bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and characterization of a novel amphioxus dopamine D1‐like receptor
Authors: Burman Chloe , Reale Vincenzina , Srivastava Deepak P. , Evans Peter D.
Published: July 2009

Dopamine receptors function to control many aspects of motor control and other forms of behaviour in both vertebrates and invertebrates. They can be divided into two main groups (D1and D2) based on sequence similarity, ligand affinity and effector coupling. However, little is known about the pharmacology and functionality of dopamine receptors in the deuterostomian invertebrates, such as the cephalochordate amphioxus (Branchiostoma floridae)which has recently been placed as the most basal of all the chordates. A bioinformatic study shows that amphioxus has at least three dopamine D1‐like receptor sequences. One of these receptors, AmphiD1/β, was found to have high levels of sequence similarity to both vertebrate D1receptors and to β‐adrenergic receptors. Here, we report on the cloning of AmphiD1/β from an adult amphioxus cDNA library, and its pharmacological characterization subsequent to its expression in both mammalian cell lines andXenopusoocytes. It was found that AmphiD1/β has a similar pharmacology to vertebrate D1receptors, including responding to benzodiazepine ligands. The pharmacology of the receptor exhibits ‘agonist‐specific coupling’ depending upon the second messenger pathway to which it is linked. Moreover, no pharmacological characteristics were observed to suggest that AmphiD1/β may be an amphioxus orthologue of vertebrate β‐adrenergic receptors.
PolyADP‐ribosylation is required for long‐term memory formation in mammals
Authors: Goldberg Shmuel , Visochek Leonid , Giladi Eliezer , Gozes Illana , Cohen‐Armon Malka
Published: July 2009

PolyADP‐ribosylation is a post‐translational modification of nuclear proteins, catalyzed by polyADP‐ribose polymerases (PARPs). In the nucleus, polyADP‐ribosylation catalyzed by PARP‐1 alters protein–protein and protein–DNA interactions, and is implicated in chromatin remodeling, DNA transcription, and repair. Previous results linked the activation of PARP‐1 with long‐term memory formation during learning in the marine molluskAplysia(Science2004, 304:1820–1822). Furthermore, PARP‐1 was highly activated in mammalian cerebral neurons treated with neurotrophins and neurotrophic peptides promoting neurite outgrowth and synaptic plasticity. Here, we examine the possibility that PARP‐1 activation is required for memory formation during learning in mammals. Mice were tested in two learning paradigms, object recognition and fear conditioning. PolyADP‐ribosylation of PARP‐1 and histone H1 were detected in their cerebral cortex and hippocampus immediately after their training session. Moreover, in both behavioral paradigms, suppression of PARP activity in the CNS during learning impaired their long‐term memory formation, without damaging their short‐term memory. These findings implicate PARP‐1 activation in molecular processes underlying long‐term memory formation during learning.
Higher genetic diversity in introduced than in native populations of the mussel Mytella charruana: evidence of population admixture at introduction sites
Authors: Gillis Nancy K. , Walters Linda J. , Fernandes Flavio C. , Hoffman Eric A.
Published: July 2009

Aim  Levels of genetic diversity can be used to determine haplotype frequency, population size and patterns of invasive species distribution. In this study, we sought to investigate the genetic structure of the invasive marine mussel Mytella charruana and compare variation from invasive populations with variation found within three native populations.

Location  Invaded areas in the USA (Florida, Georgia); native areas in Ecuador, Colombia and Brazil.

Methods  We sequenced 722 bp of the mitochondrial COI gene from 83 M. charruana samples from four invasive populations (USA) and 71 samples from two natural populations (Ecuador, Columbia). In addition, we sequenced 31 individuals of a congeneric species, Mytella guyanensis, from Salvador, Brazil. We constructed the phylogenetic relationship among all haplotypes and compared diversity measures among all populations.

Results  We found significantly higher levels of nucleotide diversity in invasive populations than in native populations, although the number of haplotypes was greater in the native populations. Moreover, mismatch distribution analyses resulted in a pattern indicative of population admixture for the invasive populations. Conversely, mismatch distributions of native populations resulted in a pattern indicative of populations in static equilibrium.

Main conclusion  Our data present compelling evidence that the M. charruana invasion resulted from admixture of at least two populations, which combined to form higher levels of genetic diversity in invasive populations. Moreover, our data suggest that one of these populations originated from the Caribbean coast of South America. Overall, this study provides an analysis of genetic diversity within invasive populations and explores how that diversity may be influenced by the genetic structure of native populations and how mass dispersal may lead to invasion success.
The Informational Role of Bond Analysts
Authors: DE FRANCO GUS , VASVARI FLORIN P. , WITTENBERG‐MOERMAN REGINA
Published: July 2009

This study uses a large sample of sell‐side bond analysts' reports to examine the properties of recommendations provided by bond analysts and the impact of these recommendations on bond securities. First, we document that the distribution of bond analysts' buy, hold, and sell recommendations is skewed positively, but less so than the distribution of equity analysts' recommendations. The positive skewness in bond analysts' recommendations is greater for low than for high credit quality bonds. Second, we find that bond analysts' reports generate bond trading and return reactions that are both economically significant and greater for low credit quality bonds. The bond market reaction is greater for bond analysts' reports than for equity analysts' reports. Finally, while both bond and equity analysts lead rating agency announcements, we find no evidence of a difference in timeliness between bond and equity analysts' reports. Overall, our results are consistent with bond analysts issuing more negative reports than equity analysts and providing more information about low credit quality bonds as a result of the asymmetric demand for negative information by bond investors.
Escaping immune surveillance in cancer: is denbinobin the panacea?
Authors: Magwere Tapiwanashe
Published: July 2009

The bane of anti‐cancer therapy is usually the development of resistance to apoptosis in malignant cells. Identification of strategies to re‐sensitize cancer cells to apoptosis has now become a top priority in anti‐cancer research. Denbinobin is a novel, naturally occurring phenathroquinone isolated from orchids of the genus Dendrobium that has remarkable anti‐cancer activities demonstrated both in vitro and in vivo. Recently denbinobin has been shown to diminish the levels of expression of the decoy receptor‐3 and also to act synergistically with Fas ligand to induce apoptosis in a pancreatic adenocarcinoma cell line. There is hope that denbinobin could be developed as an adjuvant in combination therapies aimed at killing cancers that rely on decoy receptors to evade the host's immune surveillance.
Fructose‐1,6‐bisphosphate reduces inflammatory pain‐like behaviour in mice: role of adenosine acting on A1 receptors
Authors: Valério DA , Ferreira FI , Cunha TM , Alves‐Filho JC , Lima FO , De Oliveira JR , Ferreira SH , Cunha FQ , Queiroz RH , Verri Jr WA
Published: July 2009

Background and purpose:  D‐Fructose‐1,6‐bisphosphate (FBP) is an intermediate in the glycolytic pathway, exerting pharmacological actions on inflammation by inhibiting cytokine production or interfering with adenosine production. Here, the possible antinociceptive effect of FBP and its mechanism of action in the carrageenin paw inflammation model in mice were addressed, focusing on the two mechanisms described above.

Experimental approach:  Mechanical hyperalgesia (decrease in the nociceptive threshold) was evaluated by the electronic pressure‐metre test; cytokine levels were measured by elisa and adenosine was determined by high performance liquid chromatography.

Key results:  Pretreatment of mice with FBP reduced hyperalgesia induced by intraplantar injection of carrageenin (up to 54%), tumour necrosis factor α (40%), interleukin‐1 β (46%), CXCL1 (33%), prostaglandin E2 (41%) or dopamine (55%). However, FBP treatment did not alter carrageenin‐induced cytokine (tumour necrosis factor α and interleukin‐1 β) or chemokine (CXCL1) production. On the other hand, the antinociceptive effect of FBP was prevented by systemic and intraplantar treatment with an adenosine A1 receptor antagonist (8‐cyclopentyl‐1,3‐dipropylxanthine), suggesting that the FBP effect is mediated by peripheral adenosine acting on A1 receptors. Giving FBP to mice increased adenosine levels in plasma, and adenosine treatment of paw inflammation presented a similar antinociceptive mechanism to that of FBP.

Conclusions and implications:  In addition to anti‐inflammatory action, FBP also presents an antinociceptive effect upon inflammatory hyperalgesia. Its mechanism of action seems dependent on adenosine production but not on modulation of hyperalgesic cytokine/chemokine production. In turn, adenosine acts peripherally on its A1 receptor inhibiting hyperalgesia. FBP may have possible therapeutic applications in reducing inflammatory pain.
Inhibition of vascular calcium‐gated chloride currents by blockers of KCa1.1, but not by modulators of KCa2.1 or KCa2.3 channels
Authors: Sones WR , Leblanc N , Greenwood IA
Published: July 2009

Background and purpose:  Recent pharmacological studies have proposed there is a high degree of similarity between calcium‐activated Cl‐ channels (CaCCs) and large conductance, calcium‐gated K+ channels (KCa1.1). The goal of the present study was to ascertain whether blockers of KCa1.1 inhibited calcium‐activated Cl‐ currents (IClCa) and if the pharmacological overlap between KCa1.1 and CaCCs extends to intermediate and small conductance, calcium‐activated K+ channels.

Experimental approaches:  Whole‐cell Cl‐ and K+ currents were recorded from murine portal vein myocytes using the whole‐cell variant of the patch clamp technique. CaCC currents were evoked by pipette solutions containing 500 nM free [Ca2+].

Key results:  The selective KCa1.1 blocker paxilline (1 µM) inhibited IClCa by ∼90%, whereas penitrem A (1 µM) and iberiotoxin (100 and 300 nM) reduced the amplitude of IClCa by ∼20%, as well as slowing channel deactivation. Paxilline also abolished the stimulatory effect of niflumic acid on the CaCC. In contrast, an antibody against the Ca2+‐binding domain of murine KCa1.1 had no effect on IClCa while inhibiting spontaneous KCa1.1 currents. Structurally different modulators of small and intermediate conductance calcium‐activated K+ channels (KCa2.1 and KCa2.3), namely 1‐EBIO, (100 µM); NS309, (1 µM); TRAM‐34, (10 µM); UCL 1684, (1 µM) had no effect on IClCa.

Conclusions and implications:  These data show that the selective KCa1.1 blockers also reduce IClCa considerably. However, the pharmacological overlap that exists between CaCCs and KCa1.1 does not extend to the calcium‐binding domain or to other calcium‐gated K+ channels.
Chronic treatment with pravastatin prevents early cardiovascular changes in spontaneously hypertensive rats
Authors: Kassan M , Montero MJ , Sevilla MA
Published: July 2009

Background and purpose:  This study investigates the effect of pravastatin on blood pressure, cardiovascular remodelling and impaired endothelial function induced as early signs of cardiovascular disease in young spontaneously hypertensive rats (SHR).

Experimental approach:  Eight‐week‐old SHR were treated for 4 weeks with pravastatin (20 mg·kg−1·day−1). Systolic blood pressure was measured periodically during the study using the tail‐cuff method. At the end of the study, the left ventricular weight /body weight ratio was used as an index of left ventricular hypertrophy (LVH). Vascular function, superoxide (O2−.) production and structure were studied in aortic rings. Lipid peroxidation was measured in plasma (thiobarbituric acid reactive substances assay).

Key results:  Systolic blood pressure was lower in treated SHR than in control SHR, at the end of the study (171 ± 1 vs. 159 ± 2 mmHg, P < 0.05), and LVH was significantly reduced by pravastatin (2.7 ± 0.02 vs. 2.5 ± 0.01 mg·g−1, P < 0.05). Vascular responses to sodium nitroprusside and phenylephrine were similar in both groups; nevertheless, the relaxation response to acetylcholine was higher in the treated rats (45.6 ± 2.6 vs. 58.1 ± 3.2 %, P < 0.05). Vascular O2−. and plasma thiobarbituric acid reactive substances were reduced by pravastatin treatment, and urinary nitrites was elevated. Finally aortic wall became thinner after pravastatin treatment.

Conclusions and implications:  Chronic treatment with pravastatin attenuated the increase of systolic blood pressure in SHR, prevented early LVH and improved vascular structure and function. These effects were accompanied by decreased measures of oxidative stress and improvements in NO production.
Antinociceptive effects of NCX‐701 (nitro‐paracetamol) in neuropathic rats: enhancement of antinociception by co‐administration with gabapentin
Authors: Curros‐Criado M Mar , Herrero Juan F
Published: July 2009

Background and purpose: Neuropathic pain is characterized by a poor response to classic analgesics. In the present study, we have assessed the antinociceptive activity of NCX‐701 (nitro‐paracetamol) in neuropathic rats, after systemic and intrathecal (i.t.) administration. In addition, we analysed the possible benefit of the combination of NCX‐701 and gabapentin, a well‐known potent analgesic, in the treatment of neuropathic pain

Experimental approach: The antinociceptive effects of i.v. and i.t. NCX‐701 and paracetamol were studied in spinal cord neuronal responses from neuropathic adult male Wistar rats, using the recording of single motor units technique. The effect of i.v. and i.t. NCX‐701 in combination with i.v. gabapentin was studied by isobolographic analysis.

Key results: The experiments showed that NCX‐701, but not paracetamol, dose‐dependently reduced the nociceptive responses evoked by noxious mechanical and electrical stimulation, after i.v. (ID50542 ± 5 µmol·kg−1for noxious mechanical stimulation) or i.t. (ID50932 ± 16 nmol·kg−1) administration. The combined administration of i.v. or i.t. NCX‐701 and i.v. gabapentin induced a more intense antinociceptive effect than any of the two drugs given alone. The isobolographic analysis showed a synergistic effect.

Conclusions and implications: NCX‐701 is an effective antinociceptive compound in situations of neuropathy‐induced sensitization, with an action mainly located in the spinal cord. The combination of NCX‐701 and gabapentin induces a synergistic enhancement of the depression of nociceptive responses evoked by natural noxious stimulation. The use of NCX‐701 alone or in combination with gabapentin might open up new and promising perspectives in the treatment of neuropathic pain.
Characteristic changes in coronary artery at the early hyperglycaemic stage in a rat type 2 diabetes model and the effects of pravastatin
Authors: Kajikuri J , Watanabe Y , Ito Y , Ito R , Yamamoto T , Itoh T
Published: July 2009

Background and purpose: Diabetes is a risk factor for the development of coronary artery disease but it is not known whether the functions of endothelium‐derived nitric oxide (NO) and endothelium‐derived hyperpolarizing factor (EDHF) in coronary arteries are altered in the early stage of diabetes. Such alterations and the effects of pravastatin were examined in left anterior descending coronary arteries (LAD) from Otsuka Long‐Evans Tokushima Fatty (OLETF) rats (type 2 diabetes model) at the early hyperglycaemic stage [vs. non‐diabetic Long‐Evans Tokushima Otsuka (LETO) rats].

Experimental approach: Isometric tension, membrane potential and superoxide production were measured, as were protein expression of NAD(P)H oxidase components and endothelial NO synthase (eNOS).

Key results: Superoxide production and the protein expressions of both the nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] oxidase components and eNOS were increased in OLETF rats. These changes were normalized by pravastatin administration. Not only acetylcholine (ACh)‐induced endothelial NO production but also functions of endothelium‐derived NO [from (i) the absolute tension induced by epithio‐thromboxane A2(STA2) or high K+; (ii) enhancement of the STA2‐contraction by a nitric oxide synthase (NOS) inhibitor; and (iii) the ACh‐induced endothelium‐dependent relaxation of high K+‐induced contraction] or EDHF [from (iv) ACh‐induced endothelium‐dependent smooth muscle cell hyperpolarization and relaxation in the presence of a NOS inhibitor] were similar between LETO and OLETF rats [whether or not the latter were pravastatin‐treated or ‐untreated].

Conclusions and implications: Under conditions of increased vascular superoxide production, endothelial function is retained in LAD in OLETF rats at the early hyperglycaemic stage, partly due to enhanced endothelial NOS protein expression. Inhibition of superoxide production may contribute to the beneficial vascular effects of pravastatin.
Epidemiology of Helicobacter pylori Infection in Asymptomatic Children: A Prospective Population‐Based Study from the Czech Republic. Application of a Monoclonal‐Based Antigen‐in‐Stool Enzyme Immunoassay
Authors: Sýkora Josef , Siala Konrad , Varvařovská Jana , Pazdiora Petr , Pomahačová Renáta , Huml Michal
Published: July 2009

Background:  Acquisition of Helicobacter pylori occurs mainly in childhood and is significantly influenced by geographical variations. The aim of this study is to evaluate the prevalence of H. pylori infection in a population‐based sample of asymptomatic children in the Czech Republic. Furthermore, this study aims to identify potential risk factors associated with this infection.

Materials and Methods:  A prospective, cross‐sectional, population‐based study was undertaken in 1545 asymptomatic Czech children (aged 0–15 years; male 49.3%). Active H. pylori infection was diagnosed by monoclonal antibody‐based antigen‐in‐stool enzyme immunoassay. Socio‐demographic details of each subject were analyzed using a self‐administered standardized questionnaire. Multiple regression analysis was performed.

Results:  Overall, 7.1% of asymptomatic children were diagnosed with H. pylori infection. Of the infected children, 5.8% lived in the general population. A positive association was found with increasing age, although not with gender. Independent risk factors associated with H. pylori infection in our pediatric population were: the number of children in a household (odds ratio [OR] 4.26; confidence interval [CI] 1.91–9.80); lack of formal education of fathers (OR 0.23; CI 0.18–0.64) and institutionalized children (OR 6.33; CI 2.25–26.50).

Conclusions:  This study of a large cohort of children demonstrated that, independent of gender, H. pylori infection in the Czech Republic is among the lowest reported in Europe. Socioeconomically disadvantaged children, unfortunately, are still at risk of harboring this potentially preventable infection in this low‐prevalence region.
Helicobacter pylori Seroprevalence in Symptomatic Veterans: A Study of 7310 Patients Over 11 Years
Authors: Carmack Susanne W. , Genta Robert M.
Published: July 2009

Background and Aims:  The prevalence of Helicobacter pylori infection has been decreasing in the USA, but recent data are lacking. This study evaluates the seroprevalence for anti‐H. pylori antibodies in symptomatic veterans tested over the past 11 years.

Materials and Methods:  The same serum anti‐H. pylori IgG detection system has been used at a tertiary care Veterans Affairs hospital since late 1996. Results of all tests performed from 1997 to 2007 were analyzed.

Results:  Of 7310 unique patients tested, 3982 (54.5%) were positive. Seropositivity declined from 70.8% in 1997 to 48.6% in 2002, then reached a plateau around 50%. A strong birth cohort effect was present, from a seropositivity of 72.7% for the veterans born before 1920 to 22% for those born between after 1980.

Conclusions:  Despite a constant birth cohort effect, H. pylori seropositivity among symptomatic veterans leveled down at ~50% after declining steadily from 1997 to 2002.
Current Experimental Perspectives on the Clinical Progression of Alcoholic Liver Disease
Authors: Breitkopf Katja , Nagy Laura E. , Beier Juliane I. , Mueller Sebastian , Weng Honglei , Dooley Steven
Published: July 2009

Chronic alcohol abuse is an important cause of morbidity and mortality throughout the world. Liver damage due to chronic alcohol intoxication initially leads to accumulation of lipids within the liver and with ongoing exposure this condition of steatosis may first progress to an inflammatory stage which leads the way for fibrogenesis and finally cirrhosis of the liver. While the earlier stages of the disease are considered reversible, cirrhotic destruction of the liver architecture beyond certain limits causes irreversible damage of the organ and often represents the basis for cancer development. This review will summarize current knowledge about the molecular mechanisms underlying the different stages of alcoholic liver disease (ALD). Recent observations have led to the identification of new molecular mechanisms and mediators of ALD. For example, plasminogen activator inhibitor 1 was shown to play a central role for steatosis, the anti‐inflammatory adipokine, adiponectin profoundly regulates liver macrophage function and excessive hepatic deposition of iron is caused by chronic ethanol intoxication and increases the risk of hepatocellular carcinoma development.
Local Industrial Conditions and Entrepreneurship: How Much of the Spatial Distribution Can We Explain?
Authors: Glaeser Edward L. , Kerr William R.
Published: July 2009

Why are some places more entrepreneurial than others? We use Census Bureau data to study local determinants of manufacturing startups across cities and industries. Demographics have limited explanatory power. Overall levels of local customers and suppliers are only modestly important, but new entrants seem particularly drawn to areas with many smaller suppliers, as suggested by Chinitz (1961). Abundant workers in relevant occupations also strongly predict entry. These forces plus city and industry fixed effects explain between 60% and 80% of manufacturing entry. We use spatial distributions of natural cost advantages to address partially endogeneity concerns.
Abandoned Metal Mine Stability Risk Evaluation
Authors: Bétournay Marc C.
Published: July 2009

The abandoned mine legacy is critical in many countries around the world, where mine cave‐ins and surface subsidence disruptions are perpetual risks that can affect the population, infrastructure, historical legacies, land use, and the environment. This article establishes abandoned metal mine failure risk evaluation approaches and quantification techniques based on the Canadian mining experience. These utilize clear geomechanics considerations such as failure mechanisms, which are dependent on well‐defined rock mass parameters. Quantified risk is computed using probability of failure (probabilistics using limit‐equilibrium factors of safety or applicable numerical modeling factor of safety quantifications) times a consequence impact value. Semi‐quantified risk can be based on failure‐case‐study‐based empirical data used in calculating probability of failure, and personal experience can provide qualified hazard and impact consequence assessments. The article provides outlines for land use and selection of remediation measures based on risk.
An Exposure Assessment of Methyl Mercury via Fish Consumption for the Japanese Population
Authors: Zhang Ying , Nakai Satoshi , Masunaga Shigeki
Published: July 2009

The objective of this article was to propose an exposure assessment model to describe the relationship between fish consumption and body methyl mercury (MeHg) levels in the Japanese population. Individual MeHg intake was estimated by the summation of species‐specific fish consumption multiplied by species‐specific fish MeHg levels. The distribution of fish consumed by individuals and the MeHg level in each fish species were assigned based on published data from Japanese government institutions. The probability of MeHg intake for a population was accomplished through a Monte Carlo simulation by the random sampling of fish consumption and species‐specific MeHg levels. Internal body MeHg levels in blood and hair were estimated using a one‐compartment model. Overall, the mean value of MeHg intake for the Japanese population was estimated to be 6.76 μg/day or 0.14 μg/kg body weight per day (bw/day), while the mean value for the hair mercury level was 2.02 μg/g. Compared with the survey data that tabulated hair mercury levels in a cross‐section of the Japanese population, the simulation results matched the hair mercury survey data very well for women, but somewhat underestimated for men and all of the population. This exposure assessment model is a useful attempt at further risk assessment with respect to a risk‐benefit analysis.
Good to Pet and Eat: The Keeping and Consuming of Dogs and Cats in South Korea
Authors: Podberscek Anthony L.
Published: July 2009

Over the past few decades, there has been mounting criticism, mainly from Western societies, of the practice of consuming dogs and cats in South Korea. In the current study, I researched historical, cultural, and demographic details on, and South Korean people's attitudes to, this practice. Data were collected in two ways. Firstly, relevant information on the history and current status of dog and cat use, including consumption, was sourced from the academic literature, newspaper reports, websites, and animal welfare organizations. Secondly, in 2004, the polling agency Market & Opinion Research International (MORI) was contracted to survey 1,000 adults (15 years and above) in South Korea on their attitudes to keeping cats and dogs as pets and to the consumption of these species. The consumption of dogs has a long history in South Korea while the consumption of cats is more recent. Pet ownership is a more recent phenomenon and is growing steadily. Banning the eating of dogs was not supported in the survey. Unlike cat consumption, dog consumption is strongly linked to national identity in South Korea, and it seems that calls from the West to ban the practice are viewed by South Koreans as an attack on their culture.
Having Our Dogs and Eating Them Too: Why Animals Are a Social Issue
Authors: Serpell James A.
Published: July 2009

Until recently, the study of people's relationships and interactions with other (nonhuman) animals has received scant attention from the social sciences. The preceding articles in this issue illustrate some of the important insights such studies can bring to the field. Animals, by their nature, occupy an intermediate boundary zone between the world of human subjects and the world of insensate objects or “things.” This ambiguity allows us to exploit most of them with relative impunity, while simultaneously endowing some of them with the status of quasi‐human social partners or even kin. It also confronts us with fundamental questions about what it means to be “human” and how far, if at all, our moral responsibilities should extend beyond the taxonomic limits of our species. Our efforts to reconcile these competing and opposing perspectives have generated extraordinary inconsistencies in attitudes and behavior toward animals: inconsistencies that pose significant challenges to current understandings of human psychology, sociology, and morality.
A Global Sensitivity Test for Evaluating Statistical Hypotheses with Nonidentifiable Models
Authors: Todem D. , Fine J. , Peng L.
Published: July 2009

SummaryWe consider the problem of evaluating a statistical hypothesis when some model characteristics are nonidentifiable from observed data. Such a scenario is common in meta‐analysis for assessing publication bias and in longitudinal studies for evaluating a covariate effect when dropouts are likely to be nonignorable. One possible approach to this problem is to fix a minimal set of sensitivity parameters conditional upon which hypothesized parameters are identifiable. Here, we extend this idea and show how to evaluate the hypothesis of interest using an infimum statistic over the whole support of the sensitivity parameter. We characterize the limiting distribution of the statistic as a process in the sensitivity parameter, which involves a careful theoretical analysis of its behavior under model misspecification. In practice, we suggest a nonparametric bootstrap procedure to implement this infimum test as well as to construct confidence bands for simultaneous pointwise tests across all values of the sensitivity parameter, adjusting for multiple testing. The methodology's practical utility is illustrated in an analysis of a longitudinal psychiatric study.
Hierarchical and Joint Site‐Edge Methods for Medicare Hospice Service Region Boundary Analysis
Authors: Ma Haijun , Carlin Bradley P. , Banerjee Sudipto
Published: July 2009

SummaryHospice service offers a convenient and ethically preferable health‐care option for terminally ill patients. However, this option is unavailable to patients in remote areas not served by any hospice system. In this article, we seek to determine the service areas of two particular cancer hospice systems in northeastern Minnesota based only on death counts abstracted from Medicare billing records. The problem is one of spatial boundary analysis, a field that appears statistically underdeveloped for irregular areal (lattice) data, even though most publicly available human health data are of this type. In this article, we suggest a variety of hierarchical models for areal boundary analysis that hierarchically or jointly parameterize both the areas and the edge segments. This leads to conceptually appealing solutions for our data that remain computationally feasible. While our approaches parallel similar developments in statistical image restoration using Markov random fields, important differences arise due to the irregular nature of our lattices, the sparseness and high variability of our data, the existence of important covariate information, and most importantly, our desire for full posterior inference on the boundary. Our results successfully delineate service areas for our two Minnesota hospice systems that sometimes conflict with the hospices' self‐reported service areas. We also obtain boundaries for the spatial residuals from our fits, separating regions that differ for reasons yet unaccounted for by our model.
Controlling False Discoveries in Multidimensional Directional Decisions, with Applications to Gene Expression Data on Ordered Categories
Authors: Guo Wenge , Sarkar Sanat K. , Peddada Shyamal D.
Published: July 2009

Summary Microarray gene expression studies over ordered categories are routinely conducted to gain insights into biological functions of genes and the underlying biological processes. Some common experiments are time‐course/dose‐response experiments where a tissue or cell line is exposed to different doses and/or durations of time to a chemical. A goal of such studies is to identify gene expression patterns/profiles over the ordered categories. This problem can be formulated as a multiple testing problem where for each gene the null hypothesis of no difference between the successive mean gene expressions is tested and further directional decisions are made if it is rejected. Much of the existing multiple testing procedures are devised for controlling the usual false discovery rate (FDR) rather than the mixed directional FDR (mdFDR), the expected proportion of Type I and directional errors among all rejections. Benjamini and Yekutieli (2005, Journal of the American Statistical Association 100, 71–93) proved that an augmentation of the usual Benjamini–Hochberg (BH) procedure can control the mdFDR while testing simple null hypotheses against two‐sided alternatives in terms of one‐dimensional parameters. In this article, we consider the problem of controlling the mdFDR involving multidimensional parameters. To deal with this problem, we develop a procedure extending that of Benjamini and Yekutieli based on the Bonferroni test for each gene. A proof is given for its mdFDR control when the underlying test statistics are independent across the genes. The results of a simulation study evaluating its performance under independence as well as under dependence of the underlying test statistics across the genes relative to other relevant procedures are reported. Finally, the proposed methodology is applied to a time‐course microarray data obtained by Lobenhofer et al. (2002, Molecular Endocrinology 16, 1215–1229). We identified several important cell‐cycle genes, such as DNA replication/repair gene MCM4 and replication factor subunit C2, which were not identified by the previous analyses of the same data by Lobenhofer et al. (2002) and Peddada et al. (2003, Bioinformatics 19, 834–841). Although some of our findings overlap with previous findings, we identify several other genes that complement the results of Lobenhofer et al. (2002).
Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study
Authors: Albores‐Saavedra Jorge , Batich Kristen , Chable‐Montero Freddy , Sagy Noa , Schwartz Arnold M. , Henson Donald Earl
Published: July 2009

Background: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor arising predominantly on sun‐exposed skin of older and usually immunosuppressed individuals.

Methods: Using data from NCI's SEER (Surveillance, Epidemiology, and End Results) Program from 1973 to 2006, we analyzed the demographics and survival of MCC.

Results: SEER had recorded 3870 cases of MCC. The incidence was higher in men (2380 cases, 61.5%) than in women (1490 cases, 38.5%). Most patients were White (94.9%) between 60 and 85 years of age. MCC was rare in Blacks. The most common location was the head and neck. The salivary glands, nasal cavity, lip, lymph nodes, vulva, vagina and esophagus were the most common extracutaneous sites. The 10‐year relative survival rate was higher in women than men (64.8% vs. 50.5%, p < 0.001). Patients 50–69 years had the highest 10‐year relative survival rate (59.6%). Stage of disease was the best predictor of survival.

Conclusions: MCC arises predominantly in the skin of head and neck in White men above 70 years of age. Cases also occurred in extracutaneous sites. Age did not predict survival, yet gender, site and tumor size revealed clear differences. The most significant predictor of survival was tumor stage.
Zileuton prevents the activation of the leukotriene pathway and reduces sebaceous lipogenesis
Authors: Zouboulis Christos C. , Seltmann Holger , Alestas Theodosios
Published: July 2009

Please cite this paper as:Zileuton prevents the activation of the leukotriene pathway and reduces sebaceous lipogenesis. Experimental Dermatology 2010; 19: 148–150.

Abstract: Arachidonic acid (AA) activates the 5‐lipoxygenase, induces leukotriene‐B4(LTB4) synthesis, enhances interleukin‐6 (IL‐6) release and increases intracellular neutral lipids in human sebocytes. Moreover, the enzymes of LTB4biosynthesis are activated in acne‐involved sebaceous glands. Zileuton a 5‐lipoxygenase inhibitor, reduces the number of inflammatory acne lesions and lipogenesis in patients with acne. In this study, we investigated the activity of zileuton on LTB4generation, lipid content and IL‐6 and ‐8 release from human SZ95 sebocytesin vitro. Pretreatment with zileuton partially prevented the AA‐induced LTB4and IL‐6 release and increased neutral lipid content. IL‐6 release and neutral lipid content were also reduced under long‐term zileuton treatment. In conclusion, zileuton prevents the activation of the leukotriene pathway and enhancement of lipogenesis by AA in human sebocytesin vitro.
Does erythropoietin modulate human hair follicle melanocyte activities in situ?
Authors: Bodó Enikő , Wiersma Friederike , Funk Wolfgang , Kromminga Arno , Jelkmann Wolfgang , Paus Ralf
Published: July 2009

Abstract:  Erythropoietin (EPO) is now appreciated for not only drive erythopoiesis, but also to exert additional functions. Since we had previously shown that human hair follicles (HFs) are both an extra‐renal source and an extra‐medullary target of EPO, we have now studied whether one such function is the regulation of HF pigmentation. Human anagen VI HFs were treated with EPO (100 IU/ml) in serum‐free organ culture. Unexpectedly, we noticed greatly divergent pigmentary effects of EPO, since both up‐ and down‐regulation of HF melanin content and tyrosinase activity in situ was seen in HF derived from different individuals. These divergent effects could not be attributed to differences in skin regions, the total HF melanocyte number or specific traits of individual HF donors. Our pilot study provides first evidence suggesting that EPO may modulate normal human melanocyte functions under physiologically relevant conditions in situ.
Diagnosis and Therapy of Localized Scleroderma
Authors: Kreuter Alexander , Krieg Thomas , Worm Margitta , Wenzel Jörg , Gambichler Thilo , Kuhn Annegret , Aberer Elisabeth , Scharffetter‐Kochanek Karin , Hunzelmann Nicolas
Published: July 2009

Localized scleroderma is a rare autoimmune disease with primary affection of the skin, and occasional involvement of the fat tissue, muscle, fascia, and bone. Depending on the clinical subtype, the spectrum of skin lesions ranges from singular plaque lesions to severe generalized or linear subtypes which may lead to movement restrictions and permanent disability. This German S1‐guideline proposes a classification of localized scleroderma that, considering the extent and depth of fibrosis, distinguishes limited, generalized, linear, and deep forms of localized scleroderma, together with its associated subtypes. The guideline includes a description of the pathogenesis, of differential diagnoses, and particular aspects of juvenile localized scleroderma, as well as recommendations for histopathologic, serologic, and biometric diagnostic procedures. Based on studies of topical and systemic treatments as well as phototherapy for localized scleroderma published in international literature, a treatment algorithm was developed which takes account of the different subtypes and the extent of disease.
Biochemical and molecular characterization of purified chicken pancreatic phospholipase A2
Authors: Karray Aida , Frikha Fakher , Ben Bacha Abir , Ben Ali Yassine , Gargouri Youssef , Bezzine Sofiane
Published: July 2009

Chicken pancreatic phospholipase A2 (ChPLA2) was purified from delipidated pancreases using ammonium sulfate and ethanol precipitation, followed by sequential column chromatography steps on MonoQ Sepharose and size exclusion HPLC columns. ChPLA2 was found to be a nonglycosylated monomeric protein with a molecular mass of 14 kDa and a specific activity of 400 U·mg−1 in the presence of 1 mm sodium taurodeoxycholate and 4 mm CaCl2 with phosphatidylcholine as substrate. The N‐terminal sequence of the first 15 amino acids of ChPLA2 was determined, and showed a high degree of homology with known mammal pancreatic phospholipases A2. The gene encoding the mature ChPLA2 was cloned and sequenced. The deduced amino acid sequence of the mature ChPLA2 confirmed the high level of identity with mammal pancreatic PLA2. To investigate the structure–activity relationships, a 3D model of group IB ChPLA2 was built using the porcine pancreatic phospholipase A2 structure as template.
Pfkfb3is transcriptionally upregulated in diabetic mouse liver through proliferative signals
Authors: Duran Joan , Obach Mercè , Navarro‐Sabate Aurea , Manzano Anna , Gómez Marta , Rosa Jose L. , Ventura Francesc , Perales Jose C. , Bartrons Ramon
Published: July 2009

The ubiquitous isoform of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase (uPFK‐2), a product of thePfkfb3gene, plays a crucial role in the control of glycolytic flux. In this study, we demonstrate thatPfkfb3gene expression is increased in streptozotocin‐induced diabetic mouse liver. ThePfkfb3/‐3566promoter construct linked to the luciferase reporter gene was delivered to the liver via hydrodynamic gene transfer. This promoter was upregulated in streptozotocin‐induced diabetic mouse liver compared with transfected healthy cohorts. In addition, increases were observed inPfkfb3mRNA and uPFK‐2 protein levels, and intrahepatic fructose‐2,6‐bisphosphate concentration. During streptozotocin‐induced diabetes, phosphorylation of both p38 mitogen‐activated protein kinase and Akt was detected, together with the overexpression of the proliferative markers cyclin D and E2F. These findings indicate that uPFK‐2 induction is coupled to enhanced hepatocyte proliferation in streptozotocin‐induced diabetic mouse liver. Expression decreased when hepatocytes were treated with either rapamycin or LY 294002. This shows that uPFK‐2 regulation is phosphoinositide 3‐kinase–Akt–mammalian target of rapamycin dependent. These results indicate that fructose‐2,6‐bisphosphate is essential to the maintenance of the glycolytic flux necessary for providing energy and biosynthetic precursors to dividing cells.
B‐cell depletion with rituximab for refractory head and neck Wegener’s granulomatosis: a cohort study
Authors: Martinez Del Pero M. , Chaudhry A. , Jones R.B. , Sivasothy P. , Jani P. , Jayne D.
Published: July 2009

Objectives:  This study aimed to evaluate the response of refractory Wegener’s granulomatosis affecting the ear, nose and throat and granulomatous eye disease to B‐cell depletion with rituximab.

Design:  A retrospective case note review.

Setting:  Tertiary Centre.

Participants:  All patients who received rituximab for refractory Wegener’s granulomatosis affecting the head and neck were included.

Main outcome measures:  Demographic and follow‐up data at five time points were recorded. Response was measured using change in the Birmingham Vasculitis Activity Score and prednisolone dose. Secondary outcomes included changes in additional immunomodulators and anti‐neutrophil cytoplasm antibodies serology. Adverse events were recorded for the duration of follow‐up.

Results:  Thirty‐four patients were included in the analysis. The median age was 47, the male to female ratio was 3 : 2 and the overall median follow‐up was 25.5 months. At six months, nine (26%) patients had a partial response, twenty‐one (62%) were in remission and four (12%) did not respond. All four non‐responders went into remission after a second course of rituximab. Total Birmingham Vasculitis Assessment score decreased after rituximab at all time points (P < 0.001). Four of five patients with retro‐orbital involvement responded well to treatment. Two patients were considered secondary failures requiring alternative therapy after an initial response. Adverse events included four major chest infections, two cancers and six infusion reactions.

Conclusions:  Our cohort derived considerable benefit from rituximab permitting a reduction in immunosuppressive exposure and prednisolone dose with few major adverse effects. There was an 80% (4/5) response in patients with retro‐orbital granulomas. The effect of rituximab was most noticeable in the first 6 months (88% response).
Beyond a Joke: Types of Conversational Humour
Authors: Dynel Marta
Published: July 2009

The main objective of this article is to list and briefly characterise several semantic and pragmatic types ofverbal humour, primarily those which cannot be reduced to (canned) jokes. First of all, a distinction is drawn between jokes andconversational humour, an umbrella term covering a variety of semantic and pragmatic types of humour, which recur in interpersonal communication, whether real‐life (everyday conversations or TV programmes) or fictional (film and book dialogues). On a different axis representing formal structure, stylistic figures are distinguished, such as irony, puns and allusions.
Helicobacter pylori infection, host genetics and gastric cancer
Authors: SHANKS Anne‐Marie , EL‐OMAR Emad M.
Published: July 2009

Helicobacter pylori infects half the world's population and is responsible for a considerable global health burden, including peptic ulcer disease and gastric cancer. The infection causes a chronic gastritis, the severity and distribution of which determine the clinical outcome. Bacterial, environmental and host genetic factors combine to define the degree of gastric damage. Most patients have a limited mild pan‐gastritis with no significant clinical consequences. Antral‐predominant gastritis is associated with high gastric acid output and an increased risk of duodenal ulcers. Corpus‐predominant gastritis is associated with a reduction in gastric acid, multifocal gastric atrophy and an increased risk of gastric cancer. Host genetic factors are particularly important in defining the severity and extent of Helicobacter‐induced gastritis. The most relevant and consistent genetic factors uncovered thus far are in the interleukin‐1 and tumor necrosis factor‐A gene clusters. These cytokines appear to play a key role in the pathophysiology of gastric cancer and their roles have been confirmed in animal models that mimic human gastric neoplasia. More genetic factors have also been uncovered and, with advancing technology, there is every prospect of defining a full genetic risk profile in the next decade. This will aid in targeting the testing and treatment of Helicobacter pylori, which offers a true opportunity to prevent and defeat this global killer.
Diagnostic value of a group of biochemical markers of liver fibrosis in patients with non‐alcoholic steatohepatitis
Authors: LESMANA C. Rinaldi A. , HASAN Irsan , BUDIHUSODO Unggul , GANI Rino A. , KRISNUHONI Ening , AKBAR Nurul , LESMANA Laurentius A.
Published: July 2009

OBJECTIVE:  The objectives of this study were to investigate the use of non‐invasive biochemical markers to evaluate the severity of liver fibrosis in patients with non‐alcoholic steatohepatitis (NASH).

METHODS:  This was a cross‐sectional study of patients with histopathologically confirmed NASH between January 2005 and December 2006. The patients’ characteristics were recorded and the body mass index was calculated for each patient. All patients underwent ultrasound‐guided liver biopsy and a fibrosis assessment was performed using the Brunt criteria. The non‐invasive laboratory markers measured were insulin resistance, tumor necrosis factor (TNF‐α), type IV collagen and hyaluronic acid (HA).

RESULTS:  Thirty patients were recruited, of whom 18 (60%) were men. Their mean age was 45 ± 13.9 (18–71) years. About 83% of patients had fibrosis stage 1–2. In bivariate analysis, age, TNF‐α and type IV collagen concentrations showed a weak but significant correlation with the fibrosis stage. When the patients were grouped into mild fibrosis (stages 1–2) and advanced fibrosis (stages 3–4), the mean concentrations of HA and type IV collagen were significantly higher in those with advanced fibrosis than those with mild fibrosis (180.8 ± 49.63 vs 543.6 ± 360.45 ng/mL; for HA; P = 0.026 and 125.3 ± 32.11 vs 288.0 ± 171.22 ng/mL for type IV collagen; P = 0.010).

CONCLUSION:  Our study showed that the degree of liver fibrosis was significantly correlated with age, TNF‐α and type IV collagen concentrations. The level of HA and type IV collagen could differentiate between mild (F1–2) and advanced fibrosis (F3–4).