bluuebunny/crossref_metadata_2025 huggingface dataset:
Preclinical and Clinical Pharmacology of DOV 216,303, a “Triple” Reuptake Inhibitor
Authors: Skolnick Phil , Krieter Philip , Tizzano Joseph , Basile Anthony , Popik Piotr , Czobor Pal , Lippa Arnold
Published: August 2006

DOV 216,303 [(±)‐1‐(3,4‐dichlorophenyl)‐3‐azabicyclo‐[3.1.0]hexane hydrochloride] is the prototype of a class of compounds referred to as “triple” reuptake inhibitors. Such compounds inhibit the reuptake of norepinephrine (NE), serotonin (5‐HT), and dopamine (DA), the three neurotransmitters most closely linked to major depressive disorder. DOV 216,303 inhibits [3H]NE, [3H]5‐HT, and [3H]DA uptake to the corresponding human recombinant transporters (expressed in HEK 293 cells) with IC50 values of ∼20, 14, and 78 nM, respectively. DOV 216,303 is active in tests predictive of antidepressant activity including the mouse forced swim test and reversal of tetrabenazine‐induced ptosis and locomotor depression. The pharmacodynamic, pharmacokinetic, and toxicological profile of DOV 216,303 in animals prompted us to initiate clinical studies. In both single and multiple dose studies using normal volunteers, DOV 216,303 was safe and well‐tolerated. Furthermore, both Cmax and AUC values were dose‐proportional between 5–150 mg. The plasma concentrations of DOV 216,303 at doses >10 mg were in excess of the IC50 values for inhibition of biogenic amine reuptake. In a Phase II study designed to explore the safety and tolerability of DOV 216,303 in depressed individuals, patients received either 100 mg DOV 216,303 (50 mg b.i.d.) or 40 mg citalopram (20 mg, b.i.d.) for two weeks. A placebo arm was not employed in this study because several institutional review boards required administration of an active control to severely depressed individuals. Time dependent reductions in HAM‐D scores (the primary outcome measure) were observed in both the DOV 216,303 and citalopram groups compared to baseline scores (p < 0.0001). The side effect profile was not remarkably different between treatment arms. These findings provide preliminary evidence of a clinically meaningful antidepressant action with a molecule capable of inhibiting the three transmitters most closely linked to major depressive disorder.
Involvement of Calpain Activation in Neurodegenerative Processes
Authors: Camins Antoni , Verdaguer Ester , Folch Jaume , Pallàs Mercè
Published: August 2006

One of the challenges in the coming years will be to better understand the mechanisms of neuronal cell death with the objective of developing adequate drugs for the treatment of neurodegenerative disorders. Caspases and calpains are among the best‐characterized cysteine proteases activated in brain disorders. Likewise, during the last decade, extensive research revealed that the deregulation of calpains activity is a key cytotoxic event in a variety of neurodegenerative disorders. Moreover, interest in the role of calpain in neurodegenerative processes is growing due to implication of the involvement of cdk5 in neurodegenerative diseases. Since calpain inhibitors appear to not only protect brain tissue from ischemia, but also to prevent neurotoxicity caused by such neurotoxins as β‐amyloid or 3‐nitropropionic acid, the currently available data suggest that calpain and cdk5 play a key role in neuronal cell death. It seems clear that the inappropriate activation of cysteine proteases occurs not only during neuronal cell death, but may also contribute to brain pathology in ischemia and traumatic brain disorders. Pharmacological modulation of calpain activation may, therefore, be useful in the treatment of neurodegenerative disorders. It is possible, although difficult, to develop synthetic inhibitors of cysteine proteases, specifically calpains. The inhibition of calpain activation has recently emerged as a potential therapeutic target for the treatment of neurodegenerative diseases.
C‐Reactive Protein (CRP)‐Lowering Agents
Authors: Prasad Kailash
Published: August 2006

C‐reactive protein (CRP) plays a role in the pathogenesis of cardiovascular disease. It is a marker and predictor of cardiovascular disease. CRP possesses numerous cardiovascular effects (clotting, generation of oxygen radicals, increase in the expression of adhesion molecules and plasminogen activator inhibitor‐1, plaque destabilization) that could result in cardiovascular disease. This review describes the effects of various cardiovascular drugs on the levels of CRP in health and disease. Cyclooxygenase inhibitors (aspirin, rofecoxib, celecoxib), platelet aggregation inhibitors (clopidogrel, abciximab), lipid lowering agents (statins, ezetimibe, fenofibrate, niacin, diets), β‐adrenoreceptor antagonists and antioxidants (vitamin E), as well as angiotensin converting enzyme (ACE) inhibitors (ramipril, captopril, fosinopril), reduce serum levels of CRP; while enalapril and trandolapril have not been shown to have the same effect. Angiotensin receptor blockers (ARBs) (valsartan, irbesartan, olmesartan, telmisartan) markedly reduce serum levels of CRP. The findings with other ARBs (losartan and candesartan) were inconsistent. Antidiabetic agents (rosiglitazone and pioglitazone) reduce CRP levels, while insulin is ineffective. Calcium channel antagonists have variable effects on CRP levels. Hydrochlorothiazide and oral estrogen do not affect CRP. The CRP‐lowering effect of statins is more pronounced than their lipid lowering effect and is not dependent on their hypolipemic activity. The effect of atorvastatin on CRP seems to be dose‐dependent. CRP‐lowering effect of statins is likely to contribute to the favorable outcome of statin therapy. The data suggest that lipid lowering agents, ACE inhibitors, ARBs, antidiabetic agents, antiinflammatory and antiplatelet agents, vitamin E, and β‐adrenoreceptor antagonists lower serum or plasma levels of CRP, while vitamin C, oral estrogen and hydrochlorothiazide do not affect CRP levels.
Cardiac Effects of ST‐6, a Novel Cyclohexane Dicarboximide Derivative
Authors: Takeo Satoshi , Tanonaka Kouichi
Published: August 2006

Na+ channel blockade is thought to be involved in the cardioprotection against ischemia/reperfusion injury. We synthesized various cyclohexane dicarboximides and examined their cardioprotective actions. Some of these derivatives had local anesthetic action and were capable of enhancing post‐hypoxic contractile recovery of the isolated perfused rat heart. Among them, 2‐[4‐[4‐(4‐chlorophenyl)‐4‐hydroxy‐1‐piperidinyl]butyl]hexahydro‐1H‐isoindol‐1,3(2H)‐dione hydrochloride (ST‐6) was most effective in the enhancement of post‐hypoxic contractile recovery of isolated perfused rat hearts subjected to 20‐min hypoxia and 45‐min reoxygenation. This enhanced recovery by 30 mg/min of ST‐6 was associated with attenuation of Na+, but not of Ca2+, accumulation during ischemia and prevention of creatine kinase release from the heart during reperfusion. When hearts subjected to 30‐min ischemia followed by 60‐min reperfusion were pretreated with 30 μM ST‐6, the post‐ischemic contractile recovery was enhanced and ischemia‐induced accumulation of Na+, as well as reperfusion‐induced accumulation of Na+ and Ca2+, was attenuated. Also the reperfusion‐induced release of creatine kinase was reduced, while restoration of myocardial high‐energy phosphates was enhanced during reperfusion. Na+ channel blockade by ST‐6, as assessed by the depression of the Vmax of the action potential, was similar to that produced by flecainide but more pronounced than with either lidocaine or disopyramide. ST‐6, 1, or 2 mg/kg i.v. or 10 mg/kg i.p., abolished ventricular fibrillation induced by 4 min of ischemia and subsequent 4 min of reperfusion in rats. The prevention of ventricular fibrillation by the continuous injection of 0.2 mg/kg per min ST‐6 from the first min after ischemia to the end of reperfusion was similar in degree to that produced by 0.1 mg/kg/min lidocaine or 0.5 mg/kg/min diltiazem. The former treatment elicited a transient decrease in the systemic blood pressure in anesthetized rats during ischemia, whereas treatment with the latter did not reduce systemic blood pressure. These findings suggest that ST‐6 may have cardioprotective effects in ischemia/reperfusion injury.
Nonlesional Frontal Lobe Epilepsy (FLE) of Childhood: Clinical Presentation, Response to Treatment and Comorbidity
Authors: Prévost Julie , Lortie Anne , Nguyen Dang , Lassonde Maryse , Carmant Lionel
Published: August 2006

Summary:  Rationale: Few studies have looked at long‐term epileptic and cognitive outcome of frontal lobe epilepsy (FLE) in children. Most are limited by inclusion of lesional and nonlesional patients.

Goal: To define the epileptic and functional outcome of children with nonlesional FLE.

Methods: We reviewed medical records and neuropsychological evaluations of patients with nonlesional FLE diagnosed between 1994 and 2004. We included children with either focal or regional frontal EEG and/or functional imaging abnormalities. We reviewed their charts for seizure and neuropsychological outcome.

Results: We included 21 children. Twelve (57.1%) presented with daily seizures. Seizures were nocturnal in 8 of 21, secondarily generalized in 6 of 21, adversive in 5 of 21, and focal motor in 6 of 21. Although, initial seizure control was poor in 14 of 21, long‐term control was achieved in 10 of 21 after 14.6 ± 22.3 months. Early development was normal in 12 of 21 but at later formal neuropsychological evaluation only 3 of 12 still had a normal profile. The majority of children had learning difficulties requiring special education prior to seizure onset (6 of 10). A clearly defined regression after seizure onset was observed in three children. The majority exhibited attention deficit and hyperactivity or impulsivity (14 of 21), behavioral problems (8 of 21), and cognitive impairments (10 of 21). Early seizure control was associated with a better cognitive outcome.

Conclusion: Nonlesional FLE is associated with poor seizure and behavioral outcomes. Whether this is secondary to MRI‐silent developmental lesions or to the progressive repercussion of seizures on frontal lobe functions remains uncertain. A prospective study with early neuropsychological assessment could help confirm the latter.
An experimental model of peripheral neuropathy induced in rats by Karwinskia humboldtiana (buckthorn) fruit
Authors: Salazar‐Leal Martha E. , Flores M.S. , Sepulveda‐Saavedra Julio , Romero‐Diaz Viktor J. , Becerra‐Verdin Eduardo M. , Tamez‐Rodriguez Victor A. , Martinez Hector R. , Piñeyro‐Lopez Alfredo , Bermudez M.V.
Published: August 2006

Abstract  Intoxication by Karwinskia humboldtiana (buckthorn) fruit presents a neurological picture similar to that of Guillain‐Barré syndrome. In this report, we describe an experimental animal model of peripheral neuropathy induced by buckthorn fruit. Four groups of Wistar rats received one oral dose of 1.5 g/kg followed by oral doses of 0.5 g/kg at days 3, 7, 10, and 14 of dried and ground buckthorn fruit in aqueous suspension. Rats were sacrificed at 24, 48, 58, and 112 days after initial dose. Treated animals developed progressive paralysis through 58 days, then completely recovered by 112 days. Sciatic nerves showed segmental demyelination and cellular infiltrates until 58 days after exposure and then remyelinating changes at 112 days. This experimental model for peripheral neuropathy is reproducible and easy to handle. Its manipulation is relatively innocuous and allows us to study reversible peripheral nerve damage. This model can be developed in other animal species and may be useful to test new therapies for peripheral neuropathy.
Evidence for direct axonal toxicity in vincristine neuropathy
Authors: Silva Angelica , Wang Qingbo , Wang Minsheng , Ravula Surendra K. , Glass Jonathan D.
Published: August 2006

Abstract  There is a long‐standing debate concerning the localization of the primary insult that results in distal axonal degeneration, or ‘dying back’ neuropathy. To address this question, we created an in vitro model of vincristine neuropathy in rat dorsal root ganglia (DRG). DRGs were grown in compartmentalized chambers, allowing for isolated exposure of the cell body or the axon to vincristine. Initial dose‐finding studies identified a dose of vincristine that showed differential effects on cell death when delivered to either the cell body or the axonal compartment. At this dose of 0.05 μM, exposure of the cell bodies had no effect on the growth of axons, whereas addition of vincristine to the axonal compartment caused axonal shortening without affecting the growth of unexposed ‘sister’ axons. Toxicity was seen only with exposure of the growing axonal tips. These data support localized axonal toxicity as a cause of distal axonal degeneration due to vincristine.
Nociceptin and its receptor in rat dorsal root ganglion neurons in neuropathic and inflammatory pain models: implications on pain processing
Authors: Chen Yong , Sommer Claudia
Published: August 2006

Abstract Nociceptin (NC), by activating its receptor, the opioid receptor‐like 1 (ORL1) receptor, exerts an effect on a number of functions in the nervous system including locomotion, learning and memory, and processing of pain signals. Data on the expression of NC and ORL1 receptor in dorsal root ganglion (DRG) neurons and on its modulation after nerve injury and inflammation are controversial. We therefore sought to investigate the immunoreactivity (IR) of NC and ORL1 receptor in DRG neurons in two pain models, a pure neuropathic pain model, namely partial sciatic nerve transection (PST), and an inflammatory pain model, complete Freund’s adjuvant (CFA) injection into the hindpaw. In intact DRG neurons, both NC and ORL1 receptor IR were present in mainly small‐ and medium‐sized neurons, NC IR in 31% and ORL1 receptor IR in 33% of all neuronal profiles. Both NC and ORL1 receptor IR were upregulated 7 days after nerve injury (to 56 and 55%) and inflammation (to 53 and 48%), respectively. Activating transcription factor 3 (ATF3), a neuronal marker of nerve injury, was induced in DRG neurons 7 and 14 days after PST and 7 days after CFA injection. Double labeling with ATF3 revealed expression of NC and ORL1 receptor in intact as well as in injured primary afferent neurons. Thus, NC and the ORL1 receptor may be involved in the modulation of neuropathic and inflammatory pain at the level of the primary afferent neuron.
Expression of capsaicin receptor immunoreactivity in human peripheral nervous system and in painful neuropathies
Authors: Lauria Giuseppe , Morbin Michela , Lombardi Raffaella , Capobianco Raffaella , Camozzi Francesca , Pareyson Davide , Manconi Mauro , Geppetti Pierangelo
Published: August 2006

Abstract We describe the expression of the capsaicin receptor (TRPV1) in human peripheral nervous system (PNS) and its changes in sural nerve and skin nerve fibers of patients with painful neuropathy. Dorsal root ganglion (DRG), root, and spinal cord autopsy specimens from subjects without PNS diseases were immunoassayed with anti‐TRPV1 antibodies. Bright‐field and confocal microscope studies using anti‐TRPV1, protein gene product 9.5 (PGP 9.5), and unique‐β‐tubulin (TuJ1) antibodies were performed in skin biopsies from 15 healthy subjects and 10 painful neuropathies. The density of intraepidermal nerve fiber (IENF) labeled by each antibody was quantified. Sural nerve biopsies from three patients with painful, one patient with nonpainful diabetic neuropathy, and two patients with multifocal motor neuropathy used as controls were immunoassayed with anti‐TRPV1 antibodies and investigated by immunoelectron microscopy. TRPV1 strongly labeled laminae I and II of dorsal horns, most small‐size and some medium‐size DRG neurons, and small‐diameter axons of dorsal roots. In sural nerve, TRPV1 was expressed within the cytoplasm of most unmyelinated and some small myelinated axons, in the muscular lamina of epineural vessels, and in the endothelium of endoneurial vessels. The density of IENF labeled by TRPV1, PGP 9.5, and TuJ1 did not differ. TRPV1 colocalized with TuJ1 in all IENF and dermal nerve bundles. Painful neuropathies showed a diffuse loss of TRPV1‐positive axons both in the sural nerve and in the skin. Our findings demonstrated that TRPV1 is normally expressed throughout the nociceptive pathway of PNS and that TRPV1‐positive peripheral nerve fibers degenerate in painful neuropathies.
Shrunken p‐Values for Assessing Differential Expression with Applications to Genomic Data Analysis
Authors: Ghosh Debashis
Published: August 2006

Summary In many scientific problems involving high‐throughput technology, inference must be made involving several hundreds or thousands of hypotheses. Recent attention has focused on how to address the multiple testing issue; much focus has been devoted toward the use of the false discovery rate. In this article, we consider an alternative estimation procedure titled shrunken p‐values for assessing differential expression (SPADE). The estimators are motivated by risk considerations from decision theory and lead to a completely new method for adjustment in the multiple testing problem. In addition, the decision‐theoretic framework can be used to derive a decision rule for controlling the number of false positive results. Some theoretical results are outlined. The proposed methodology is illustrated using simulation studies and with application to data from a prostate cancer gene expression profiling study.
Computational Biology: Toward Deciphering Gene Regulatory Information in Mammalian Genomes
Authors: Ji Hongkai , Wong Wing Hung
Published: August 2006

SummaryComputational biology is a rapidly evolving area where methodologies from computer science, mathematics, and statistics are applied to address fundamental problems in biology. The study of gene regulatory information is a central problem in current computational biology. This article reviews recent development of statistical methods related to this field. Starting from microarray gene selection, we examine methods for finding transcription factor binding motifs andcis‐regulatory modules in coregulated genes, and methods for utilizing information from cross‐species comparisons and ChIP‐chip experiments. The ultimate understanding ofcis‐regulatory logic in mammalian genomes may require the integration of information collected from all these steps.
Are Flexible Designs Sound?
Authors: Burman Carl‐Fredrik , Sonesson Christian
Published: August 2006

Summary Flexible designs allow large modifications of a design during an experiment. In particular, the sample size can be modified in response to interim data or external information. A standard flexible methodology combines such design modifications with a weighted test, which guarantees the type I error level. However, this inference violates basic inference principles. In an example with independent N(μ, 1) observations, the test rejects the null hypothesis of μ≤ 0 while the average of the observations is negative. We conclude that flexible design in its most general form with the corresponding weighted test is not valid. Several possible modifications of the flexible design methodology are discussed with a focus on alternative hypothesis tests.
Logistic Regression with Exposure Biomarkers and Flexible Measurement Error
Authors: Sugar Elizabeth A. , Wang Ching‐Yun , Prentice Ross L.
Published: August 2006

Summary Regression calibration, refined regression calibration, and conditional scores estimation procedures are extended to a measurement model that is motivated by nutritional and physical activity epidemiology. Biomarker data, available on a small subset of a study cohort for reasons of cost, are assumed to adhere to a classical measurement error model, while corresponding self‐report nutrient consumption or activity‐related energy expenditure data are available for the entire cohort. The self‐report assessment measurement model includes a person‐specific random effect, the mean and variance of which may depend on individual characteristics such as body mass index or ethnicity. Logistic regression is used to relate the disease odds ratio to the actual, but unmeasured, dietary or physical activity exposure. Simulation studies are presented to evaluate and contrast the three estimation procedures, and to provide insight into preferred biomarker subsample size under selected cohort study configurations.
Diverse phenotype of Brooke–Spiegler syndrome associated with a nonsense mutation in the CYLD tumor suppressor gene
Authors: Zhang Guolong , Huang Yijin , Yan Kailin , Li Wei , Fan Xing , Liang Yanhua , Sun Liangdan , Li Hui , Zhang Shumei , Gao Min , Du Wenhui , Yang Sen , Liu Jianjun , Zhang Xuejun
Published: August 2006

Abstract:  Brooke–Spiegler syndrome (BSS) is an autosomal dominant disease characterized by cylindromas, trichoepitheliomas and occasionally spiradenomas. The disease gene was mapped to 16q12‐13, and mutations in the CYLD gene were identified in families with BSS. In the present report, we describe a large consanguineous Chinese family with BSS showing an intra‐family phenotypic variability. Clinically, some affected individuals only revealed discrete small skin‐coloured tumors whereas the proband showed an expansion of multiple large tumors on the back of nose and numerous dome‐shaped papules on her scalp. Histologically, both trichoepitheliomas and cylindromas were found in the affected individuals. By sequence analysis, we identified a recurrent mutation 2272C>T (R758X) of the CYLD gene in the affected individuals of this family, which was previously identified in other ethnic families with familial cylindromatosis. Our result provided additional information for phenotype–genotype correlation in BSS.
Patterns of phenotypic and genetic variability show hidden diversity in Scottish Arctic charr
Authors: Adams C. E. , Fraser D. , Wilson A. J. , Alexander G. , Ferguson M. M. , Skulason S.
Published: August 2006

Abstract –  This study examined the degree and pattern of variability in trophic morphology in Arctic charr (Salvelinus alpinus L.) at three spatial scales: across 22 populations from Scotland and between and within two adjacent catchments (Laxford and Shin) in northern Scotland. In addition, the variability at six microsatellite loci between and within the Laxford and Shin systems was determined. Habitat use by charr differed significantly between populations. The pattern of variability in trophic morphology, known to influence foraging ability in charr, showed a very high degree of between‐population variation with at least 52% of population pairs showing significant differences in head shape. Trophic morphology and genetic variation was also high over small geographical scales; variation being as high between charr from lakes within the same catchment, as between adjacent catchments. The pattern of both phenotypic and genotypic variation suggests a mosaic of variation across populations with geographically close populations often as distinct from each other as populations with much greater separation. Very low levels of effective migrants between populations, even within the same catchment, suggest that this variation is being maintained by very low straying rates between phenotypically and genetically distinct populations, even when there is no apparent barrier to movement. We conclude that the genetic and phenotypic integrity of charr populations across Scotland is high and that this adaptive radiation constitutes a ‘hidden’ element of diversity in northern freshwater systems. Two consequences of this are that the population (rather than the species) makes a more rational unit for the consideration of conservation strategies and that the habitat requirements and therefore management needs may differ significantly between populations.
Evidence for a specific crevicular lymphocyte profile in aggressive periodontitis
Authors: Sigusch B. W. , Wutzler A. , Nietzsch T. , Glockmann E.
Published: August 2006

Background and Objective:  It is undisputed that the periodontal pocket is a particular region of the host defense that is dominated by polymorphonuclear leukocytes. However, little is known about the lymphocytes in the crevice. It was the aim of this study to analyse the proportions of T cells (CD3+), T‐helper cells (CD4+), T‐suppressor cells (CD8+), and B cells (CD20+) in the crevice of patients with localized aggressive periodontitis (LAP), generalized aggressive periodontitis (GAP), and generalized chronic periodontitis (CP). The results were compared with those obtained from periodontally healthy controls.

Material and Methods:  Crevicular cells were collected according to a previously described method. The lymphocyte subpopulations were analysed by using an indirect immunofluorescence method.

Results:  Significant differences were established between the test groups and the controls regarding the mean number of CD8+ lymphocytes (LAP > CP and controls; p < 0.05) and CD20+ lymphocytes (LAP/GAP > CP, p < 0.05 and LAP/GAP > controls; p < 0.001). Significant variations in the CD4+/CD8+ ratio were observed (LAP < controls and GAP < controls; p < 0.01), as well as a correlation between the number of T cells and the degree of inflammation.

Conclusion:  In the present study, patients with LAP and patients with GAP were found to have increased numbers of crevicular T‐suppressor/cytotoxic and B cells. This supports the hypothesis of a changed immune pathology in patients with aggressive periodontitis.
Analysis of interleukin‐1β‐modulated mRNA gene transcription in human gingival keratinocytes by epithelia‐specific cDNA microarrays
Authors: Steinberg T. , Dannewitz B. , Tomakidi P. , Hoheisel J. D. , Müssig E. , Kohl A. , Nees M.
Published: August 2006

Background/objectives:  Proinflammatory cytokines such as interleukin‐1β are known to be synthesized in oral gingivitis and periodontitis and lead to the activation of the transcription factor nuclear factor‐κB (NF‐κB). Although numerous effects of interleukin‐1β on mesenchymal cells are known, e.g. up‐regulation of intercellular adhesion moelcule‐1 in endothelial cells, little is known of the effects of interleukin‐1β on oral keratinocytes. The purpose of the present study was to seek interleukin‐1β‐mediated alterations in mRNA gene transcription and a putative activation of NF‐κB in oral gingival keratinocytes.

Methods:  As an in vitro model for gingivitis and periodontitis, immortalized human gingival keratinocytes (IHGK) were stimulated with the proinflammatory cytokine interleukin‐1β. An epithelia‐specific cDNA microarray was used to analyze mRNA expression profiles from IHGK cells treated with 200 units interleukin‐1β/ml for 3, 6, 9, 12, and 24 h. Indirect immunofluorescence was carried out to detect NF‐κB in IHGK following interleukin‐1β treatment.

Results:  Detailed analysis revealed distinct patterns of time‐dependent changes, including genes induced or repressed early (3–6 h) or late (12–24 h) after interleukin‐1β treatment. Differentially expressed genes were involved in (i) cell stress, (ii) DNA repair, (iii) cell cycle and proliferation, (iv) anti‐pathogen response, (v) extracellular matrix turnover, and (vi) angiogenesis. A large number of genes were responsive to NF‐κB and induction was concomitant with nuclear translocation of the p65 RelA subunit of NF‐κB. Interestingly, many of these genes contain multiple NF‐κB binding sites in their promoters.

Conclusion:  Analysis of altered gene expression allows identification of gene networks associated with inflammatory responses. In addition to a number of well‐known genes involved in gingivitis and periodontitis, we identified novel candidates that might be associated with the onset and maintenance of an inflammatory disease.
Reduced oxidative damage in ALS by high‐dose enteral melatonin treatment
Authors: Weishaupt Jochen H. , Bartels Claudia , Pölking Esther , Dietrich Jeannine , Rohde Gundula , Poeggeler Burkhard , Mertens Nina , Sperling Swetlana , Bohn Matthias , Hüther Gerald , Schneider Armin , Bach Alfred , Sirén Anna‐Leena , Hardeland Rüdiger , Bähr Mathias , Nave Klaus‐Armin , Ehrenreich Hannelore
Published: August 2006

Abstract:  Amyotrophic lateral sclerosis (ALS) is the collective term for a fatal motoneuron disease of different etiologies, with oxidative stress as a common molecular denominator of disease progression. Melatonin is an amphiphilic molecule with a unique spectrum of antioxidative effects not conveyed by classical antioxidants. In preparation of a possible future clinical trial, we explored the potential of melatonin as neuroprotective compound and antioxidant in: (1) cultured motoneuronal cells (NSC‐34), (2) a genetic mouse model of ALS (SOD1G93A‐transgenic mice), and (3) a group of 31 patients with sporadic ALS. We found that melatonin attenuates glutamate‐induced cell death of cultured motoneurons. In SOD1G93A‐transgenic mice, high‐dose oral melatonin delayed disease progression and extended survival. In a clinical safety study, chronic high‐dose (300 mg/day) rectal melatonin was well tolerated during an observation period of up to 2 yr. Importantly, circulating serum protein carbonyls, which provide a surrogate marker for oxidative stress, were elevated in ALS patients, but were normalized to control values by melatonin treatment. This combination of preclinical effectiveness and proven safety in humans suggests that high‐dose melatonin is suitable for clinical trials aimed at neuroprotection through antioxidation in ALS.
Impaired long‐term memory and long‐term potentiation in N‐type Ca2+channel‐deficient mice
Authors: Jeon D. , Kim C. , Yang Y‐M. , Rhim H. , Yim E. , Oh U. , Shin H‐S.
Published: August 2006

Voltage‐dependent N‐type Ca2+channels, along with the P/Q‐type, have a crucial role in controlling the release of neurotransmitters or neuromodulators at presynaptic terminals. However, their role in hippocampus‐dependent learning and memory has never been examined. Here, we investigated hippocampus‐dependent learning and memory and synaptic plasticity at hippocampal CA3–CA1 synapses in mice deficient for the α1Bsubunit of N‐type Ca2+channels. The mutant mice exhibited impaired learning and memory in the Morris water maze and the social transmission of food preference tasks. In particular, long‐term memory was impaired in the mutant mice. Interestingly, among activity‐dependent long‐lasting synaptic changes, theta burst‐ or 200‐Hz‐stimulation‐induced long‐term potentiation (LTP) was decreased in the mutant, compared with the wild‐type mice. This type of LTP is known to require brain‐derived neurotrophic factor (BDNF). It was found that both BDNF‐induced potentiation of field excitatory postsynaptic potentials and facilitation of the frequency of miniature excitatory postsynaptic currents (mEPSCs) were reduced in the mutant. Taken together, these results demonstrate that N‐type Ca2+channels are required for hippocampus‐dependent learning and memory, and certain forms of LTP.
Altered gene expression in mice selected for high maternal aggression
Authors: Gammie S. C. , Auger A. P. , Jessen H. M. , Vanzo R. J. , Awad T. A. , Stevenson S. A.
Published: August 2006

We previously applied selective breeding on outbred mice to increase maternal aggression (maternal defense). In this study, we compared gene expression within a continuous region of the central nervous system (CNS) involved in maternal aggression (hypothalamus and preoptic regions) between lactating selected (S) and nonselected control (C) mice (n= 6 per group). Using microarrays representing over 40 000 genes or expressed sequence tags, two statistical algorithms were used to identify significant differences in gene expression: robust multiarray and the probe logarithmic intensity error method. Approximately 200 genes were identified as significant using an intersection from both techniques. A subset of genes was examined for confirmation by real‐time polymerase chain reaction (PCR). Significant decreases were found in S mice for neurotensin and neuropeptide Y receptor Y2 (both confirmed by PCR). Significant increases were found in S mice for neuronal nitric oxide synthase (confirmed by PCR), the K+ channel subunit, Kcna1 (confirmed by PCR), corticotrophin releasing factor binding protein (just above significance using PCR; P= 0.051) and GABA A receptor subunit 1A (not confirmed by PCR, but similar direction). S mice also exhibited significantly higher levels of the neurotransmitter receptor, adenosine A1 receptor and the transcription factors, c‐Fos, and Egr‐1. Interestingly, for 24 genes related to metabolism, all were significantly elevated in S mice, suggesting altered metabolism in these mice. Together, this study provides a list of candidate genes (some previously implicated in maternal aggression and some novel) that may play an important role in the production of this behavior.
Skin grafting of a chronic leg ulcer with combined Versajet™‐V.A.C. therapy
Authors: Stetter Christoph , Plaza Tobias , Von Den Driesch Peter
Published: August 2006

A new method for surgical wound de‐bridement is the Versajet™ hydrosur‐gery technique.This technique uses a high velocity jet of sterile saline with a speed up to 1 078 km/h (670 miles/h). By using the Venturi effect (fluid speeds up in a restriction, reducing its pressure and producing a partial vacuum), a simultaneous vacuum is created across the operating window of the handpiece. The application of this high velocity fluid jet to a chronic wound enables precise debridement without collateral tissue damage. The vacuum‐assisted closure (V.A.C.) therapy is used for chronic wounds to induce faster wound healing. This system creates a vacuum‐induced negative pressure to a specific wound area resulting in an accelerated formation of granulation tissue in the wound bed.We present a patient who experienced rapid wound healing when both of these techniques were combined to clean the wound. After split‐thickness skin grafting, V.A.C. therapy was continued. The result was excellent graft acceptance with complete wound healing. This case is unique in that a combination of both therapies resulted in complete wound healing.
MAGNETIC RESONANCE IMAGING APPEARANCE OF THE CISTERNA CHYLI
Authors: JOHNSON VICTORIA S. , SEILER GABRIELA
Published: August 2006

Thoracolumbar spinal magnetic resonance imaging (MRI) examinations in dogs frequently include the region of the cisterna chyli within the field of view. It is important to be aware of the appearance and location of this structure to avoid confusing it for a pathologic periaortic lesion. MRI examinations of the thoracolumbar spine were reviewed in 30 dogs. The cisterna chyli was identified in 26 dogs and was most commonly located caudal to the diaphragmatic crura at the level of L4; afferent and efferent lymphatics were seen in all dogs. Transverse T2‐weighted images were the most useful to locate the cisterna chyli. It was isointense to fluid on T2‐weighted images and isointense to muscle on T1‐weighted images. Mild contrast enhancement was seen in three dogs. The cisterna always wrapped around the aorta, but varied in shape, with the most common being the wide right dorsolateral ellipse. The thoracic duct was also visible in 30 dogs. MRI may have potential for noninvasive evaluation of the abdominal and thoracic lymphatic ducts in dogs.
M‐MODE ECHOCARDIOGRAPHIC PARAMETERS AND INDICES IN THE NORMAL GERMAN SHEPHERD DOG
Authors: KAYAR ABDULLAH , GONUL REMZİ , ERMAN OR MEHMET , UYSAL ABDULKADİR
Published: August 2006

M‐mode echocardiographic measurements were made from 50 healthy German Shepherd dogs (30 males and 20 females). The dogs were awake and unsedated, in right lateral recumbent position. The following parameters were measured on the echocardiographic images: interventricular septal thickness at end‐diastole (IVSd), interventricular septal thickness at end‐systole (IVSs), left ventricular internal dimension at end‐diastole (LVIDd), left ventricular internal dimension at end‐systole (LVIDs), left ventricular posterior wall thickness at end‐diastole (LVPWd), left ventricular posterior wall thickness at end‐systole (LVPWs), left atrial dimension (LAD), aortic root dimension (AOD), left atrial to aortic root ratio (LAD/AOD), right ventricular internal dimension at end‐diastole (RVID), amplitude of mitral valve excursion (DE amplitude), velocity of mitral valve opening (D–E slope), and velocity of mitral valve closure (E–F slope). Fractional shortening (FS) was also calculated. The effect of gender and age on each echocardiographic parameter was analyzed and the relationship between body weight (BW) and each parameter was also investigated. There was a significant relationship between gender and LVPW in systole and diastole and FS. Significant association was also found between BW and IVS, LVID, and LVPW in systole and diastole, FS, LAD, AOD, RVID, DE amplitude, and D–E slope of the mitral valve.
ULTRASONOGRAPHIC AND COMPUTED TOMOGRAPHIC EXAMINATIONS OF THE AVIAN EYE: PHYSIOLOGIC APPEARANCE, PATHOLOGIC FINDINGS, AND COMPARATIVE BIOMETRIC MEASUREMENT
Authors: GUMPENBERGER MICHAELA , KOLM GABRIELA
Published: August 2006

Ultrasonography (US) and computed tomography (CT) were performed after routine ophthalmologic and ophthalmoscopic examinations in 190 eyes of six various diurnal (common buzzard [Buteo buteo L., 1758], n=20; common kestrel [Tinnunculus tinnunculus L., 1758], n=20) and nocturnal raptor species (barn owl [Tyto alba L., 1758], n=22; tawny owl [Strix aluco L., 1758], n=8; long‐eared owl [Asio otus L., 1758], n=5; horned owl [Bubo bubo L., 1758], n=1); and domestic pigeons (Columba livia, Gmel., 1789; n=19), with a total of 95 individuals. Pathologic findings such as lens subluxation and luxation, intravitreal hemorrhage, detached retina, post‐traumatic partial sequestration, or malformation of the pecten could be demonstrated with diagnostic imaging tools, while opacities of cornea or lens constrained direct ophthalmoscopic examination. The results proved US to be a quick noninvasive imaging technique for detailed ocular diagnoses. CT provided detailed information of the bony skull and bony scleral rings as well as adequate visualization of shape, size, and margination of the eye and lens. Nevertheless, CT was unable to differentiate subtle structures within the vitreous like the pecten oculi or hemorrhage. Biometric measurements were carried out to objectify imaging results. Results showed good correlation of depth and width of the anterior eye chamber, lens and vitreous, length of the bulbus, and the pecten but no correlation of cornea and posterior wall thickness was found.
Shifting Models of Welfare: Issues in Relocation from an Institution and the Organization of Community Living
Authors: Bigby Christine
Published: August 2006

Abstract  The closure of institutions and relocation of people with intellectual disabilities to community living has been the focus of many nations’ intellectual disability policies in the past three decades. The author studied the relocation of 58 people from a large institution to 11 small group homes in several Australian communities. Organizational factors that contributed to a mismatch of expectations on such dimensions as individualized support and inclusion were examined. The author discusses these in a broader context of social policy developments, including the privatization and contracting‐out of service provision that shifted the government’s role to one of purchaser rather than provider of services; regulatory concerns in employment practices that impacted the flow of information about residents; and contract specifications that focused on individuals, leaving responsibility for tackling systemic issues uncertain. Recommendations that draw attention to the renewed emphasis on partnerships rather than business relationships and attend to broader community development strategies that have concurrently occurred in Australia are provided.
Medical Conditions and Healthcare Utilization among Adults with Intellectual Disabilities Living in Group Homes in New York City
Authors: Levy Joel M. , Botuck Shelly , Damiani Marco R. , Levy Philip H. , Dern Thomas A. , Freeman Stephen E.
Published: August 2006

Abstract  The shift in living situations for adults with intellectual and other developmental disabilities (ID/DD) from family homes to group homes has raised questions about their healthcare needs and access to appropriate healthcare services. This study was undertaken to describe the disability characteristics and medical conditions in a sample of adults living in group homes in order to better understand the relationship of these variables with patterns of healthcare utilization. We examined the demographic and disability characteristics, medical conditions, and healthcare utilization of a group of individuals with ID/DD, living in 2‐ to 14‐bed group homes operated by a large provider, who were accessing their healthcare services from a single medical practice. The data showed that this sample represented a diverse and complex group in terms of functioning, behavioral and medical conditions, presentation of high rates of challenging behaviors, rate of obesity/overweight, and utilization of health care and psychiatric services. The authors concluded that there needs to be a reexamination of the healthcare needs of individuals living in community settings, particularly with regard to the integration of healthcare and psychiatric services.
Presidential Leadership and Administrative Coordination: Examining the Theory of a Unified Executive
Authors: WEST WILLIAM F.
Published: August 2006

Although presidential management is often prescribed as an antidote to the fragmentation of American bureaucracy, scholars have given relatively little explicit empirical attention to the premises that sustain this theory. Indeed, the premises themselves have remained vague in important respects. This article examines the effects of presidential management as manifested in the most direct and systematic effort to oversee administrative policy making to date. Regulatory review has produced coordination of a reactive nature. It has not, however, led to the kind of top‐down planning and coordination that some authorities at least implicitly associate with a unified executive. In conjunction with other evidence, this has important implications for our understanding of the institutional motives and capabilities that link the president to the administrative process.
“Peace without Conquest”: Lyndon Johnson's Speech of April 7, 1965
Authors: YURAVLIVKER DROR
Published: August 2006

This article explores the speech that President Lyndon Johnson delivered on April 7, 1965 entitled “Peace without Conquest.” He sought to answer Vietnam critics with “unconditional discussions” and a billion‐dollar electrification project for Southeast Asia, but he also reaffirmed his determination not to withdraw. This article analyzes the situation leading to the speech, the speech itself, and public reaction, concluding that although LBJ's speech failed to bring peace to Southeast Asia, it succeeded in mollifying critics enough for the administration to escalate the war. Johnson's speech exemplifies the powers and dangers of rhetoric—a lesson still relevant today.
The Contemporary Presidency: The Decline and Resurgence and Decline (and Resurgence?) of Congress: Charting a New Imperial Presidency
Authors: RUDALEVIGE ANDREW
Published: August 2006

The presidency was designed to have limited power, suspended in a series of checks and balances. But executive authority expanded dramatically over time. It took the presidential excesses of Vietnam and Watergate to prompt a legislative resurgence, a sequence bookended by Arthur M. Schlesinger, Jr.'s The Imperial Presidency and James Sundquist's The Decline and Resurgence of Congress. Yet even before September 11, assertive presidents and fragmented Congresses had allowed the presidency to regain much of the initiative lost in the 1970s; and in the global war on terror, a “new” imperial presidency has been cemented, grounded in broad claims to a “unitary” executive branch. Will there be another legislative resurgence in response? The question goes to the legitimacy of representative government's responses to the crises that already define the twenty‐first century.
Structural and biochemical characterization of a human adenovirus 2/12 penton base chimera
Authors: Zubieta Chloe , Blanchoin Laurent , Cusack Stephen
Published: August 2006

The vertex of the adenoviral capsid is formed by the penton, a complex of two proteins, the pentameric penton base and the trimeric fiber protein. The penton contains all necessary components for viral attachment and entry into the host cell. After initial attachment via the head domain of the fiber protein, the penton base interacts with cellular integrins through an Arg‐Gly‐Asp (RGD) motif located in a hypervariable surface loop, triggering virus internalization. In order to investigate the structural and functional role of this region, we replaced the hypervariable loop of serotype 2 with the corresponding, but much shorter, loop of serotype 12 and compared it to the wild type. Here, we report the 3.6 Å crystal structure of a human adenovirus 2/12 penton base chimera crystallized as a dodecamer. The structure is generally similar to human adenovirus 2 penton base, with the main differences localized to the fiber protein‐binding site. Fluorescence anisotropy assays using a trimeric fiber protein mimetic called the minifiber and wild‐type human adenovirus 2 and chimeric penton base demonstrate that fiber protein binding is independent of the hypervariable loop, with a Kd for fiber binding estimated in the 1–2 µm range. Interestingly, competition assays using labeled and unlabeled minifiber demonstrated virtually irreversible binding to the penton base, which we ascribe to a conformational change, on the basis of comparisons of all available penton base structures.
Diagnosing Premature Ejaculation: A Review
Authors: Shabsigh Ridwan
Published: August 2006

Introduction

Premature ejaculation (PE) is one of the most prevalent male sexual dysfunctions, yet it is frequently misdiagnosed or overlooked as a result of numerous patient and physician barriers. In particular, there is no universally used definition of the condition. There are no validated assessments or laboratory assays which distinguish men with PE from men without PE, and there are no risk factors or definitive correlates identified for this condition. Patients fail to seek medical help because of the stigma and embarrassment over the condition. In addition, patients (and clinicians) often misdiagnose PE as erectile dysfunction (ED).

Aim

To review the barriers to diagnosing PE, the factors to consider in diagnosing PE and how to diagnose PE.

Methods

The Sexual Medicine Society of North America hosted a State of the Art Conference on Premature Ejaculation on June 24–26, 2005 in collaboration with the University of South Florida. The purpose was to have an open exchange of contemporary research and clinical information on PE. There were 16 invited presenters and discussants; the group focused on several educational objectives.

Main Outcome Measure

Data were utilized from the American Urological Association (AUA) Guideline on the Pharmacologic Management of Premature Ejaculation.

Results

The AUA recommends the diagnosis of PE be based solely upon sexual history. In addition to a shortened latency time, recent research has identified three key factors associated with—and necessary for—a diagnosis of PE: (i) patient reports of reduced control over ejaculation; (ii) patient (and/or partner) reports of reduced satisfaction with sexual intercourse; and (iii) patient (and/or partner) distress over the condition.

Conclusions

The diagnosis of PE is based upon sexual history of a shortened latency time, poor control over ejaculation, low satisfaction with intercourse, and distress regarding the condition.