bluuebunny/crossref_metadata_2025 huggingface dataset:
Legal and ethical implications of inherited cardiac disease in clinical practice within the UK: Figure 1
Authors: Hall Alison E , Burton Hilary
Published: November 2010

Increasing genetic knowledge over the last decade has enabled hundreds of genetic variants associated with inherited cardiac conditions to be identified, many of which cause increased risk of sudden cardiac death. While individually these conditions are rare, taken together they impose a significant burden. The severity of these conditions—the possibility that they might cause sudden unheralded death of a teenager or young adult—juxtaposed with uncertainty about the pathology linked with many of the genetic variants is significant in terms of professional practice because, increasingly, clinicians have been encouraged to cascade out genetic testing from the proband or consultand to other family members who may be at risk of developing the same condition. This process often involves sharing human tissue samples, DNA or personal information. This paper reviews the legal and regulatory frameworks which may apply when tissue and DNA samples are collected, used and retained, both for the purpose of diagnosis and for benefiting other family members, when a suspected or definitive diagnosis of an inherited cardiovascular condition is made. Sometimes the interests of family members may conflict, and it may be difficult for practitioners to reconcile the interests of one family member with another, particularly if the balance of benefits and harms from testing is unclear. The paper then examines some of the ethical tensions which may arise in practice and concludes that all involved should be conversant with the legal and ethical frameworks that apply.
Developing ethics guidance for HIV prevention research: the HIV Prevention Trials Network approach: Table 1
Authors: Rennie Stuart , Sugarman Jeremy
Published: November 2010

More than 25 years into the HIV epidemic, in excess of 2 million new infections continue to occur each year. HIV prevention research is crucial for groups at heightened risk for HIV, but the design and conduct of HIV prevention research with vulnerable populations worldwide raises considerable ethical challenges. The HIV Prevention Trials Network (HPTN) is a global collaborative network that conducts clinical and behavioural studies on non-vaccine interventions to reduce the transmission of HIV. In 2003, the HPTN developed ethical guidance to enhance the responsible conduct of its research activities and as a distinctive contribution to global research ethics. In what follows, the developments that motivated the drafting of a revised ethics document in 2009 are described, including the process by which that revision took place and some of the key differences between the HPTN ethics guidance and other relevant guidelines in the field.
The ethics of screening for abdominal aortic aneurysm in men
Authors: Brownsword Roger , Earnshaw Jonothan J
Published: November 2010

Approximately 6000 men die every year from ruptured abdominal aortic aneurysm in England and Wales. Randomised clinical trials and a large pilot study have shown that ultrasound screening of men aged 65 years can prevent about half of these deaths. However, there is a significant perioperative morbidity and mortality from interventions to repair the detected aneurysm. This paper explores the ethical issues of screening men for abdominal aortic aneurysm. It is concluded that a population screening programme for abdominal aortic aneurysm offers a clear balance of good over harm. It is therefore ethically justified, as long as men are given adequate information at every stage of the process. Each man has the right to be properly informed, regardless of whether he accepts the invitation to be screened and, if an aneurysm is detected, whether or not he accepts treatment.
A new law on advance directives in Germany
Authors: Wiesing U , Jox R J , Heßler H-J , Borasio G D
Published: November 2010

This article presents the new German law on advance directives from 1 September 2009. The history of the parliamentary process of this law is described, the present regulations are explained, their relevance for medical practice discussed and shortcomings are identified. Finally, the new law is compared with other regulations in the international context. Previously established legal practice in Germany has now become largely confirmed by the new law: An advanced directive must be respected in any decision concerning medical treatment, regardless of the stage of the illness. It can be informally revoked at any time, even with limited decision-making capacity. Nobody may be obliged to issue a directive in any way. Advance directives do not need notarisation or routine updating after certain time intervals. Provided that the patient, who is no longer mentally competent, has issued a lasting power of attorney (Bevollmächtiger), or provided that the patient has been appointed a healthcare proxy by the courts (Betreuer), this authorised surrogate must assert the patient's will. The role of the guardianship court is clarified: it only needs to be involved in cases of disagreement as to the patient's will. The new German law thus combines more legal certainty with a liberal emphasis on patient autonomy and flexible, adaptable regulations.
Ethical review reporting of Chinese trials records in WHO primary registries
Authors: Xuemei Liu , Youping Li , Shangqi Song , Senlin Yin , Williams Shawna
Published: November 2010

Objective

To investigate the report rate of ethical review in registered Chinese trials records.

Methods

Chinese trials recorded in WHO primary registries andhttp://clinicaltrials.govto 14 July 2009 were identified. The report rates of ethical review and each of the 20 items in WHO's Trial Registration Data Set were calculated. Correlation of the item's report rate with the ethical review report rate was assessed. PubMed, EMBASE, CNKI and CBM (from the establishment of each database to 14 July 2009) were also searched to collect the full texts of completed trials to calculate the report rate of ethical review in the result publications.

Results

A total of 1247 records were identified, and 687 (55.1%) reported ethical review. The records reporting secondary sponsor(s), contact for public queries and key secondary outcomes were more likely to report ethical review information (66.3% vs 44.3%, 38.1% vs 28.5%, 53.9% vs 51.8%). The ethical review report rate of trials sponsored by industry was lower than those sponsored by non-industry (40.9% vs 51.9%). The report rates of ethical review for self-supported trials (83.5%) and trials with unidentified sources of monetary or material support (66.7%) were lower than the average ethical review report rate for records in the Chinese Clinical Trial Registration Center (ChiCTR). The ethical review report rate was not high in the result publications (84.3% inhttp://clinicaltrials.gov, 50.0% in ChiCTR).

Conclusion

Registered Chinese trials records report ethical review inadequately. Incomplete registration is correlated with not reporting ethical review. Medical journals should inspect ethical review more critically.
The actuality and the historical background of covert Euthanasia in Albania
Authors: Boçari Gëzim , Shaqiri Elmaz , Vyshka Gentian
Published: November 2010

Euthanasia is not legal in Albania, yet there is strong evidence that euthanising a terminally ill patient is not an unknown concept for the Albanians. The first mentioned case of euthanasia is found in 7thcentury AD mythology and during the communist regime (1944–1989), allegations of euthanising political prisoners and possible rivals in the struggle for power have widely been formulated. There is a trend among relatives and laymen taking care of terminally ill patients to apply tranquilisers in an abusive dosage, or even against medical advice, aiming at sedating the ailing patient. These actions, the refusal to keep on consistently applying life prolonging treatment, and other data, suggest that covert euthanasia is a practice and legal interventions are needed towards formalising it. This might well improve end-of-life care standards, since the inadequacy of structures, such as hospices and residential asylums, is becoming a major drawback in the struggle for dignity and accessible socio-medical help for third age persons and terminal patients.
Conflict and emotional exhaustion in obstetrician-gynaecologists: a national survey
Authors: Yoon John D , Rasinski Kenneth A , Curlin Farr A
Published: November 2010

Context

Conflicts over treatment decisions have been linked to physicians' emotional states.

Objective

To measure the prevalence of emotional exhaustion and conflicts over treatment decisions among US obstetrician/gynaecologists (ob/gyns), and to examine the relationship between the two and the physician characteristics that predict each.

Methods

Mailed survey of a stratified random sample of 1800 US ob/gyn physicians. Criterion variables were levels of emotional exhaustion and frequency of conflict with colleagues and patients. Predictors included physicians' religious characteristics and self-perceived empathy.

Results

Response rate among eligible physicians was 66% (1154/1760). 36% of ob/gyns reported high levels of emotional exhaustion, and majorities reported conflict with colleagues (59%) and patients (61%). Those reporting conflict were much more likely to report emotional exhaustion (58% vs 29% who never conflict, OR, 95% CI 2.8, 1.6 to 4.8 for conflict with colleagues; 55% versus 26%, OR, 95% CI 2.2, 1.4 to 3.5 for conflict with patients). Physicians with lower self-perceived empathy were more likely to report physician-patient conflicts (65% vs 58% with higher empathy, OR, 95% CI 1.4, 1.0 to 1.9), as were female ob/gyns (66% vs 57% of males, OR, 95% CI 1.5, 1.1 to 2.0). Foreign-born physicians were less likely to report such conflicts (47% vs 64% of US born, OR, 95% CI 0.5, 0.4 to 0.8). Physicians' religious characteristics were not significantly associated with reporting conflict.

Conclusions

Conflicts over treatment decisions are associated with physicians' empathy, gender, immigration history and level of emotional exhaustion. With respect to the latter, conflict in the clinical encounter may represent an overlooked source or sign of burnout among ob/gyns.
Use of the Outreach distal access catheter as an intracranial platform facilitates coil embolization of select intracranial aneurysms: technical note
Authors: Hauck Erik F , Tawk Rabih G , Karter Nicholas S , Binning Mandy J , Khalessi Alexander A , Natarajan Sabareesh K , Hopkins L Nelson , Levy Elad I , Siddiqui Adnan H
Published: November 2010

Objective

The Outreach distal access catheter (DAC; Concentric Medical, Mountain View, California, USA) has been designed to assist the Merci device (Concentric Medical) with clot retrieval in the setting of acute stroke. Its application for coil embolization of intracranial aneurysms was investigated.

Methods

Between December 2008 and January 2010, 150 aneurysms were treated with endovascular methods. In 18 cases of small aneurysms and/or increased parent vessel tortuosity, the DAC was used for additional support. Merits and complications related to the use of this catheter are reviewed.

Results

The mean aneurysm size was 7.1 mm (range 3.5–25). In each case, the DAC was used as an intracranial platform catheter in close proximity to the target aneurysm. This catheter (outer diameter 3.9 or 4.3 French) increased the stability and reduced the redundancy of the microcatheter. As a result, handling and control of the microcatheter were improved. In three cases, the coiling procedure could not be completed because of difficulties not related to the DAC. Aneurysms in the remaining patients were treated successfully with complete (n=12) or near complete (n=3) angiographic occlusion.

Conclusion

For smaller or distal intracranial aneurysms with difficult access, use of the DAC as an additional platform in close proximity to the target aneurysm subjectively enhanced microcatheter control and safety.
Patent foramen ovale associated with the unusual presentation of unilateral paramedian thalamic perforating artery infarction after embolic occlusion of ‘artery of Percheron’: case report and review of the literature
Authors: Yarmohammadi Hirad , Carasca Andrei , Yarmohammadi Hooman , Hsu Daniel P
Published: November 2010

‘Artery of Percheron’ is a rare variation in blood supply in which a solitary arterial trunk arises from one of the proximal segments of the posterior cerebral arteries and supplies the paramedian thalami bilaterally. A young patient (in their early 30s) who presented with sudden onset of visual disturbance and speech difficulties is reported. A review of literature from 1981 to 2009 and review of the most widely reported clinical signs and symptoms are provided.
Virulence gene profiles and intimin subtypes of Shiga toxin‐producingEscherichia coliisolated from healthy and diarrhoeic calves
Authors: Badouei M. Askari , Salehi T. Zahraei , Khorasgani M. Rabbani , Tadjbakhsh H. , Brujeni G. Nikbakht , Nadalian M. G.
Published: November 2010

The virulence properties of Shiga toxin‐producingEscherichia coli(STEC) strains isolated from diarrhoeic and non‐diarrhoeic calves were compared. The strains were also tested for O157:H7, O111 and O26 serotypes, using PCR and conventional serotyping methods.E colistrains isolated from 297 faecal samples, from 200 diarrhoeic and 97 non‐diarrhoeic calves, were screened by multiplex PCR assay for thestx1,stx2,eaeandEhlyvirulence genes. STECs were recovered from 8 per cent of diarrhoeic calves and 10.3 per cent of non‐diarrhoeic calves. The predominant virulence gene profile wasstx1/eae/Ehly(47.3 per cent) among isolates from diarrhoeic calves andeae/Ehly(36.8 per cent) among isolates from non‐diarrhoeic calves. Among three tested serogroups, the predominant serogroup was O26 (18.4 per cent), and O157:H7 was not detected. Intimin subtyping by restriction fragment length polymorphism analysis revealed only three intimin subtypes (β, γ and θ). A significant difference was observed in the distribution of Int‐θ between two groups. Int‐θ was present in 50 per cent of the isolates from diarrhoeic calves and in 11.1 per cent of the isolates from non‐diarrhoeic calves; this difference was statistically significant (P=0.01).
Brain and skull lesions resulting from use of percussive bolt, cervical dislocation by stretching, cervical dislocation by crushing and blunt trauma in turkeys
Authors: Erasmus M. A. , Turner P. V. , Nykamp S. G. , Widowski T. M.
Published: November 2010

Three experiments were conducted to assess brain damage resulting from percussive bolt shooting and cervical dislocation by crushing (neck crushing) in turkey hens (mean [se] bodyweight 11.4 [0.1] kg); percussive bolt shooting and blunt trauma in turkey toms (13.1 [0.2] kg); and percussive bolt shooting, blunt trauma and cervical dislocation by stretching (neck stretching) in broiler turkeys (3.9 [0.3] kg). Brain and skull damage were assessed using macroscopic and microscopic evaluations and CT. Macroscopic subcutaneous haemorrhage was significantly greater with the percussive bolt in all three experiments (hens P=0.01, toms P=0.02, broilers P=0.0003), and skull fractures were more severe for toms (P<0.0001) and broilers (P=0.03) killed with the percussive bolt versus blunt trauma. In a subsample of turkeys, microscopic brain damage was present in all turkeys killed by percussive bolt shooting (five hens, 10 toms and four broilers) and blunt trauma (nine toms and three broilers), but only in one of four turkeys killed by neck crushing and one of four turkeys killed by neck stretching. Percussive bolt shooting and blunt trauma most likely caused death by directly disrupting brain function, whereas neck stretching and neck crushing probably resulted in death from cerebral hypoxia and ischaemia.
KNOWLEDGE EXTRACTION FROM EVOLVING SPIKING NEURAL NETWORKS WITH RANK ORDER POPULATION CODING
Authors: SOLTIC SNJEZANA , KASABOV NIKOLA
Published: November 2010

This paper demonstrates how knowledge can be extracted from evolving spiking neural networks with rank order population coding. Knowledge discovery is a very important feature of intelligent systems. Yet, a disproportionally small amount of research is centered on the issue of knowledge extraction from spiking neural networks which are considered to be the third generation of artificial neural networks. The lack of knowledge representation compatibility is becoming a major detriment to end users of these networks. We show that a high-level knowledge can be obtained from evolving spiking neural networks. More specifically, we propose a method for fuzzy rule extraction from an evolving spiking network with rank order population coding. The proposed method was used for knowledge discovery on two benchmark taste recognition problems where the knowledge learnt by an evolving spiking neural network was extracted in the form of zero-order Takagi-Sugeno fuzzy IF-THEN rules.
ON THE PROBABILISTIC OPTIMIZATION OF SPIKING NEURAL NETWORKS
Authors: SCHLIEBS STEFAN , KASABOV NIKOLA , DEFOIN-PLATEL MICHAËL
Published: November 2010

The construction of a Spiking Neural Network (SNN), i.e. the choice of an appropriate topology and the configuration of its internal parameters, represents a great challenge for SNN based applications. Evolutionary Algorithms (EAs) offer an elegant solution for these challenges and methods capable of exploring both types of search spaces simultaneously appear to be the most promising ones. A variety of such heterogeneous optimization algorithms have emerged recently, in particular in the field of probabilistic optimization. In this paper, a literature review on heterogeneous optimization algorithms is presented and an example of probabilistic optimization of SNN is discussed in detail. The paper provides an experimental analysis of a novel Heterogeneous Multi-Model Estimation of Distribution Algorithm (hMM-EDA). First, practical guidelines for configuring the method are derived and then the performance of hMM-EDA is compared to state-of-the-art optimization algorithms. Results show hMM-EDA as a light-weight, fast and reliable optimization method that requires the configuration of only very few parameters. Its performance on a synthetic heterogeneous benchmark problem is highly competitive and suggests its suitability for the optimization of SNN.
CASE STUDY ON A SELF-ORGANIZING SPIKING NEURAL NETWORK FOR ROBOT NAVIGATION
Authors: NICHOLS ERIC , McDAID L. J. , SIDDIQUE N. H.
Published: November 2010

This paper presents a Spiking Neural Network (SNN) architecture for mobile robot navigation. The SNN contains 4 layers where dynamic synapses route information to the appropriate neurons in each layer and the neurons are modeled using the Leaky Integrate and Fire (LIF) model. The SNN learns by self-organizing its connectivity as new environmental conditions are experienced and consequently knowledge about its environment is stored in the connectivity. Also a novel feature of the proposed SNN architecture is that it uses working memory, where present and previous sensor states are stored. Results are presented for a wall following application.
ENERGY NORM A POSTERIORI ERROR ESTIMATION FOR hp-ADAPTIVE DISCONTINUOUS GALERKIN METHODS FOR ELLIPTIC PROBLEMS IN THREE DIMENSIONS
Authors: ZHU LIANG , GIANI STEFANO , HOUSTON PAUL , SCHÖTZAU DOMINIK
Published: November 2010

We develop the energy norm a posteriori error estimation for hp-version discontinuous Galerkin (DG) discretizations of elliptic boundary-value problems on 1-irregularly, isotropically refined affine hexahedral meshes in three dimensions. We derive a reliable and efficient indicator for the error measured in terms of the natural energy norm. The ratio of the efficiency and reliability constants is independent of the local mesh sizes and weakly depending on the polynomial degrees. In our analysis we make use of an hp-version averaging operator in three dimensions, which we explicitly construct and analyze. We use our error indicator in an hp-adaptive refinement algorithm and illustrate its practical performance in a series of numerical examples. Our numerical results indicate that exponential rates of convergence are achieved for problems with smooth solutions, as well as for problems with isotropic corner singularities.
NUMERICAL STRATEGIES FOR STROKE OPTIMIZATION OF AXISYMMETRIC MICROSWIMMERS
Authors: ALOUGES FRANÇOIS , DESIMONE ANTONIO , HELTAI LUCA
Published: November 2010

We propose a computational method to solve optimal swimming problems, based on the boundary integral formulation of the hydrodynamic interaction between swimmer and surrounding fluid and direct constrained minimization of the energy consumed by the swimmer.

We apply our method to axisymmetric model examples. We consider a classical model swimmer (the three-sphere swimmer of Golestanian et al.) as well as a novel axisymmetric swimmer inspired by the observation of biological micro-organisms.
TOPIC TRACKING WITH IMPROVED REPRESENTATION MODEL AND JOINT TRACKING METHOD
Authors: ZHANG XIAOYAN , WANG TING
Published: November 2010

Topic tracking is to monitor a stream of stories to find additional stories on a topic identified by several samples. However, the predefined information about a tracked topic does not provide enough information to deal with the new information occurred in the tracking procedure. To overcome this problem, we proposed a joint tracking method using both the topic-specific information from the predefined information and the non-topic-specific information from the data on other topics. Besides, to overcome the limitation of the representation model and the topic drift problem, we have also used two other improvements: a topic-based weighting method is used to measure the features of both tracked topics and single testing stories; a dynamic topic model is extended with the information brought by the incoming related stories and the noise is filtered out with the information in the incoming unrelated stories. The implemented tracking systems are evaluated on the Chinese subset of TDT4 corpus by the TDT2003 evaluation method. The experimental results indicate that the above methods all improve the tracking performance. More importantly, these techniques are complementary to one another and not mutually exclusive.
ON THE SIZE OF SETS IN A POLYNOMIAL VARIANT OF A PROBLEM OF DIOPHANTUS
Authors: DUJELLA ANDREJ , JURASIĆ ANA
Published: November 2010

In this paper, we prove that there does not exist a set of 8 polynomials (not all constant) with coefficients in an algebraically closed field of characteristic 0 with the property that the product of any two of its distinct elements plus 1 is a perfect square.
DISCRIMINANTS CUBIQUES ET PROGRESSIONS ARITHMÉTIQUES
Authors: BELABAS KARIM , FOUVRY ÉTIENNE
Published: November 2010

Nous calculons la densité des discriminants des corps sextiques galoisiens de groupe S3, démontrant un nouveau cas de la conjecture de Malle ainsi qu'un cas particulier de sa généralisation par Ellenberg et Venkatesh. Plus généralement, nous étudions la densité des discriminants de corps cubiques dans une progression arithmétique, avec une zone d'uniformité la plus large possible.

We compute the density of discriminants of Galois sextic fields with group S3, thereby proving a new case of Malle's conjecture as well as a special case of its generalization by Ellenberg and Venkatesh. Further, we study the density of cubic discriminants in an arithmetic progression, in the largest possible uniformity with respect to the modulus.
TWISTED BORCHERDS PRODUCTS ON HILBERT MODULAR SURFACES AND THE REGULARIZED THETA LIFT
Authors: EHLEN STEPHAN
Published: November 2010

We construct a lifting from weakly holomorphic modular forms of weight 0 for SL 2(ℤ) with integral Fourier coefficients to meromorphic Hilbert modular forms of weight 0 for the full Hilbert modular group of a real quadratic number field with an infinite product expansion and a divisor given by a linear combination of twisted Hirzebruch–Zagier divisors. The construction uses the singular theta lifting by considering a suitable twist of a Siegel theta function. We generalize the work by Bruinier and Yang who showed the existence of the lifting for prime discriminants using a different approach.
MONOGENEITY IN CYCLOTOMIC FIELDS
Authors: ROBERTSON LEANNE
Published: November 2010

A number field is said to be monogenic if its ring of integers is a simple ring extension ℤ[α] of ℤ. It is a classical and usually difficult problem to determine whether a given number field is monogenic and, if it is, to find all numbers α that generate a power integral basis {1, α, α2, …, αk} for the ring. The nth cyclotomic field ℚ(ζn) is known to be monogenic for all n, and recently Ranieri proved that if n is coprime to 6, then up to integer translation all the integral generators for ℚ(ζn) lie on the unit circle or the line Re (z) = 1/2 in the complex plane. We prove that this geometric restriction extends to the cases n = 3k and n = 4k, where k is coprime to 6. We use this result to find all power integral bases for ℚ(ζn) for n = 15, 20, 21, 28. This leads us to a conjectural solution to the problem of finding all integral generators for cyclotomic fields.
EXACT AVERAGES OF CENTRAL VALUES OF TRIPLE PRODUCT L-FUNCTIONS
Authors: FEIGON BROOKE , WHITEHOUSE DAVID
Published: November 2010

We obtain exact formulas for central values of triple product L-functions averaged over newforms of weight 2 and prime level. We apply these formulas to non-vanishing problems. This paper uses a period formula for the triple product L-function proved by Gross and Kudla.
GENERATING FUNCTIONS OF CHEBYSHEV-LIKE POLYNOMIALS
Authors: BOSTAN ALIN , SALVY BRUNO , TRAN KHANG
Published: November 2010

In this short note, we give simple proofs of several results and conjectures formulated by Stolarsky and Tran concerning generating functions of some families of Chebyshev-like polynomials.
ON THE SUM OF A PRIME AND A FIBONACCI NUMBER
Authors: LEE K. S. ENOCH
Published: November 2010

We show that the set of the numbers that are the sum of a prime and a Fibonacci number has positive lower asymptotic density.
FORMAL GROUPS OF JACOBIAN VARIETIES OF HYPERELLIPTIC CURVES
Authors: SAIRAIJI FUMIO
Published: November 2010

Let k be a field of characteristic zero. In this paper, we discuss two explicit constructions of the formal groups Ĵ of the Jacobian varieties J of hyperelliptic curves C over k. Our results are generalizations of the classical constructions of formal groups of elliptic curves. As an application of our results, we may decide the type of bad reduction of J modulo p when C is a hyperelliptic curve over ℚ.
Nitric oxide-mediated inhibition of taurocholate uptake involvesS-nitrosylation of NTCP
Authors: Schonhoff Christopher M. , Ramasamy Umadevi , Anwer M. Sawkat
Published: November 2010

The sodium-taurocholate (TC) cotransporting polypeptide (NTCP) facilitates bile formation by mediating sinusoidal Na+-TC cotransport. During sepsis-induced cholestasis, there is a decrease in NTCP-dependent uptake of bile acids and an increase in nitric oxide (NO) levels in hepatocytes. In rat hepatocytes NO inhibits Na+-dependent uptake of taurocholate. The aim of this study was to extend these findings to human NTCP and to further investigate the mechanism by which NO inhibits TC uptake. Using a human hepatoma cell line stably expressing NTCP (HuH-NTCP), we performed experiments with the NO donors sodium nitroprusside and S-nitrosocysteine and demonstrated that NO inhibits TC uptake in these cells. Kinetic analyses revealed that NO significantly decreased the Vmaxbut not the Kmof TC uptake by NTCP, indicating noncompetitive inhibition. NO decreased the amount of NTCP in the plasma membrane, providing a molecular mechanism for the noncompetitive inhibition of TC uptake. One way that NO can modify protein function is through a posttranslational modification known as S-nitrosylation: the binding of NO to cysteine thiols. Using a biotin switch technique we observed that NTCP is S-nitrosylated under conditions in which NO inhibits TC uptake. Moreover, dithiothreitol reversed NO-mediated inhibition of TC uptake and S-nitrosylation of NTCP, indicating that NO inhibits TC uptake via modification of cysteine thiols. In addition, NO treatment led to a decrease in Ntcp phosphorylation. Taken together these results indicate that the inhibition of TC uptake by NO involves S-nitrosylation of NTCP.
Investigation of anal motor characteristics of the sensorimotor response (SMR) using 3-D anorectal pressure topography
Authors: Cheeney Gregory , Remes-Troche Jose M. , Attaluri Ashok , Rao Satish S. C.
Published: November 2010

Desire to defecate is associated with a unique anal contractile response, the sensorimotor response (SMR). However, the precise muscle(s) involved is not known. We aimed to examine the role of external and internal anal sphincter and the puborectalis muscle in the genesis of SMR. Anorectal 3-D pressure topography was performed in 10 healthy subjects during graded rectal balloon distention using a novel high-definition manometry system consisting of a probe with 256 pressure sensors arranged circumferentially. The anal pressure changes before, during, and after the onset of SMR were measured at every millimeter along the length of anal canal and in 3-D by dividing the anal canal into 4 × 2.1-mm grids. Pressures were assessed in the longitudinal and anterior-posterior axis. Anal ultrasound was performed to assess puborectalis morphology. 3-D topography demonstrated that rectal distention produced an SMR coinciding with desire to defecate and predominantly induced by contraction of puborectalis. Anal ultrasound showed that the puborectalis was located at mean distance of 3.5 cm from anal verge, which corresponded with peak pressure difference between the anterior and posterior vectors observed at 3.4 cm with 3-D topography ( r = 0.77). The highest absolute and percentage increases in pressure during SMR were seen in the superior-posterior portion of anal canal, reaffirming the role of puborectalis. The SMR anal pressure profile showed a peak pressure at 1.6 cm from anal verge in the anterior and posterior vectors and distinct increase in pressure only posteriorly at 3.2 cm corresponding to puborectalis. We concluded that SMR is primarily induced by the activation and contraction of the puborectalis muscle in response to a sensation of a desire to defecate.
Colonic soluble mediators from the maternal separation model of irritable bowel syndrome activate submucosal neurons via an interleukin-6-dependent mechanism
Authors: O'Malley Dervla , Liston Martin , Hyland Niall P. , Dinan Timothy G. , Cryan John F.
Published: November 2010

Irritable bowel syndrome (IBS) is characterized by episodic bouts of abdominal pain, bloating, and altered bowel habit. Accumulating evidence has linked immune activation with IBS, including reports of increases in circulating levels of the proinflammatory cytokine interleukin (IL)-6. However, it is unknown whether IL-6 contributes directly to disease manifestation. As enteric nervous activity mediates motility and secretory function, the aims of this study were to determine the effects of IL-6 on submucosal neurons and related gastrointestinal (GI) function. In these studies, we examined the colons of maternally separated (MS) rats, which exhibit elevated circulating levels of IL-6 in addition to GI dysfunction. To our knowledge, these studies are the first to provide evidence of the sensitivity of submucosal neurons to colonic secretions from MS rats ( n = 50, P < 0.05), thus recapitulating clinical biopsy data. Moreover, we demonstrated that the excitatory action is IL-6 dependent. Thereafter, the impact of IL-6 on neuronal and glial activation and absorpto/secretory function was pharmacologically characterized. Other proinflammatory cytokines including IL-8 ( n = 30, P > 0.05), IL-1β ( n = 56, P > 0.05), and TNF-α ( n = 56, P > 0.05) excited fewer neurons. Both muscarinic and nicotinic cholinergic receptors participate in the effect and cause downstream activation of ERK, JAK-STAT, and NF-κB signaling cascades. Functionally, IL-6 increases transepithelial resistance and enhances neurally and cholinergically mediated ion transport. These data provide a role for IL-6 in colonic secretory functions and relate these effects to GI dysfunction in an animal model of IBS, thereby elucidating a potential relationship between circulating levels of IL-6 and aberrant GI function.
Tumor suppressor FOXO3 mediates signals from the EGF receptor to regulate proliferation of colonic cells
Authors: Qi Wentao , Weber Christopher R. , Wasland Kaarin , Roy Hemant , Wali Ramesh , Joshi Suhasini , Savkovic Suzana D.
Published: November 2010

Epithelial proliferation, critical for homeostasis, healing, and colon cancer progression, is in part controlled by epidermal growth factor receptor (EGFR). Proliferation of colonic epithelia can be induced by Citrobacter rodentium infection, and we have demonstrated that activity of tumor suppressor FOXO3 was attenuated after this infection. Thus the aim of this study was to determine the contribution of FOXO3 in EGFR-dependent proliferation of intestinal epithelia and colon cancer cell lines. In this study we show that, during infection with C. rodentium, EGFR was significantly phosphorylated in colonic mucosa and Foxo3 deficiency in this model lead to an increased number of bromodeoxyuridine-positive cells. In vitro, in human colon cancer cells, increased expression and activation of EGFR was associated with proliferation that leads to FOXO3 phosphorylation (inactivation). Following EGFR activation, FOXO3 was phosphorylated (via phosphatidylinositol 3-kinase/Akt) and translocated to the cytosol where it was degraded. Moreover, inhibition of proliferation by overexpressing FOXO3 was not reversed by the EGFR signaling, implicating FOXO3 as one of the regulators downstream of EGFR. FOXO3 binding to the promoter of the cell cycle inhibitor p27kip1 was decreased by EGFR signaling, suggesting its role in EGFR-dependent proliferation. In conclusion, we show that proliferation in colonic epithelia and colon cancer cells, stimulated by EGFR, is mediated via loss of FOXO3 activity and speculate that FOXO3 may serve as a target in the development of new pharmacological treatments of proliferative diseases.
Genes and biochemical pathways in human skeletal muscle affecting resting energy expenditure and fuel partitioning
Authors: Wu Xuxia , Patki Amit , Lara-Castro Cristina , Cui Xiangqin , Zhang Kui , Walton R. Grace , Osier Michael V. , Gadbury Gary L. , Allison David B. , Martin Mitchell , Garvey W. Timothy
Published: November 2010

Genes influencing resting energy expenditure (REE) and respiratory quotient (RQ) represent candidate genes for obesity and the metabolic syndrome because of the involvement of these traits in energy balance and substrate oxidation. We aim to explore the molecular basis for individual variation in REE and fuel partitioning as reflected by RQ. We performed microarray studies in human vastus lateralis muscle biopsies from 40 healthy subjects with measured REE and RQ values. We identified 2,392 and 1,115 genes significantly correlated with REE and RQ, respectively. Genes correlated with REE and RQ encompass a broad array of functions, including carbohydrate and lipid metabolism, gene expression, mitochondrial processes, and membrane transport. Microarray pathway analysis revealed that REE was positively correlated with upregulation of G protein-coupled receptor signaling (meet criteria/total genes: 65 of 283) involved in autonomic nervous system functions, including those receptors mediating adrenergic, dopamine, γ-aminobutyric acid (GABA), neuropeptide Y (NPY), and serotonin action (meet criteria/total genes: 46 of 176). Reduced REE was associated with an increase in genes participating in ubiquitin-proteasome-dependent proteolytic pathways (58 of 232). Serine-type peptidase activity (9 of 76) was positively correlated with RQ, while genes involved in the protein phosphatase type 2A complex (4 of 9), mitochondrial function and cellular respiration (38 of 315), and unfolded protein binding (19 of 97) were associated with reduced RQ values and a preference for lipid fuel metabolism. Individual variations in whole body REE and RQ are regulated by differential expressions of specific genes and pathways intrinsic to skeletal muscle.
Electric field stimulation of precision-cut lung slices
Authors: Schlepütz Marco , Uhlig Stefan , Martin Christian
Published: November 2010

The precision-cut lung slice (PCLS) technique is widely used to examine airway responses in different species. We developed a method to study nerve-dependent bronchoconstriction by the application of electric field stimulation (EFS) to PCLS. PCLS prepared from Wistar rats were placed between two platinum electrodes to apply serial rectangular impulses (5–100 Hz), and bronchoconstriction was studied by videomicroscopy. The extent of airway contractions increased with higher frequencies. Stable repeated airway contractions were obtained at a frequency of 50 Hz, a width of 1 ms, and an output of 200 mA for 2.5 s each minute. Larger airways showed stronger responses. The EFS-triggered contractions were increased by the acetylcholine esterase inhibitor neostigmine (10 μM) and reversed by the muscarinic antagonist atropine (10 μM), whereas the thromboxane protanoid receptor antagonist SQ29548 (10 μM) had no effect. Magnesium ions (10 mM) antagonized airway contractions induced by EFS, but not by methacholine, indicating that nerve endings remain intact in PCLS. Our data further show that the electrically evoked airway contractions in PCLS are mediated by cholinergic nerves, independent of thromboxane and more prominent in larger airways. Taken together these findings show that nerve endings remain intact in PCLS, and they suggest that the present method is useful to study neurogenic responses in airways of different size.
Control of cerebral blood velocity with furosemide-induced hypovolemia and upright tilt
Authors: Romero Steven A. , Moralez Gilbert , Rickards Caroline A. , Ryan Kathy L. , Convertino Victor A. , Fogt Donovan L. , Cooke William H.
Published: November 2010

The purpose of this study was to test the hypothesis that exacerbated reductions of cerebral blood velocity (CBV) during upright tilt with dehydration are associated with impaired cerebrovascular control. Nine healthy men were tilted head-up (HUT) to 70° for 10 min on two occasions separated by 7 days under euhydration (EUH) and dehydration (DEH; 40 mg of furosemide and water restriction) conditions. Beat-by-beat arterial pressures and CBV were measured during a 5-min supine baseline and during the first (T1) and last (T2) 5 min of HUT. Cerebral autoregulation and arterial baroreflex sensitivity were assessed in the frequency domain with cross-spectral techniques. DEH reduced plasma volume by 10% ( P = 0.008) and supine mean CBV (CBVmean) by 11% ( P = 0.002). Mean arterial pressure (MAP), stroke volume, and baroreflex sensitivity decreased during HUT ( P ≤ 0.002), but absolute reductions were similar between hydration conditions, with the exception of stroke volume, which was lower at T1 during DEH than EUH ( P = 0.04). CBVmeanduring DEH was lower (7 cm/s) over the course of the entire 10 min of HUT ( P ≤ 0.004) than during EUH. Low-frequency oscillations (0.07-0.2 Hz) of MAP and CBVmeanand MAP-CBVmeancoherence were higher during DEH than EUH at T1 ( P ≤ 0.02), but not at T2. Our results suggest that increased coherence between arterial pressure and CBV with the combination of DEH and HUT are indicative of altered cerebrovascular control. Increased CBV oscillations with DEH may reflect acute protective mechanisms to ensure adequate cerebral perfusion under conditions of reduced central blood volume.
Evidence for impaired neurovascular transmission in a murine model of Duchenne muscular dystrophy
Authors: Bagher Pooneh , Duan Dongsheng , Segal Steven S.
Published: November 2010

Duchenne muscular dystrophy (DMD) is a muscle-wasting disease caused by mutations in the dystrophin gene. Little is known about how blood flow control is affected in arteriolar networks supplying dystrophic muscle. We tested the hypothesis that mdx mice, a murine model for DMD, exhibit defects in arteriolar vasomotor control. The cremaster muscle was prepared for intravital microscopy in pentobarbital sodium-anesthetized mdx and C57BL/10 control mice ( n ≥ 5 per group). Spontaneous vasomotor tone increased similarly with arteriolar branch order in both mdx and C57BL/10 mice [pooled values: first order (1A), 6%; second order (2A), 56%; and third order (3A), 61%] with no difference in maximal diameters between groups measured during equilibration with topical 10 μM sodium nitroprusside (pooled values: 1A, 70 ± 3 μm; 2A, 31 ± 3 μm; and 3A, 19 ± 3 μm). Concentration-response curves to acetylcholine (ACh) and norepinephrine added to the superfusion solution did not differ between mdx and C57BL/10 mice, nor did constriction to elevated (21%) oxygen. In response to local stimulation from a micropipette, conducted vasodilation to ACh and conducted vasoconstriction to KCl were also not different between groups; however, constriction decayed with distance ( P < 0.05) whereas dilation did not. Remarkably, arteriolar constriction to perivascular nerve stimulation (PNS) at 2, 4, and 8 Hz was reduced by ∼25–30% in mdx mice compared with C57BL/10 mice ( P < 0.05). With intact arteriolar reactivity to agonists, attenuated constriction to perivascular nerve stimulation indicates impaired neurovascular transmission in arterioles controlling blood flow in mdx mice.
Assessment of Sleep Impairment in Persistent Allergic Rhinitis Patients Using Polysomnography
Authors: Meng J. , Xuan J. , Qiao X. , Li X. , Liu S. , Lukat K.F. , Zhang N. , Bachert C.
Published: November 2010

Background: Although questionnaires have demonstrated an association between impairment of quality of sleep and symptoms in allergic rhinitis (AR) patients, to date there is no report of an objective assessment of sleep in patients with persistent allergic rhinitis (PER) as defined by ARIA guidelines. The aim of the present study was therefore to assess sleep disturbance in PER patients by polysomnography (PSG). Methods: Ninety-eight PER patients with moderate-to-severe nasal obstruction and 30 healthy volunteers were included in the study. All patients underwent PSG during nocturnal sleep to assess the presence and severity of sleep disorders. Peak nasal inspiratory flow (PNIF) was also measured to assess nasal resistance. Results: There were statistically significant, though clinically modest, differences between PER patients and healthy controls in most PSG parameters including sleep efficiency, arousal index, average SaO2, lowest SaO2, time spent with a saturation below 90%, and snoring time. Although the apnea-hypopnea index (AHI) was not significantly different between the 2 groups, 17 subjects (17.3%) in the PER group but none of the control subjects had an AHI >5. Patients with higher T5SS scores (12 ≤ T5SS ≤ 15) had a greater tendency to snore than did patients with lower scores (8 ≤ T5SS ≤ 11). Finally, PNIF in the PER group was significantly lower than in the control group. Weak correlations between the arousal index and PNIF, average SaO2, and PNIF were found. Conclusion: PSG showed modest changes in PER patients versus control subjects.
Immediate-Type Hypersensitivity to Succinylated Corticosteroids
Authors: Walker Annett Isabel , Räwer Helen-Caroline , Sieber Wolfgang , Przybilla Bernhard
Published: November 2010

Background: Despite their frequent use, systemic corticosteroids have rarely elicited immediate-type reactions. Objective: We report two male patients, aged 26 and 70 years, respectively, with severe immediate-type hypersensitivity secondary to the administration of corticosteroids esterified with succinate. Methods: Skin tests, basophil activation tests and challenge tests were performed for diagnostic evaluation. Results: In both patients, immediate-type skin test reactions were found to methylprednisolone sodium hemisuccinate (MSH) and prednisolone sodium hemisuccinate (PSH). In contrast, nonsuccinylated corticosteroids (including methylprednisolone and prednisolone in one patient) yielded no test reactions. Basophils from one patient exhibited a stimulated expression of the activation marker CD63 upon in vitro incubation with PSH or hydrocortisone sodium succinate, but not with hydrocortisone. Skin tests and basophil activation tests were negative in controls. One patient was challenged with the incriminated drugs. He developed flush, conjunctivitis, tachycardia and dyspnea 2 min after injection of MSH, and dyspnea shortly after intravenous administration of PSH. Oral and intravenous challenge tests with nonsuccinylated corticosteroids were tolerated well by both patients. Conclusions: These case reports should alert clinicians to rare, but severe immediate-type reactions to corticosteroids, related to the succinate moiety in our patients. In case of allergic reactions to corticosteroids, it is mandatory to identify the causative agent and find safe alternatives.
Micronucleus in Cervical Intraepithelial Lesions and Carcinoma
Authors: Samanta Swapan , Dey Pranab , Nijhawan Raje
Published: November 2010

Aims and Objectives: To score and compare micronucleus (MN) in the whole spectrum of cervical lesions including normal, inflammatory, abnormal squamous cell of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL) and invasive cancer (IC) and to evaluate the role of MN as a biomarker in different pre-neoplastic and neoplastic lesions. Materials and Methods: A total of 224 slides, comprised of normal (40), inflammatory (40), ASC-US (30), LSIL (38), HSIL (30) and IC (46), were studied. All the cases of HSIL, IC and ASC-US had histopathology. The LSIL, normal and inflammatory smears were again reviewed by 2 experienced cytopathologists independently. Two observers separately and independently counted the number of micronucleated cells per 1,000 of epithelial cells in oil immersion magnification (×100 objective) which was expressed as MN score per 1,000 cells. Results: The mean MN scores ± SD in normal, inflammatory, ASC-US, LSIL, HSIL and IC cases of cervical lesions were 1.02 ± 1.59, 0.4250 ± 0.71208, 2.87 ± 2.21, 4.7368 ± 5.62179, 21.30 ± 17.18 and 18.50 ± 9.54, respectively. MN scores of IC and HSIL were significantly high compared to the normal (p < 0.000), the inflammatory (p < 0.000), the ASC-US (p < 0.000) and to the LSIL (p < 0.000) group (analysis of variance test). LSIL showed significant difference with the normal (p = 0.043), the inflammatory (p = 0.019), the HSIL (p < 0.000) and the IC (p < 0.000) group but not with the ASC-US (p = 0.342) group. Conclusions: MN scoring on the epithelial cells of cervix could be used as a biomarker in cancer screening. This is an easy, simple, reliable, reproducible and objective test which can be performed on routinely stained smears.