bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro metabolic inhibition of the human lymphocyte: Influence on the expression of interleukin‐2 receptors
Authors: KARLSSON H. , NÄSSBERGER L. 
Published: July 2007

SummaryWe have investigated the effects of energy depletion in human lymphocytes on the expression of the membrane‐bound interleukin‐2 receptor (IL‐2R) and the release of soluble IL‐2R. Concanavalin‐A (Con‐A) and IL‐2‐transformed lymphocytes were incubated with sodium fluoride, inhibiting the Embden‐Meyerhof pathway, rotenone and 2,4‐dinitrophenol (2,4‐DNP), which are known to disturb mitochondria 1 high energy production. Rotenone was found to be the most potent inhibitor, with a half maximal effect at 10 nmol/L. 2,4‐DNP and sodium fluoride, although not as potent as rotenone, showed marked inhibitory effects in higher concentrations, with half maximal effects at 50 μmol/L and 5 mmol/L respectively. No difference in the inhibition pattern for membrane‐bound IL‐2R compared with sIL‐2R was observed. It is concluded that intracellular synthesis, transport and subsequent membrane insertion or release of receptors important for immunoregulation require high energy phosphate compounds and are sensitive to disturbances in intracellular energy levels.
T cell memory: A role for MHC class II molecules on T cells?
Authors: ZOLA HEDDY 
Published: July 2007

SummaryA proportion of human T cells express MHC class II molecules. In this paper, the hypothesis is advanced that these MHC class II molecules present antigenic peptides acquired from interaction with other antigen‐presenting cells (e.g. during the primary response) and can therefore interact in a cognitive manner with T cells with the same specificity. Memory is maintained in the physical form as clusters of T cells expressing T cell receptors and the cognate peptide‐MHC class II complex; by virtue of their cognate interaction with each other these cells turn over gradually and return to the cluster when they recirculate. When fresh antigen is introduced, it is presented to some of these T cells by non‐T antigen‐presenting cells that provide a second signal leading to vigorous activation of the T cell. The proximity and cognate interaction of other T cells of the same specificity allows a chain reaction to occur, leading to rapid development of the secondary response. The hypothesis, which is testable, is proposed because of doubts concerning the current concept of memory as applied to T cells, and a need to understand the consequences of the expression of MHC class II molecules by a subset of T cells.
An hypothesis to explain why cell‐mediated immunity alone can contain infections by certain intracellular parasites and how immune class regulation of the response against such parasites can be subverted
Authors: BRETSCHER PETER A. 
Published: July 2007

SummaryCells with a low density of parasite‐specific antigens on their surface are postulated to be susceptible to a cell‐mediated attack but not to effector mechanisms normally activated following the binding of specific antibody to the infected cell. It is further postulated that such infected cells normally induce a cell‐mediated response, and that cells infected with slow‐growing intracellular parasites have a low density of parasite‐specific antigens on their surface. Despite these general postulates, cell‐mediated immunity is not invariably induced following natural infection by certain slow‐growing parasites, such as those responsible for leprosy, tuberculosis, and the leishmaniases, and antibody can be induced that is exclusive of a strong, cell‐mediated response. It is proposed that certain events in such cases subvert the normal regulatory processes that control the class of immunity induced. In these cases, the parasite‐infected cells, bearing a low representation of parasite antigens, induce antibody even though they are not susceptible to antibody‐dependent effector mechanisms, and so they are not eliminated. In this case, chronic infection and uncontrolled growth of the parasiteoccurs, often with fatal consequences.
Value issues in biomedical science: Public concerns and professional complacency
Authors: BELLETT A.J.D. 
Published: July 2007

SummaryBiomedical research was once an unquestioned good, and generous funding for a short time allowed researchers to work on whatever interested them. Two contradictory pressures have changed this. As costs have risen and economic rationalism has become politically dominant, governments, private corporations and granting agencies have increasingly demanded compliance with their own priorities, instrumental values and performance criteria. On the other hand, social and ethical critics have characterized biomedical research as being out of touch with real health needs and community values and as being an agent of social control that entrenches the power of a technocratic hegemony. The profession has largely acquiesced in bureaucratic and corporate intervention in exchange for continued funding, and assumed that social concerns could be allayed by ‘top down’ paternalistic education of the public. However, this response tends to add weight to the criticism that biomedicine is an agent of social control. What is needed is a spirited defence of the value of independent scholarship and research that is not limited to science but includes the humanities. Equally important is a process of community education in which scientists not only transmit their knowledge and enthusiasm to the public, but themselves become open to the social and ethical concerns of the community.
Lymphoid tissue in rat oral mucosa: Structure and function
Authors: SMINIA TAEDE , SWART SIEBE J. , STEENBERGEN JOKE J. E. , BIEWENGA JEIKE 
Published: July 2007

SummaryLymphocyte and macrophage/dendritic cell populations in the oral cavity of the rat were studied by immunohistochemistry. Furthermore, the reactivity of the oral mucosa towards antigen and its position in the mucosal immune system was investigated by staining antibody‐forming cells and comparing serum and saliva antibody titres. Although numerous lymphocytes and non‐lymphoid cells were present in the oral mucosa, organized lymphoid tissue could not be found. The majority of the lymphocytes are T cells, particularly of the T‐helper phenotype. Macrophages were found only in the connective tissue, whereas dendritic cells also occurred in the epithelium. The possible functions of the cells in the different sites of the oral mucosa are discussed. Antibody‐forming cells were mainly detected in the draining superficial and posterior cervical lymph nodes and in the submandibular glands. The roles of the various compartments of the oral mucosal immune system are discussed with particular reference to the epithelium and connective tissue as induction sites, the draining lymph nodes as sites of proliferation and differentiation, and the submandibular glands as effector sites.
What is the selective pressure that maintains the gene loci encoding the antigen receptors of T and B cells? A hypothesis
Authors: LANGMAN RODNEY E. , COHN MELVIN 
Published: July 2007

SummaryThe dominant view is that the gene loci encoding the B cell antigen receptor (BAr) or the T cell antigen receptor (TAr) specify a vast array of combining sites. The ‘germline’ repertoire is estimated to be > 1010 by multiplying numbers of subunit complements by DN‐region variability. This implies that the germline can be maintained by a selection imposed by all or most of the antigenic universe. Its unchallenged popularity, notwithstanding, this neo‐germline view is untenable and hence the need for a competing concept, as presented here. The immunoglobulin (Ig) loci are under a totally different selection from the T loci. The Ig loci are selected upon largely by carbohydrate determinants on pathogens that vary more slowly than the proteins produced by the Ig loci, which are necessary to rid these selective antigens. By contrast, the T loci are selected to recognize the allele‐specific determinants on restricting elements encoded in the major histocompati‐bility complex (MHC). The expression of the germline results in a high copy number (HCN) repertoire; this repertoire is the substrate for ‘mutation’ that yields the low copy number (LCN) repertoire. For the B cell, these two repertoires interact to optimize the response to the unexpected. For the T cell, only the LCN repertoire is functional. The immunoglobulin (Ig) loci are selected upon as light(L)‐heavy (H) pairs; the T loci are selected upon as single units α or β (i.e. the VT‐gene segments act as a single pool). This competing concept carries with it many important and testable consequences.
Macrophages in protective immunity to Hymenolepis nana in mice
Authors: ASANO K. , MURAMATSU K. , ITO A. , OKAMOTO K. 
Published: July 2007

SummaryWhen mice were treated with carrageen just before infection with eggs of Hymenolepis nana, they failed to exhibit sterile immunity to the egg challenge, with evidence of a decrease in the number of peripheral macrophages (Mø) and the rate of carbon clearance. Although there were high levels of interleukin‐1 (IL‐1) released into the intestinal tracts of the parasitized mice at challenge infection, there was almost no release of IL‐1 in those treated with carrageen just before challenge. These results strongly suggest that Mo have an important role in protective immunity to H. nana in mice.
A transgenic window on peripheral T cell tolerance
Authors: MILLER JACQUES F. A. P. 
Published: July 2007

SummaryThere is convincing evidence for the imposition of self‐tolerance by means of the clonal deletion of self‐reactive T cells within the thymus. Since not all self components may be encountered there, the question must be asked whether tolerance can occur post‐thymically. To test this, we have used transgenic technology to direct expression of a‘non‐self gene, H‐2Kb, to the insulin‐producing β cells of the pancreas in mice. These‘RIP‐Kb’transgenic mice were specifically tolerant of H‐2Kb‐bearing skin grafts. To test the fate of potentially reactive H‐2Kb ‐specific T cells in these tolerant mice, the RIP‐Kb mice were mated to a second series of transgenic mice with rearranged T cell receptor (TCR) genes encoding an H‐2Kb‐specific TCR to produce‘double transgenic’offspring. The TCR was detectable by a clonotype‐specific antibody. Although there was some evidence of intrathymic deletion of those T cells that expressed the highest density of the H‐2Kb‐specific TCR, lower density cells were present in the periphery. These may have been either indifferent to the H‐2Kb molecule expressed on the p cells or functionally silenced by it. Further experiments are planned to determine which of these two situations exists.
Advancing the analysis of treatment process
Authors: Stout Robert L. 
Published: July 2007

ABSTRACTAims To review the role of process research in clinical research, to summarize progress in statistical methods for process analyses, and to describe a dynamic analytical approach that can provide new insights into the processes responsible for the effects of treatments and other variables.Summary Process research helps us to understand what happens during our interventions, and can yield valuable knowledge regardless of whether an intervention is found to have significant effects. This is a review of recent statistical advances for dealing with missing data, tests for mediation and hierarchical modeling and demonstrate how these advances can help process researchers overcome obstacles that had limited past studies. However, the standard paradigm for process analysis, although conceptually sound, is based upon a static model that does little justice to the dynamics of treatment. Therefore, it is proposed that the paradigm is extended to study the time–course of dynamic processes, using existing statistical methods. Hierarchical linear modeling, structural regression modeling and event history methods are among the most promising tools for more advanced process analyses because of their ability to incorporate time‐varying predictors.Conclusions The function of process analysis is to probe into the mechanisms of action of treatment to locate both weaknesses and strengths, but methods for process research are still rudimentary. By conceptualizing process analysis as a problem of relating multiple time‐series, many new analytical opportunities, and challenges, present themselves. Modern statistical methods can help to lead to broad advances in our understanding of the processes that affect treatment success.
Disentangling social selection and social influence effects on adolescent smoking: the importance of reciprocity in friendships
Authors: Mercken Liesbeth , Candel Math , Willems Paul , De Vries Hein 
Published: July 2007

ABSTRACTAims  The goal of this study was to examine social selection and social influence within reciprocal and non‐reciprocal friendships, and the role of parents and siblings, as factors explaining similarity of smoking behaviour among adolescent friends. A new social selection–social influence model is proposed.Design  Longitudinal design with two measurements.Setting  Data were gathered among Dutch high school students in the control group of the European Smoking prevention Framework Approach (ESFA) study.Participants  The sample consisted of 1886 adolescents with a mean age of 12.7 years.Measurements  The main outcome measures were the smoking behaviours of the respondents, best friends, parents and siblings. We tested the social selection–social influence model with structural equation modelling techniques.Findings  Social selection and social influence both played an important role in explaining similarity of smoking behaviour among friends. Within non‐reciprocal friendships, only social selection explained similarity of smoking behaviour, whereas within reciprocal friendships, social influence and possibly also social selection explained similarity of smoking behaviour. Sibling smoking behaviour was a more important predictor of adolescent smoking behaviour than parental smoking behaviour.Conclusions  Social selection and social influence both promote similarity of smoking behaviour, and the impact of each process differs with the degree of reciprocity of friendships. These insights may contribute to further refinement of smoking prevention strategies.
Effect of acute paracetamol overdose on changes in serum and urine electrolytes
Authors: Pakravan N. , Bateman D. N. , Goddard J. 
Published: July 2007

What is already known about this subject • Paracetamol causes renal failure in overdose. Experimental studies have shown that paracetamol can inhibit COX II systemically in a manner similar to selective COX‐II inhibitors.• In overdose nonsteroidal anti‐inflammatory drugs such as ibuprofen, cause dose‐dependent increase in urinary potassium excretion (FeK) and sodium retention, probably due to vasoconstriction. What this study adds • Paracetamol overdose is associated with dose‐related hypokalaemia and kaliuresis of short duration (<24 h), suggesting a specific renal effect of paracetamol in overdose.• This effect seems likely to be via cyclo‐oxygenase inhibition and may be separate from the nephrotoxic effects of paracetamol.AimsTo investigate the effects of acute paracetamol overdose on renal function, serum and urine electrolyte excretion in man.MethodsTwo studies were performed in patients admitted with paracetamol overdose: a retrospective study examining changes in serum electrolytes, and a prospective study evaluating changes in serum and urine electrolytes. A control group with SSRI overdose was included in the prospective study.ResultsThere was a significant dose‐dependent relationship between admission (4 h) paracetamol concentration and fall in serum potassium in the retrospective study (P < 0.01) and a significant positive relationship between serum paracetamol at 4 h and fractional excretion of potassium at 12 h postingestion (P < 0.01) in the prospective study. No changes were seen in the control group. No cases developed renal failure.ConclusionsParacetamol overdose is associated with dose‐related hypokalaemia, and kaliuresis of short duration (<24 h), suggesting a specific renal effect of paracetamol in overdose perhaps via cyclo‐oxygenase inhibition. This effect seems distinct from any nephrotoxic effect of paracetamol.
Pharmacokinetic interaction between TMC114/ritonavir and tenofovir disoproxil fumarate in healthy volunteers
Authors: Hoetelmans Richard M. W. , Mariën Kris , De Pauw Martine , Hill Andrew , Peeters Monika , Sekar Vanitha , De Doncker Piet , Woodfall Brian , Lefebvre Eric 
Published: July 2007

What is already known about this subject • Tenofovir disoproxil fumarate and some of the HIV protease inhibitors show drug–drug interactions that cannot be predicted based on their metabolic profiles.• Tenofovir disoproxil fumarate and HIV protease inhibitors are often combined as part of antiretroviral therapy. What this study adds • TMC114 (darunavir) is the latest HIV protease inhibitor approved by the US Food and Drug Administration and is used in combination with low‐dose ritonavir.• This study shows for the first time the extent of the drug–drug interaction between tenofovir disoproxil fumarate and TMC114 combined with low‐dose ritonavir and compares the interaction observed with other HIV protease inhibitors.AimTMC114 is a new HIV protease inhibitor, used in combination with low‐dose ritonavir (TMC114/r) as a pharmacokinetic enhancer. Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor. Both antiretrovirals show activity against wild‐type and resistant HIV. An open‐label crossover study was conducted in HIV – healthy volunteers to investigate the potential for a pharmacokinetic interaction between TMC114/r and tenofovir.MethodsTwo groups, each of six volunteers, were evaluated in two consecutive sessions. In session 1, volunteers received TMC114/r (300/100 mg bid) for 7 days, followed by a wash‐out period of at least 6 days. In session 2, volunteers received TMC114/r (300/100 mg bid) plus TDF (300 mg qd).ResultsWhen TMC114/r and TDF were coadministered, tenofovir plasma concentrations (Cmin and Cmax), and area under the curve (AUC24 h) increased by 37%, 24% and 22%, respectively. When TDF and ritonavir were coadministered, TMC114 plasma Cmin, Cmax and AUC12 h increased by 24%, 16% and 21%, respectively. There were no changes in the urinary excretion of unchanged tenofovir or TMC114 during coadministration. Administration of TMC114/r in HIV– healthy volunteers with or without TDF was well tolerated.ConclusionsThe interaction between TMC114/r and tenofovir is not clinically relevant and no dose adjustments are required when these drugs are coadministered.
The pharmacokinetics and effects of a long‐acting preparation of superoxide dismutase (PC‐SOD) in man
Authors: Broeyer F. J. F. , Van Aken B. E. , Suzuki J. , Kemme M. J. B. , Schoemaker H. C. , Cohen A. F. , Mizushima Y. , Burggraaf J. 
Published: July 2007

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Reactive oxygen species (ROS), like superoxide anion, play an important role in different disease states.• Superoxide dismutase (SOD) acts as a free radical scavenger by catalysing the dismutation of superoxide.• Over the last decade, therapeutic use of SOD has been explored, but the results of these experiments have indicated that this has been of limited value, probably due to unfavourable pharmaceutical characteristics of the compounds. WHAT THIS STUDY ADDS • Single intravenous administrations of PC‐SOD (SOD covalently linked to lecithin) in doses up to 80 mg was well tolerated and biologically active for a period of 19 ± 6 h in healthy White volunteers.• This suggests that PC‐SOD has pharmaceutically appropriate characteristics and may be a possible protective agent for patients in clinical conditions characterized by acute high radical overload.AIMTo study the pharmacokinetics (PK), safety and tolerability of single rising doses up to 80 mg of superoxide dismutase covalently linked to lecithin (PC‐SOD) in healthy White volunteers.METHODSThis double‐blind, placebo‐controlled, four‐period cross‐over study was performed in eight healthy volunteers (four male/four female). Three doses of PC‐SOD (20, 40 and 80 mg) and placebo were administered intravenously in randomized order. Serum and urinary PC‐SOD concentrations were measured predose and up to 96 h after dosing. In addition to standard safety measurements, the urinary excretion of N‐acetyl‐β‐glucosaminidase, α‐glutathione S‐transferase (α‐GST) and π‐GST was measured to evaluate renal function. The PK of PC‐SOD was analysed using noncompartmental and compartmental methods.RESULTSAll treatments were well tolerated, and no obvious relationship between adverse events and treatment was observed. No effects of PC‐SOD on renal function could be detected. Dose normalized Cmax and AUC were not different between the different dosages, indicating linearity of plasma concentrations with dose. Estimated PC‐SOD clearance was 2.54 ml min−1[95% confidence interval (CI) 2.07, 2.83]. The terminal half‐life was estimated to be 1.54 days (95% CI 0.93, 2.15). SOD activity was elevated above baseline for 19 ± 6 h after the 80‐mg dose.CONCLUSIONSSingle intravenous administrations of PC‐SOD in doses up to 80 mg were well tolerated in healthy White male and female volunteers. With the doses used, SOD activity was linearly related to the dose; after the 80‐mg dose it was present for an appreciable period. These findings suggest that it is worthwhile to investigate PC‐SOD in clinical conditions characterized by a high radical overload.