bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of KCNJ10 protein expression abolishes endocochlear potential and causes deafness in Pendred syndrome mouse model
Authors: Wangemann Philine , Itza Erin M , Albrecht Beatrice , Wu Tao , Jabba Sairam V , Maganti Rajanikanth J , Ho Lee Jun , Everett Lorraine A , Wall Susan M , Royaux Ines E , Green Eric D , Marcus Daniel C 
Published: August 2004

Abstract
Background
Pendred syndrome, a common autosomal-recessive disorder characterized by congenital deafness and goiter, is caused by mutations of SLC26A4, which codes for pendrin. We investigated the relationship between pendrin and deafness using mice that have (Slc26a4+/+) or lack a complete Slc26a4 gene (Slc26a4-/-).

Methods
Expression of pendrin and other proteins was determined by confocal immunocytochemistry. Expression of mRNA was determined by quantitative RT-PCR. The endocochlear potential and the endolymphatic K+ concentration were measured with double-barreled microelectrodes. Currents generated by the stria marginal cells were recorded with a vibrating probe. Tissue masses were evaluated by morphometric distance measurements and pigmentation was quantified by densitometry.

Results
Pendrin was found in the cochlea in apical membranes of spiral prominence cells and spindle-shaped cells of stria vascularis, in outer sulcus and root cells. Endolymph volume in Slc26a4-/- mice was increased and tissue masses in areas normally occupied by type I and II fibrocytes were reduced. Slc26a4-/- mice lacked the endocochlear potential, which is generated across the basal cell barrier by the K+ channel KCNJ10 localized in intermediate cells. Stria vascularis was hyperpigmented, suggesting unalleviated free radical damage. The basal cell barrier appeared intact; intermediate cells and KCNJ10 mRNA were present but KCNJ10 protein was absent. Endolymphatic K+ concentrations were normal and membrane proteins necessary for K+ secretion were present, including the K+ channel KCNQ1 and KCNE1, Na+/2Cl-/K+ cotransporter SLC12A2 and the gap junction GJB2.

Conclusions
These observations demonstrate that pendrin dysfunction leads to a loss of KCNJ10 protein expression and a loss of the endocochlear potential, which may be the direct cause of deafness in Pendred syndrome.
The intensity of neutrophil infiltration controls the number of antigen-primed CD8 T cells recruited into cutaneous antigen challenge sites
Authors: Engeman Tara , Gorbachev Anton V , Kish Danielle D , Fairchild Robert L 
Published: August 2004

AbstractRecruitment of antigen-specific T cells into the skin is a critical initiating event during immune responses to many parasites and tumors as well as T cell-mediated, cutaneous, allergic responses and autoimmune diseases. Mechanisms directing T cell trafficking into skin remain largely undefined. Here, we show that cutaneous contact with reactive antigen induces KC/CXC chemokine ligand 1 production and neutrophil infiltration in an antigen, dose-dependent manner. The intensity of neutrophil infiltration into cutaneous antigen challenge sites, in turn, controls the number of antigen-primed T cells recruited into the site and the magnitude of the immune response elicited. The absence of responses in immune animals challenged with suboptimal doses of antigen is overcome by manipulating neutrophil infiltration that then directs antigen-primed T cell infiltration into the challenge site. This inflammation also directs T cells primed to one antigen (dinitrofluorobenzene) into the site when challenged with a completely different antigen (oxazolone). These results identify the intensity of neutrophil infiltration into cutaneous, antigen-deposition sites as a critical parameter for the level of antigen-primed T cell recruitment to mediate the adaptive immune response. This interplay between the innate and adaptive responses suggests a strategy to modulate, in a positive or negative manner, antigen-primed T cell infiltration into cutaneous inflammation sites.
Modulation of effector cell functions in experimental autoimmune encephalomyelitis by leflunomide— mechanisms independent of pyrimidine depletion
Authors: Korn Thomas , Magnus Tim , Toyka Klaus , Jung Stefan 
Published: August 2004

AbstractLeflunomide inhibits de novo pyrimidine synthesis and is a novel, immunosuppressive agent that has been successfully used to treat rheumatoid arthritis. Here, we investigated the efficacy of leflunomide and its mode of action in experimental autoimmune encephalomyelitis (EAE), which is a T helper cell type 1 cell-borne disease model to simulate inflammatory aspects of multiple sclerosis and was induced in Lewis rats by adoptive transfer of myelin basic protein (MBP)-specific T line cells. Given in vivo for 7 days after cell transfer, leflunomide suppressed clinical signs of disease even in uridine-substituted animals. MBP-specific T line cells that had been antigen-activated in vitro in the presence of A77 1726 (active metabolite of leflunomide) produced less interferon-γ, whereas interleukin (IL)-10 secretion had a tendency to be increased without changes in signal transducer and activator of transcription 6 trafficking. Furthermore, these T cells exhibited reduced chemotaxis and induced a significantly mitigated disease course upon transfer into naive rats. The effects of leflunomide on MBP-specific memory type T line cells in vitro may not be mediated by pyrimidine depletion, as they were not reversible by exogenous uridine. Moreover, A77 1726 led to increased expression of CD86 (B7-2) and secretion of IL-10 in cultured microglial cells in vitro, strengthening their down-modulatory impact on activated, autoantigen-specific T cells. In conclusion, our observations underline that the immunomodulatory potential of leflunomide in effector cells of EAE is clinically relevant and is not exclusively dependent on the depletion of cellular pyrimidine pools.
Reduction of the multiple organ injury and dysfunction caused by endotoxemia in 5-lipoxygenase knockout mice and by the 5-lipoxygenase inhibitor zileuton
Authors: Collin Marika , Rossi Antonietta , Cuzzocrea Salvatore , Patel Nimesh S A , Di Paola Rosanna , Hadley Julia , Collino Massimo , Sautebin Lidia , Thiemermann Christoph 
Published: August 2004

AbstractThe role of 5-lipoxygenase (5-LOX) in the pathophysiology of the organ injury/dysfunction caused by endotoxin is not known. Here, we investigate the effects of treatment with 5-LOX inhibitor zileuton in rats and targeted disruption of the 5-LOX gene in mice (5-LOX−/−) on multiple organ injury/dysfunction caused by severe endotoxemia. We also investigate the expression of β2-integrins CD11a/CD18 and CD11b/CD18 on rat leukocytes by flow cytometry. Zileuton [3 mg/kg intravenously (i.v.)] or vehicle (10% dimethyl sulfoxide) was administered to rats 15 min prior to lipopolysaccharide (LPS; Escherichia coli, 6 mg/kg i.v.) or vehicle (saline). 5-LOX−/− mice and wild-type littermate controls were treated with LPS (E. coli, 20 mg/kg intraperitoneally) or vehicle (saline). Endotoxemia for 6 h in rats or 16 h in mice resulted in liver injury/dysfunction (increase in the serum levels of aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, alkaline phosphatase, bilirubin), renal dysfunction (creatinine), and pancreatic injury (lipase, amylase). Absence of functional 5-LOX (zileuton treatment or targeted disruption of the 5-LOX gene) reduced the multiple organ injury/dysfunction caused by endotoxemia. Polymorphonuclear leukocyte infiltration (myeloperoxidase activity) in the lung and ileum as well as pulmonary injury (histology) were markedly reduced in 5-LOX−/− mice. Zileuton also reduced the LPS-induced expression of CD11b/CD18 on rat leukocytes. We propose that endogenous 5-LOX metabolites enhance the degree of multiple organ injury/dysfunction caused by severe endotoxemia by promoting the expression of the adhesion molecule CD11b/CD18 and that inhibitors of 5-LOX may be useful in the therapy of the organ injury/dysfunction associated with endotoxic shock.
The effect of particle concentration in a magneto rheological suspension on the performance of a boundary lubricated contact
Authors: Leung W. C. , Bullough W. A. , Wong P. L. , Feng C 
Published: August 2004

The tribological effects of several different concentrations of the same solid particle in a magnetorheological suspension (MRS) were examined on an apparatus operating in the boundary lubricated regime, using two different base fluids. The choice of optimum magnetorheological (MR) particle concentration is nominally restricted by the provision of desirable rheological effects in the fluid mix, such as the yield strength responsiveness to an applied magnetic field and low zero excitation viscosity. However, the aim of the present work is to identify the desirable range of particle concentrations for magnetorheological suspensions from a tribological viewpoint alone for one readily available particle type and two smooth bearing surfaces, one relatively hard and the other soft. The results provide a useful reference towards the formulation of an MRS and the prediction of friction and wear when the MRS is used between slipping surfaces. Experimental studies were carried out in order to understand and uncover the boundary lubricated wear mechanisms of the MRS with different particle concentrations. The friction and wear that occur in seals and bearings that have to cope with such fluids can be a major impediment to application should they be operated in unduly adverse conditions. Generally these sliding surfaces operate outside of the area affected by the rheology controlling magnetic field, with one or two exceptions. Hence, the tests have been undertaken in unexcited conditions. Considering that the carbonyl iron powders used in the MRS are relatively high in concentration, their effect on a boundary lubricated contact of two smooth steel surfaces may or may not be adequately described by the typical three-body abrasive wear mechanism since the particles are also comparatively soft and pass through an extremely small gap (nominally smaller than the typical dimension of the MR particles). This scenario is not well-addressed by tribologists whose concerns traditionally involve low concentrations of particles of higher hardness than surfaces such as wear debris. Would the damaging effect be controlled by controlling the particle concentration of the MRS? Two different base oils were used to mix with carbonyl iron powders, which were extracted from a commercial MR fluid from Lord Corporation, as different specimen fluids. The two different base oils are a pure mineral oil and a hydraulic oil with extreme pressure (EP) additives.
Wittig Type Methylenation of Ketones with Bis(iodozincio)methane and Ionic Liquid
Authors: Yoshino Hideaki , Kobata Masami , Yamamoto Yuhei , Oshima Koichiro , Matsubara Seijiro 
Published: August 2004

Abstract
Ketones were transformed into alkenes via methylenation with bis(iodozincio)methane and ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF6]) in the absence of additional metal salt such as titanium chlorides.
A General Heuristic for Production Planning Problems
Authors: Pochet Yves , Van Vyve Mathieu 
Published: August 2004

We consider production planning problems with the restriction that all integer variables model setups. Since finding a feasible solution of such problems is in general NP-complete, the classical approaches have been the use of heuristics to find good feasible solutions on the one hand, or branch and cut on the other hand. In the case of the former, a dual bound is not available, and there is no guarantee of solution quality. For the latter, the accent has been on improving the dual bound and only the simplest schemes have been used to find good feasible solutions. Here we first show that such simple schemes may run into trouble, even when applied to very simple problems. This motivates the proposed heuristic, IPE, which is designed to be used within a branch-and-cut approach. We test the performance of the heuristic on various published lot-sizing and network-design problems, with and without tightened reformulations. We compare these results with other heuristics and with time truncated branch-and-bound searches. IPE appears to be the best choice for large problems with weak formulations.
Error Bounds for Perturbing Nonexponential Queues
Authors: van Dijk Nico M. , Miyazawa Masakiyo 
Published: August 2004

A general framework is provided to derive analytic error bounds for the effect of perturbations and inaccuracies of nonexponential service or arrival distributions in single- and multiserver queues. The general framework is worked out in detail for the three types of finite or infinite buffer queues: GI/G/1/N, M/G/c/N, and GI/M/c/N. First, for the standard GI/G/1/N queue, it is illustrated how the general error bound result can lead to error bounds for different performance measures like the throughput, mean queue length, and stationary queue length distribution. Next, for the M/G/c/N queue, an error bound and monotonicity result are established for the throughput. M/G/c/N queues can so be compared even when hazard rates are not ordered. Finally, for the GI/M/c/N queue, a similar result is obtained with a perturbation of the interarrival time distribution. The error bound results are supported by asymptotic expressions for the M/M/c/N queue and numerical results for the GI/G/1/N queue.
Population Pharmacokinetics I: Background, Concepts, and Models
Authors: Ette Ene I , Williams Paul J 
Published: August 2004

OBJECTIVE To present and emphasize the background, foundations, utility, and conceptual underlying theory of the population pharmacokinetic (PPK) approach with an examination of the advantages when compared with other approaches of pharmacokinetic modeling. DATA SOURCES Information on PPK was retrieved from a MEDLINE search (1979—June 2002) of literature and a bibliographic review of review articles and books. STUDY SELECTION AND DATA EXTRACTION All articles identified from data sources were evaluated and relevant information was included in this review. DATA SYNTHESIS PPK plays a pivotal role in developing dosing strategies for direct patient care and in drug development. PPK is valuable because it targets the patient group that will eventually receive the drug of interest, quantitates pharmacokinetic variability at several levels, and seeks to explain those sources of variability. CONCLUSIONS PPK models have great utility and the applications are many. They are very different from single-subject pharmacokinetic models and therefore require different approaches to model development.
Physical and Chemical Stability of Palonosetron HCl in 4 Infusion Solutions
Authors: Trissel Lawrence A , Xu Quanyun A 
Published: August 2004

BACKGROUND Palonosetron HCl is a selective 5-HT3 receptor antagonist used for the prevention of chemotherapy-induced nausea and vomiting. Palonosetron HCl may be diluted in an infusion solution for administraton. Consequently, stability information is needed for palonosetron HCl admixed in common infusion solutions. OBJECTIVE To evaluate the physical and chemical stability of palonosetron HCl in concentrations of 5 and 30 μg/mL in dextrose 5% injection, NaCl 0.9% injection, dextrose 5% in NaCl 0.45% injection, and dextrose 5% in lactated Ringer's injection. METHODS Triplicate test samples of palonosetron HCl at each concentration in each diluent were tested. Samples were stored and evaluated at appropriate intervals for up to 48 hours at room temperature (~23 °C) and 14 days under refrigeration (4 °C). Physical stability was assessed using turbidimetric and particulate measurement, as well as visual inspection. Chemical stability was assessed by HPLC. RESULTS All of the admixtures were initially clear and colorless when viewed in normal fluorescent room light and with a Tyndall beam. Measured turbidity and particulate content were low initially and remained low throughout the study. The drug concentration was unchanged in any of the samples at either temperature throughout the study. CONCLUSIONS Palonosetron HCl is physically and chemically stable in all 4 common infusion solutions for at least 48 hours at room temperature and 14 days under refrigeration.
Impact of Pharmacists' Interventions on the Pediatric Discharge Medication Process
Authors: Voirol Pierre , Kayser Steven R , Chang Chi Y , Chang Q Laura , Youmans Sharon L 
Published: August 2004

BACKGROUND To our knowledge, as of August 19, 2004, the impact of pharmacists' interventions on pediatric patients and their caregivers' ability to obtain discharge medications from community pharmacies in a timely fashion has not been described. OBJECTIVE To evaluate the impact of pharmacists' interventions on patients' likelihood of obtaining medications within 24 hours of hospital discharge. METHODS Patients meeting study criteria were randomized to an intervention or control group. The intervention was a proactive program of discharge planning by the pharmacy team. All study patients received a follow-up telephone interview to assess the amount of time needed to obtain medications and caregivers' knowledge of how to administer medications. A multivariate linear regression was conducted to assess the association between variables such as insurance, place of residence, number of prescribed medications, and the probability to obtain medications within 24 hours of hospital discharge. RESULTS The final analysis included 81 control patients and 91 intervention patients. After controlling for a number of factors, the intervention group was able to have obtained medications within 24 hours more often than the control group (84% vs 69%; p = 0.027). Caregivers' knowledge of how to correctly administer medications did not differ between the 2 groups. CONCLUSIONS Our results suggest that the coordinated efforts of pharmacists' interventions during the discharge process may have a positive impact. Our observations may be used to establish criteria for identifying patients at risk for problems with obtaining medications at discharge.
Sirolimus-Associated Hepatotoxicity in Liver Transplantation
Authors: Neff Guy W , Ruiz Phillip , Madariaga Juan R , Nishida Seigo , Montalbano Marzia , Meyer Doug , Levi David M , Tzakis Andreas G , O'Brien Christopher B 
Published: August 2004

BACKGROUND Sirolimus is an immunosuppressant that exerts anti-rejection activity by inhibiting T-cell activity and is used to treat chronic rejection and calcineurin-related nephrotoxicity. Unlike tacrolimus and cyclosporine, it has no effect on calcineurin activity in liver transplant recipients. OBJECTIVE To report correlates of survival outcomes in a series of patients with putative sirolimus-related hepatotoxicity after liver transplant. METHODS We retrospectively reviewed the medical records of patients who underwent a liver transplant for chronic hepatitis C virus (HCV) and who received sirolimus immunosuppressive therapy between November 2000 and November 2003. Extracted data included sirolimus serum concentrations, frequency of sirolimus-related adverse effects, drug-related clinical hepatitis, and survival outcomes. RESULTS Ten patients were found to have been treated with sirolimus for either renal insufficiency (n = 6) or chronic rejection (n = 4). Six patients had liver biopsies, while the remaining 4 patients were clinically diagnosed with rejection. Two of the 6 patients demonstrated changes consistent with sinusoidal congestion and one with eosinophilia, consistent with an allergic drug reaction. HCV viral load increased slightly, from 600 000 to 700 000 IU/mL. Mean baseline transaminase levels were 45 IU/L for aspartate aminotransferase and 50 IU/L for alanine aminotransferase, with peak levels of 210 and 180 IU/L, respectively. The time to transaminase increase was a mean of 21 days when sirolimus was added, with resolution within 27 days (mean) after its discontinuation. No changes were evident in antiviral therapy. Combination sirolimus and tacrolimus concentrations were maintained at >10 ng/mL; average monotherapy with sirolimus was 12 ng/mL, and average time on therapy was 25 weeks. CONCLUSIONS Sirolimus-related hepatotoxicity is an important complication after liver transplant. Immediate recognition is critical to avoid confusion with other causes of abnormal serum aminotransferases after liver transplant, and discontinuation of the drug may be required.
Matrix metalloproteinases, inflammation and atherosclerosis: therapeutic perspectives
Authors: Beaudeux Jean-Louis , Giral Philippe , Bruckert Eric , Foglietti Marie-José , Chapman M. John 
Published: August 2004

AbstractMatrix metalloproteinases (MMPs), also called matrixins, are proteinases that participate in extracellular matrix remodelling and degradation. Under normal physiological conditions, the activities of MMPs are precisely regulated at the level of transcription, of activation of the pro-MMP precursor zymogens and of inhibition by endogenous inhibitors (tissue inhibitors of metalloproteinases; TIMPs). Alteration in the regulation of MMP activity is implicated in diseases such as cancer, fibrosis, arthritis and atherosclerosis. The pathological effects of MMPs and TIMPs in cardiovascular diseases involve vascular remodelling, atherosclerotic plaque instability and left ventricular remodelling after myocardial infarction. Since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression (including plaque disruption), MMPs represent a potential target for therapeutic intervention aimed at modification of vascular pathology by restoring the physiological balance between MMPs and TIMPs. This review describes the members of the MMP and TIMP families and discusses the structure, function and regulation of MMP activity; finally, pharmacological approaches to MMP inhibition are highlighted.