bluuebunny/crossref_metadata_2025 huggingface dataset:
Case-based seminars in medical ethics education: how medical students define and discuss moral problems
Authors: Donaldson Thomas M , Fistein Elizabeth , Dunn Michael
Published: October 2010

Discussion of real cases encountered by medical students has been advocated as a component of medical ethics education. Suggested benefits include: a focus on the actual problems that medical students confront; active learner involvement; and facilitation of an exploration of the meaning of their own values in relation to professional behaviour. However, the approach may also carry risks: students may focus too narrowly on particular clinical topics or show a preference for discussing legal problems that may appear to have clearer solutions. Teaching may therefore omit areas generally considered to be important components of the curriculum. In this paper, the authors present an analysis of the moral problems raised by medical students in response to a request to describe ethically problematic cases they had encountered during two clinical attachments, for the purpose of educational discussion at case-based seminars. We discuss the problems raised and compare the content of the cases to the UK Consensus Statement on core content of learning. The authors also describe the approaches that the students used to undertake an initial analysis of the problems raised, and consider possible implications for the development of medical ethics education.
When choosing the traits of children is hurtful to others
Authors: Murphy Timothy F
Published: October 2010

Some commentators object to the use of embryonic and fetal diagnostic technologies by parents who wish to avoid disabilities in their children. In particular, they say this use is hurtful in the meaning it expresses, namely that the lives of people with disabilities are not valuable or are less valuable than the lives of others. Other commentators have tried to show that this meaning does not necessarily belong to parents' choices and is not therefore credible as a general moral objection. However, this analysis overlooks the way in which the use of these technologies can be legitimately interpreted as hurtful. Once we admit to these hurtful effects felt by people with disabilities and those who hold them dear, it becomes important to ask whether that hurt can justify limits on parents' choices. Because the use of these technologies does not hurt people with disabilities directly and because there is no requirement that people having children work to ensure the continued existence of people with disabilities, no justification for limiting parents' choices is to be found in the hurt some people experience in steps taken to avoid disabilities in children.
Deception as treatment: the case of depression
Authors: Blease Charlotte
Published: October 2010

Is it ever right to prescribe placebos to patients in clinical practice? The General Medical Council is ambivalent about the issue; the American Medical Association asserts that placebos can be administered only if the patient is (somehow) ‘informed’. The potential problem with placebos is that they may involve deception: indeed, if this is the case, an ethical tension arises over the patient's autonomy and the physician's requirement to be open and honest, and the notion that medical care should be the primary concern. This paper examines the case of depression as an entry point for understanding the complexities of the prescription of placebos. Recent important meta-analyses of antidepressants claim that they are not significantly more effective in a clinical setting than placebos. Given that antidepressants have numerous adverse side effects and are hugely expensive, this provocative research has serious potential ethical and practical implications for patients and medical providers. Should placebos be prescribed in place of antidepressants? The case of depression highlights another important issue which medical ethical codes have hitherto overlooked: well-being is not synonymous with being realistic about oneself, one's circumstances and the future. While severely depressed individuals are unduly pessimistic about themselves and the world around them, treatment of depressed individuals can be deemed successful when patients have successfully attained those positive illusions that are indicative of psychological health. This is exactly what successful psychological treatments of depression seem to achieve. It is therefore possible that there may be a limited unavoidable role for deception in medicine.
Mortality related to temperature and persistent extreme temperatures: a study of cause-specific and age-stratified mortality
Authors: Rocklöv Joacim , Ebi Kristie , Forsberg Bertil
Published: October 2010

Objectives

High and low ambient temperatures are associated with large numbers of deaths annually. Many studies show higher mortalities during heatwaves. However, such effects are rarely explicitly incorporated in models of temperature and mortality, although dehydration followed by cardiovascular stress is more likely to occur. The authors aim to establish time-series models in which the effects of persistent extreme temperature and temperature in general can be disentangled.

Methods

The authors established time-series Poisson regression models based on cause-specific mortality and age-stratified mortality in Stockholm County (Sweden), 1990–2002, adjusting for time trends and potential confounders, and studied the effects of temperature and persistence of extreme temperature.

Results

Persistent extremely high temperature was associated with additional deaths, and the risk of death increased significantly per day of extended heat exposure. Extreme exposure to heat was associated with higher death rates in adults and for cardiovascular causes of death, compared with a rise in temperature. Warmer temperatures increase daily mortality from natural causes, while decreasing colder temperatures increase the risk of cardiovascular deaths. Furthermore, the impact of warm and cold temperatures decreases within the season, while the impact of persistent extremely high temperatures remains similar throughout the summer.

Conclusions

The authors found the mortality impact of persistence of extreme high temperatures to increase proportionally to the length of the heat episode in addition to the effects of temperature based on the temperature–mortality relationship. Thus, the additional effect of persistent extreme heat was found to be important to incorporate for models of mortality related to ambient temperatures to avoid negatively biased attributed risks, especially for cardiovascular mortality. Moreover, the effects associated with non-extreme temperatures may decline as the pool of fragile individuals shrink as well as due to acclimatisation/adaptation. However, a similar decline was not observed for the effects associated with extreme heat episodes.
BOREL SUMMABILITY OF $\varphi^{4}_4$ PLANAR THEORY VIA MULTISCALE ANALYSIS
Authors: PORTA MARCELLO , SIMONELLA SERGIO
Published: October 2010

We review the issue of Borel summability in the framework of multiscale analysis and renormalization group, by discussing a proof of Borel summability of the [Formula: see text] massive Euclidean planar theory; this result is not new, since it was obtained by Rivasseau and 't Hooft. However, the techniques that we use have already been proved effective in the analysis of various models of consended matter and field theory; therefore, we take the [Formula: see text] planar theory as a toy model for future applications.
A UNIFIED TREATMENT OF CONVEXITY OF RELATIVE ENTROPY AND RELATED TRACE FUNCTIONS, WITH CONDITIONS FOR EQUALITY
Authors: JENČOVÁ ANNA , RUSKAI MARY BETH
Published: October 2010

We consider a generalization of relative entropy derived from the Wigner–Yanase–Dyson entropy and give a simple, self-contained proof that it is convex. Moreover, special cases yield the joint convexity of relative entropy, and for Tr K* ApK B1-pLieb's joint concavity in (A, B) for 0 < p < 1 and Ando's joint convexity for 1 < p ≤ 2. This approach allows us to obtain conditions for equality in these cases, as well as conditions for equality in a number of inequalities which follow from them. These include the monotonicity under partial traces, and some Minkowski type matrix inequalities proved by Carlen and Lieb for [Formula: see text]. In all cases, the equality conditions are independent of p; for extensions to three spaces they are identical to the conditions for equality in the strong subadditivity of relative entropy.
PARALLEL TRANSPORT OVER PATH SPACES
Authors: CHATTERJEE SAIKAT , LAHIRI AMITABHA , SENGUPTA AMBAR N.
Published: October 2010

We develop a differential geometric framework for parallel transport over path spaces and a corresponding discrete theory, an integrated version of the continuum theory, using a category-theoretic framework.
Structure-function activity of the human sodium-dependent multivitamin transporter: role of His115 and His254
Authors: Ghosal Abhisek , Said Hamid M.
Published: October 2010

Intestinal absorption of biotin occurs via a Na+-dependent carrier-mediated process that involves the sodium-dependent multivitamin transporter (SMVT; product of the Slc5a6 gene). The SMVT system is exclusively expressed at the apical membrane domain of the polarized intestinal epithelial cells. Whereas previous studies from our laboratory and others have characterized different physiological and biological aspects of SMVT, little is currently known about its structure-function activity relationship. Using site-directed mutagenesis approach, we examined the role of the positively charged histidine (His) residues of the human SMVT (hSMVT) in transporting the negatively charged biotin. Of the seven conserved (across species) His residues in the hSMVT polypeptide, only His115 and His254 were found to be important for the function of hSMVT as their mutation led to a significant reduction in carrier-mediated biotin uptake. This inhibition was mediated via a significant reduction in the maximal velocity ( Vmax), but not the apparent Michaelis constant ( Km), of the biotin uptake process and was not related to the charge of the His residue. The inhibition was also not due to changes in transcriptional or translational efficiency of the mutated hSMVT compared with wild-type carrier. However, surface biotinylation assay showed a significant reduction in the level of expression of the mutated hSMVT at the cell surface, a finding that was further confirmed by confocal imaging. Our results show important role for His115 and His254 residues in hSMVT function, which is most probably mediated via an effect on level of hSMVT expression at the cell membrane.
Chronic hypoxia increases insulin-stimulated glucose uptake in mouse soleus muscle
Authors: Gamboa J. L. , Garcia-Cazarin Mary L. , Andrade Francisco H.
Published: October 2010

People living at high altitude appear to have lower blood glucose levels and decreased incidence of diabetes. Faster glucose uptake and increased insulin sensitivity are likely explanations for these findings: skeletal muscle is the largest glucose sink in the body, and its adaptation to the hypoxia of altitude may influence glucose uptake and insulin sensitivity. This study tested the hypothesis that chronic normobaric hypoxia increases insulin-stimulated glucose uptake in soleus muscles and decreases plasma glucose levels. Adult male C57BL/6J mice were kept in normoxia [fraction of inspired O2 = 21% (Control)] or normobaric hypoxia [fraction of inspired O2 = 10% (Hypoxia)] for 4 wk. Then blood glucose and insulin levels, in vitro muscle glucose uptake, and indexes of insulin signaling were measured. Chronic hypoxia lowered blood glucose and plasma insulin [glucose: 14.3 ± 0.65 mM in Control vs. 9.9 ± 0.83 mM in Hypoxia ( P < 0.001); insulin: 1.2 ± 0.2 ng/ml in Control vs. 0.7 ± 0.1 ng/ml in Hypoxia ( P < 0.05)] and increased insulin sensitivity determined by homeostatic model assessment 2 [21.5 ± 3.8 in Control vs. 39.3 ± 5.7 in Hypoxia ( P < 0.03)]. There was no significant difference in basal glucose uptake in vitro in soleus muscle (1.59 ± 0.24 and 1.71 ± 0.15 μmol·g−1·h−1 in Control and Hypoxia, respectively). However, insulin-stimulated glucose uptake was 30% higher in the soleus after 4 wk of hypoxia than Control (6.24 ± 0.23 vs. 4.87 ± 0.37 μmol·g−1·h−1, P < 0.02). Muscle glycogen content was not significantly different between the two groups. Levels of glucose transporters 4 and 1, phosphoinositide 3-kinase, glycogen synthase kinase 3, protein kinase B/Akt, and AMP-activated protein kinase were not affected by chronic hypoxia. Akt phosphorylation following insulin stimulation in soleus muscle was significantly (25%) higher in Hypoxia than Control ( P < 0.05). Neither glycogen synthase kinase 3 nor AMP-activated protein kinase phosphorylation changed after 4 wk of hypoxia. These results demonstrate that the adaptation of skeletal muscles to chronic hypoxia includes increased insulin-stimulated glucose uptake.
Allosteric modulation by S-nitrosation in the low-O2affinity myoglobin from rainbow trout
Authors: Helbo Signe , Fago Angela
Published: October 2010

Myoglobin (Mb) serves in the facilitated diffusion and storage of O2in heart and skeletal muscle, where it also regulates O2consumption via nitric oxide (NO) scavenging or generation. S-nitrosation at reactive cysteines may generate S-nitroso Mb (Mb-SNO) and contribute further to NO homeostasis. In being a monomer, Mb is commonly believed to lack allosteric control of heme reactivity. Here, we test whether in rainbow trout, a fast swimmer living in well-aerated water, the Mb-O2affinity is regulated by ionic cofactors and S-nitrosation. O2equilibria showed the lowest O2affinity ever reported among vertebrate Mbs (P50= 4.92 ± 0.29 mmHg, 25°C), a small overall heat of oxygenation (Δ H = −12.03 kcal/mol O2), and no effect of chloride, pH, or lactate. Although the reaction with 4,4′-dithiodipyridine (4-PDS) showed 1.3–1.9 accessible thiols per heme, the reaction of Mb with S-nitroso cysteine (Cys-NO) and S-nitrosoglutathione (GSNO) to generate Mb-SNO yielded ∼0.3–0.6 and ∼0.1 SNO/heme, respectively, suggesting S-nitrosation at only one cysteine (likely Cys10). At ∼60% S-nitrosation, trout Mb-SNO showed a higher O2affinity (P50= 2.23 ± 0.19 mmHg, 20°C) than unmodified Mb (3.36 ± 0.11 mmHg, 20°C). Total SNO levels measured by chemiluminescence in trout myocardial preparations decreased after hypoxia, but not significantly, indicating that transnitrosation reactions between thiols may occur in vivo. Our data reveal a novel, S-nitrosation-dependent allosteric mechanism in this low-affinity Mb that may contribute to targeted O2-linked SNO release in the hypoxic fish heart and be of importance in preserving cardiac function during intense exercise.
CX43 expression, phosphorylation, and distribution in the normal and autoimmune orchitic testis with a look at gap junctions joining germ cell to germ cell
Authors: Pelletier R.-Marc , Akpovi Casimir D. , Chen Li , Day Robert , Vitale María L.
Published: October 2010

Spermatogenesis requires connexin 43 (Cx43).This study examines normal gene transcription, translation, and phosphorylation of Cx43 to define its role on germ cell growth and Sertoli cell's differentiation, and identifies abnormalities arising from spontaneous autoimmune orchitis (AIO) in mink, a seasonal breeder and a natural model for autoimmunity. Northern blot analysis detected 2.8- and a 3.7-kb Cx43 mRNA bands in seminiferous tubule-enriched fractions. Cx43 mRNA increased in seminiferous tubule-enriched fractions throughout development and then seasonally with the completion of spermatogenesis. Cx43 protein levels increased transiently during the colonization of the tubules by the early-stage spermatocytes. Cx43 phosphorylated (PCx43) and nonphosphorylated (NPCx43) in Ser368 decreased during the periods of completion of meiosis and Sertoli cell differentiation, while Cx43 mRNA remained elevated throughout. PCx43 labeled chiefly the plasma membrane except by stage VII when vesicles were also labeled in Sertoli cells. Vesicles and lysosomes in Sertoli cells and the Golgi apparatus in the round spermatids were NPCx43 positive. A decrease in Cx43 gene expression was matched by a Cx43 protein increase in the early, not the late, phase of AIO. Total Cx43 and PCx43 decreased with the advance of orchitis. The study makes a novel finding of gap junctions connecting germ cells. The data indicate that Cx43 protein expression and phosphorylation in Ser368 are stage-specific events that may locally influence the acquisition of meiotic competence and the Sertoli cell differentiation in normal testis. AIO modifies Cx43 levels, suggesting changes in Cx43-mediated intercommunication and spermatogenic activity in response to cytokines imbalances in Sertoli cells.
Sympathetic blockade prevents the decrease in cardiac VEGF expression and capillary supply in experimental renal failure
Authors: Amann K. , Odoni G. , Benz K. , Campean V. , Jacobi J. , Hilgers K. F. , Hartner A. , Veelken R. , Orth S. R.
Published: October 2010

Uremic cardiomyopathy of men and rodents is characterized by lower myocardial capillary supply that in rats could be prevented by central and peripheral blockade of the sympathetic nervous system. The underlying pathomechanisms remain largely unknown. We investigated whether alterations of cardiac vascular endothelial growth factor (VEGF) gene and protein expression were involved. In our long-term experiment, we analyzed whether VEGF gene and protein expression was altered in the heart of male Sprague-Dawley rats with either sham operation (sham, n = 10) or subtotal nephrectomy (SNX, n = 10). In our short-term experiment (17 sham, 24 SNX), the effect of a putative downregulation of sympathetic nervous activity by surgical renal denervation (interruption of renal afferent pathways) on cardiac gene expression of VEGF, flt-1, and flk-1 and on myocardial capillary supply was analyzed. In the long-term study, cardiac capillary supply and vascular endothelial growth factor gene and protein expression were significantly lower in SNX than in sham. In the short-term experiment, cardiac VEGF mRNA expression was significantly lower in untreated SNX (4,258 ± 2,078 units) than in both sham groups (11,709 ± 4,169 and 8,998 ± 4,823 units); this decrease was significantly prevented by renal denervation (8,190 ± 3,889, P < 0.05). We conclude that cardiac VEGF gene and protein expression is reduced in experimental renal failure, and this may be considered as one potential reason for impaired myocardial adaptation under the situation of cardiac hypertrophy. The beneficial effect of sympathetic downregulation on cardiac structure and function in renal failure may be at least in part explained by increased cardiac VEGF gene expression.
Conditional Perception Under Stimulus Ambiguity: Polarization- and Azimuth-Sensitive Neurons in the Locust Brain Are Inhibited by Low Degrees of Polarization
Authors: Pfeiffer Keram , Negrello Mario , Homberg Uwe
Published: October 2010

Sensory perception often relies on the integration and matching of multisensory inputs. In the brain of desert locusts, identified neurons that signal the sun's direction relative to the animal's head integrate information about the polarization pattern of the sky with information on the color and intensity contrast of the sky. The cloudless blue sky exhibits a gradient from unpolarized sunlight to strongly polarized light at 90° from the sun. Therefore the percentage of polarized light in the sky is highest at dusk and dawn and lowest when the sun is in the zenith. We investigated the effect of different degrees of polarization on neurons of the anterior optic tubercle of the desert locust through intracellular recordings. Whereas dorsal presentation of strongly polarized light largely excited the neurons, weakly polarized light, i.e., a blend of polarized light of many orientations, led to inhibition. The data suggest that the polarization input to these neurons is inhibited within a radius of 50° around the sun, thereby avoiding conflicting input from the polarization and direct sunlight channels. These properties can be regarded as sensory filters to avoid ambiguous signaling during sky compass orientation.
Behavior of the Oculomotor Vermis for Five Different Types of Saccade
Authors: Kojima Yoshiko , Soetedjo Robijanto , Fuchs Albert F.
Published: October 2010

Single unit and lesion studies have implicated the oculomotor vermis of the cerebellum in the control of targeting saccades to jumping visual targets. However, saccades can be made in a variety of other target situations where they can occur with different reaction times (express or delayed saccades) in response to a remembered target location (memory-guided saccades) or between several targets that are always visible (scanning saccades). Here we ask whether the oculomotor vermis contributes to generating all these types of saccades by examining the simple spike discharge of its Purkinje cells. Twenty-six of 32 P-cells (81%) exhibited qualitatively similar phasic firing patterns for targeting, express, scanning, delayed, and memory-guided saccades. The remaining six exhibited a different pattern for just scanning saccades. Although a sensitive test of discharge patterns revealed significant differences for some pairs of saccade types in ∼29% of P-cells, there was no cell-to-cell consistency as to which pairs were associated with different patterns. Also, a less sensitive comparison identified substantially fewer cells (∼15%) with different patterns. Thus the lack of any consistent difference in firing for different saccade types leads us to conclude that the oculomotor vermis is not likely to contribute differently to targeting, express, scanning, delayed, or memory-guided saccades.
Identification and Modulation of Voltage-Gated Ca2+Currents in Zebrafish Rohon-Beard Neurons
Authors: Won Yu-Jin , Ono Fumihito , Ikeda Stephen R.
Published: October 2010

Electrically excitable cells have voltage-dependent ion channels on the plasma membrane that regulate membrane permeability to specific ions. Voltage-gated Ca2+channels (VGCCs) are especially important as Ca2+serves as both a charge carrier and second messenger. Zebrafish ( Danio rerio) are an important model vertebrate for studies of neuronal excitability, circuits, and behavior. However, electrophysiological properties of zebrafish VGCCs remain largely unexplored because a suitable preparation for whole cell voltage-clamp studies is lacking. Rohon-Beard (R-B) sensory neurons represent an attractive candidate for this purpose because of their relatively large somata and functional homology to mammalian dorsal root ganglia (DRG) neurons. Transgenic zebrafish expressing green fluorescent protein in R-B neurons, ( Isl2b:EGFP)ZC7, were used to identify dissociated neurons suitable for whole cell patch-clamp experiments. Based on biophysical and pharmacological properties, zebrafish R-B neurons express both high- and low-voltage-gated Ca2+current (HVA- and LVA- ICa, respectively). Ni+-sensitive LVA- ICaoccur in the minority of R-B neurons (30%) and ω-conotoxin GVIA-sensitive CaV2.2 (N-type) Ca2+channels underlie the vast majority (90%) of HVA- ICa. To identify G protein coupled receptors (GPCRs) that modulate HVA- ICa, a panel of neurotransmitters was screened. Application of GABA/baclofen or serotonin produced a voltage-dependent inhibition while application of the mu-opioid agonist DAMGO resulted in a voltage-independent inhibition. Unlike in mammalian neurons, GPCR-mediated voltage-dependent modulation of ICaappears to be transduced primarily via a cholera toxin-sensitive Gα subunit. These results provide the basis for using the zebrafish model system to understanding Ca2+channel function, and in turn, how Ca2+channels contribute to mechanosensory function.
Neuromodulatory Effect of GnRH on the Synaptic Transmission of the Olfactory Bulbar Neural Circuit in Goldfish, Carassius auratus
Authors: Kawai Takafumi , Abe Hideki , Akazome Yasuhisa , Oka Yoshitaka
Published: October 2010

Gonadotropin-releasing hormone (GnRH) is well known as a hypophysiotropic hormone that is produced in the hypothalamus and facilitates the release of gonadotropins from the pituitary gonadotropes. On the other hand, the functions of extrahypothalamic GnRH systems still remain elusive. Here we examined whether the activity of the olfactory bulbar neural circuits is modulated by GnRH that originates mainly from the terminal nerve (TN) GnRH system in goldfish ( Carassius auratus). As the morphological basis, we first observed that goldfish TNs mainly express salmon GnRH (sGnRH) mRNA and that sGnRH-immunoreactive fibers are distributed in both the mitral and the granule cell layers. We then examined by extracellular recordings the effect of GnRH on the electrically evoked in vitro field potentials that arise from synaptic activities from mitral to granule cells. We found that GnRH enhances the amplitude of the field potentials. Furthermore, these effects were observed in both cases when the field potentials were evoked by stimulating either the lateral or the medial olfactory tract, conveying functionally different sensory information, separately, and suggesting that GnRH may modulate the responsiveness to wide categories of odorants in the olfactory bulb. Because GnRH also changed the paired-pulse ratio, it is suggested that the increased amplitude of the field potential results from changes in the presynaptic glutamate release of mitral cells rather than the increase in the glutamate receptor sensitivity of granule cells. These results suggest that TN regulates the olfactory responsiveness of animals appropriately by releasing sGnRH peptides in the olfactory bulbar neural circuits.
Combinatorial Regulation of Neuroblastoma Tumor Progression by N-Myc and Hypoxia Inducible Factor HIF-1α
Authors: Qing Guoliang , Skuli Nicolas , Mayes Patrick A. , Pawel Bruce , Martinez Daniel , Maris John M. , Simon M. Celeste
Published: October 2010

In human neuroblastoma, amplification of the MYCN gene predicts poor prognosis and resistance to therapy. Because hypoxia contributes to aggressive tumor phenotypes, predominantly via two structurally related hypoxia inducible factors, HIF-1α and HIF-2α, we examined hypoxia responses in MYCN-amplified neuroblastoma cells. We demonstrate here that HIF-1α, but not HIF-2α, is preferentially expressed in both MYCN-amplified neuroblastoma cells and primary tumors in comparison to samples without MYCN amplification. Our results showed that interplay between N-Myc and HIF-1α plays critical roles in neuroblastoma. For example, high levels of N-Myc override HIF-1α inhibition of cell cycle progression, enabling continued proliferation under hypoxia. Furthermore, both HIF-1α and N-Myc are essential for the Warburg effect (aerobic glycolysis) in neuroblastomas by activating the transcription of multiple glycolytic genes. Of note, expressions of Phosphoglycerate Kinase 1 (PGK1), Hexokinase 2 (HK2), and Lactate Dehydrogenase A (LDHA) were each significantly higher in MYCN-amplified neuroblastomas than in tumors without MYCN amplification. Interestingly, MYCN-amplified neuroblastoma cells are “addicted” to LDHA enzymatic activity, as its depletion completely inhibits tumorigenesis in vivo. Thus, our results provide mechanistic insights explaining how MYCN-amplified neuroblastoma cells contend with hypoxic stress and paradoxically how hypoxia contributes to neuroblastoma aggressiveness through combinatorial effects of N-Myc and HIF-1α. These results also suggest that LDHA represents a novel, pharmacologically tractable target for neuroblastoma therapeutics. Cancer Res; 70(24); 10351–61. ©2010 AACR.
Hypoxia and Hypoxia-Inducible Factors: Master Regulators of Metastasis
Authors: Lu Xin , Kang Yibin
Published: October 2010

Hypoxia is a common condition found in a wide range of solid tumors and is often associated with poor prognosis. Hypoxia increases tumor glycolysis, angiogenesis, and other survival responses, as well as invasion and metastasis by activating relevant gene expressions through hypoxia-inducible factors (HIF). HIF-1α and HIF-2α undergo oxygen-dependent regulation, and their overexpression is frequently associated with metastasis and poor clinical outcomes. Recent studies show that each step of the metastasis process, from the initial epithelial-mesenchymal transition to the ultimate organotropic colonization, can potentially be regulated by hypoxia, suggesting a master regulator role of hypoxia and HIFs in metastasis. Furthermore, modulation of cancer stem cell self-renewal by HIFs may also contribute to the hypoxia-regulated metastasis program. The hypoxia-induced metastatic phenotype may be one of the reasons for the modest efficacy of antiangiogenic therapies and may well explain the recent provocative findings that antiangiogenic therapy increased metastasis in preclinical models. Multiple approaches to targeting hypoxia and HIFs, including HIF inhibitors, hypoxia-activated bioreductive prodrugs, and gene therapies may become effective treatments to prevent or reduce metastasis. Clin Cancer Res; 16(24); 5928–35 ©2010 AACR.
The Retrograde Ventriculovenous Shunts: The El-Shafei Retrograde Ventriculojugular and Ventriculosinus Shunts
Authors: El-Shafei Ismail L. , El-Shafei Hassan I.
Published: October 2010

Retrograde ventriculovenous (RVV) shunts utilize the impact pressure of the venous bloodstream to maintain the intraventricular pressure more than the pressure in the draining venous channel and to maintain a continuous flow of cerebrospinal fluid (CSF) to the venous circulation at a rate equal to and dependent upon the rate of its formation regardless of changes in posture or intrathoracic pressure, create impact zones which discourage stagnation and clotting of blood at the venous end of the connection and utilize collapse of the internal jugular vein in the erect posture to prevent siphonage. During the past 40 years, 229 RVV shunts were implanted; 219 of the patients (95.63%) benefited from the shunt, and only 2 of them needed a single shunt revision. The manifestations of increased intracranial pressure disappeared, different degrees of regression of the ventriculomegaly occurred in patients with closed craniums but not in infants and young children with open craniums, and there were no problems related to improper CSF drainage or venous thrombosis. The follow-up period is up to 40 years (mean 9 years 8 months).
The P-Type ATPase Superfamily
Authors: Chan Henry , Babayan Vartan , Blyumin Elya , Gandhi Charmy , Hak Kunal , Harake Danielle , Kumar Kris , Lee Perry , Li Tze T. , Liu Hao Yi , Lo Tony Chung Tung , Meyer Cynthia J. , Stanford Steven , Zamora Krista S. , Saier Jr. Milton H.
Published: October 2010

P-type ATPases function to provide homeostasis in higher eukaryotes, but they are essentially ubiquitous, being found in all domains of life. Thever and Saier [J Memb Biol 2009;229:115–130] recently reported analyses of eukaryotic P-type ATPases, dividing them into nine functionally characterized and 13 functionally uncharacterized (FUPA) families. In this report, we analyze P-type ATPases in all major prokaryotic phyla for which complete genome sequence data are available, and we compare the results with those for eukaryotic P-type ATPases. Topological type I (heavy metal) P-type ATPases predominate in prokaryotes (approx. tenfold) while type II ATPases (specific for Na+,K+, H+ Ca2+, Mg2+ and phospholipids) predominate in eukaryotes (approx. twofold). Many P-type ATPase families are found exclusively in prokaryotes (e.g. Kdp-type K+ uptake ATPases (type III) and all ten prokaryotic FUPA familes), while others are restricted to eukaryotes (e.g. phospholipid flippases and all 13 eukaryotic FUPA families). Horizontal gene transfer has occurred frequently among bacteria and archaea, which have similar distributions of these enzymes, but rarely between most eukaryotic kingdoms, and even more rarely between eukaryotes and prokaryotes. In some bacterial phyla (e.g. Bacteroidetes, Flavobacteria and Fusobacteria), ATPase gene gain and loss as well as horizontal transfer occurred seldom in contrast to most other bacterial phyla. Some families (i.e. Kdp-type ATPases) underwent far less horizontal gene transfer than other prokaryotic families, possibly due to their multisubunit characteristics. Functional motifs are better conserved across family lines than across organismal lines, and these motifs can be family specific, facilitating functional predictions. In some cases, gene fusion events created P-type ATPases covalently linked to regulatory catalytic enzymes. In one family (FUPA Family 24), a type I ATPase gene (N-terminal) is fused to a type II ATPase gene (C-terminal) with retention of function only for the latter. Several pseudogene-encoded nonfunctional ATPases were identified. Genome minimalization led to preferential loss of P-type ATPase genes. We suggest that in prokaryotes and some unicellular eukaryotes, the primary function of P-type ATPases is protection from extreme environmental stress conditions. The classification of P-type ATPases of unknown function into phylogenetic families provides guides for future molecular biological studies.
Sudden Cardiac Arrest during Acute Coronary Occlusion – Who Is at Risk?
Authors: Meier Pascal , Seiler Christian
Published: October 2010

Many people with acute myocardial infarction die from sudden cardiac arrest before reaching the hospital. The current clinical understanding of the mechanisms and risk factors surrounding sudden cardiac death is limited. However, 2 factors related to sudden death, namely the occluded coronary vessel (right coronary, left circumflex, or left anterior descending artery) and the extent of collateral circulation, are of potential relevance. Recent data suggest that the risk differs between the different coronary arteries and that coronary collateral circulation seems to have an important protective ‘antiarrhythmic’ effect. This editorial will address possible mechanisms and potential implications in clinical practice.
Relation of Diastolic and Systolic Function, Exercise Capacity and Brain Natriuretic Peptide in Adults after Mustard Procedure for Transposition of the Great Arteries
Authors: Schaefer Arnd , Tallone Ezequiel M. , Westhoff-Bleck Mechthild , Klein Gunnar , Drexler Helmut , Röntgen Philipp
Published: October 2010

Objectives: To evaluate the relation of echocardiographic parameters of diastolic function, exercise capacity (expressed as peakVO2) and NT-proBNP in patients with transposition of the great arteries (TGA) and Mustard procedure. Methods: Diastolic function was determined by measuring tricuspid flow velocities (Ea/Aa ratio), isovolumic relaxation time (IVRT), and deceleration time (DT). E/Ea ratios were calculated. For assessment of systolic function, CMR was applied. Results: E/A (r = 0.07, p = 0.66), E/Ea medial (r = 0.03, p = 0.84), E/Ea lateral (r = –0.01, p = 0.92), IVRT (r = –0.13, p = 0.44), and DT (r = –0.05, p = 0.76) were not correlated with peakVO2. NT-proBNP showed a significant correlation with IVRT (r = 0.44, p = 0.004) and Ea/Aa medial (r = –0.34, p = 0.025). No correlation was found between RV systolic function and peakVO2 (r = 0.07, p = 0.63). Conclusions: Exercise capacity in patients with TGA and Mustard procedure is not related to echocardiographic parameters of diastolic function. NT-proBNP is associated with selected echocardiographic parameters of diastolic function.
Left Ventricular Hypercontractility Immediately after Tilting Triggers a Disregulated Cardioinhibitory Reaction in Vasovagal Syncope: Echocardiographic Evaluation during the Head-Up Tilt Test
Authors: Moon Jeonggeun , Kim Hyunsu , Kim Jong-Youn , Chung Soreen , Choi Eui-Young , Min Pil-Ki , Lee Byoung Kwon , Hong Bum-Kee , Kwon Hyuck Moon , Rim Se-Joong
Published: October 2010

Objectives: Vasovagal syncope (VVS) has been believed to occur when mechanoreceptors are discharged by vigorous ventricular contraction. However, previous investigators have reported divergent observations regarding the presence of left ventricular (LV) hypercontractility in VVS. Because the autonomic nervous system can be promptly activated after certain stimuli, we postulated that instantaneously increased LV contractility at the time of venous pooling may trigger the disregulated vasovagal reaction in VVS. Methods: Forty-seven patients (31 males, mean age 41 ± 18 years) with unexplained syncope were enrolled. Echocardiography was performed during the head-up tilt test (HUTT) as follows: baseline, passive tilting (0 and 20 min), and tilting with isoproterenol administration (5 and 10 min). Patients were divided into 2 groups according to the results of the HUTT; group 1 (n = 12) had a positive result and group 2 had a negative response. Results: LV ejection fraction (LVEF), determined immediately after tilting, increased in group 1, whereas LVEF decreased in group 2 (p = 0.032). Although left atrial and LV volumes decreased similarly during the test, group 1 showed a progressive reduction in LVEF, while LVEF progressively increased in group 2 (p = 0.007). Conclusion: Patients with HUTT-induced VVS presented LV hypercontractions immediately after tilting and a subsequent decrease in LV contractility. An instantaneous activation of the sympathetic nervous system at the time of venous pooling may trigger an early disregulated vasovagal reflex via an increase in LV contractility in VVS.
Daily Short-Term Intratympanic Dexamethasone Treatment Alone as an Initial or Salvage Treatment for Idiopathic Sudden Sensorineural Hearing Loss
Authors: Kakehata Seiji , Sasaki Akira , Futai Kazunori , Kitani Rei , Shinkawa Hideichi
Published: October 2010

Objective: Intratympanic (IT) steroid therapy has been proposed as an alternative treatment option for patients with idiopathic sudden sensorineural hearing loss (ISSNHL). However, the number and frequency of IT treatments and drug delivery methods remain to be determined. The purpose of this study was to evaluate the efficacy of daily short-term IT dexamethasone (DEX) treatment alone in ISSNHL patients using laser-assisted myringotomy (LAM) for the drug delivery route as an initial and/or salvage treatment. Study Design: Retrospective study. Setting: University hospital. Patients: Seventy-six ISSNHL patients receiving IT DEX. Patients with low-tone hearing loss, unilateral or bilateral fluctuating hearing loss or contralateral hearing loss were excluded. Intervention: DEX (4 mg/ml) was injected through a perforation made by LAM. IT DEX administration was performed on 8 sequential days. Main Outcome Measures: Pre- and postprocedure hearing levels. The average hearing level was determined by 5 frequencies (250, 500, 1000, 2000 and 4000 Hz). Results: Nineteen out of 76 patients fit the criteria for initial treatment in the study (group I), while 24 patients, who had failed systemic therapy, received salvage treatment (group S). The mean age of the patients in groups I and S was 56.2 years with a range from 31 to 73 years of age and 46.0 years with a range from 11 to 76 years of age, respectively. The mean number of days from onset of symptoms to IT therapy in groups I and S was 4.8 days with a range of 1–23 days and 15.3 days with a range of 6–28 days, respectively. In group I, 18 of the 19 patients (95%) showed improvement of more than 10 dB in the pure-tone audiogram, with a mean improvement of 40 dB. Twelve patients (63%) recovered completely and 16 patients (84%) demonstrated successful results with an improvement of more than 30 dB. In group S, 14 of the 24 patients (58%) showed improvement of more than 10 dB with a mean improvement of 16 dB. Two (8%) of the 7 patients (29%) with successful results recovered completely. Conclusions: Daily short-term IT DEX administration using LAM for ISSNHL patients without concurrent therapy showed a high response rate and high cure rate and proved to be an alternative therapeutic option to high-dose systemic steroids as a first- and/or second-line treatment.
Effects of Parents’ Education and Occupation on Adolescent Smoking and the Mediating Role of Smoking-Specific Parenting and Parent Smoking
Authors: Ringlever Linda , Otten Roy , de Leeuw Rebecca N.H. , Engels Rutger C.M.E.
Published: October 2010

The current study examined the independent effects of parents’ educational attainment and occupational status on adolescent smoking and mediation of smoking-specific communication and parents’ smoking behaviours on this link. Data were collected in a multi-informant, full-family design in two sampling waves separated by 3 years (n = 358). Education, occupational status, communication, and smoking were assessed via parent and child report. Different effects were found for the indicators of father and mother’s socioeconomic status (education and occupation) for three study outcomes (adolescent lifetime smoking, smoking onset, and smoking continuation). Bootstrapping procedures revealed no mediation in any of the socioeconomic status adolescent smoking associations. Study limitations and implications are discussed.
Removal of Ventricular Shunts
Authors: Al-Holou Wajd N. , Sack Jayson A. , Garton Hugh J.L. , Muraszko Karin M. , Maher Cormac O.
Published: October 2010

Background: Although most patients with an implanted ventriculoperitoneal shunt device will require cerebrospinal fluid diversion over the course of their lifetime, there appears to be a small number of patients that are shunt independent and may benefit from shunt removal. Methods: We retrospectively analyzed 661 patients with hydrocephalus treated over a 10-year period at a single institution. In 10 patients, a systematic shunt weaning protocol was attempted before removal of the cerebrospinal fluid shunt. Results: Ten patients underwent an attempt at shunt removal. Seven of these patients were successfully weaned and 3 were not. The indications to attempt shunt removal for the 7 patients that were successfully weaned were recurrent complications and infections requiring multiple shunt externalizations and revisions in 4 patients, asymptomatic shunt disconnection in 2 patients, and symptomatic overdrainage in 1 patient. None of the patients that were successfully weaned had a history of shunt failure resulting in ventriculomegaly. Two of the 3 patients who failed shunt weaning attempts had a history of shunt failure that resulted in ventriculomegaly. Conclusion: A small number of patients with shunted hydrocephalus may benefit from removal of their shunt.
The Impact of a ‘Resident Replacement’ Nurse Practitioner on an Academic Pediatric Neurosurgical Service
Authors: Holleman Judie , Johnson Amanda , Frim David M.
Published: October 2010

Introduction: The introduction of 80-hour workweek limitations has challenged resident training programs with creative scheduling while maintaining comprehensive training experiences. The work hour restrictions may be more adaptable to a medical service, but have been very challenging to an academic surgical program. The particular challenges include maximizing academic learning opportunities, operating room experiences and direct bedside patient care while adhering to the 80-hour restriction. This paper examines the addition of a pediatric nurse practitioner (NP) to a pediatric neurosurgical academic program in response to the resident work hour restrictions. Method: A survey questionnaire asking for responses to questions on a 1–10 rating scale was distributed to physicians, nurses and allied care providers approximately 1 year after addition of the NP. Participants were asked to rate satisfaction with the service’s availability, responsiveness and assessment of patient clinical satisfaction prior to the addition of the NP and at the time of questionnaire distribution. In addition, the hospital paging log was reviewed over a several-month epoch before and after addition of the NP. Finally, the number of quality assurance sentinel events was reviewed for the year prior to and the year after the initiation of the NP program. Results: The satisfaction scores in all categories, including overall satisfaction, significantly improved (p < 0.001) after the addition of the NP to the neurosurgery service. Also, during the NP on-duty coverage hours, the number of paging calls received by the residents was reduced commensurate to the large number of calls received by the NP. This change was presumed to be due to the confidence of other services in obtaining a timely and appropriate response. Finally, the number of sentinel event reports remained stable. Discussion: The addition of an NP in response to resident training changes has been a positive influence on satisfaction with the pediatric neurosurgical service while reducing the reliance on residents for bedside clinical care. Patient safety appears not to have been affected. Presumably, this response to resident work hour limitations will provide the needed time to enhance resident didactic and intraoperative training experiences.
Electroencephalography Features of Primary Epileptogenic Regions in Surgically Treated MRI-Negative Infantile Spasms
Authors: Hur Yun Jung , Lee Joon Soo , Kim Dong Seok , Hwang Taegyu , Kim Heung Dong
Published: October 2010

Objective: To evaluate the surgical outcome for intractable, MRI-negative infantile spasms (IS), and to identify diagnostic targets in the focal epileptogenic area by methods other than MRI. Methods: We retrospectively studied 9 patients who had had surgery for intractable IS, and whose lesions did not appear on MRI. We analyzed video/electroencephalography (EEG), single photon emission computed tomography (SPECT) and positron emission tomography (PET) findings and their surgical outcomes. In 7 patients who were seizure free after surgery, we analyzed the EEG parameters for characteristics expected in the primary epileptogenic region. Results: All patients underwent resective surgery including frontal lobectomy and multilobar resection. Seven patients showed an Engel class I outcome, and 2 patients showed a class III outcome. Interictal SPECT results showed 66.7% concordance for the hemisphere affected (lateralization), and 55.6% for lesion location (localization). Ictal SPECT showed 71.4% concordance for lateralization and localization. PET showed 66.7% concordance for lateralization, and 55.6% for localization. EEG parameters, including localized paroxysmal fast activities, spindle-shaped fast activities, repetitive or rhythmic sharp/spike wave discharges, and subclinical seizures showed highly localized specificity, and may serve to identify the epileptogenic lesion. Conclusion: Surgical treatment of MRI-negative IS should be justified using a combination of diagnostic methods.
Mechanisms and Clinical Implications of the Placebo Effect: Is There a Potential for the Elderly? A Mini-Review
Authors: Bingel Ulrike , Colloca Luana , Vase Lene
Published: October 2010

In recent years, the placebo effect has been a topic of considerable interest both in the scientific and the clinical community. In this time, the placebo effect has evolved from being considered a nuisance in clinical and pharmacological research to becoming a neurobiological phenomenon worthy of scientific investigation in its own right. Recent research shows that placebo effects are genuine psychobiological events attributable to the overall therapeutic context, and that these effects can be robust in both laboratory and clinical settings. These psychosocially induced biochemical changes in a patient’s brain and body may in turn affect the course of a disease and the response to a therapy. Here we summarize and discuss the current insights into placebo mechanisms and discuss the potentially widespread implications for research and clinical practice. Even though a systematic knowledge of placebo effects across the lifespan is lacking, we aim at highlighting specific aspects related to the care of elderly patients and those suffering from neurodegenerative diseases.