bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetics of antifibroblast activation protein monoclonal antibody F19 in cancer patients
Authors: Tanswell Paul , Garin‐Chesa Pilar , Rettig Wolfgang J. , Welt Sydney , Divgi Chaitanya R. , Casper Ephraim S. , Finn Ronald D. , Larson Steven M. , Old Lloyd J. , Scott Andrew M. 
Published: December 2003

Aims  The population pharmacokinetics of 131I‐mAbF19, a radiolabelled murine monoclonal antibody against fibroblast activation protein and a potential antitumour stroma agent, were investigated during two phase I studies in cancer patients.Methods  131I‐mAbF19 serum concentration‐time data were obtained in 16 patients from two studies involving imaging and dosimetry in colorectal carcinoma and soft tissue sarcoma. Doses of 0.2, 1 and 2 mg antibody were administered as 60 min intravenous infusions. The data were analysed by nonlinear mixed effect modelling.Results  The data were described by a two‐compartment model. Population mean values were 109 ml h−1 for total serum clearance, 3.1 l for the volume of distribution of the central compartment, and 4.9 l for the volume of distribution at steady state. Mean terminal half‐life was 38 h. Intersubject variability was high, but no patient covariates could be identified that further explained this variability. In particular, there was no influence of tumour type or mAbF19 dose.Conclusions  The pharmacokinetics of antistromal mAbF19 were well defined in these two studies with different solid tumour types, and were comparable with those of other murine monoclonal antibodies that do not bind to normal tissue antigens or blood cells.
Human autoimmune anti-proteinase 3 scFv from a phage display library
Authors: FINNERN R , PEDROLLO E , FISCH I , WIESLANDER J , MARKS J D , LOCKWOOD C M , OUWEHAND W H 
Published: December 2003

SUMMARY
This is the first study describing recombinant human antibody fragments directed to the autoantigen proteinase 3 (PR3) from an immune B cell source. Detection of these autoantibodies has proven valid for the diagnosis and monitoring of Wegener's granulomatosis. The described antibody fragment (scFv) was isolated from a phage display library prepared from the IgG-positive splenic lymphocytes of a patient with systemic autoimmunity. The cloning strategy was designed to maintain the diversity of the antibody variable gene repertoire, and sequencing of several variable genes demonstrated that all major heavy and light chain families were represented. We found an over-representation of particular heavy chain variable domains in splenic lymphocytes which differ from the ones frequently found in peripheral blood lymphocytes. It was possible to obtain specific scFv to PR3 after a single round of selection and the binding could be inhibited by the patients' sera. Although the antibody fragments in the splenic repertoire were found to be highly mutated, it was interesting to find that the selected scFv showed only limited somatic mutation. Furthermore, we could demonstrate that the removal of the mutations had no effect on binding specificity.
Proinflammatory cytokines regulate FcαR expression by human mesangial cells in vitro
Authors: BAGHERI N , CHINTALACHARUVU S R , EMANCIPATOR S N 
Published: December 2003

SUMMARY
IgA nephropathy (IgAN) is defined by the predominant deposition of IgA immune complexes (IC) in the glomerular mesangium. Interaction between IgA immune complexes and mesangial cells (MC) could be a linchpin for the genesis of IgAN. We studied the modulation of MC expression of IgA receptors (FcαR) by selected cytokines. Binding of 125I-IgA to quiescent human MC showed 2.55 ×105 sites/cell with an affinity (Ka) of 3.2 ×107 M−1. Addition of selected recombinant cytokines had no significant influence on Ka, but increased the number of sites/cell relative to unstimulated cells. Northern hybridization using the pHuFcαR cDNA probe showed time-dependent increases in mRNA expression in stimulated versus control cells. IL-6 and tumour necrosis factor-alpha (TNF-α) had a biphasic effect on the FcαR mRNA level; at 48 h, IL-6 increased steady state mRNA levels about six-fold relative to control, TNF-α increased mRNA four-fold, and interferon-gamma (IFN-γ) induced FcαR mRNA two-fold. By reverse transcriptase-polymerase chain reaction (RT-PCR), the FcαR expressed on human MC appears highly homologous to that expressed by U937 cells. Altered FcαR expression in response to cytokines may influence the pathogenesis of IgAN by affecting deposition and/or clearance of IgA-IC in the mesangium.
Diagnostic value of CD45RO expression on circulating T lymphocytes of fetuses and newborn infants with pre-, peri- or early post-natal infections
Authors: BRU¨NING T , DAIMINGER A , ENDERS G 
Published: December 2003

SUMMARY
We examined the expression of the CD45RO antigen, which characterizes the antigen primed/memory phenotype of T lymphocytes, as a marker for congenital infection in blood samples of newborns and fetuses. CD45RO expression on T cells was determined by triple-colour fluorescence flow cytometry. In total 537 blood samples of newborns and infants up to an age of 3 months and 89 fetal blood samples from gestational weeks 19–31 were analysed. Of the newborns and infants, 74 had a clinically, serologically and/or antigenically evident infection, and four of the fetuses had a confirmed intra-uterine infection. In 35 infants with acute predominantly bacterial infections such as sepsis or pneumonia, 17 (48.6%) had elevated CD45RObright expression. In 39 infants with proven pre-, peri- or early post-natal infections with toxoplasmosis, cytomegalovirus (CMV), rubella, herpes simplex virus (HSV) or human herpes virus type 6 (HHV6), 25 (64.1%) exhibited enhanced CD45RObright expression. Three of four fetuses with confirmed intra-uterine infection (three with CMV, one with parvovirus B19) exhibited elevated CD45RObright expression. The specificity of the CD45RO assay for detecting microbial infections was 94.6% for newborns and infants up to 3 months and 90.6% for fetuses. It is concluded that elevated numbers of CD45RObright T cells in infants up to 3 months of age strongly suggest an infection. However, the sensitivity of the CD45RO assay is not sufficient to enable the test to be used as a general marker for prescreening infants to detect pre-, peri- or early post-natally acquired infections.
Systemic acute-phase reactants, C-reactive protein and haptoglobin, in adult periodontitis
Authors: EBERSOLE J L , MACHEN R L , STEFFEN M J , WILLMANN D E 
Published: December 2003

SUMMARY
Capture ELISAs with biotinylated monospecific antibodies were developed to detect both C-reactive protein (CRP) and haptoglobin (Hp) in serum of adult periodontitis (AP) patients and normal subjects. Each acute-phase reactant was significantly increased in serum from AP patients with CRP at 9.12 ±1.61 mg/l versus 2.17 ± 0.41 mg/l (P &lt; 0.001) and Hp at 3.68 ± 0.37 g/l versus 1.12 ± 0.78 g/l (P &lt; 0.001). Assessment of clinical characteristics of the patients' periodontal disease indicated that CRP and Hp levels were significantly increased in patients with the most frequent disease active episodes (P &lt; 0.02 and P &lt; 0.001, respectively). Longitudinal examination of the Hp levels showed a significant decrease following scaling and root planing (3.68 versus 2.38 g/l; P &lt; 0.01). After a 2-year administration of 50 mg/b.i.d. Flurbiprofen (a non-steroidal anti-inflammatory drug), significantly decreased Hp levels were noted (P &lt; 0.005). CRP levels declined by 35–40% after 1–2 years of treatment with the drug (P &lt; 0.05). The findings indicated that localized infections resulting in increased inflammation and tissue loss in the periodontium elicit systemic host changes manifest by increases in two acute-phase reactants. The conclusions are that either these molecules are formed locally and distributed to the serum, or these presumably localized infections impact upon the systemic components of the host protective responses.
Induction of hypoglycaemia in Japanese encephalitis virus infection: the role of T lymphocytes
Authors: KHANNA N , MATHUR A , BHARADWAJ M , CHATURVEDI U C 
Published: December 2003

SUMMARY
We report here development of hypoglycaemia in the convalescent phase of Japanese encephalitis virus (JEV) infection in mice by the induction of antigen-specific Ly1−2+ T cells in the spleen which mediate hypoglycaemia through the generation of soluble T cell hypoglycaemic factor (TCHF). The TCHF acted in a dose-dependent manner and was found to be trypsin-sensitive and thermolabile. It was purified on Superose-12 high performance liquid chromatography (HPLC) gel filtration column and purified protein migrated as a ∼25-kD band on SDS–PAGE. The JEV-induced hypoglycaemia coincided with an increased circulating glucagon level, without any alterations in blood insulin and growth hormone concentrations. These effects were mimicked by TCHF. These results indicate that JEV-primed T lymphocytes mediate hypoglycaemia through the production of a soluble hypoglycaemic factor.
Expression of Bruton's tyrosine kinase in B lymphoblastoid cell lines from X-linked agammaglobulinaemia patients
Authors: DE WEERS M , DINGJAN G M , BROUNS G S , KRAAKMAN M E M , MENSINK R G J , LOVERING R C , SCHUURMAN R K B , BORST J , HENDRIKS R W 
Published: December 2003

SUMMARY
X-linked agammaglobulinaemia (XLA) is an immunodeficiency caused by mutations in Bruton's tyrosine kinase (Btk) and is characterized by an almost complete arrest of B cell development. We analysed expression of Btk in B lymphoblastoid cell lines (BLCL) derived from four unrelated XLA patients. In one patient, with a 3.5 kb genomic deletion encompassing the first (untranslated) exon, mRNA levels and in vitro kinase activities were very low. The patient manifested a mild phenotype with a delayed onset of the disease. Another mutation, in which the intron 3 donor splice site is lost, was also associated with very low mRNA levels and an absence of detectable Btk protein. Patients with this mutation showed extensive heterogeneity of the immunological phenotype. In the BLCL of a third patient, with an Arg288 substitution in the SH2 domain, the mutation did not appear to affect the expression level, nor to abrogate in vitro phosphorylation activity. In the BLCL of the fourth patient, with an Arg28 mutation in the PH domain, tyrosine kinase activity in BTK precipitates appeared to be decreased compared with control BLCL.
Impaired hepatosplenic elimination of circulating cryoglobulins in patients with essential mixed cryoglobulinaemia and hepatitis C virus (HCV) infection
Authors: ROCCATELLO D , MORSICA G , PICCIOTTO G , CESANO G , ROPOLO R , BERNARDI M T , CACACE G , CAVALLI G , SENA L M , LAZZARIN A , PICCOLI G , RIFAI A 
Published: December 2003

SUMMARY
The pathogenic mechanisms that lead to renal deposition of the cryoprecipitable IgM rheumatoid factor–IgG complexes in essential mixed cryoglobulinaemia (EMC) are unknown. Defective removal of cryoprecipitable complexes from the circulation has been postulated in EMC-associated nephritis. To test this hypothesis, the kinetics and fate of a trace dose of 123I-radiolabelled autologous cryoglobulins were analysed in 13 patients with EMC grouped according to renal involvement. The time course of radioactivity distribution in the blood and organ uptake were measured by gamma camera scintigraphy. In blood sampled 30–300 s after injection, only a minor fraction (&lt; 15%) of the circulating cryoglobulins bound to the erythrocytes, suggesting the elimination mechanisms are independent of binding to CR1 on erythrocytes. The overall blood disappearance curve showed a fast (≤ 1 min) and slow (&gt; 4 h) biphasic pattern. In patients with quiescent or mild nepthritis, the liver and to a lesser extent the spleen were the major organs that mediated the rapid uptake and processing of the cryoglobulins from the circulation. In contrast, patients with active mesangiocapillary glomerulonephritis showed significantly (P &lt; 0.001) less hepatic uptake, low liver-to-precordium ratio, and slower processing of cryoglobulins, prolonged liver mean transit time, than quiescent patients or mild nephritis patients. To elucidate the role and influence of HCV infection in the pathogenesis of EMC-nephritis, sera and cryoglobulins from all patients were assayed for HCV. None of the control group cases without nephritis showed any evidence of HCV-RNA in serum or cryoglobulin pellet. In contrast, all 10 EMC-nephritis patients' sera, and eight corresponding cryoglobulin pellets contained HCV-RNA. Collectively, these findings suggest an impaired reticuloendothelial system removal of IgM–IgG–HCV complexes may underlie their renal deposition.
Anti-CD2 (OX34) MoAb treatment of adjuvant arthritic rats: attenuation of established arthritis, selective depletion of CD4+ T cells, and CD2 down-modulation
Authors: HOFFMANN J C , HERKLOTZ C , ZEIDLER H , BAYER B , WESTERMANN J 
Published: December 2003

SUMMARY
Anti-CD2 MoAbs have previously been shown to induce tolerance and to block B cell differentiation, T cell and monocyte activation. Since these immune functions are important in joint inflammation, we asked whether administration of the anti-CD2 MoAb OX34 has a beneficial effect on established rat adjuvant arthritis, a model of human rheumatoid arthritis, and how it affects CD2-bearing leucocyte subsets. Female Lewis rats with established adjuvant arthritis received a total of 5 mg OX34 or isotype-matched control MoAb starting on day 15 after adjuvant injection. Weight and arthritis score (AS) were measured in a blinded fashion. Peripheral blood cells were analysed for numbers of leucocyte subsets at various time points. Animals were killed on day 30 and lymphatic organs were processed for immunohistology. Clinically, OX34 treatment led to increased body weight and reduced AS. Although OX34 binds to CD4+ and CD8+ T cells in a comparable fashion, OX34 treatment reduced CD4+ T cells, but not CD8+ T cells. Among CD4+ T cells CD45RC+ (‘naive’) T cells virtually disappeared; CD45RC− (‘recently activated’) T cells were slightly reduced. A reduction of CD4+ T cells was also found in the lung, liver, bone marrow, spleen and lymph nodes. Down-modulation of the CD2 molecule by OX34, again, affected CD4+ T cells, suggesting a specific signal for CD4+ but not CD8+ T cells. In conclusion, the anti-CD2 MoAb OX34 attenuates established rat adjuvant arthritis. In spite of similar binding to CD4+ and CD8+ T cells, OX34 depletes only CD4+ T cells and down-modulates the CD2 molecule on these cells. These results suggest a therapeutic benefit from CD2-directed therapy for chronic types of arthritis.
CTLA-4 gene polymorphism confers susceptibility to insulin-dependent diabetes mellitus (IDDM) independently from age and from other genetic or immune disease markers
Authors:   THE BELGIAN DIABETES REGISTRY, VAN DER AUWERA B J , VANDEWALLE C L , SCHUIT F C , WINNOCK F , DE LEEUW I H , VAN IMSCHOOT S , LAMBERIGTS G , GORUS F K 
Published: December 2003

SUMMARY
Apart from genes in the HLA complex (IDDM1) and the variable number of tandem repeats in the 5′ region of the insulin gene (INS VNTR, IDDM2), several other loci have been proposed to contribute to IDDM susceptibility. Recently, linkage and association have been shown between the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) gene on chromosome 2q and IDDM. In a registry-based group of 525 recent-onset IDDM patients &lt; 40 years old we investigated the possible interactions of a CTLA-4 gene A-to-G transition polymorphism with age at clinical disease onset and with the presence or absence of established genetic (HLA-DQ, INS VNTR) and immune disease markers (autoantibodies against islet cell cytoplasm (ICA); insulin (IAA); glutamate decarboxylase (GAD65-Ab); IA-2 protein tyrosine phosphatase (IA-2-Ab)) determined within the first week of insulin treatment. In new-onset IDDM patients, G-allele-containing CTLA-4 genotypes (relative risk (RR) = 1.5; 95% confidence interval (CI) = 1.2–2.0; P &lt; 0.005) were not preferentially associated with age at clinical presentation or with the presence of other genetic (HLA-DR3 or DR4 alleles; HLA-DQA1*0301-DQB1*0302 and/or DQA1*0501-DQB1*0201 risk haplotypes; INS VNTR I/I risk genotype) or immune (ICA, IAA, IA-2-Ab, GAD65-Ab) markers of diabetes. For 151 patients, thyrogastric autoantibodies (anti-thyroid peroxidase, anti-thyroid-stimulating hormone (TSH) receptor, anti-parietal cell, anti-intrinsic factor) were determined, but association between CTLA-4 risk genotypes and markers of polyendocrine autoimmunity could not be demonstrated before or after stratification for HLA- or INS-linked risk. In conclusion, the presence of a G-containing CTLA-4 genotype confers a moderate but significant RR for IDDM that is independent of age and genetic or immune disease markers.
Removing the Roadblocks to Medical and Health Student Training in Rural Hospitals in Victoria
Authors: Jones Graeme I. , Alford Katrina A. , Russell Ursula J. , Simmons David 
Published: December 2003

ABSTRACTObjective:  To assess the extent of undergraduate health student placements in regional hospitals in northern Victoria in 1999, prior to substantial changes in rural undergraduate medical education in Australia. Method:  Cross sectional postal survey with telephone follow‐up in north‐east Victoria. Subjects were all 17 regional and rural hospitals involved in health student teaching in North‐east Victoria. Main outcome measures were the numbers, duration and discipline of health students placements and reported barriers to such placements. Results:  Large regional hospitals accounted for two‐thirds of all undergraduate health student placements. Smaller sites placed few allied health students. Barriers to a larger, more sustainable system of rural placements and rotations included accommodation shortages and funding constraints, particularly in smaller rural hospitals. Conclusions:  Adequate resourcing of placements of a meaningful duration, stronger institutional support, and improved resourcing of regional accommodation is required to facilitate a larger, more systematic and sustainable system of medical and health student placements in rural areas. What is already known:  The extent of training of health professionals in rural Australia is increasing rapidly. Fears have been expressed that the capacity to deliver quality experience in rural practice may be limited. What this study adds:  This cross sectional survey of rural Victorian hospitals shows that there is a major untapped potential in rural hospitals of all sizes to assist with training in rural practice, but that a number of barriers to such training need to be removed to reach full capacity.
Rural General Practitioner Apprehension About Work Related Violence in Australia
Authors: Tolhurst Helen , Talbot Jane , Baker Louise , Bell Pam , Murray Gillian , Sutton Amber , Dean Sarah , Treloar Carla , Harris Gillian 
Published: December 2003

ABSTRACTAims:  To identify levels of Australian rural general practitioners’ apprehension about violence, factors effecting apprehension and the effect of apprehension on service provision. Method:  Six focus groups were held with rural GPs from Western Australia, New South Wales and Victoria. A questionnaire was developed on the basis of the focus group data and all GPs in these three areas were surveyed. Results:  The results indicated GPs were more apprehensive about providing after hours care than during business hours. Significant gender differences were found with women being more often apprehensive than men and more likely to withdraw after hours services. Conclusion:  This study shows that that levels of apprehension about violence affect GPs’ willingness to provide after hours services. Future provision of general practice after hours services and home visits in rural areas requires the availability of a safe working environment to reduce GPs’ apprehension about workplace violence. What Is Already Known:  Overseas research has shown that many GPs are apprehensive about workplace violence and that female GPs are more likely to be apprehensive about it than male GPs. No Australian studies about GPs’ levels of apprehension about workplace violence have previously been undertaken. What this study adds:  This study showed that many Australian rural GP respondents feel apprehensive about work‐related violence especially after hours and when undertaking home visits after hours. Female respondents were significantly more likely to feel apprehensive about workplace violence than male respondents and to make changes to services because of the risk of violence than male GPs, most commonly by not providing services such as home visits or after hours surgery attendances.
Evidence‐Based Practice in Rural and Remote Clinical Practice: Where is the Evidence?
Authors: Parsons Jacqueline E. , Merlin Tracy L. , Taylor Judy E. , Wilkinson David , Hiller Janet E. 
Published: December 2003

ABSTRACTObjective:  To critically review the evidence regarding barriers to implementing research findings in rural and remote settings, and the ways those barriers have been addressed. Design:  A systematic review that included searching several electronic databases, Internet sites and reference lists of relevant articles, assessment of methodological quality of the studies, and data extraction and analysis where possible. Eligibility for the review was not limited by study design. Settings/Participants:  Studies that reported on: (1) barriers to the implementation of evidence by health professionals in rural and remote areas, or (2) interventions for implementing evidence‐based practice or an element of evidence‐based practice in rural and remote areas. Results:  There were no experimental data available on the implementation of research findings in rural and remote clinical settings. The small amounts of empirical research undertaken (surveys) showed that some of the problems experienced by general practitioners were exacerbated by rural and remote location, particularly with relation to isolation, lack of time and locum cover, and poor information technology infrastructure. Conclusion:  There is a paucity of empirical literature on implementing evidence‐based practice in rural and remote settings. This is in contrast to the large amount of literature available on implementing evidence in other clinical settings. A clear finding from the literature was that getting evidence into practice needs to be context‐specific and yet very little research has been conducted into the rural and remote context. Research is needed into how evidence can be implemented in contextually specific ways in rural and remote areas. What is already known:  There is a substantial body of literature about the barriers to implementing research findings into clinical practice and how to address these barriers. This literature includes many systematic reviews and even overviews of systematic reviews. One of the consistent findings of the literature is that the implementation of research findings needs to be context‐specific to have any chance of making lasting and worthwhile changes to practice. There is little work, however, on the context of rural and remote clinical practice. What this study adds:  This study aimed to review the literature on the implementation of evidence based practice in rural and remote settings. No experimental studies were found and the limited empirical evidence from surveys found that the rural and remote context exacerbated some of the problems experienced by health professionals in other settings, particularly those related to lack of time, inability to get locum cover and poor and unreliable information technology infrastructure. More research is required to isolate the aspects of rural and remote practice that influence the uptake of research findings.