CI: 1.07-6.04).

Conclusion

Unstable angina, LVEF ≤50%, post-operative AF, and post-operative hypotension are independent risk factors of recurrent stroke in CABG patients with a previous history of stroke.
Intestinal absorbability of three Radix Puerariae isoflavones including daidzein, daidzin and puerarin
Authors: Zhang Li , Pan Siu Antony Kin , Lin Ge , Zuo Zhong
Published: November 2011

Background

Radix Puerariae (Gegen) contains abundant isoflavones in the forms of glycosides and aglycones, such as daidzein, daidzin and puerarin. This study aims to investigate the intestinal absorbability and mechanism of these three structurally related isoflavones.

Methods

The bi-directional transport of these three isoflavones in Caco-2 monolayer model was performed to evaluate their absorbability and involvement of transporters in Transwell. In vitro incubation of daidzin and puerarin with rat intestinal microvilli preparation was conducted to estimate their potential form of absorption in vivo.

Results

Daidzein demonstrated passive diffusion transport while puerarin did not. Daidzin showed basolateral-to-apical transport and the absorption extent could be reduced by 50% in the presence of MK571, a multidrug resistance-associated protein inhibitor (MRP). The in vitro incubation study of daidzin and puerarin indicated that daidzin was hydrolyzed to daidzein whereas puerarin remained unchanged.

Conclusion

While daidzein was transported more efficiently, puerarin was resistant to intestinal hydrolysis and inefficiently transported across intestinal epithelium. Daidzin demonstrated a low intestinal absorbability due to a significant efflux transport mediated by MRPs. Daidzin was likely to be hydrolyzed by intestinal microvilli and subsequently released daidzein for intestinal absorption.
The rising problem of antimicrobial resistance in the intensive care unit
Authors: Brusselaers Nele , Vogelaers Dirk , Blot Stijn
Published: November 2011

Mainly due to its extremely vulnerable population of critically ill patients, and the high use of (invasive) procedures, the intensive care unit (ICU) is the epicenter of infections. These infections are associated with an important rise in morbidity, mortality, and healthcare costs. The additional problem of multidrug-resistant pathogens boosts the adverse impact of infections in ICUs. Several factors influence the rapid spread of multidrug-resistant pathogens in the ICU, e.g., new mutations, selection of resistant strains, and suboptimal infection control. Among gram-positive organisms, the most important resistant microorganisms in the ICU are currently methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. In gram-negative bacteria, the resistance is mainly due to the rapid increase of extended-spectrum Beta-lactamases (ESBLs) in Klebsiella pneumonia, Escherichia coli, and Proteus species and high level third-generation cephalosporin Beta-lactamase resistance among Enterobacter spp. and Citrobacter spp., and multidrug resistance in Pseudomonas aeruginosa and Acinetobacter species. To conclude, additional efforts are needed in the future to slow down the emergence of antimicrobial resistance. Constant evaluation of current practice on basis of trends in MDR and antibiotic consumption patterns is essential to make progress in this problematic matter.
Evaluation of a novel closed-loop fluid-administration system based on dynamic predictors of fluid responsiveness: an in silico simulation study
Authors: Rinehart Joseph , Alexander Brenton , Manach Yannick Le , Hofer Christoph K , Tavernier Benoit , Kain Zeev N , Cannesson Maxime
Published: November 2011

Introduction

Dynamic predictors of fluid responsiveness have made automated management of fluid resuscitation more practical. We present initial simulation data for a novel closed-loop fluid-management algorithm (LIR, Learning Intravenous Resuscitator).

Methods

The performance of the closed-loop algorithm was tested in three phases by using a patient simulator including a pulse-pressure variation output. In the first phase, LIR was tested in three different hemorrhage scenarios and compared with no management. In the second phase, we compared LIR with 20 practicing anesthesiologists for the management of a simulated hemorrhage scenario. In the third phase, LIR was tested under conditions of noise and artifact in the dynamic predictor.

Results

In the first phase, we observed a significant difference between the unmanaged and the LIR groups in moderate to large hemorrhages in heart rate (76 ± 8 versus 141 ± 29 beats/min), mean arterial pressure (91 ± 6 versus 59 ± 26 mm Hg), and cardiac output (CO; (6.4 ± 0.9 versus 3.2 ± 1.8 L/min) (P < 0.005 for all comparisons). In the second phase, LIR intervened significantly earlier than the practitioners (16.0 ± 1.3 minutes versus 21.5 ± 5.6 minutes; P < 0.05) and gave more total fluid (2,675 ± 244 ml versus 1,968 ± 644 ml; P < 0.05). The mean CO was higher in the LIR group than in the practitioner group (5.9 ± 0.2 versus 5.2 ± 0.6 L/min; P < 0.05). Finally, in the third phase, despite the addition of noise to the pulse-pressure variation value, no significant difference was found across conditions in mean, final, or minimum CO.

Conclusion

These data demonstrate that LIR is an effective volumetric resuscitator in simulated hemorrhage scenarios and improved physician management of the simulated hemorrhages.
Clinical relevance of single nucleotide polymorphisms within the entire NLRP3 gene in patients with major blunt trauma
Authors: Zhang An-Qiang , Zeng Ling , Gu Wei , Zhang Lian-Yang , Zhou Jian , Jiang Dong-po , Du Ding-Yuan , Hu Ping , Yang Ce , Yan Jun , Wang Hai-Yan , Jiang Jian-Xin
Published: November 2011

Introduction

The nucleotide-binding oligomerization domain-like receptor (NLR) family has been recognized as comprising intracellular pattern recognition receptors in which NLRP3 (NLR family, pyrin domain containing 3) plays an important role in the initiation of host immune inflammatory responses. The genetic variants have been recognized to be critical determinants of interindividual differences in both inflammatory responses and clinical outcomes in critical illness. However, little is known about the clinical relevance of NLRP3 gene polymorphisms in critical illness.

Methods

A total of 718 patients with major blunt trauma were included in this study. Six tag SNPs (tSNPs) were selected from the entire NLRP3 gene through construction of haplotype bins, and they were genotyped using a pyrosequencing method. They were analyzed in relation to sepsis morbidity rate, multiple organ dysfunction (MOD) scores and IL-1β production. Moreover, the functionality of the rs2027432 polymorphism was assessed by the observation of its effect on transcriptional activities.

Results

Among the six tSNPs genotyped in this study, two of them (rs2027432 and rs12048215) were significantly associated with sepsis morbidity rate and MOD scores. A significant association was also observed between these two polymorphisms and IL-1β production by peripheral leukocytes in response to ex vivo lipopolysaccharide stimulation. However, no combined effects were found between these two polymorphisms. In addition, the rs2027432 polymorphism could significantly enhance the promoter activities of the NLRP3 gene.

Conclusions

rs2027432 and rs12048215 polymorphisms might be used as relevant risk estimates for the development of sepsis and MOD syndrome in patients with major trauma, in which rs2027432 might be a functional SNP.
Scale properties of the seismic wavefield perspectives for full-waveform matching
Authors: Maraschini Margherita , Boiero Daniele , Foti Sebastiano , Valentina Socco Laura
Published: November 2011

Starting from the nondimensionalization of equations of motion we partition the set of the velocity models in equivalence classes, such that the full waveform of an element in a given class can be calculated from the full waveform of any other element in the same class by scaling model parameters. We give a formal derivation of the seismic wavefield scale properties and we prove their capability through the use of numerical examples. Besides this, we introduce how the scale properties can be used to save computational time in full waveform modeling and inversion. In forward modeling we can use them for the calculation of the full waveform of any model in the same equivalence class of a model whose full waveform has been previously calculated. In full waveform inversion, scale properties can be used for full waveform matching: Given an experimental seismogram and a synthetic one, we can choose, in the same class of the synthetic model, another element whose waveform is closer to the experimental one.
TSH Regulates Pendrin Membrane Abundance and Enhances Iodide Efflux in Thyroid Cells
Authors: Pesce Liuska , Bizhanova Aigerim , Caraballo Juan Carlos , Westphal Whitney , Butti Maria L. , Comellas Alejandro , Kopp Peter
Published: November 2011

Thyroid hormones are essential for normal development and metabolism. Their synthesis requires transport of iodide into thyroid follicles. The mechanisms involving the apical efflux of iodide into the follicular lumen are poorly elucidated. The discovery of mutations in the SLC26A4 gene in patients with Pendred syndrome (congenital deafness, goiter, and defective iodide organification) suggested a possible role for the encoded protein, pendrin, as an apical iodide transporter. We determined whether TSH regulates pendrin abundance at the plasma membrane and whether this influences iodide efflux. Results of immunoblot and immunofluorescence experiments reveal that TSH and forskolin rapidly increase pendrin abundance at the plasma membrane through the protein kinase A pathway in PCCL-3 rat thyroid cells. The increase in pendrin membrane abundance correlates with a decrease in intracellular iodide as determined by measuring intracellular 125iodide and can be inhibited by specific blocking of pendrin. Elimination of the putative protein kinase A phosphorylation site T717A results in a diminished translocation to the membrane in response to forskolin. These results demonstrate that pendrin translocates to the membrane in response to TSH and suggest that it may have a physiological role in apical iodide transport and thyroid hormone synthesis.
The Inhibitory Effects of Neurokinin B on GnRH Pulse Generator Frequency in the Female Rat
Authors: Kinsey-Jones James S. , Grachev Pasha , Li Xiao Feng , Lin Yuan Shao , Milligan Stuart R. , Lightman Stafford L. , O'Byrne Kevin T.
Published: November 2011

Neurokinin B (NKB) and its receptor (neurokinin-3 receptor) are coexpressed with kisspeptin and dynorphin A (Dyn) within neurons of the hypothalamic arcuate nucleus, the suggested site of the GnRH pulse generator. It is thought that these neuropeptides interact to regulate gonadotropin secretion. Using the ovariectomized (OVX) and OVX 17β-estradiol-replaced rat models, we have carried out a series of in vivo neuropharmacological and electrophysiological experiments to elucidate the hierarchy between the kisspeptin, NKB, and Dyn signaling systems. Rats were implanted with intracerebroventricular cannulae and cardiac catheters for frequent (every 5 min) automated serial blood sampling. Freely moving rats were bled for 6 h, with intracerebroventricular injections taking place after a 2-h control bleeding period. A further group of OVX rats was implanted with intra-arcuate electrodes for the recording of multiunit activity volleys, which coincide invariably with LH pulses. Intracerebroventricular administration of the selective neurokinin-3 receptor agonist, senktide (100–600 pmol), caused a dose-dependent suppression of LH pulses and multiunit activity volleys. The effects of senktide did not differ between OVX and 17β-estradiol-replaced OVX animals. Pretreatment with a selective Dyn receptor (κ opioid receptor) antagonist, norbinaltorphimine (6.8 nmol), blocked the senktide-induced inhibition of pulsatile LH secretion. Intracerebroventricular injection of senktide did not affect the rise in LH concentrations after administration of kisspeptin (1 nmol), and neither did kisspeptin preclude the senktide-induced suppression of LH pulses. These data show that NKB suppresses the frequency of the GnRH pulse generator in a Dyn/κ opioid receptor-dependent fashion.
GH Does Not Modulate the Early Fasting-Induced Release of Free Fatty Acids in Mice
Authors: Steyn F. J. , Leong J. W. , Huang L. , Tan H. Y. , Xie T. Y. , Nelson C. , Waters M. J. , Veldhuis J. D. , Epelbaum J. , Chen C.
Published: November 2011

Fasting results in the mobilization of adipose stores and the elevation of levels of free fatty acids (FFA). In humans, this process is driven by a release in GH. Little is known regarding the role of GH in modulating this process during early stages of fasting in the mouse. Confirmation of the role of GH in modulating FFA release in the fasting mouse is of particular importance given the frequent use of mouse models to study metabolic mechanisms. Here, we correlate the initial release of FFA throughout fasting in mice with pulsatile GH secretion. Observations illustrate the rapid release of FFA in response to food withdrawal. This does not correlate with a rise in GH secretion. Rather, we observed a striking loss in pulsatile secretion of GH throughout the first 6 h of fasting, suggesting that GH does not modulate the initial release of FFA in the mouse in response to fasting. This was confirmed in GH receptor knockout mice, in which we observed a robust fasting-induced rise in FFA. We further illustrate the dynamic relationship between the orexigenic and anorexigenic hormones ghrelin and leptin during fasting in the mouse. Our findings show an initial suppression of leptin and the eventual rise in circulating levels of acyl-ghrelin with fasting. However, altered acyl-ghrelin and leptin secretion occurs well after the rise in FFA and the suppression of GH secretion. Consequently, we conclude that although acyl-ghrelin and leptin may modulate the physiological response to drive food intake, these changes do not contribute to the initial loss of pulsatile GH secretion. Rather, it appears that the suppression of GH secretion in fasting may occur in response to an elevation in fasting levels of FFA or physiological stress. Observations highlight a divergent role for GH in modulating FFA release between man and mouse.
Metformin differentially activates ER stress signaling pathways without inducing apoptosis
Authors: Quentin Thomas , Steinmetz Michael , Poppe Andrea , Thoms Sven
Published: November 2011

Endoplasmic reticulum stress signaling (ERSS) plays an important role in the pathogenesis of diabetes and heart disease. The latter is a common comorbidity of diabetes and worsens patient outcome. Results from clinical studies suggest beneficial effects of metformin – a widely used oral drug for the treatment of type 2 diabetes – on the heart of diabetic patients with heart failure. We therefore analyzed the effect of metformin on ERSS in primary rat cardiomyocytes. We found that metformin activates the PERK-ATF4 but not the ATF6 or IRE1-XBP1 branch in ERSS and leads to a strong upregulation of CHOP mRNA and protein. Surprisingly, long-term induction of CHOP by metformin is not accompanied by apoptosis even though CHOP is regarded to be a mediator of ER-stress-induced apoptosis. In conclusion, metformin induces distinct ER stress pathways in cardiomyocytes and our results indicate that CHOP is not necessarily a mediator of apoptosis. Metformin might exert its cardioprotective effect through selective activation of ERSS pathways in the cardiomyocyte.
BTN1, the Saccharomyces cerevisiae homolog to the human Batten disease gene, is involved in phospholipid distribution
Authors: Padilla-López Sergio , Langager Deanna , Chan Chun-Hung , Pearce David A.
Published: November 2011

BTN1, the yeast homolog to human CLN3 (which is defective in Batten disease), has been implicated in the regulation of vacuolar pH, potentially by modulating vacuolar-type H+-ATPase (V-ATPase) activity. However, we report that Btn1p and the V-ATPase complex do not physically interact, suggesting that any influence that Btn1p has on V-ATPase is indirect. Because membrane lipid environment plays a crucial role in the activity and function of membrane proteins, we investigated whether cells lacking BTN1 have altered membrane phospholipid content. Deletion of BTN1 (btn1-Δ) led to a decreased level of phosphatidylethanolamine (PtdEtn) in both mitochondrial and vacuolar membranes. In yeast there are two phosphatidylserine (PtdSer) decarboxylases, Psd1p and Psd2p, and these proteins are responsible for the synthesis of PtdEtn in mitochondria and Golgi-endosome, respectively. Deletion of both BTN1 and PSD1 (btn1-Δ psd1-Δ) led to a further decrease in levels of PtdEtn in ER membranes associated to mitochondria (MAMs), with a parallel increase in PtdSer. Fluorescent-labeled PtdSer (NBD-PtdSer) transport assays demonstrated that transport of NBD-PtdSer from the ER to both mitochondria and endosomes and/or vacuole is affected in btn1-Δ cells. Moreover, btn1-Δ affects the synthesis of PtdEtn by the Kennedy pathway and impairs the ability of psd1-Δ cells to restore PtdEtn to normal levels in mitochondria and vacuoles by ethanolamine addition. In summary, lack of Btn1p alters phospholipid levels and might play a role in regulating their subcellular distribution.
Behavioural evidence for colour vision in an elasmobranch
Authors: Van-Eyk Sarah M. , Siebeck Ulrike E. , Champ Connor M. , Marshall Justin , Hart Nathan S.
Published: November 2011

Little is known about the sensory abilities of elasmobranchs (sharks, skates and rays) compared with other fishes. Despite their role as apex predators in most marine and some freshwater habitats, interspecific variations in visual function are especially poorly studied. Of particular interest is whether they possess colour vision and, if so, the role(s) that colour may play in elasmobranch visual ecology. The recent discovery of three spectrally distinct cone types in three different species of ray suggests that at least some elasmobranchs have the potential for functional trichromatic colour vision. However, in order to confirm that these species possess colour vision, behavioural experiments are required. Here, we present evidence for the presence of colour vision in the giant shovelnose ray (Glaucostegus typus) through the use of a series of behavioural experiments based on visual discrimination tasks. Our results show that these rays are capable of discriminating coloured reward stimuli from other coloured (unrewarded) distracter stimuli of variable brightness with a success rate significantly different from chance. This study represents the first behavioural evidence for colour vision in any elasmobranch, using a paradigm that incorporates extensive controls for relative stimulus brightness. The ability to discriminate colours may have a strong selective advantage for animals living in an aquatic ecosystem, such as rays, as a means of filtering out surface-wave-induced flicker.
Social snails: the effect of social isolation on cognition is dependent on environmental context
Authors: Dalesman Sarah , Lukowiak Ken
Published: November 2011

Social isolation is often considered to have negative effects on cognitive function in a wide range of species. Here we assess how environmental context alters the effect of isolation on long-term memory formation (24 h) in the pond snail Lymnaea stagnalis. We operantly trained snails to reduce aerial respiration in hypoxia following exposure to one of three social conditions: (1) maintained and trained in groups; (2) maintained in groups, trained in isolation; or (3) maintained and trained in isolation. In addition, snails also experienced four stress exposure levels: control, exposure to low calcium availability, predator kairomone exposure during training or a combination of low calcium and predator kairomones. Snails isolated during training alone demonstrated no difference in memory formation compared with the snails trained in groups. Maintaining snails in social isolation for 8 days prior to training had a neutral effect on memory in control conditions or in the presence of predator kairomones alone. However, social isolation enhanced long-term memory formation in snails exposed to low calcium conditions, a stress that blocks memory formation in snails maintained in groups. Conversely, when exposed to low calcium and predator kairomones combined, grouped snails normally demonstrate long-term memory, but following maintenance in isolation long-term memory was blocked. Therefore, the effect of social isolation on cognitive function is highly dependent on the environmental context in which it is experienced.
Osteopetrosis in pregnancy: a rare case report
Authors: Peer Michaela , O'Donoghue Keelin
Published: November 2011

Osteopetrosis is a genetic syndrome characterized by the failure of osteoclasts to resorb bone. This leads to skeletal fragility despite increased bone mass, with fractures, dental abscesses, osteoarthritis and scoliosis being the most common complications. There are few reports of patients with type II osteopetrosis undergoing pregnancy and delivery. This case outlines the management of pregnancy and a successful delivery in a woman with this rare condition.
Structural effects of linkage disequilibrium on the transcriptome
Authors: Martin Joshua S. , Halvorsen Matthew , Davis-Neulander Lauren , Ritz Justin , Gopinath Chetna , Beauregard Arthur , Laederach Alain
Published: November 2011

A majority of SNPs (single nucleotide polymorphisms) map to noncoding and intergenic regions of the genome. Noncoding SNPs are often identified in genome-wide association studies (GWAS) as strongly associated with human disease. Two such disease-associated SNPs in the 5′ UTR of the human FTL (Ferritin Light Chain) gene are predicted to alter the ensemble of structures adopted by the mRNA. High-accuracy single nucleotide resolution chemical mapping reveals that these SNPs result in substantial changes in the structural ensemble in agreement with the computational prediction. Furthermore six rescue mutations are correctly predicted to restore the mRNA to its wild-type ensemble. Our data confirm that the FTL 5′ UTR is a “RiboSNitch,” an RNA that changes structure if a particular disease-associated SNP is present. The structural change observed is analogous to that of a bacterial Riboswitch in that it likely regulates translation. These data further suggest that specific pairs of SNPs in high linkage disequilibrium (LD) will form RNA structure-stabilizing haplotypes (SSHs). We identified 484 SNP pairs that form SSHs in UTRs of the human genome, and in eight of the 10 SSH-containing transcripts, SNP pairs stabilize RNA protein binding sites. The ubiquitous nature of SSHs in the transcriptome suggests that certain haplotypes are conserved to avoid RiboSNitch formation.
99mTc(CO)3-Ibritumomab tiuxetan; a novel radioimmunoimaging (RII) agent of B cell non-Hodgkin’s lymphoma (NHL)
Authors: Shah Syed Qaiser , Khan Aakif Ullah , Khan Mohammad Rafiullah
Published: November 2011

To exploit the B-lymphocyte antigen-CD20 binding capa­city of the Ibritumomab tiuxetan (IBTN) monoclonal antibody (mAb) for imaging, the over-expression of B cells in non-Hodgkin’s lymphoma (NHL) (a myeloproliferative disorder of the lymphatic system) was investigated. In the current investigation, we present the labeling of the IBTN with technetium-99m (99mTc) through [99mTc(CO)3]+ precursor for radioimmunoimaging (RII) of the tumor prior to its treatment with 90Y labeled IBTN. Labeled IBTN was radiobiologically characterized in terms of radiochemical purity, in vitro stability in human plasma, immunoreactivity, binding with Raji and Ramos cells and biodistribution in a female nude mouse (FNM) model. It was observed that the reduced IBTN (rIBTN) showed more promising radiobiologic characteristics than the nonreduced IBTN. Significantly higher transchelation was seen in excess cysteine compared with histidine. The radioconjugate showed higher saturated binding affinity with CD20 antigen. Significantly higher target (tumor) to background ratios were observed 1 h post-injection (p.i.). Based on radiochemical purity, in vitro stability, immunoreactivity, binding and biodistrubtion in the FNM model, we recommend the radiolabeling of the rIBTN using tricarbonyl technique as a potential RII agent.
Decoding Effector-Dependent and Effector-Independent Movement Intentions from Human Parieto-Frontal Brain Activity
Authors: Gallivan Jason P. , McLean D. Adam , Smith Fraser W. , Culham Jody C.
Published: November 2011

Our present understanding of the neural mechanisms and sensorimotor transformations that govern the planning of arm and eye movements predominantly come from invasive parieto-frontal neural recordings in nonhuman primates. While functional MRI (fMRI) has motivated investigations on much of these same issues in humans, the highly distributed and multiplexed organization of parieto-frontal neurons necessarily constrain the types of intention-related signals that can be detected with traditional fMRI analysis techniques. Here we employed multivoxel pattern analysis (MVPA), a multivariate technique sensitive to spatially distributed fMRI patterns, to provide a more detailed understanding of how hand and eye movement plans are coded in human parieto-frontal cortex. Subjects performed an event-related delayed movement task requiring that a reach or saccade be planned and executed toward one of two spatial target positions. We show with MVPA that, even in the absence of signal amplitude differences, the fMRI spatial activity patterns preceding movement onset are predictive of upcoming reaches and saccades and their intended directions. Within certain parieto-frontal regions we show that these predictive activity patterns reflect a similar spatial target representation for the hand and eye. Within some of the same regions, we further demonstrate that these preparatory spatial signals can be discriminated from nonspatial, effector-specific signals. In contrast to the largely graded effector- and direction-related planning responses found with fMRI subtraction methods, these results reveal considerable consensus with the parieto-frontal network organization suggested from primate neurophysiology and specifically show how predictive spatial and nonspatial movement information coexists within single human parieto-frontal areas.
Neuronal Loss in the Rostral Ventromedial Medulla in a Rat Model of Neuropathic Pain
Authors: Leong Mai Lan , Gu Ming , Speltz-Paiz Rebecca , Stahura Eleanor I. , Mottey Neli , Steer Clifford J. , Wessendorf Martin
Published: November 2011

Cell death has been reported in the CNS in models of neuropathic pain (Sugimoto et al., 1990; Whiteside and Munglani, 2001; Scholz et al., 2005; Fuccio et al., 2009). In our present study, we examined the effects of spinal nerve ligation (SNL) on the number of neurons in the rostral ventromedial medulla (RVM), a brainstem region involved in modulation of nociception. In rats receiving SNL, we found that the number of RVM neurons decreased by 23% in the side ipsilateral to the surgery. The loss of RVM neurons was also associated with a bilateral increase in the number of glia as well as bilateral activation of both astrocytes and microglia. Administration of tauroursodeoxycholic acid (TUDCA), which reportedly inhibits apoptosis, significantly reduced the loss of neurons, the increase in glia, and the mechanical hypersensitivity induced by SNL.

Among RVM neurons, we found that serotonergic (5-hydroxytryptamine, 5-HT) neurons decreased by 35% ipsilateral to SNL. Consistent with these findings, the density of 5-HT-immunoreactive varicosities in the superficial dorsal horn of the spinal cord was 15–30% lower, ipsilateral to SNL. To test the function of the remaining 5-HT neurons, we administered the 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). Interestingly, after 5,7-DHT, mechanical withdrawal thresholds increased significantly. We conclude that nerve injury induces death of antinociceptive RVM neurons that can be reduced or abolished by TUDCA. We propose that the loss of RVM neurons shifts the balance of descending control from pain inhibition to pain facilitation.
Organized Representation of Spectrotemporal Features in Songbird Auditory Forebrain
Authors: Kim Gunsoo , Doupe Allison
Published: November 2011

Much of our understanding of the functional organization of auditory cortex is based on relatively simple stimuli, and the cortical representation of complex sounds remains poorly understood. With their rich vocal communication and learning behaviors, songbirds can offer insights into the neural processing of complex acoustic signals analogous to human speech. In the primary forebrain auditory area field L (primary auditory cortex analog) of zebra finches, previous studies identified a limited set of spectrotemporal receptive field (STRF) types, but whether these were spatially organized remained unclear. Here, we investigated the spatial organization of field L in multiple anatomical planes, using multielectrode array recordings and a stimulus that captures aspects of spectrotemporal modulations of song. Our data demonstrate two separate axes along which spectrotemporal aspects of sound are mapped: width of spectral tuning changes systematically from narrow to broad mediolaterally, whereas width of temporal tuning changes markedly, from narrow to broad, from the input to the output layers. These spatial patterns, which are evident in STRFs computed from both multiple and single units, result in a mapping of basic STRF types to subregions of field L. This highly organized representation of spectrotemporal features of sound contrasts with current views of mammalian auditory cortex, where no strong spatial organization of STRF shapes has been seen thus far. Our data identify a coherent initial cortical representation of sound features and suggest that forebrain filtering for basic perceptual qualities of sound occurs in a spatially organized and segregated manner in the songbird auditory system.
Sensitivity of Noisy Neurons to Coincident Inputs
Authors: Rossant Cyrille , Leijon Sara , Magnusson Anna K. , Brette Romain
Published: November 2011

How do neurons compute? Two main theories compete: neurons could temporally integrate noisy inputs (rate-based theories) or they could detect coincident input spikes (spike timing-based theories). Correlations at fine timescales have been observed in many areas of the nervous system, but they might have a minor impact. To address this issue, we used a probabilistic approach to quantify the impact of coincidences on neuronal response in the presence of fluctuating synaptic activity. We found that when excitation and inhibition are balanced, as in the sensory cortexin vivo, synchrony in a very small proportion of inputs results in dramatic increases in output firing rate. Our theory was experimentally validated within vitrorecordings of cortical neurons of mice. We conclude that not only are noisy neurons well equipped to detect coincidences, but they are so sensitive to fine correlations that a rate-based description of neural computation is unlikely to be accurate in general.
Layer- and Cell-Type-Specific Subthreshold and Suprathreshold Effects of Long-Term Monocular Deprivation in Rat Visual Cortex
Authors: Medini Paolo
Published: November 2011

Connectivity and dendritic properties are determinants of plasticity that are layer and cell-type specific in the neocortex. However, the impact of experience-dependent plasticity at the level of synaptic inputs and spike outputs remains unclear along vertical cortical microcircuits. Here I compared subthreshold and suprathreshold sensitivity to prolonged monocular deprivation (MD) in rat binocular visual cortex in layer 4 and layer 2/3 pyramids (4Ps and 2/3Ps) and in thick-tufted and nontufted layer 5 pyramids (5TPs and 5NPs), which innervate different extracortical targets. In normal rats, 5TPs and 2/3Ps are the most binocular in terms of synaptic inputs, and 5NPs are the least. Spike responses of all 5TPs were highly binocular, whereas those of 2/3Ps were dominated by either the contralateral or ipsilateral eye. MD dramatically shifted the ocular preference of 2/3Ps and 4Ps, mostly by depressing deprived-eye inputs. Plasticity was profoundly different in layer 5. The subthreshold ocular preference shift was sevenfold smaller in 5TPs because of smaller depression of deprived inputs combined with a generalized loss of responsiveness, and was undetectable in 5NPs. Despite their modest ocular dominance change, spike responses of 5TPs consistently lost their typically high binocularity during MD. The comparison of MD effects on 2/3Ps and 5TPs, the main affected output cells of vertical microcircuits, indicated that subthreshold plasticity is not uniquely determined by the initial degree of input binocularity. The data raise the question of whether 5TPs are driven solely by 2/3Ps during MD. The different suprathreshold plasticity of the two cell populations could underlie distinct functional deficits in amblyopia.
Hippocampal and Prefrontal Projections to the Basal Amygdala Mediate Contextual Regulation of Fear after Extinction
Authors: Orsini Caitlin A. , Kim Jee Hyun , Knapska Ewelina , Maren Stephen
Published: November 2011

Knowing when and where to express fear is essential to survival. Recent work in fear extinction paradigms reveals that the contextual regulation of fear involves a neural network involving the hippocampus, medial prefrontal cortex, and amygdala. The amygdaloid basal nuclei (BA) receive convergent input from the ventral hippocampus (VH) and prelimbic (PL) prefrontal cortex and may integrate VH and PL input to regulate fear expression. To examine the functional organization of this neural circuit, we used cellular imaging of c-fos expression in anatomically defined neuronal populations and circuit disconnections to identify the pathways involved in the contextual control of extinguished fear. Before behavioral testing, we infused a retrograde tracer into the amygdala to label BA-projecting neurons in VH and PL. Rats then underwent fear conditioning and extinction and were tested for their fear to the extinguished conditioned stimulus (CS) in either the extinction context or in another context; freezing behavior served as the index of conditional fear. CS presentation outside the extinction context renewed conditional freezing and was associated with significantly more c-fos expression in BA-projecting neurons in the VH and PL than that induced by CS presentation in the extinction context. We next examined whether direct or indirect projections of VH to BA mediate fear renewal. Interestingly, disconnections of the VH from either the BA or PL eliminated renewal. These findings suggest that convergent inputs from both the VH and PL in the BA mediate the contextual control of fear after extinction.
A Cdk5-Dependent Switch Regulates Lis1/Ndel1/Dynein-Driven Organelle Transport in Adult Axons
Authors: Pandey Jai P. , Smith Deanna S.
Published: November 2011

Lissencephaly is a human developmental brain abnormality caused by LIS1 haploinsufficiency. This disorder is in large part attributed to altered mitosis and migration in the developing brain. LIS1 and an interacting protein, NDEL1, bind to cytoplasmic dynein, a microtubule motor protein. While the tripartite complex is clearly important for developmental events, we are intrigued by the fact that Lis1 and Ndel1 expression remain high in the adult mouse nervous system. Dynein plays a crucial role in retrograde axonal transport, a process that is used by mature neurons. Here, we monitored acidic organelles moving in axons of adult rat sensory neurons to determine whether Lis1 and Ndel1 contribute to axonal transport. Lis1 RNAi significantly reduced axon transport of these organelles. Ndel1 RNAi had little impact, but combined Lis1 and Ndel1 RNAi caused a more severe phenotype than Lis1 RNAi alone, essentially shutting down transport. Lis1 overexpression stimulated retrograde transport, while a Lis1 dynein-binding mutant severely disrupted transport. Overexpression of Ndel1 or a Lis1 Ndel1-binding mutant only mildly perturbed transport. However, expressing a mutant Ndel1 lacking key phosphorylation sites shut down transport completely, as did a dominant-negative Cdk5 construct. We propose that, in axons, unphosphorylated Ndel1 inhibits the capacity of dynein to transport acidic organelles. Phosphorylation of Ndel1 by Cdk5 not only reduces this inhibition but also allows Lis1 to further stimulate the cargo transport capacity of dynein. Our data raise the possibility that defects in a Lis1/Ndel1 regulatory switch could contribute to neurodegenerative diseases linked to axonal pathology in adults.
Separate Inhibitory and Excitatory Components Underlying Receptive Field Organization in Superficial Medullary Dorsal Horn Neurons
Authors: Kato Go , Kosugi Masafumi , Mizuno Masaharu , Strassman Andrew M.
Published: November 2011

Extracellular recording has shown that dorsal horn neurons can have an inhibitory surround outside their excitatory receptive field, but cannot reveal inhibitory inputs within the excitatory field, or show the underlying excitatory and inhibitory synaptic inputs that determine net output. To study the underlying components of receptive field organization,in vivopatch-clamp recording was used to compare the size and distribution of subthreshold, suprathreshold, and inhibitory fields, in neurons in the mouse superficial medullary dorsal horn that were characterized by their responses to noxious and innocuous mechanical facial stimulation. Subthreshold excitatory fields typically extended some distance beyond the borders of the suprathreshold field, and also commonly exhibited broader stimulus selectivity, in that the majority of nociceptive-specific neurons exhibited subthreshold responses to brush. Separate voltage-clamp recording of excitatory and inhibitory inputs using different holding potentials revealed that inhibition could be evoked from both within and outside the excitatory field. In nociceptive neurons, inhibition tended to be maximal at the excitatory receptive field center, and was usually greater for pinch than brush, although the selectivity for pinch versus brush was not as great as with excitatory responses. Based on current data on dorsal horn organization, we propose that the localized peak of inhibition at the excitatory field center could be mediated by local interneurons, while the more widespread surrounding inhibition may depend on supraspinal circuitry.
Keratan Sulfate Restricts Neural Plasticity after Spinal Cord Injury
Authors: Imagama Shiro , Sakamoto Kazuma , Tauchi Ryoji , Shinjo Ryuichi , Ohgomori Tomohiro , Ito Zenya , Zhang Haoqian , Nishida Yoshihiro , Asami Nagamasa , Takeshita Sawako , Sugiura Nobuo , Watanabe Hideto , Yamashita Toshihide , Ishiguro Naoki , Matsuyama Yukihiro , Kadomatsu Kenji
Published: November 2011

Chondroitin sulfate (CS) proteoglycans are strong inhibitors of structural rearrangement after injuries of the adult CNS. In addition to CS chains, keratan sulfate (KS) chains are also covalently attached to some proteoglycans. CS and KS sometimes share the same core protein, but exist as independent sugar chains. However, the biological significance of KS remains elusive. Here, we addressed the question of whether KS is involved in plasticity after spinal cord injury. Keratanase II (K-II) specifically degraded KS, i.e., not CS,in vivo. This enzyme digestion promoted the recovery of motor and sensory function after spinal cord injury in rats. Consistent with this, axonal regeneration/sprouting was enhanced in K-II-treated rats. K-II and the CS-degrading enzyme chondroitinase ABC exerted comparable effectsin vivoandin vitro. However, these two enzymes worked neither additively nor synergistically. These data and furtherin vitrostudies involving artificial proteoglycans (KS/CS-albumin) and heat-denatured or reduced/alkylated proteoglycans suggested that all three components of the proteoglycan moiety, i.e., the core protein, CS chains, and KS chains, were required for the inhibitory activity of proteoglycans. We conclude that KS is essential for, and has an impact comparable to that of CS on, postinjury plasticity. Our study also established that KS and CS are independent requirements for the proteoglycan-mediated inhibition of axonal regeneration/sprouting.