bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired host defense to Klebsiella pneumoniae infection in mice treated with the PDE4 inhibitor rolipram
Authors: Soares A C , Souza D G , Pinho V , Vieira A T , Barsante M M , Nicoli J R , Teixeira M 
Published: October 2003

The increase in levels of cAMP in leukocytes by selective inhibitors of PDE4 may result in reduction of inflammation, and may be useful in the treatment of pulmonary inflammatory disorders in humans. Here, we have assessed whether oral treatment with the prototype PDE4 inhibitor, rolipram, interfered with the antibacterial host response following pulmonary infection of mice with Klebsiella pneumoniae.
K. pneumoniae infection induced a marked increase in the recruitment of neutrophils to the lungs and the production of proinflammatory cytokines and chemokines, including tumor necrosis factor‐α (TNF‐α) and keratinocyte‐derived chemokine (KC), in bronchoalveolar (BAL) fluid and lung tissue. There were also detectable amounts of interleukin‐10 (IL‐10) and significant lethality.
Treatment with rolipram (3–30 mg kg−1) was associated with earlier lethality and significant inhibition of the TNF‐α production. This was associated with enhanced production of IL‐10 in lung tissue of rolipram‐treated animals. Rolipram treatment did not affect KC expression and the recruitment of neutrophils in the lung tissue.
Over 70% of neutrophils that migrated into the BAL fluid following K. pneumoniae infection ingested bacteria. Treatment with rolipram inhibited the percentage of neutrophils undergoing phagocytosis of K. pneumoniae in a dose‐dependent manner. Maximal inhibition (62%) occurred at doses equal to or greater than 10 mg kg−1.
Thus, treatment of mice with the PDE4 inhibitor rolipram is accompanied by earlier lethality, enhanced bacterial load and decreased capacity of the responding host to produce TNF‐α and of neutrophils to phagocytose bacteria. It will be important to investigate whether the shown ability of PDE4 inhibitors to inhibit neutrophil phagocytosis and control experimental bacterial infection will translate into an inhibition of the ability of neutrophils to deal with infectious microorganisms in the clinical setting.

British Journal of Pharmacology (2003) 140, 855–862. doi:10.1038/sj.bjp.0705517
Block of cardiac delayed‐rectifier and inward‐rectifier K+ currents by nisoldipine
Authors: Missan Sergey , Zhabyeyev Pavel , Dyachok Oksana , Jones Stephen E , McDonald Terence F 
Published: October 2003

The objective of this study was to determine the concentration‐dependent effects of nisoldipine, a dihydropyridine Ca2+ channel blocker, on K+ currents in guinea‐pig ventricular myocytes.
Myocytes in the conventional whole‐cell configuration were bathed in normal Tyrode's solution or K+‐free Tyrode's solution for the measurement of the effects of 0.01–100 μM nisoldipine on rapidly activating delayed‐rectifier K+ current (IKr), slowly activating delayed‐rectifier K+ current (IKs), inwardly rectifying K+ current (IK1), and reference L‐type Ca2+ current (ICa,L).
Nisoldipine inhibited IKr with an IC50 of 23 μM, and IKs with an IC50 of 40 μM. The drug also had weak inhibitory effects on inward‐ and outward‐directed IK1; the IC50 determined for outward‐directed current was 80 μM.
Investigation of nisoldipine action on IKs showed that inhibition occurred in the absence of previous pulsing, and with little change in the time courses of activation and deactivation. However, the drug‐induced inhibition was significantly weaker at +30 mV than at +10 mV.
We estimate that nisoldipine is about 30 times less selective for delayed‐rectifier K+ channels than for L‐type Ca2+ channels in fully polarised guinea‐pig ventricular myocytes, and several orders less selective in partially depolarised myocytes.

British Journal of Pharmacology (2003) 140, 863–870. doi:10.1038/sj.bjp.0705518
Identification and characterisation of GPR100 as a novel human G‐protein‐coupled bradykinin receptor
Authors: Boels Katrin , Schaller H Chica 
Published: October 2003

G‐protein‐coupled receptor 100 (GPR100) was discovered by searching the human genome database for novel G‐protein‐coupled peptide receptors.
Full‐length GPR100 was amplified from a cDNA library of the neuroendocrine cell line BON, which is derived from a human pancreas carcinoid. The open‐reading frame, present on a single exon, coded for a protein of 374 amino acids with highest sequence identity (43%) to the human orphan somatostatin‐ and angiotensin‐like peptide receptor. The analysis of chromosomal localisation mapped the GPR100 gene to chromosome 1q21.2–q21.3.
The stable expression of GPR100 in Chinese hamster ovary cells together with aequorin as calcium sensor and the promiscuous G‐protein subunit α16 as signal transducer revealed bradykinin and kallidin as effectors to elicit a calcium response. Dose–response curves yielded EC50 values for both ligands in the low nanomolar range, while the respective analogues without arginine at the carboxy‐terminus were inactive. Calcium mobilisation was inhibited by the phospholipase C blocker U73122, but not by pertussis toxin, suggesting the involvement of the G‐protein subunit αq and not αi or αo in signal transduction.
In line with the main function of kinins as peripheral hormones, we found that GPR100 was expressed predominantly in tissues like pancreas, heart, skeletal muscle, salivary gland, bladder, kidney, liver, placenta, stomach, jejunum, thyroid gland, ovary, and bone marrow, but smaller amounts were also detected in the brain and in cell lines derived from tumours of various origins.

British Journal of Pharmacology (2003) 140, 932–938. doi:10.1038/sj.bjp.0705521
Host and donor risk factors before and after liver transplantation that impact HCV recurrence
Authors: Berenguer Marina 
Published: October 2003

Key points
1. The natural history of hepatitis C after liver transplantation is variable. Several factors, including those related to the virus, the host, the environment and the donor, are probably implicated in the outcome.
2. The immune status per se likely represents the main significant variable in influencing disease severity in hepatitis C virus-infected patients. Findings that support this statement include the higher aggressivity of hepatitis C in immunocompromised liver transplant recipients as compared with that observed in immunocompetent patients, both before and after the development of compensated cirrhosis, and the significant association described between the degree of immunosuppression and disease severity.
3. Similar to that observed in the immunocompetent population, the age at the time of infection (age of the donor) strongly affects posttransplantation hepatitis C virus-related disease progression.
4. Hepatitis C-related disease progression is faster in patients who underwent transplantation in recent years as compared with those who underwent transplantation in earlier cohorts. The increasing age of the donor and the use of stronger immunosuppression may, in part, explain the worse outcomes seen in recent years.
5. Additional host-related variables predictive of outcome include the immunogenetic background, the timing of recurrence, and the early histologic findings.
Liver biopsy, viral kinetics, and the impact of viremia on severity of hepatitis C virus recurrence
Authors: Charlton Michael 
Published: October 2003

Key points
1. Nearly all recipients who are chronically infected with hepatitis C virus (HCV) at the time of liver transplantation will have HCV RNA detectable postoperatively.
2. HCV replication can begin as early as the first postoperative week.
3. HCV levels fall significantly during the anhepatic phase of liver transplantation and continue to fall during the first 12-24 hours posttransplantation.
4. Serum HCV RNA levels typically increase rapidly from the second week posttransplantation and peak by the fourth postoperative month. HCV RNA levels at one year posttransplantation are 10-20 fold greater than pretransplant levels.
5. Corticosteroid treatment for acute cellular rejection is associated with large increases in HCV RNA levels.
6. HCV RNA levels do not appear to vary with choice of calcineurin inhibitor.
7. Early HCV RNA levels are predictive of subsequent histological severity of recurrence.
8. A correlation between early levels of viremia and subsequent allograft injury suggests that initiation of antiviral therapy early in the posttransplant course might be desirable.
Treatment of patients with hepatitis C virus on the waiting list
Authors: Everson Gregory T. 
Published: October 2003

Key points
1. Over 90% of patients with hepatitis C on the waiting list might be candidates for therapy with interferon plus ribavirin.
2. One must exercise caution in the treatment of these patients. Those with Child-Turcotte-Pugh score >11 or Model for End-Stage Liver Disease score >25 should be excluded from treatment.
3. Sustained virologic response (hepatitis C virus RNA-negative) is mainly dependent on viral genotype, with 50% of genotype 2 and 3 patients achieving sustained virologic response.
4. The ability to achieve sustained virologic response in genotype 1 patients is dependent on dose and duration of treatment.
5. Patients rendered hepatitis C virus RNA-negative pretransplantation may not experience posttransplantation recurrence.
The natural history and outcome of liver transplantation in hepatitis C virus-infected recipients
Authors: Gane Edward 
Published: October 2003

Key points
1. Recurrence of hepatitis C infection is universal and immediate after liver transplantation.
2. Graft and patient survival is reduced in liver transplantation recipients with recurrent hepatitis C virus infection compared with hepatitis C virus-negative recipients.
3. The natural history of chronic hepatitis C is accelerated after liver transplantation compared with nontransplantation chronic hepatitis C; 20% to 40% of patients progress to allograft cirrhosis within 5 years, compared with less than 5% of nontransplantation patients.
4. The rate of fibrosis progression is not uniform and may change over time.
5. The rate of progression from cirrhosis to decompensation is accelerated after liver transplantation. The rate of decompensation is >40% at 1 year and >60% at 3 years, compared with <5% and <10%, respectively, in immunocompetent patients.
6. The rate of progression from decompensation to death is also accelerated after liver transplantation. The 3-year survival is <10% after the onset of hepatitis C virus-related allograft failure, compared with 60% after decompensation in immunocompetent patients.
The use of hepatitis C-infected grafts in liver transplantation
Authors: Arenas Juan I. , Vargas Hugo E. , Rakela Jorge 
Published: October 2003

Key points
1. Liver grafts from hepatitis C virus (HCV)-infected deceased donors can be used safely in HCV-infected recipients.
2. Histological assessment of the graft before orthotopic liver transplantation (OLT) is advised.
3. Recipients of these grafts should give consent accordingly.
4. The course of HCV disease after OLT parallels that in patients who received noninfected organs.
Hepatitis C pathogenesis: Mechanisms of viral clearance and liver injury
Authors: Rosen Hugo R. 
Published: October 2003

Key points
1. The development of hepatitis C virus (HCV) quasispecies has a number of biological consequences, including the development of escape mutants to humoral or cellular immunity, the generation of “defective” viral particles, variable cell tropism, and the development of drug resistance.
2. Accumulating evidence shows that HCV affects the early innate immune response mediated by natural killer and dendritic cells.
3. Recent data suggest that clearance of HCV bestows antibody to HCV immunity that affords partial protection against persistent infection. However, after spontaneous recovery from HCV infection, titers of HCV-specific antibodies decline and disappear in a subset of patients, whereas viral-specific CD4+ and CD8+ T-cell responses persist for decades.
4. HCV-specific CD8+ T-cell responses are phenotypically and functionally diverse and may be associated with either viral eradication or chronic hepatic immunopathologic states.
5. Novel HCV genome-wide screening approaches have shown that the breadth of the immune response is considerably greater than was initially appreciated using more conventional assays, but why the majority of patients remain chronically infected despite the presence of viral-specific immune responses remains undefined
Natural history and risk factors for progression of hepatitis C virus disease and development of hepatocellular cancer before liver transplantation
Authors: Shiffman Mitchell L. 
Published: October 2003

Key points
1. Chronic infection with hepatitis C virus (HCV) is the leading cause of cirrhosis and the most common indication for liver transplantation in many countries throughout the world.
2. The most significant factors leading to fibrosis progression in patients with chronic HCV infection include the degree of inflammation present on liver biopsy and ongoing alcohol use.
3. Patients with cirrhosis secondary to chronic HCV infection are at increased risk for developing hepatocellular carcinoma (HCC).
4. Achieving a sustained virological response after treatment with interferon, with or without ribavirin, is associated with a reduced risk for the development of cirrhosis and HCC and prolonged survival.
Prophylactic and preemptive therapies for hepatitis C virus-infected patients undergoing liver transplantation
Authors: Terrault Norah A. 
Published: October 2003

Key points
1. Preclinical data from chimpanzees and studies in hepatitis B virus/hepatitis C virus (HCV) coinfected transplant recipients suggest prophylactic HCV antibody therapy may have a role in the prevention of HCV recurrence.
2. There are insufficient data available to evaluate the efficacy of this therapeutic approach. A small study found no benefit. Other ongoing studies using alternative antibody preparations and more intensive dosing schedules are underway.
3. Preemptive antiviral therapy, started within the first 4 weeks posttransplantation and prior to the onset of clinical signs and symptoms, is effective in some patients (5-33%) and is not associated with an increased risk of acute rejection. Tolerability of antiviral agents in the early posttransplantation period may be a factor limiting treatment efficacy.
4. It is unclear whether the preemptive antiviral treatment is superior to delaying treatment until recurrent disease is present and controlled trials addressing this issue are needed.
Retransplantation for recurrent hepatitis C: The argument against
Authors: Wall William J. , Khakhar Anand 
Published: October 2003

Key points
1. Cirrhosis from chronic hepatitis C is the most common indication for liver grafting today. The course of hepatitis C is accelerated after liver transplantation, and no current therapy reliably prevents or arrests it.
2. It is anticipated that 20% or more of hepatitis C virus-positive transplant recipients will develop allograft cirrhosis, and the only solution will be retransplantation.
3. Results of retransplantation are inferior to primary transplantation.
4. Recipient risk factors that adversely affect mortality after repeated liver grafting include age older than 50 years, renal insufficiency, and severity of hyperbilirubinemia. When present, they reduce survival after retransplantation to approximately 40% or less.
5. Retransplantation on a large scale for recurrent hepatitis C is problematic from the perspectives of outcome, resource utilization, and fairness to candidates awaiting primary grafts.
The role of immunosuppression in recurrence of hepatitis C
Authors: Lake John R. 
Published: October 2003

Key points
1. Recurrent hepatitis C is an increasing problem posttransplantation.
2. It is difficult to determine histologically if alloimmunity, i.e., rejection, is also plays a role in posttransplantation hepatitis C.
3. Change in the degree of immunosuppression, rather than the absolute amount of immunosuppression, is bad for HCV-infected recipients.
4. Corticosteroid boluses are bad for HCV-infected recipients.
Impact of immunosuppression on immunopathogenesis of liver damage in hepatitis C virus-infected recipients following liver transplantation
Authors: McCaughan Geoffrey W. , Zekry Amany 
Published: October 2003

Key points
1. Hepatitis C virus (HCV) infection in the allograft occurs in the setting of greater viral burdens than in patients pretransplantation.
2. Viral burden is increased by such immunosuppressive therapies as corticosteroids and interleukin-2 receptor antibodies.
3. Cholestatic HCV infection occurs in the setting of very high viral load and is almost certainly induced by overimmunosuppression. It is managed best by rapid reduction in levels of immunosuppression.
4. The more common chronic hepatitic HCV disease seems to behave at the molecular/cellular level in a fashion similar to the nontransplantation setting with activation of T helper subtype 1 inflammatory, profibrotic, and proapoptotic pathways. The role of immunosuppression in the acceleration of this disease is unclear, and rapid reduction in immunosuppressive doses may be detrimental.
5. Changes to definitions of types of HCV disease recurrence, disease severity, and acute allograft rejection in the presence of HCV infection are required to improve understanding of the pathogenesis.
Macro- and Microfillers as Reinforcing Agents for Polyurethane Elastomers
Authors: Bharadwaj-Somaskandan S. , Krishnamurthi B. , Sergeeva T. , Shutov F. 
Published: October 2003

The main goals of the research were to develop the new types of inexpensive reinforced polyurethane (PUR) elastomers and to study the effect of different commercial fillers on the density and mechanical properties of the developed materials. Two types of inexpensive commercial fillers based on synthetic and natural polymers have been studied: expandable polystyrene beads (macrofillers) of size 0.254-2.54 mm, and wood flour and starch (microfillers) of size 0.212-0.425 mm. The quantitative relationships between the filler nature, size, content, density, and various mechanical properties have been developed. For both fillers it was found that PUR elastomers produced with less filler content (up to 5-10%) showed improved mechanical properties over the composites made with higher filler content (up to 10-30%). Regardless of the filler content, all filled elastomers demonstrated improvement of tensile properties over unfilled elastomers. The maximal improvement of tensile properties has been found as 10% for macrofillers, and 5% for microfillers. All developed materials are based on commercial formulations and mixing, metering, and pouring equipment. Thus, these materials are easy to commercialize. The developed reinforced cold-curing PUR composites have been recommended as inexpensive materials for structural, thermal insulation, and packaging applications, especially for in situ production.
Immobilization of α-[di-(β-Chloroethyl)-Amide]-N-(m-Nitrobenzoyl)-D,L-Asparagic Acid on Xanthan
Authors: Marcel Popa , Lăcrămioara Bălăită Rusu , Valeriu Şunel 
Published: October 2003

The paper studies the coupling reaction, through ester-type covalent bonds, of an oxazolone derived from the N-(m-nitrobenzoyl)-L-asparagic acid, the cycle of which is opened with an N-mustard derivative, on xanthan (a polysaccharide of microbian synthesis), in conditions of activation with dicyclohexyl carbodiimide. The coupling product has been characterized through elemental analysis and IR spectroscopy. For the establishment of the capacity of the active principle's controlled release by the polymer-active principle system thus obtained, active principle's release kinetics from the polysaccharide support, in conditions of basic hydrolysis, is studied. In vivo tests realized on mice proved the antitumoral activity of the compounds resulted by chemical bonding of the N-mustard derivative on xanthan.
Combined Finite Element Analysis - Genetic Algorithm Method for the Design of Ultrasonic Motors
Authors: Bouchilloux Philippe , Uchino Kenji 
Published: October 2003

The operation of a linear or rotary ultrasonic motor relies on the production of an elliptical vibration at the surface of the stator. To achieve a suitable vibration state, many ultrasonic motors use a combination of structural modes of the stator. Because these modes may be different in nature, designing a viable stator is not trivial. In addition, the design may be complicated by other considerations, such as the electromechanical coupling coefficient of the piezoelectric elements, the amplitude of the vibrations, and the force factor of the device. Similarly, it may also be desired to incorporate parameters such as the operation frequency, geometrical dimensions and weight, electrical current and so on, which may render the design problem extremely difficult to solve. To help in designing such ultrasonic structures, it is proposed to use the genetic optimization method in combination with the finite element method. The combination of these two design tools is innovative and provides a unique approach to the complex problem of ultrasonic motor design. In this paper, the general aspects of the method utilized are reviewed and an application example that includes experimental verification data is provided.
A Plastic-Damage Model for Stress-Strain Behavior of Soils
Authors: Al-Shayea N. A. , Mohib K. R. , Baluch M. H. 
Published: October 2003

This paper presents a constitutive model for soil, which combines elements of plasticity with damage mechanics to simulate the stress-strain behavior. The model is primarily suitable for soil types that exhibit a postpeak strain-softening behavior, such as dense sand and stiff clay. The postpeak stress drop is captured by the elasto-damage formulation, while the plasticity is superimposed beyond the elastic range. The total strain increment is composed of an elasto-damage strain increment and a plastic strain increment. The elasto-damage strain increment is found using the elasto-damage formulation, while the plastic strain increment is found using either the Drucker-Prager classical plasticity model or as a function of damage strain. To implement this model, an experimental program was conducted on local cohesive and cohesionless soils. Various physical and mechanical properties of these soils were determined. Both triaxial tests and hydrostatic tests were performed under different confining pressures, in order to obtain the model parameters. These parameters were used to calibrate the model, which was coded in computer programs to simulate the stress-strain behavior of soils. The model was verified and found to be a good predictor of the geomaterial response for the selected stress path.