bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single dose and steady state pharmacokinetics of temocapril and temocaprilat in young and elderly hypertensive patients
Authors: Püchler K. , Sierakowski B. , Roots I. 
Published: November 2003

Aims
The aim of this study was to determine the potential impact of age on the pharmacokinetics of temocapril and its pharmacologically active diacid metabolite, temocaprilat, in hypertensive patients.
Methods
Male and female patients with mild to moderate essential hypertension (DBP 95–114 mmHg inclusive) were allocated to two age groups: young, ≤40 years; elderly, ≥69 years, (n=18 per group). In Part I of the study, subjects took a single oral tablet dose of 20 mg temocapril hydrochloride following an overnight fast. In Part II they took seven once daily oral tablet doses of 20 mg temocapril hydrochloride. Pharmacokinetic profiles were determined after the single and the last dose. Trough plasma samples were taken before each dose in Part II. Urine was collected for 24 h following the single and the last dose.
Results
Steady state was reached within 1 week in both groups. Statistically significant differences were detected in AUC and AUCss for temocaprilat as well as in CLR for temocapril and temocaprilat, respectively, after a single dose and at steady state. All other pharmacokinetic parameters for temocapril and temocaprilat did not show any significant difference.
Conclusions
The pharmacokinetic differences detected in the elderly do not require a dose adjustment per se. Nonetheless, a lower starting dose may be appropriate as elderly hypertensive patients are usually considered to be at an increased risk of first dose hypotension at the onset of treatment with an ACE inhibitor.
A novel mutation (Leu817Pro) causing type 2A von Willebrand disease
Authors: Gemmati D. , Serino M. L. , Moratelli S. , Ballerini G. , Furbetta M. , Lunghi B. , Marchetti G. , Bernardi F. 
Published: November 2003

We studied a patient affected by von Willebrand disease type 2A who experienced several mild bleeding episodes and was characterized by markedly reduced haemostatic parameters. In the exon 28 of von Willebrand factor (vWF) gene a T to C transition at nucleotide 8680, resulting in the missense mutation Leu817Pro, was found in the heterozygous form in the patient and in two affected relatives.As suggested by the presence in platelets of a complete spectrum of vWF multimers as well as by the increased vWF antigen levels and improved haemostasis after DDAVP treatment, the mutation is compatible with normal multimerization, and could be responsible for a reduced stability or an impaired physiological secretion of vWF.
Splenectomy as an adjuvant measure in the treatment of severe aplastic anaemia
Authors: Speck B. , Tichelli A. , Widmer E. , Harder F. , Kissling M. , Würsch A. , Stebler Gysi Ch , Signer E. , Bargetzi M. , Orth B. , Gratwohl A. , Nissen C. 
Published: November 2003

The role of splenectomy in aplastic anaemia (AA) is controversial. The hazards of operating on a severely pancytopenic patient, the fear of compromising the patient’s immune function, and the improvement of non‐surgical treatment have made splenectomy unpopular in this disease.We have evaluated positive and adverse effects of splenectomy in 80 patients with severe aplastic anaemia (SAA) treated with antilymphocyte globulin (ALG) (group A), using 52 nonsplenectomized ALG patients as controls (group B). All patients survived the operation. Nonfatal complications of surgery occurred in 10 (12.5%). Splenectomy induced a significant increase of peripheral blood neutrophils, reticulocytes and platelets within 2 weeks, followed by a continuous increase of all values over the following weeks. 28/132 patients (21%) developed a late clonal disorder of haemopoiesis, paroxysmal nocturnal haemoglobinuria (PNH) or myelodysplastic syndrome (MDS), or both. Their incidence was identical in groups A and B. 13/28 (59%) died, 10/17 (59%) in group A and 3/11 (27%) in group B (not significant (n.s.)). Overall probability of survival at 18 years after ALG was 51 ± 6% for group A and 61 ± 7% for group B (n.s.).We conclude that splenectomy in AA is safe. It induces an immediate increase of peripheral blood counts and, thereafter, a continuous improvement of haemopoiesis. It does not increase the incidence of late clonal complications but has a borderline effect on mortality from these disorders. Splenectomy should be reconsidered in selective nontransplanted patients who have prolonged transfusion requirements despite otherwise optimal treatment.
Regulated plasma levels of colony‐stimulating factors, interleukin‐6 and interleukin‐10 in patients with acute leukaemia and non‐Hodgkin's lymphoma undergoing cytoreductive chemotherapy
Authors: Reisbach Gilbert , Kamp Torsten , Welzl Gerhard , Giez Christiane , Abedinpour Fariborz , Lodri Antal , Kaboth Werner , Dörmer Peter , Nerl Christoph 
Published: November 2003

Endogenous plasma levels of granulocyte colony stimulating factor (G‐CSF), granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), IL‐6 and IL‐10 were measured in a total of 70 patients undergoing cytoreductive chemotherapy for treatment of acute leukaemia or non‐Hodgkin’s lymphomas. The diagnoses were acute myeloid leukaemia (AML; n = 30), acute lymphoblastic leukaemia (ALL; n = 6), non‐Hodgkin’s lymphomas (NHL; n = 11) and other malignant haematological disorders including myelodysplastic syndromes (n = 23). After chemotherapy, plasma G‐CSF was elevated (mean 5.6 ng/ml; range 1.2–10 ng/ml), and was inversely correlated with white blood cell counts (WBC) (r = −0.7, P < 0.001). Occurrence of fever (T>38.0°C) during severe myelosuppression (WBC<1 × 109/l) was associated with an additional increase of G‐CSF levels (P < 0.001). Plasma IL‐6 correlated significantly with fever (range <1 to 1100 pg/ml, mean 130 pg/ml; r = 0.5, P < 0.001) but revealed only a weak association with WBC or platelet counts. In patients treated with recombinant G‐CSF (n = 9), an association between IL‐6 and fever was still observed after chemotherapy. During the nonfebrile status (total n = 242; AML n = 124), IL‐6 levels remained <9 pg/ml in 90% of cases, whereas G‐CSF increased with leucopenia (r = −0.72; P < 0.001). In contrast, endogenous GM‐CSF remained normal and IL‐10 showed only a slight increase (21% of samples; maximum 22 pg/ml) in severe leucopenia. In particular, IL‐10 levels did not correlate with G‐CSF or IL‐6 levels.We conclude that systemic release of G‐CSF and IL‐6 is obviously not abrogated by cytoreductive chemotherapy in acute leukaemia and NHL and may add to the therapeutic efficacy of recombinant cytokines. Also, plasma levels of G‐, GM‐CSF or IL‐6 appear to be regulated by separate mechanisms.
Feasibility of peripheral blood progenitor cell harvest and transplantation in patients with poor‐risk myelodysplastic syndromes
Authors: Demuynck H. , Delforge M. , Verhoef G. E. G. , Zachee P. , Vandenberghe P. , Van Den Berghe H. , Boogaerts M. A. 
Published: November 2003

Myelodysplastic syndromes (MDS) are a group of clonal haematological disorders with a highly unfavourable prognosis. Allogeneic bone marrow transplantation offers the sole possibility for cure and prolonged survival, but is only available for a minority of patients. Therefore, we investigated the feasibility of PBPC collection and transplantation in 11 patients with high‐risk myelodysplasia who were not eligible for allogeneic bone marrow transplantation. In six patients, PBPC were harvested after mobilization with G‐CSF alone. Five patients were harvested during the recovery phase of intensive chemotherapy combined with G‐CSF. This resulted in seven patients in an adequate CD34 progenitor yield >1 × 106/kg. Six patients obtained a CFU‐GM content of the PBPC harvest >10 ×104/kg. Five patients were subsequently transplanted following a standard BuCy4 regimen. The median to ANC (absolute neutrophil count) ≥0.5 and 1.0 × 109/l was respectively 14 d (range 10–18) and 16 d (range 11–25). Platelets were self‐supporting ≥20 × 109/l after a median of 41 d (range 8–144). One patient had a persistent lack of platelet engraftment unresponsive to infusion of back‐up bone marrow.These data demonstrate that in selected patients with high‐risk MDS, adequate PBPC collection appears feasible, enabling the harvest of sufficient cell numbers required for rapid and stable engraftment after reinfusion. Improvement in mobilization efficiency may enable the collection of higher CD34+ progenitor cell numbers required for more rapid platelet engraftment. PBPC transplantation may be an alternative treatment option for patients who lack an allogeneic marrow donor. Follow‐up is, however, still too limited to draw any conclusion regarding the long‐term cure rate.
Angioid streaks are part of a familial syndrome of dyserythropoietic anaemia (CDA III)
Authors: Sandström Herbert , Wahlin Anders , Eriksson Mikael , Holmgren Gösta , Lind Lisbeth , Sandgren Ola 
Published: November 2003

Congenital dyserythropoietic anaemia type III (CDA III) is a rare disease inherited in an autosomal dominant way and characterized by mild to moderate haemolytic anaemia. Most patients are adapted to their disease and have no or few complaints. Bone marrow examination shows a characteristic picture with erythroid hyperplasia and multinucleate erythroblasts. 20% of patients in a Swedish family affected with the CDA III condition have monoclonal gammopathy or multiple myeloma. By linkage and recombination analysis in the same family, the gene linked to the CDA III condition (CDAN3) has been located to chromosome 15q22.In this paper we report the observation of visual disturbances with macular degeneration and angioid streaks in six patients with CDA III and discuss the apparent association between CDA III, angioid streaks and monoclonal gammopathy. We suggest that this triad forms a previously unreported syndrome.
Murine endothelial cells support fetal liver erythropoiesis and myelopoiesis via distinct interactions
Authors: Ohneda Osamu , Bautch Victoria L. 
Published: November 2003

Endothelial cells are an important component of the haemopoietic microenvironment. To investigate how endothelial cells are involved in haemopoiesis, two established murine endothelial cell lines were assayed in stromal cultures with fetal liver haemopoietic cells. Both endothelial cell lines allowed for the proliferation and differentiation of erythroid and monocyte‐macrophage precursors, suggesting that support for haemopoiesis is a general property of endothelial cells.Erythropoiesis was dependent on the addition of erythropoietin (Epo), whereas myelopoiesis was independent of added Epo. Haemopoietic colonies developed in close contact with the endothelial cells. Erythroid colonies did not develop when transwell filters were used between the stroma and haemopoietic cells, or when conditioned medium was used in place of stromal cells. In contrast, monocyte‐macrophage colonies formed in the presence of transwell filters or conditioned medium. Thus close cell contact is necessary for erythropoiesis but not myelopoiesis under these conditions. These results suggest that different molecular mechanisms are used by endothelial cells to support erythroid development and myeloid development in the mouse fetal liver.
Atypical lymphocyte morphology: an adverse prognostic factor for disease progression in stage A CLL independent of trisomy 12
Authors: Oscier D. G. , Matutes E. , Copplestone A. , Pickering R. M. , Chapman R. , Gillingham R. , Catovsky D. , Hamblin T. J. 
Published: November 2003

We studied 270 patients with Binet stage A chronic lymphocytic leukaemia looking for adverse prognostic factors. In a multivariate analysis the following features were found to be risk factors for disease progression: atypical lymphocyte morphology (defined as either > 10% prolymphocytes or > 15% lymphocytes with cleaved nuclei or lymphoplasmacytoid cells); more than two karyotypic abnormalities; lymphocyte count > 30 × 109/l; lymphocyte doubling time < 1 year; enlargement of one or more lymph node groups.In a univariate analysis the presence of trisomy 12 also correlated with progressive disease, but this was largely a consequence of the association between trisomy 12 and atypical lymphocyte morphology. Atypical lymphocyte morphology is an important prognostic factor in stage A CLL, and one which incurs no additional investigational cost.
Synthetic peptides based on Chlamydia trachomatis antigens identify cytotoxic T lymphocyte responses in subjects from a trachoma-endemic population
Authors: Holland M J , Conway D J , Blanchard T J , Mahdi O M S , Bailey R L , Whittle H C , Mabey D C W 
Published: November 2003

Abstract
CD8+ cytotoxic T lymphocytes (CTL) recognize peptide antigens in the context of class I MHC antigen molecules. To identify peptides capable of eliciting anti-Chlamydia trachomatis CTL responses, 13 synthetic peptides conforming to human leucocyte antigen (HLA)-B8- or -B35-predicted binding motifs were synthesized using sequences based on C. trachomatis major outer membrane protein (MOMP) and heat shock protein 60 (hsp60). Two of 11 HLA-B35-predicted binding peptides were able to stabilize HLA-B35 in an in vitro binding assay. All peptides were tested in CTL assays using peripheral blood mononuclear cells (PBMC) isolated from 26 HLA-B8 or -B35 individuals resident in a trachoma-endemic community. Responses to MOMP and hsp60 peptides were identified in a minority of both HLA-B8 and -B35 individuals. Two of 12 HLA-B8 subjects responded to MOMP and 1/13 to hsp60 peptides. Responses in HLA-B35 subjects were similar, 1/13 subjects responding to MOMP and 2/13 to hsp60 peptides. CTL responses were observed only in children resolving current infection and in adults without scarring of the conjunctiva. These results suggest that anti-chlamydial CTL occur at low levels in peripheral blood, but may be important in the resolution of naturally acquired human ocular chlamydial infection.
Cross-linking of antigen receptor via Ig-β (B29, CD79b) can induce both positive and negative signals in CD40-activated human B cells
Authors: VAN KOOTEN C , GALIBERT L , SEON B K , GARRONE P , LIU Y-J , BANCHEREAU J 
Published: November 2003

SUMMARY
Antigen-dependent activation of B lymphocytes is mediated through surface immunoglobulins and their associated molecules Ig-α (CD79a, Mb1) and Ig-β (CD79b, B29). Here we show that an antibody directed against the extracellular part of human Ig-β can, when cross-linked by CD32-transfected L cells, induce an IL-2-dependent proliferation of tonsil B cells. With the use of L cells stably transfected with both CD32 and CD40L, anti-Ig-β activation of B cells was combined with CD40 triggering, an important component of the T cell-dependent B cell activation. This dual cellular activation resulted in two different phases, with initially synergistic proliferative effects, both without and with IL-2 or IL-10. Then, after 5–6 days of culture, cells stimulated with both anti-Ig-β and CD40L underwent massive cell death, in contrast to B cells activated with CD40L alone. Cell death was not prevented by the addition of IL-2 or IL-10, but was prevented by the addition of IL-4. These results are discussed in the context of positive and negative selection of mature B cells.
Modulation of Fas-mediated apoptosis of human thyroid epithelial cells by IgG from patients with Graves' disease (GD) and idiopathic myxoedema
Authors: KAWAKAMI A , EGUCHI K , MATSUOKA N , TSUBOI M , URAYAMA S , KAWABE Y , TAHARA K , ISHIKAWA N , ITO K , NAGATAKI S 
Published: November 2003

SUMMARY
The expression of two autoimmune thyroid diseases, GD and idiopathic myxoedema, is associated with antibodies to the thyroid-stimulating hormone (TSH) receptor. Thyroid stimulating antibodies (TSAb) in GD are TSH agonists and cause hyperthyroidism as well as goitre, whereas thyroid stimulation blocking antibodies (TSBAb) in idiopathic myxoedema are TSH antagonists and cause hypothyroidism and thyroid atrophy. We investigated the effect of antibodies to TSH receptor on Fas-mediated apoptosis of thyroid epithelial cells (thyrocytes). Human IgG was isolated from healthy donors, patients with GD and idiopathic myxoedema. Human thyrocytes were obtained from surgical specimens. Thyrocytes were cultured in the presence or absence of human IgG with or without interferon-gamma (IFN-γ) or IL-1β for a specified time. After incubation, we examined the level of cAMP in cultured supernatants and both Fas and Bcl-2 expression on thyrocytes. In addition, we examined anti-Fas-mediated apoptosis of thyrocytes. Fas expression on thyrocytes was significantly down-regulated by Graves' IgG and TSH, although idiopathic myxoedema IgG did not affect Fas expression on thyrocytes. Idiopathic myxoedema IgG abrogated the effect of TSH on both cAMP production and inhibition of Fas expression on thyrocytes. Treatment of thyrocytes with IL-1β or IFN-γ caused a marked augmentation of Fas expression on thyrocytes. The increase of Fas expression of thyrocytes induced by IL-1β or IFN-γ was significantly suppressed in the presence of TSH or Graves' IgG. Anti-Fas-induced apoptosis of thyrocytes was observed in thyrocytes treated with IL-1β or IFN-γ, but was markedly inhibited in the presence of TSH or Graves' IgG. Furthermore, idiopathic myxoedema IgG abrogated most of the inhibitory effect of TSH on Fas-mediated apoptosis of thyrocytes treated with IL-1β or IFN-γ. Bcl-2 expression of thyrocytes did not change after stimulation with TSH, Graves' IgG, idiopathic myxoedema IgG, IL-1β or IFN-γ. These results suggest that TSAb found in Graves' patients may be potentially involved in the development of goitre by inhibition of Fas-mediated apoptosis of thyrocytes. In addition, TSBAb inhibit the action of TSH and increase the sensitivity toward Fas-mediated apoptosis of thyrocytes, inducing thyroid atrophy seen in patients with idiopathic myxoedema.
Antibodies protect mice against challenge with tick-borne encephalitis virus (TBEV)-infected macrophages
Authors: KREIL T R , BURGER I , BACHMANN M , FRAISS S , EIBL M M 
Published: November 2003

SUMMARY
TBEV is a flavivirus highly pathogenic for humans. By transfer of antibodies directed to the TBEV surface glycoprotein E into mice, immune protection against subsequent inoculation with free TBEV particles could be achieved. After natural TBEV infection via the skin, however, cells of the monocyte/macrophage lineage were recently demonstrated to represent an important source of local virus replication before viraemia occurs. Whether antibodies can protect against virus challenge when contracted in the form of infected cells, however, is still unclear. In the current study, TBEV antibodies protected mice against challenge with either free virus or TBEV-infected macrophages equally well. This observation may be of more general significance.
N-3 polyunsaturated fatty acids modulate the expression of functionally associated molecules on human monocytes and inhibit antigen presentation in vitro
Authors: HUGHES D A , PINDER A C 
Published: November 2003

SUMMARY
N-3 polyunsaturated fatty acid (PUFA)-rich diets are associated with suppression of cell-mediated immune responses, but the mechanisms are unclear. Specific immune responses are initiated by antigen-presenting cells (APC). We have previously shown in vitro that the n-3 PUFA, eicosapentaenoic acid (EPA), inhibits the expression of HLA-DR, an MHC class II molecule required for normal APC function on human blood monocytes. In contrast, docosahexaenoic acid (DHA) enhanced the expression of this molecule on unstimulated monocytes, but both n-3 PUFA suppressed its expression on interferon-gamma (IFN-γ)-activated monocytes. In the present study we show that when EPA and DHA were combined at the same ratio as is commonly found in fish oil supplement capsules (3:2) there was no significant effect in vitro on the expression of HLA-DR on unstimulated monocytes, but the expression on IFN-γ-activated monocytes remained significantly inhibited. In the same in vitro system a significant reduction in the ability of IFN-γ-activated monocytes to present tetanus toxoid antigen to autologous lymphocytes was observed following culture with the combined n-3 PUFA. These findings support previous animal studies which suggest that n-3 PUFA can inhibit the antigen-presenting function of mononuclear phagocytes.
Circadian rhythm of leucocytes and lymphocyte subsets and its possible correlation with the function of the autonomic nervous system
Authors: SUZUKI S , TOYABE S , MORODA T , TADA T , TSUKAHARA A , IIAI T , MINAGAWA M , MARUYAMA S , HATAKEYAMA K , ENDOH K , ABO T 
Published: November 2003

SUMMARY
There are physiological variations in the levels of leucocytes. Among these, the circadian rhythm is very important in terms of the magnitude. Since newly identified lymphocyte subsets (i.e. extrathymic T cells) have recently been detected, a comprehensive study of the circadian rhythm was conducted. All leucocytes were found to vary in number or proportion with a circadian rhythm and were classified into two groups. One group—granulocytes, macrophages, natural killer (NK) cells, extrathymic T cells, γδ T cells, and CD8+ subset—showed an increase in the daytime (i.e. daytime rhythm). The other group—T cells, B cells, αβ T cells, and CD4+ subset—showed an increase at night. Humans are active and show sympathetic nerve dominance in the daytime. Interestingly, granulocytes and lymphocyte subsets with the daytime rhythm were found to carry a high density of adrenergic receptors. On the other hand, lymphocyte subsets with the night rhythm carried a high proportion of cholinergic receptors. Reflecting this situation, exercise prominently increased the number of cells with the daytime rhythm. These results suggest that the levels of leucocytes may be under the regulation of the autonomic nervous system.
Trypanosoma cruzi induces strong IL-12 and IL-18 gene expression in vivo: correlation with interferon-gamma (IFN-γ) production
Authors: MEYER ZUM BÜSCHENFELDE C , CRAMER S , TRUMPFHELLER C , FLEISCHER B , FROSCH S 
Published: November 2003

SUMMARY
IFN-γ, produced after infection with Trypanosoma cruzi, has been shown to be crucial in the determination of resistance or susceptibility. We have performed a detailed study on the expression of IFN-γ and of the IFN-γ-inducing cytokines IL-12 and IFN-γ-inducing factor (IGIF)/IL-18 with regard to time course and tissue localization. IFN-γ was present in high amounts in the serum and in the supernatants of unseparated spleen cells and isolated CD4+ and CD8+ T cells from the spleens of infected mice which were stimulated ex vivo with T. cruzi. Using the in situ hybridization technique we demonstrate that IL-12 p40 messages were expressed in the spleen and increased during infection, correlating with the expression of IFN-γ transcripts. Furthermore, we show for the first time that the mRNA for the cytokine IL-18 was induced by a parasitic infection and that this expression increased during infection with T. cruzi. Interestingly, the message for IL-18 was produced earlier during infection and already had declined until day 38, when IFN-γ and IL-12 p40 transcripts were optimally expressed. Surprisingly, the changes in IL-12 and IL-18 mRNA production were clearly seen only by in situ hybridization, but less clearly by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR). This is possibly due to the extensive activation and proliferation of spleen cells observed during infection leading to a dilution of these specific mRNAs.