bluuebunny/crossref_metadata_2025_split 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

ABSTRACTDOV 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

ABSTRACTOne 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

ABSTRACTC‐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

ABSTRACTNa+ 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.
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.
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

SummaryA 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.
Diagnosing Premature Ejaculation: A Review
Authors: Shabsigh Ridwan 
Published: August 2006

ABSTRACT

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.
Power spectrum of HI intensity fluctuations in DDO 210
Authors: Begum Ayesha , Chengalur Jayaram N. , Bhardwaj Somnath 
Published: August 2006

Abstract
We measure the power spectrum of H i intensity fluctuations in the extremely faint (MB∼−10.9) dwarf galaxy DDO 210 using a visibility-based estimator that is well suited to very low signal-to-noise ratio regimes. DDO 210's H i power spectrum is well fitted by a power law PH i(U) = A Uα, with α= −2.75 ± 0.45 over the length-scales 80 pc to 500 pc. We also find that the power spectrum does not change with an increase in the velocity channel width, indicating that the measured fluctuations correspond mainly to density fluctuations. However, Kolmogorov turbulence (with a velocity structure function spectral slope of 2/3) cannot be ruled out from the present observations. The value of the slope α is similar to that obtained in the Milky Way. Compared with the Milky Way, DDO 210 has three orders of magnitude less H i, no spiral arms, and also no measurable ongoing star formation. The fact that the power spectrum slope is nonetheless similar in these two galaxies (and also similar to the values measured for the LMC and SMC) suggests that there is some universal, star-formation-independent phenomenon responsible for producing fine scale structure in the gas.
Knowing from Testimony
Authors: Lackey Jennifer 
Published: August 2006

AbstractTestimony is a vital and ubiquitous source of knowledge. Were we to refrain from accepting the testimony of others, our lives would be impoverished in startling and debilitating ways. Despite the vital role that testimony occupies in our epistemic lives, traditional epistemological theories have focused primarily on other sources, such as sense perception, memory, and reason, with relatively little attention devoted specifically to testimony. In recent years, however, the epistemic significance of testimony has been more fully appreciated. I shall here focus on two questions that have received the most attention in recent work in the epistemology of testimony. First, is testimonial knowledge acquired only by being transmitted from speaker to hearer? Second, must a hearer have positive reasons to justifiedly accept a speaker's testimony?
Lipopolysaccharide, Tumor Necrosis Factor Alpha, or Interleukin-1β Triggers Reactivation of Latent Cytomegalovirus in Immunocompetent Mice
Authors: Cook Charles H. , Trgovcich Joanne , Zimmerman Peter D. , Zhang Yingxue , Sedmak Daniel D. 
Published: August 2006

ABSTRACTWe have previously shown that cytomegalovirus (CMV) can reactivate in lungs of nonimmunosuppressed patients during critical illness. Our recent work has shown that polymicrobial bacterial sepsis can trigger reactivation of latent murine CMV (MCMV). We hypothesize that MCMV reactivation following bacterial sepsis may be caused by inflammatory mediators. To test this hypothesis, BALB/c mice latently infected with Smith strain MCMV received sublethal intraperitoneal doses of lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), or saline. Lung tissue homogenates were evaluated for viral reactivation 3 weeks after mediator injection. Because LPS is known to signal via Toll-like receptor 4 (TLR-4) in mice, further studies blocking this signaling mechanism were performed using monoclonal MTS510. Finally, mice were tested with intravenous TNF-α to determine whether this would cause reactivation. All mice receiving sublethal intraperitoneal doses of LPS, TNF-α, or IL-1β had pulmonary reactivation of latent MCMV 3 weeks following injection, and LPS caused MCMV reactivation with kinetics similar to those for sepsis. When TLR-4 signaling was blocked, exogenous LPS did not reactivate latent MCMV. Intravenous TNF-α administration at near-lethal doses did not reactivate MCMV. Exogenous intraperitoneal LPS, TNF-α, and IL-1β are all capable of reactivating CMV from latency in lungs of previously healthy mice. LPS reactivation of MCMV appears dependent on TLR-4 signaling. Interestingly, intravenous TNF-α did not trigger reactivation, suggesting possible mechanistic differences that are discussed. We conclude that inflammatory disease states besides sepsis may be capable of reactivating CMV from latency.
A Pseudoknot in a Preactive Form of a Viral RNA Is Part of a Structural Switch Activating Minus-Strand Synthesis
Authors: Zhang Jiuchun , Zhang Guohua , Guo Rong , Shapiro Bruce A. , Simon Anne E. 
Published: August 2006

ABSTRACT

RNA can adopt different conformations in response to changes in the metabolic status of cells, which can regulate processes such as transcription, translation, and RNA cleavage. We previously proposed that an RNA conformational switch in an untranslated satellite RNA (satC) of
Turnip crinkle virus
(TCV) regulates initiation of minus-strand synthesis (G. Zhang, J. Zhang, A. T. George, T. Baumstark, and A. E. Simon, RNA 12:147-162, 2006). This model was based on the lack of phylogenetically inferred hairpins or a known pseudoknot in the “preactive” structure assumed by satC transcripts in vitro. We now provide evidence that a second pseudoknot (Ψ
2
), whose disruption reduces satC accumulation in vivo and enhances transcription by the TCV RNA-dependent RNA polymerase in vitro, stabilizes the preactive satC structure. Alteration of either Ψ
2
partner caused nearly identical structural changes, including single-stranded-specific cleavages in the pseudoknot sequences and strong cleavages in a distal element previously proposed to mediate the conformational switch. These results indicate that the preactive structure identified in vitro has biological relevance in vivo and support a requirement for this alternative structure and a conformational switch in high-level accumulation of satC in vivo.