bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exposure to antibacterial agents with QT liability in 14 European countries: trends over an 8‐year period
Authors: Raschi Emanuel , Poluzzi Elisabetta , Zuliani Chiara , Muller Arno , Goossens Herman , De Ponti Fabrizio 
Published: October 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Several noncardiovascular drugs with QT liability are currently on the market.• Previous epidemiological studies have shown significant exposure of the general population to drugs with QT liability with similar consumption in many European countries.• Several regulatory measures have concerned medicinal products carrying a pro‐arrhythmic risk in humans. WHAT THIS STUDY ADDS • The list of antibacterial agents with documented QT liability has grown over the last few years.• Notwithstanding stringent regulatory measures, population exposure to antibiotics with QT liability is still significant in several countries.• The magnitude of the problem is clearly heterogeneous, with remarkable diversity between Northern and Southern countries (lower and higher exposure, respectively).AIMS(i) To classify antibacterial agents with QT liability on the basis of the available evidence, and (ii) to assess trends in their consumption over an 8‐year period (1998–2005) in 14 European countries.METHODSCurrent published evidence on QT liability of antibiotics was retrieved through MEDLINE search and joined to official warnings from regulatory agencies. Each drug was classified according to an already proposed algorithm based on the strength of evidence: from group A (any evidence) to group E (clinical reports of torsades de pointes and warnings on QT liability). Consumption data were provided by the European Surveillance of Antibacterial Consumption (ESAC) project and were expressed as defined daily doses per 1000 inhabitants per day (DID).RESULTSAmong 21 detected compounds, nine [six fluoroquinolones (FQs) and three macrolides (MACs)] belonged to group E. Use of group E drugs ranged from 1.3 (Sweden) to 4.1 DID (Italy) in 1998 and from 1.2 (Sweden) to 6.5 DID (Italy) in 2005. Significant exposure was observed in Italy and Spain (6.5 and 3.8 DID, respectively, in 2005). Only Denmark, Sweden and UK showed a slight decrease in use. Exposure to clarithromycin increased in 10 out of 14 countries, with a marked increment in Italy (3 DID in 2005).CONCLUSIONSNotwithstanding regulatory measures, in 2005 there was still significant exposure to antibacterials with strong evidence of QT liability and, in most countries, it was even increased. This warrants further investigation of appropriateness of use and suggests closer monitoring of group E drugs. Physicians should be aware when prescribing them to susceptible patients.
Oxycodone is associated with dose‐dependent QTc prolongation in patients and low‐affinity inhibiting of hERG activity in vitro
Authors: Fanoe Søren , Jensen Gorm Boje , Sjøgren Per , Korsgaard Mads P. G. , Grunnet Morten 
Published: October 2008

WHAT IS ALREADY KNOWN • During recent years some opioids have been associated with prolonged QT and torsade de pointes (TdP).• In vitro testing has shown that most opioids can block the cardiac potassium channels.• This indicates that QT prolongation and TdP could be a more general problem associated with the use of these drugs. WHAT THIS PAPER ADDS • This study is the first to show that oxycodone dose is associated with QT prolongation and in vitro blockade of hERG channels expressed in HEK293.• Neither morphine nor tramadol doses are associated with the QT interval length.AIMSDuring recent years some opioids have been associated with prolonged QT interval and torsade de pointes (TdP). In vitro patch clamp testing has shown that most opioids can block human ether‐a‐go‐go related gene (hERG) channels that are known to underlie cardiac repolarizing IKr current. This indicates that QT prolongation and TdP could be a more general problem associated with the use of these drugs. The aims of this study were to evaluate the association between different opioids and the QTc among patients and measure hERG activity under influence by opioids in vitro.METHODSOne hundred chronic nonmalignant pain patients treated with methadone, oxycodone, morphine or tramadol were recruited in a cross‐sectional study. The QTc was estimated from a 12‐lead ECG. To examine hERG activity in the presence of oxycodone, electrophysiological testing was conducted using Xenopus laevis oocytes and HEK293 cells expressing hERG channels.RESULTSThere were no differences in gender distribution or age between the treatment groups. The known association between methadone dose and QTc was confirmed (R2 = 0.09; P = 0.02). Higher oxycodone dose was also associated with longer QTc (R2 = 0.21; P = 0.02). A 100 mg higher oxycodone dose was associated with a 10 ms1/2 (95% CI 2–19) longer QTc. Neither morphine nor tramadol dose was associated with the QTc. Electrophysiological testing revealed low‐affinity inhibition of the potassium current through hERG channels expressed in HEK293 cells (IC50 = 171 µM oxycodone).CONCLUSIONSAmong patients treated with methadone or oxycodone, higher doses were associated with longer QTc. Oxycodone is capable of inhibiting hERG channels in vitro.
In vivotreatment with a monoclonal chimeric anti-CD4 antibody results in prolonged depletion of circulating CD4+ cells in chimpanzees
Authors: JONKER M , SLINGERLAND W , TREACY G , van EERD P , PAK K Y , WILSON E , TAM S , BAKKER K , LOBUGLIO A F , RIEBER P , RIETHMULLER G , DADDONA P E , IULIUCCI J 
Published: October 2008

SUMMARYChimeric M-T412 (cM-T412). an anti-CD4 antibody, was tolerated in chimpanzees at a dosage of 5 mg/kg per day for up to 7 consecutive days, or 5 mg/kg per dose, twice weekly for 4 weeks. All cM-T412-treated chimpanzees showed a prolonged CD4 cell depression. Weak chimpanzee antibody responses to chimeric M-T412 were observed. One of the chimpanzees on the biweekly dosage regimen exhibited a hypersensitivity reaction immediately after receiving its seventh dose. Following supportive treatment, the animal recovered and remained asymptomatic during the non-treatment observation period. The hypersensitivity reaction was not an unexpected response considering the animal received repeated intermittent i.v. administration of a foreign protein. This animal also showed a chimpanzee antibody response to chimeric M-T412 after the seventh dose. Chimeric M-T412 also induced an anti-cM-T412 response in some of the other animals. The level of this response was lower than the anti-mouse responses observed in animals treated with murinc anti-CD4. Moreover, the anti-cM-T4l 2 response was mainly directed to idiotypic determinants. The decrease in CD4+ cells observed for all chimeric M-T412-treated chimpanzees is an expected effect of the anti-CD4 antibody. The duration of this CD4+ cell decrease is. however, much longer than observed for other CD4-specific MoAbs described. No selective loss of either memory or naive CD4+ cells was observed after cither the single, 7-day or twice-weekly treatments. The CD4+ cell depression was reversible, although individual variation in time to recovery was observed. Therefore, cM-T412 could be a good candidate for clinical use in autoimmune conditions.
Immune stimulatory and anti-tumour properties of haemin
Authors: TSUJI A , WANG J , STENZEL K H , NOVOGRODSKY A 
Published: October 2008

SUMMARYIL-2 induces tumour regression in some patients with metastatic disease, but the dose of IL-2 is limited by severe toxicity. Agents that increase the expression of IL-2 receptors in the effector cells could be used to improve the effectiveness of IL-2 in mediating its anti-tumour effect. We have reported that haemin increased the expression of IL-2 receptors in human peripheral blood mononuclear cells (PBMC) and synergized with IL-2 in the induction of mitogenicity, cytotoxicity and cytokine production. We now report on haemin-induced immune stimulation and tumour regression in mice. Haemin-induced mitogenicity in mouse splenocytes was potentiated up to twofold by IL-2. The combination of haemin and IL-2 was also effective in inducing cytotoxicity for natural killer (NK)-resistant target cells. Maximal induction of cytotoxicity was attained at an optimal concentration of haemin of 10 μm. Higher concentrations were less effective. Splenocytes isolated from mice that had been treated in vivo with haemin and IL-2 incorporated twice the amount of 3H-thymidine compared with splenocytes from mice treated with either haemin or IL-2 alone. Cytotoxicity of splenocytes for NK-rcsistant target cells was not increased following in vivo administration of haemin and IL-2 when fresh splenocytes were tested. Cytotoxicity was enhanced, however, up to five-fold following 48 h in vitro incubation with IL-2. Administration of haemin and IL-2 resulted in a significant decrease (40%) of established hepatic metastases in mice. Either IL-2 or haemin alone at the dose used were ineffective. The anti-tumour effect of haemin and IL-2 was enhanced (63% decrease in metastases) by administration of the thiol compound, N-acetylcysteine. Since haemin can safely be administered to patients, it may represent a new class of biologic response modifiers that could enhance IL-2-mediated anti-tumour effects.
Suppression of autoimmune disease in NZB/W F1 mice by treatment with the novel immunomodulator BTS 63155
Authors: APPLEBY P , TELFORD G , NAYLOR G B 
Published: October 2008

SUMMARY
Autoimmune disease in NZB/W F1 mice was treated from 23 weeks of age with the novel immunomodulator BTS 63155 and, for comparative purposes, the established immunosuppressive agent cyctosporin A. Both drugs significantly improved survival compared with untreated controls. Lupus nephritis was also significantly reduced in the drug–treated groups, and this was related to reduced glomerular deposition of IgG. Autoantibody (ANA) levels were lowered by treatment with cyclosporin A, but not by BTS 63155. This latter finding may indicate a different mode of action for the two drugs. In a long term study, neither drug effected a complete cure, as autoimmune disease recurred on withdrawal of drug treatment.
The anti-arthritic and immunosuppressive effects of cyclosporin A on collagen-induced arthritis in the rhesus monkey
Authors: BAKKER N P M , VAN BESOUW N , GROENESTEIN R , JONKER M , 'tHART L A 
Published: October 2008

SUMMARYThe influence of cyclosporin A (CsA) on type II collagen-induced arthritis (CIA) in the rhesus monkey has been investigated. CsA was administered subcutaneously in a dose of 25 mg/kg per day during 9–18 days and additionally 12·5 mg/kg per day for 7 days. At this dosing regime no significant alterations of hacmalologic parameters were found, indicating that the toxicity of CsA was negligible. Administration of CsA after onset of arthritis had no beneficial effect, but when given between immunization and manifestation of clinical symptoms, CIA could be prevented completely. Moreover, these monkeys became resistant to the disease, because no arthritic activity could be observed upon a booster immunization with type II collagen (CII). The suppression of disease by CsA is reflected in reduced antibody levels to CII.
T cell activation and disease severity in HIV infection
Authors: MAHALINGAM M , PEAKMAN M , DAVIES E T , POZNIAK A , McMANUS T J , VERGANI D 
Published: October 2008

SUMMARYIn vitro studies have indicated that T lymphocyte activation may be of importance in the pathogenesis of HIV infection. In order to define the role of immune activation in vivo, we assessed the expression of the T cell activation markers HLA-DR and CD25 by flow cytometry in peripheral blood in relation to disease severity and the surrogate markers CD4 and β2-microglobulin in 157 patients with HIV infection and 53 healthy seronegative blood donors. Percentage levels of CD3+HLA-DR+ T lymphocytes were significantly higher (P&lt;0·0001) and percentage levels of CD3+CD25+ T lymphocytes significantly lower (P&lt;0·0001) in all HIV+ patients compared with controls. A significant correlation was observed between increasing percentage levels of CD3+HLA-DR+ T lymphocytes and both declining CD4 counts (r = 0·52; P&lt;0·001) and increasing β-microglobulin levels (r = 0·56; P&lt;0·001). Percentage levels of CD4+HLA-DR+ and CD4+CD25+ lymphocytes were significantly higher in all HIV+ patients compared with controls (P&lt; 0·001). Levels of activated (HLA-DR+ and CD25+) CD4+ lymphocytes showed a significant step-wise linear increase with increasing disease severity (P &lt; 0·001). High levels of CD3+ HLA-DR+ T lymphocytes were found in a greater proportion (81·8%) of asymptomatic HIV+ patients (Centres for Disease Control (CDC) group II) than low CD4 counts (51·5%) (P&lt;0·001). Compared with controls, HIV+ patients had higher percentage levels of CD8+HLA-DR+ lymphocytes (P&lt;0·001), but similar levels of CD8+CD25+ lymphocytes. These results indicate that T cell activation is not only a consistent but also an early feature in HIV infection. Monitoring levels of activated T cells and their subsets is of value in assessing progression of HIV-related disease.
Increased CD11/CD18 expression on the peripheral blood leucocytes of patients with HIV disease: relationship to disease severity
Authors: PALMER S , HAMBLIN A S 
Published: October 2008

SUMMARYIn HIV disease increased adhesion between leucocytes themselves and between leucocytes and endothelium may contribute to cell loss and viral spread. Using a novel method for the preparation of blood leucocytes for flow cytometry, we report increased expression of leucocyte adhesion molecules (LeuCAMs) (CD11/CD18) on peripheral blood leucocytes of patients with HIV disease compared with normal controls. Patients were divided into two groups on the basis of CD4 T lymphocyte numbers (those with &gt;0·5 × 109/l and those with &lt;0·2 × 109/l), and assessed for p24 antigen expression, viral load and serum tumour necrosis factor (TNF) levels as well as LeuCAM expression. Patients with &lt; 0·2 × 109/l CD4 cells had more p24 antigen and more HIV infectious virus and more serum TNF than those with &gt; 0×5 × 109/l. Whilst the percentages of only monocytes and polymorphs expressing CD11b were significantly increased in patients with the least CD4 cells, the density of LeuCAMs, expressed as mean fluorescence intensity (MFI), was significantly increased on all leucocytes, with the most significant increases being seen on patients with the fewest CD4 T cells. Our findings are consistent with leucocyte activation by a soluble factor, although we could find no correlation between levels of TNF and LeuCAM expression. The increased expression of adhesion molecules on peripheral blood leucocytes could play a role in the cellular extravasation and aggregation seen in HIV disease.
Soluble tumour necrosis factor receptors (sTNF-R) and HIV infection: correlation to CD8+ lymphocytes
Authors: KALINKOVICH A , LIVSHITS G , ENGELMANN H , HARPAZ N , BURSTEIN R , KAMINSKY M , WALLACH D , BENTWICH Z 
Published: October 2008

SUMMARYThe objective or this study was to determine sTNF-R, type I (p55) and type II (p75) in sera of HIV-infected male homosexuals and correlate them to T lymphocyte subpopulations and course of HIV infection. Serum samples were obtained from 39 HIV-1+ asymptomatic male homosexuals, 10 symptomatic (ARC and AIDS) male homosexuals and 44 HIV non-homosexual healthy controls. sTNF-R levels were determined by ELISA with specific MoAbs and polyclonal antibodies to the sTNF-R proteins. sTNF-RI and II levels were significantly elevated in 72% and 74%, respectively of HIV+ asymptomatic male homosexuals and in all of the symptomatic male homosexuals. In sequential studies a highly significant positive correlation was found between sTNF-RI and sTNF-RII (r=0·8, P&lt;0·00))and between both sTNF-R and CD8+ lymphocyte counts (r= 0·6 and 0·92. respectively, P&lt;0.01–0.001) during the asymptomatic stage of the infection. All these correlations were lost, however, during the symptomatic phase of the disease. These results suggest that: (i) HIV infection is associated with elevation of sTNF-R serum levels; (ii) sTNF-R levels arc strongly correlated to CDS+ lymphocytes during the asymptomatic stage of HIV infection.
Lysis of CD4+ lymphocytes by non-HLA-restricted cytotoxic T lymphoe from HIV-infected individuals
Authors: GRANT M D , SMAILL F M , ROSENTHAL K L 
Published: October 2008

SUMMARYIndividuals infected with HIV have elevated numbers of total and activated CD8+ lymphocytes in peripheral blood. CD8+ lymphocytes from HIV-infected individuals have been shown to mediate non-human histocompatibility-linked antigen (HLA)-restricted suppression of viral replication, HLA-restricted killing of cells expressing HIV antigens, and killing of uninfected lymphocytes. We studied CD8+ T lymphocytes that lysed autologous CD4+ lymphocytes, hetcrologous CD4+ lymphocytes from HIV-infected individuals and uninfected CD4+ lymphocytes. Killing in all cases required T cell receptor (TCR)-mediated recognition or triggering. However, these CD8 cytotoxic T lymphocytes (CTL) killed HLA class I mismatched CD4+ lymphocytes and CD4+ lymphocytes treated with a MoAb against HLA-A, B and C antigens (PA2.6) which blocks HLA class I-restricted killing. HLA class H-negativc CD4+ T lymphoma cells (CEM.NKR) were also killed by anti-CD3 inhibited CTL. Stimulation of peripheral blood lymphocytes (PBL) from HIV-infected individuals, but not uninfected controls, with concanavalin A (Con A) and IL-2, induced non-HLA-restricted TCR αβ+, CD8+ CTL which lysed CD4+ lymphocytes. Activation of CD4+ lymphocytes increased their susceptibility to CD8+ CTL-mediated lysis. In HIV infection, a population of non-HLA-restricted CTL which lyse activated CD4+ lymphocytes is expanded. The expansion of CTL with unusual characteristics is interesting, because the stimulus for this expansion is unknown. CTL which recognize activated CD4+ cells could play a role in immune regulation and the pathogenesis of A IDS.
Intrathyroidal lymphocyte subsets, including unusual CD4+CD8+ cells and CD3loTCRαβ1o/-CD4−CD8−cells, in autoimmune thyroid disease
Authors: IWATANI Y , HIDAKA V , MATSUZUKA F , KUMA K , AMINO N 
Published: October 2008

SUMMARYIntralhyroidal lymphocyte subsets were analysed in 13 cuthyroid patients with autoimmune thyroid disease by two-colour flow cytometry and compared with subsets in peripheral blood. In both Graves' and Hashimoto's diseases, proportions of intrathyroidal CDS B cells were higher than in peripheral blood. The numbers of such cells were correlated with serum levels of anti-thyroid microsomal antibodies. Proportions of T cells bearing αβ chains of T cell receptors (TCRαβ+T; Tαβ) and CD16+CD57+ natural killer (NK) cells were lower in the thyroid, but proportions of CD3hiTCRαβ− TCRγδ+ (Tγδ) cells were not different. Proportions of CD4+ Leu-8+ helper T cells and CD4+CD57+ germinal centre T cells were higher and proportions of CD4+ Leu-8+ suppressor-inducer T cells and CD8+CD57+ or CD+ CD11b+ suppressor T cells were lower than in the blood in both diseases. Proportions of CD5+ B cells were high in Graves' disease, and proportions of CD8+CD11b− cytotoxic T cells were high in Hashimoto's disease. Unexpectedly, CD4+CD8+ cells and CD3.TCRαβ CD4−CDS cells were present in thyroid tissues of both diseases. These findings suggest that: (i) an imbalance in the numbers of regulatory T cells and of NK cells that had appeared in the thyroid resulted in the proliferation of CDS B cells, which were related to thyroid autoantibody production; (ii) CD5+ B cells and cytotoxic T cells are important for the different pathological features in Graves' and Hashimoto's diseases, respectively; and (iii) intrathyroidal CD4+CD8+ cells and CD310TCRαβ10-CD4−CD8− cells may be related to the pathogenesis of autoimmune thyroid disease.
Functional analysis of TCR γδ+ T cells in tumour-infiltrating lymphocytes (TIL) of human pancreatic cancer
Authors: KITAYAMA J , ATOMI Y , NAGAWA H , KURODA A , MUTOH T , MINAMI M , JUJI T 
Published: October 2008

SUMMARYIn six patients with advanced pancreatic carcinoma, TIL and tumour-draining lymphocytes (TDL) were isolated from primary pancreatic tumour and regional lymph nodes. In comparison with TDL and peripheral blood lymphocytes (PBL), TIL contained a comparatively higher percentage of TCR γδ+ cells, although they were still a small fraction. By 2 weeks culture with rIL-2 and immobilized OKT-3 antibody, the TCR γδ+ cells in TIL were preferentially expanded at the early culture periods, although it was temporary. In four cases, the TCR γδ+ and CD8+ TCR αβ+ TIL were separated by negative sorting using flowcytometry. All the TCR γδ+ TIL were CD4−, CD8− (double negative), and one of the TIL lines was mostly composed of δTCSI+ cells, while the others were δTCS1−. In comparison with CD8+ TCRαβ+ TIL, all the TCR γδ+ TIL exhibited much stronger lytic activity against freshly isolated autologous pancreatic cancer cells. However, all the γδ+ TIL also exhibited a strong non-MHC-restricted cytoloxicity, and there was no correlation between the lytic pattern and the percentage of δTCSI+ cells. These data suggest that the TCR γδ+ T cells can proliferate vigorously in a certain condition, and if successfully expanded in vitro they might be helpful material for effective adoptive immunotherapy.
Expression of cytokine genes in human cardiac allografts: correlation of IL-6 and transforming growth factor-beta (TGF-β) with histological rejection
Authors: ZHAO X-M , FRIST W H , YEOH T-K , MILLER G G 
Published: October 2008

SUMMARYCytokines may play critical roles in allograft rejection. Currently, a clear pattern of cytokine production that correlates with rejection has not emerged. Our preliminary studies suggested a trend toward increased IL-6 and TGF-β gene expression in cardiac allografts during rejection. We have extended these studies using reverse transcriptase/polymerase chain reaction (RT/PCR) to detect the expression of IL-6. TGF-β, and T cell receptor β chain constant region (TCR-β genes in 21 additional consecutive myocardial biopsies obtained from six heart transplant patients and from five pre-transplant donor hearts. Cytokine gene expression was compared with histological diagnosis of rejection. There was strong correlation between IL-6 as well as TGF-β gene expression, and histological rejection (6/8 biopsies with versus 0/7 without rejection (P = 0·006) and 7/9 biopsies with versus 0/7 without rejection (P=0·003) respectively). Neither IL-6 nor TGF-β transcripts were detected in any pre-transplant donor heart. TCR-β chain mRNA was found in all allograft biopsies regardless of the presence of rejection, but was absent in pre-transplant donor hearts. Our results indicate that expression of IL-6 and TGF-β is highly correlated with allograft rejection and thus may play an important role in regulation of cardiac ailograft rejection. T cell infiltration of allografted myocardium is invariably detected by PCR regardless of histological rejection. The long-term functional significance of these cells in transplanted hearts needs further investigation.