bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of Bcr-Abl on C/EBP transcription-factor regulation and neutrophilic differentiation are reversed by the Abl kinase inhibitor imatinib mesylate
Authors: Schuster Christine , Forster Karin , Dierks Henning , Elsässer Annika , Behre Gerhard , Simon Nicola , Danhauser-Riedl Susanne , Hallek Michael , Warmuth Markus
Published: December 2002

The clinical progression of chronic myeloid leukemia (CML) from chronic phase to blast crisis is characterized by the increasing failure of myeloid precursors to differentiate into mature granulocytes. This study was undertaken to investigate the influence of Bcr-Abl and of the small molecule Abl tyrosine–kinase inhibitor imatinib mesylate on granulocyte colony-stimulating factor (G-CSF)–induced neutrophilic differentiation. We show that differentiation of 32Dcl3 cells into mature granulocytes is accompanied by the increased expression of the antigens macrophage adhesion molecule–1 (Mac-1) and Gr-1, of the G-CSF receptor (G-CSFR), of myeloid transcription factors (CCAAT/enhancer-binding protein–α [C/EBPα], C/EBPε, and PU.1), and of the cyclin-dependent kinase inhibitor p27Kip1. In 32Dcl3 cells transfected with thebcr-abl gene (32DBcr-Abl), G-CSF did not trigger either granulocytic differentiation or the up-regulation of C/EBPα, C/EBPε, and the G-CSFR. This could be correlated to a defect in c-Myc down-regulation. In contrast, the up-regulation of PU.1 and p27Kip1 by G-CSF was not affected by Bcr-Abl. Importantly, incubation of 32DBcr-Ablwtcells with the kinase inhibitor imatinib mesylate prior to G-CSF stimulation completely neutralized the effects of Bcr-Abl on granulocytic differentiation and on C/EBPα and C/EBPε expression. Taken together, the results suggest that the Bcr-Abl kinase induces a reversible block of the granulocytic differentiation program in myeloid cells by disturbing regulation of hematopoietic transcription factors such as C/EBPα and C/EBPε.
Hemoglobin loss from erythrocytes in vivo results from spleen-facilitated vesiculation
Authors: Willekens Frans L. A. , Roerdinkholder-Stoelwinder Bregt , Groenen-Döpp Yvonne A. M. , Bos Harry J. , Bosman Giel J. C. G. M. , van den Bos Annegeet G. , Verkleij Arie J. , Werre Jan M.
Published: December 2002

Previous studies have shown that approximately 20% of hemoglobin is lost from circulating red blood cells (RBCs), mainly during the second half of the cells' life span. Because hemoglobin-containing vesicles are known to circulate in plasma, these vesicles were isolated. Flow cytometry studies showed that most RBC-derived vesicles contain hemoglobin with all hemoglobin components present. The hemoglobin composition of the vesicles resembled that of old RBCs. RBC cohort studies using isotope-labeled glycine have been described, which showed a continuous presence of this label in hemoglobin degradation products. The label concentration of these products increased during the second half of the RBC life span, accompanied by a decrease within the RBC. It is concluded that the hemoglobin loss from circulating RBCs of all ages can be explained by shedding hemoglobin-containing vesicles. This loss occurs predominantly in older RBCs. Apparently the spleen facilitates this process since asplenia vesicle retention within RBCs of all ages has been described, accompanied by an increase in the percentage of total HbA1. The present study shows that in old RBCs of asplenic individuals, the decrease of hemoglobin content per cell such as seen in old RBCs of control individuals is absent due to an increase in the absolute amount of HbA1c and HbA1e2. It is concluded that hemoglobin-containing vesicles within old RBCs are “pitted” by the spleen.
Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase
Authors: Or Reuven , Shapira Michael Y. , Resnick Igor , Amar Avraham , Ackerstein Aliza , Samuel Simcha , Aker Memet , Naparstek Elizabeth , Nagler Arnon , Slavin Shimon
Published: December 2002

Reduced-intensity or nonmyeloablative stem cell transplantation (NST) is designed to induce host-versus-graft tolerance by engraftment of donor stem cells. The rationale behind NST is to induce optimal graft-versus-leukemia (GVL) effects for elimination of all malignant cells by donor alloreactive immunocompetent cells as an alternative to standard high-dose myeloablative chemoradiotherapy. NST based on the use of fludarabine, low-dose busulfan, and anti–T-lymphocyte globulin (ATG) was employed in 24 patients aged 3 to 63 years with chronic myeloid leukemia (CML) in first chronic phase (CP). Graft-versus-host disease (GVHD) prophylaxis consisted of low-dose cyclosporine (CSP), in some cases with low-dose methotrexate. Early discontinuation of CSP was attempted in cases of mixed chimerism in an attempt to amplify GVL effects. All 24 patients showed rapid 3-lineage engraftment, mostly without complete aplasia; 6 patients did not require transfusion of any blood products. NST was associated with minimal procedure-related toxicity. The incidence of acute GVHD (grade I or higher) was 54%; however, this incidence increased following CSP withdrawal. After a follow-up of up to 70 months (median, 42 months), 21 of 24 patients remained alive and disease free. The GVL effects induced by donor immunocompetent lymphocytes eradicated all host hematopoietic cells, as evidenced by molecular testing. The Kaplan-Meier probability of survival and disease-free survival at 5 years is 85% ± 8% (95% confidence interval, 70%-100%). NST may successfully replace myeloablative stem cell transplantation, providing a safer, well-tolerated therapeutic option for all patients with CML in first CP with a matched donor. However, this conclusion must be tested in a prospective randomized clinical trial.
B lymphopoiesis is active throughout human life, but there are developmental age-related changes
Authors: Rossi Maria Isabel D. , Yokota Takafumi , Medina Kay L. , Garrett Karla P. , Comp Philip C. , Schipul Arthur H. , Kincade Paul W.
Published: December 2002

This study addressed several questions concerning age-related changes in human B lymphopoiesis. The relative abundance of pro-B, pre-B, immature, naive, and mature B cells among the CD19+lymphocyte fraction of human bone marrow was found not to change appreciably over the interval between 24 and 88 years of age. Moreover, proliferation of pro-B and large pre-B cells in adult marrow equaled that observed with fetal marrow specimens. Exceptionally low numbers of lymphocyte precursors were found in some marrow samples, and the values obtained were used to determine parameters that best reflect B lymphopoiesis. Cord blood always contained higher incidences of functional precursors than adult cells. However, sorted CD34+ Lin− CD10+ progenitors from cord blood and adult marrow had equivalent potential for differentiation in culture, and notable age-related changes were found in more primitive subsets. A recently described subset of CD34+CD38−CD7+ cord blood cells had no exact counterpart in adult marrow. That is, all adult CD34+Lin−CD7+CD10−cells expressed CD38, displayed less CD45RA, and had little B-lineage differentiation potential. The CD7+ fractions in either site contained progenitors for erythroid and natural killer (NK) lineages, and ones sorted from marrow expressed high levels of transcripts for the CD122 interleukin 2 (IL-2)/IL-15 receptor required by NK-lineage precursors. Dramatic changes in human B lymphopoiesis occur early in life, and more information is required to construct a probable sequence of differentiation events prior to the acquisition of CD10.
Transfusion-related acute lung injury: epidemiology and a prospective analysis of etiologic factors
Authors: Silliman Christopher C. , Boshkov Lynn K. , Mehdizadehkashi Zahra , Elzi David J. , Dickey William O. , Podlosky Linda , Clarke Gwen , Ambruso Daniel R.
Published: December 2002

Transfusion-related acute lung injury (TRALI) is a life-threatening complication of hemotherapy. We report a series of 90 TRALI reactions in 81 patients secondary to transfusion with whole blood platelets (72 reactions), apheresis platelets (2), packed red cells (15), and plasma (1). The overall prevalence was 1 in 1120 cellular components. To examine the epidemiology of TRALI, we completed a nested case-control study of the first 46 patients with TRALI compared with 225 controls who had received transfusions. We then completed a prospective analysis of possible biologic response modifiers responsible for 51 of the TRALI cases, including human leukocyte antigen (HLA) class I, class II, and granulocyte antibodies in donors and neutrophil (PMN) priming activity in the plasma of the implicated units and recipients. Two groups were at risk: patients with hematologic malignancies (P < .0004) and patients with cardiac disease (P < .0006). TRALI was associated with older platelets (P = .014). In the prospective study, antileukocyte antibodies were found in only 3.6% of cases. The implicated blood components had greater PMN priming activity than controls (P < .05), and compared with pretransfusion samples, TRALI patients' plasma demonstrated increases in both interleukin 6 (IL-6) and lipid (neutral lipids and lysophosphatidylcholines) priming activity (P  < .05). We conclude that TRALI may be more frequent than previously recognized and that patient susceptibility, product age, and increased levels of bioactive lipids in components may predispose patients to TRALI. TRALI, like the acute respiratory distress syndrome, may be a 2-event phenomenon with both recipient predisposition and factors in the stored units playing major roles.
Ex vivo expansion of human umbilical cord hematopoietic progenitor cells using a coculture system with human telomerase catalytic subunit (hTERT)–transfected human stromal cells
Authors: Kawano Yutaka , Kobune Masayoshi , Yamaguchi Miki , Nakamura Kiminori , Ito Yoshinori , Sasaki Katsunori , Takahashi Sho , Nakamura Takafumi , Chiba Hiroki , Sato Tsutomu , Matsunaga Takuya , Azuma Hiroshi , Ikebuchi Kenji , Ikeda Hisami , Kato Junji , Niitsu Yoshiro , Hamada Hirofumi
Published: December 2002

We developed a new human stromal cell line that could expand human hematopoietic progenitor/stem cells. Primary human bone marrow stromal cells were infected with retrovirus containing the human telomerase catalytic subunit (hTERT) gene, resulting in increased population doubling and the acquisition of cell immortalization. Characteristics of the hTERT-transduced stromal (hTERT-stromal) cells were identical with those of the primary stromal cells in terms of morphologic appearance and expression of surface antigens. Human cord blood (CB) CD34+ cells were expanded by coculture with primary stromal or hTERT-stromal cells in the presence of stem cell factor, thrombopoietin, and Flk-2/Flt-3 ligand under serum-free condition. The degree of expansion of CD34+ cells and total number of colony-forming units in culture (CFU-Cs) after 2 weeks' coculture with the hTERT-stromal cells were nearly the same as those after 2 weeks' coculture with primary stromal cells (CD34+ cells, 118-fold ± 8-fold versus 117-fold ± 13-fold; CFU-Cs, 71-fold ± 5-fold versus 67-fold ± 5-fold of initial cell number). CB expansion on hTERT-stromal cells occurred at a similar rate through 7 weeks. In contrast, the rate of CB expansion on primary stromal cells had drastically declined at 7 weeks. In nonobese diabetic/severe combined immunodeficiency (SCID) mice, the degree of engraftment of SCID-repopulating cells that had been cocultured with hTERT-stromal cells for 4 weeks was significantly higher than that of precocultured CB cells. These results indicate that this hTERT-stromal cell line could be useful for ex vivo expansion of hematopoietic progenitor/stem cells and for analyzing the microenvironment of human bone marrow.
Expression of CD41 marks the initiation of definitive hematopoiesis in the mouse embryo
Authors: Mikkola Hanna K. A. , Fujiwara Yuko , Schlaeger Thorsten M. , Traver David , Orkin Stuart H.
Published: December 2002

Murine hematopoietic stem cells (HSCs) originate from mesoderm in a process that requires the transcription factor SCL/Tal1. To define steps in the commitment to blood cell fate, we compared wild-type and SCL−/− embryonic stem cell differentiation in vitro and identified CD41 (GpIIb) as the earliest surface marker missing from SCL−/− embryoid bodies (EBs). Culture of fluorescence-activated cell sorter (FACS) purified cells from EBs showed that definitive hematopoietic progenitors were highly enriched in the CD41+ fraction, whereas endothelial cells developed from CD41− cells. In the mouse embryo, expression of CD41 was detected in yolk sac blood islands and in fetal liver. In yolk sac and EBs, the panhematopoietic marker CD45 appeared in a subpopulation of CD41+ cells. However, multilineage hematopoietic colonies developed not only from CD45+CD41+ cells but also from CD45−CD41+ cells, suggesting that CD41 rather than CD45 marks the definitive culture colony-forming unit (CFU-C) at the embryonic stage. In contrast, fetal liver CFU-C was CD45+, and only a subfraction expressed CD41, demonstrating down-regulation of CD41 by the fetal liver stage. In yolk sac and EBs, CD41 was coexpressed with embryonic HSC markers c-kit and CD34. Sorting for CD41 and c-kit expression resulted in enrichment of definitive hematopoietic progenitors. Furthermore, the CD41+c-kit+ population was missing from runx1/AML1−/− EBs that lack definitive hematopoiesis. These results suggest that the expression of CD41, a candidate target gene of SCL/Tal1, and c-kit define the divergence of definitive hematopoiesis from endothelial cells during development. Although CD41 is commonly referred to as megakaryocyte–platelet integrin in adult hematopoiesis, these results implicate a wider role for CD41 during murine ontogeny.
Internalization of circulating apoptotic cells by splenic marginal zone dendritic cells: dependence on complement receptors and effect on cytokine production
Authors: Morelli Adrian E. , Larregina Adriana T. , Shufesky William J. , Zahorchak Alan F. , Logar Alison J. , Papworth Glenn D. , Wang Zhiliang , Watkins Simon C. , Falo Louis D. , Thomson Angus W.
Published: December 2002

Under steady-state conditions, internalization of self-antigens embodied in apoptotic cells by dendritic cells (DCs) resident in peripheral tissue followed by DC migration and presentation of self-peptides to T cells in secondary lymphoid organs are key steps for induction and maintenance of peripheral T-cell tolerance. We show here that, besides this traffic of apoptotic cells mediated by peripheral tissue–resident DCs, splenic marginal zone DCs rapidly ingest circulating apoptotic leukocytes, process apoptotic cell–derived peptides into major histocompatibility complex class II (MHC-II) molecules, and acquire CD8α during their mobilization to T-cell areas of splenic follicles. Because apoptotic cells activate complement and some complement factors are opsonins for phagocytosis and play roles in the maintenance of peripheral tolerance, we investigated the role of complement receptors (CRs) in relation to phagocytosis of apoptotic cells by DCs. Apoptotic cell uptake by marginal zone DCs was mediated in part via CR3 (CD11b/CD18) and, to a lesser extent, CR4 (CD11c/CD18) and was reduced significantly in vivo in hypocomplementemic animals. Following phagocytosis of apoptotic cells, DCs exhibited decreased levels of mRNA and secretion of the proinflammatory cytokines interleukin 1α (IL-1α), IL-1β, IL-6, IL-12p70, and tumor necrosis factor α (TNF-α), without effect on the anti-inflammatory mediator transforming growth factor β1 (TGF-β1). This selective inhibitory effect was at least partially mediated through C3bi-CD11b/CD18 interaction. Characterization of apoptotic cell/DC interaction and its outcome provides insight into the mechanisms by which apoptotic cells affect DC function without disrupting peripheral tolerance.
Dexamethasone-induced apoptosis of thymocytes: role of glucocorticoid receptor–associated Src kinase and caspase-8 activation
Authors: Marchetti Maria Cristina , Di Marco Barbara , Cifone Grazia , Migliorati Graziella , Riccardi Carlo
Published: December 2002

Glucocorticoid hormones (GCHs) regulate normal and neoplastic lymphocyte development by exerting antiproliferative and/or apoptotic effects. We have previously shown that dexamethasone (DEX)–activated thymocyte apoptosis requires a sequence of events including interaction with the glucocorticoid receptor (GR), phosphatidylinositol-specific phospholipase C (PI-PLC), and acidic sphingomyelinase (aSMase) activation. We analyzed the mechanisms of GCH-activated apoptosis by focusing on GR-associated Src kinase, cytochrome c release, and caspase-8, -9, and -3 activation. We show here that PI-PLC binds to GR-associated Src kinase, as indicated by coimmunoprecipitation experiments. Moreover, DEX treatment induces PI-PLC phosphorylation and activation. DEX-induced PI-PLC phosphorylation, activation, and apoptosis are inhibited by PP1, a Src kinase inhibitor, thus suggesting that Src-mediated PI-PLC activation is involved in DEX-induced apoptosis. Caspase-9, -8, and -3 activation and cytochrome c release can be detected 1 to 2 hours after DEX treatment. Caspase-9 inhibition does not counter cytochrome crelease, caspase-8 and caspase-3 activation, and apoptosis. Caspase-8 inhibition counters cytochrome c release, caspase-9 and caspase-3 activation, and apoptosis, thus suggesting that caspase-8 inhibitor can directly inhibit caspase-9 and/or that DEX-induced caspase-8 activation is upstream to mitochondria and can regulate caspase-3 directly or through cytochrome c release and the consequent caspase-9/caspase-3 activation. DEX-induced caspase-8 activation, like ceramide-induced caspase-8 activation, correlates with the formation of Fas-associated death domain protein (FADD)/caspase-8 complex. Caspase-8 activation is countered by the inhibition of macromolecular synthesis and of Src kinase, PI-PLC, and aSMase activation, suggesting it is downstream in the DEX-activated apoptotic pathway of thymocytes.
Common mechanism for oncogenic activation of MLL by forkhead family proteins
Authors: So Chi Wai , Cleary Michael L.
Published: December 2002

The mixed lineage leukemia (MLL) gene undergoes fusions with a diverse set of genes as a consequence of chromosomal translocations in acute leukemias. Two of these partner genes code for members of the forkhead subfamily of transcription factors designated FKHRL1 and AFX. We demonstrate here that MLL-FKHRL1 enhances the self-renewal of murine myeloid progenitors in vitro and induces acute myeloid leukemias in syngeneic mice. The long latency (mean = 157 days), reduced penetrance, and hematologic features of the leukemias were very similar to those observed for the forkhead fusion protein MLL-AFX and contrasted with the more aggressive features of leukemias induced by MLL-AF10. Transformation mediated by MLL-forkhead fusion proteins required 2 conserved transcriptional effector domains (CR2 and CR3), each of which alone was not sufficient to activate MLL. A synthetic fusion of MLL with FKHR, a third mammalian forkhead family member that contains both effector domains, was also capable of transforming hematopoietic progenitors in vitro. A comparable requirement for 2 distinct transcriptional effector domains was also displayed by VP16, which required its proximal minimal transactivation domain (MTD/H1) and distal H2 domain to activate the oncogenic potential of MLL. The functional importance of CR2 was further demonstrated by its ability to substitute for H2 of VP16 in domain-swapping experiments to confer oncogenic activity on MLL. Our results, based on bona fide transcription factors as partners for MLL, unequivocally establish a transcriptional effector mechanism to activate its oncogenic potential and further support a role for fusion partners in determining pathologic features of the leukemia phenotype.
Hematopoietic stem cell and progenitor defects in Sca-1/Ly-6A–null mice
Authors: Ito Caryn Y. , Li Carol Y. J. , Bernstein Alan , Dick John E. , Stanford William L.
Published: December 2002

Despite its wide use as a marker for hematopoietic stem cells (HSCs), the function of stem cell antigen–1 (Sca-1) (also known as lymphocyte activation protein–6A [Ly-6A]) in hematopoiesis remains poorly defined. We have previously established that Sca-1−/−T cells develop normally, although they are hyperresponsive to antigen. Here, we report detailed analysis of hematopoiesis in Sca-1–deficient animals. The differentiation potential of Sca-1–null bone marrow was determined from examination of the most mature precursors (culture colony-forming units [CFU-Cs]) to less committed progenitors (spleen CFUs [CFU-Ss]) to long-term repopulating HSCs. Sca-1–null mice are mildly thrombocytopenic with a concomitant decrease in megakaryocytes and their precursors. Bone marrow cells derived fromSca-1−/− mice also have decreased multipotential granulocyte, erythroid, macrophage, and megakaryocyte CFU (GEMM-CFU) and CFU-S progenitor activity. Competitive repopulation assays demonstrated that Sca-1−/−HSCs are at a competitive disadvantage compared with wild-type HSCs. To further analyze the potential of Sca-1−/−HSCs, serial transplantations were performed. While secondary repopulations using wild-type bone marrow completely repopulatedSca-1−/−mice, Sca-1−/−bone marrow failed to rescue one third of lethally irradiated wild-type mice receiving secondary bone marrow transplants from irradiation-induced anemia and contributed poorly to the surviving transplant recipients. These data strongly suggest that Sca-1 is required for regulating HSC self-renewal and the development of committed progenitor cells, megakaryocytes, and platelets. Thus, our studies conclusively demonstrate that Sca-1, in addition to being a marker of HSCs, regulates the developmental program of HSCs and specific progenitor populations.
Suppression of autoreactive T-cell response to glycoprotein IIb/IIIa by blockade of CD40/CD154 interaction: implications for treatment of immune thrombocytopenic purpura
Authors: Kuwana Masataka , Kawakami Yutaka , Ikeda Yasuo
Published: December 2002

The potential immunosuppressive effect of an anti-CD154 monoclonal antibody (mAb) on the pathogenic autoreactive T-cell response was evaluated using an in vitro culture system with glycoprotein IIb/IIIa (GPIIb/IIIa)–reactive T cells from patients with immune thrombocytopenic purpura (ITP). The anti-CD154 mAb did not inhibit T-cell proliferation, but suppressed anti-GPIIb/IIIa antibody production, in bulk peripheral blood mononuclear cell cultures stimulated with GPIIb/IIIa. Repeated antigenic stimulation of GPIIb/IIIa-reactive CD4+ T-cell lines in the presence of anti-CD154 mAb resulted in the loss of proliferative capacity and helper function for promoting anti-GPIIb/IIIa antibody production. These anergic T-cell lines showed a cytokine profile of low interferon γ and high interleukin 10 and suppressed anti-GPIIb/IIIa antibody production. Our results indicate that blockade of the CD40/CD154 interaction induces generation of autoantigen-specific anergic CD4+ T cells with regulatory function and could be a therapeutic option for suppressing pathogenic autoimmune responses in patients with ITP.
BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571
Authors: Donato Nicholas J. , Wu Ji Yuan , Stapley Jonathan , Gallick Gary , Lin Hui , Arlinghaus Ralph , Talpaz Moshe
Published: December 2002

Clinical studies have shown that the tyrosine kinase inhibitor STI571 effectively controls BCR-ABL–positive chronic myelogenous leukemia (CML). However, disease progression while on STI571 therapy has been reported, suggesting de novo or intrinsic resistance to BCR-ABL–targeted therapy. To investigate possible mediators of acquired STI571 resistance, K562 cells resistant to 5 μM STI571 (K562-R) were cloned and compared to the parental cell population. K562-R cells had reduced BCR-ABL expression and limited activation of BCR-ABL signaling cascades (Stat 5, CrkL, MAPK). STI571 failed to activate caspase cascades or to suppress expression of survival genes (bcl-xL) in resistant cells. Gene sequencing and tyrosine kinase activity measurements demonstrated that K562-R cells retained wild-type and active BCR-ABL tyrosine kinase that was inhibitable by in vitro incubation with STI571, suggesting that BCR-ABL was not coupled to proliferation or survival of K562-R cells. The src-related kinase LYN was highly overexpressed and activated in K562-R cells, and its inhibition reduced proliferation and survival of K562-R cells while having limited effects of K562 cells. Specimens taken from patients with advanced CML that progressed on STI571 therapy also were analyzed for LYN kinase expression, and they were found to be elevated to a level similar to that of K562-R cells. Comparison of samples from patients taken prior to and following STI571 failure suggested that expression and/or activation of LYN/HCK occurs during disease progression. Together, these results suggest that acquired STI571 resistance may be associated with BCR-ABL independence and mediated in part through overexpression of other tyrosine kinases.
Misdiagnosing sleep disorders as primary psychiatric conditions
Authors: Stores Gregory
Published: December 2002

Sleep disorders are relevant to psychiatric practice in a number of ways, including the possibility that they may be misdiagnosed as fundamentally psychiatric conditions in patients of all ages. This risk exists in a wide range of collectively very common sleep disorders which need to be considered in explaining insomnia, excessive sleepiness or disturbed episodes of behaviour associated with sleep (parasomnias). Examples given include circadian sleep–wake cycle disorders (such as the delayed sleep phase syndrome), obstructive sleep apnoea, narcolepsy, Kleine–Levin syndrome, sleep paralysis and rapid eye movement (REM) sleep behaviour disorder. Failure to recognise and treat such disorders is likely to cause and perpetuate psychological problems. Correct recognition requires familiarity with the range and manifestations of sleep disorders.
Therapeutic community treatment of personality disorder: service use and mortality over 3 years' follow-up
Authors: Davies Steffan , Campling Penelope
Published: December 2002

Background

A number of studies have demonstrated reductions in the utilisation of psychiatric services, especially acute inpatient admissions, following therapeutic community treatment of personality disorder. These studies have, however, been of limited duration (1 year) and follow-up has not always been complete.

Aims

To identify hospital admissions before and after therapeutic community treatment of personality disorder.

Method

A naturalistic clinical cohort of patients admitted between January 1993 and December 1995 was followed up for 3 years. All subjects were traced to their current consultant psychiatrist, general practitioner or death.

Results

All patients were traced at 3-year follow-up. The significant reduction in in-patient admissions seen in the first year was maintained over 3 years. Those with the poorest outcomes, suicide, accidental death or prolonged admission were all in the quartile with the shortest admissions (under 42 days) to the therapeutic community.

Conclusions

Previously reported reductions in psychiatric admissions following therapeutic community treatment of personality disorder are maintained over 3 years.
Professor Sir Ernst Gombrich, OM: a ‘hands-on’ advocate of music therapy in mental hospitals
Authors: Rollin H. R.
Published: December 2002

The outpouring of praise for the life and work of this remarkable man, who died this year, has been so fulsome that one might reasonably believe that the catalogue of his virtues had been exhausted. I would venture to suggest that two seemingly disparate virtues have been omitted or underplayed. I refer to his musicianship and his compassion. May I describe one occasion when these two virtues co-existed?
Carry on shrinking: career intentions and attitudes to psychiatry of prospective medical students
Authors: Maidment R. , Livingston G. , Katona M. , Whitaker E. , Katona C.
Published: December 2002

Aims and Method

There is a shortage of doctors in the UK, particularly in psychiatry and pathology. Little is known about prospective medical students' career intentions or attitudes. This study aimed to report on the career intentions and attitudes to psychiatry of 819 attenders at a sixth-form conference for prospective medical students.

Results

A much higher proportion of students expressed favourable attitudes to psychiatry as a career than might have been expected. The most popular career was paediatrics and the least popular was genitourinary medicine.

IMPLICATIONS

Medical schools need to be proactive in providing information, career advice and positive role models. This may counteract negative propaganda and encourage career choice in tune with students' earlier feelings and patients' needs.
The transcription factor Slug repressesE-cadherinexpression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors
Authors: Bolós Victoria , Peinado Hector , Pérez-Moreno Mirna A. , Fraga Mario F. , Esteller Manel , Cano Amparo
Published: December 2002

Transcriptional repression mechanisms have emerged as one of the crucial processes for the downregulation of E-cadherin expression during development and tumour progression. Recently, several E-cadherin transcriptional repressors have been characterized (Snail, E12/E47, ZEB-1 and SIP-1) and shown to act through an interaction with proximal E-boxes of the E-cadherin promoter. We have analyzed the participation of another member of the Snail family, Slug, and observed that it also behaves as a repressor of E-cadherin expression. Stable expression of Slug in MDCK cells leads to the full repression of E-cadherin at transcriptional level and triggers a complete epithelial to mesenchymal transition. Slug-induced repression of E-cadherin is mediated by its binding to proximal E-boxes, particularly to the E-pal element of the mouse promoter. Detailed analysis of the binding affinity of different repressors to the E-pal element indicates that Slug binds with lower affinity than Snail and E47 proteins. These results, together with the known expression patterns of these factors in embryonic development and carcinoma cell lines, support the idea that the in vivo action of the different factors in E-cadherinrepression can be modulated by their relative concentrations as well as by specific cellular or tumour contexts.
A Family of Group 4 Metal Alkoxo Complexes with an M3(μ3‐O) Core Relevant to Ziegler–Natta Catalyst Intermediates
Authors: Utko Józef , Przybylak Szymon , Jerzykiewicz Lucjan B. , Szafert Sławomir , Sobota Piotr
Published: December 2002

Reactions of [Mg(thffo)2] (1) or [Ca(thffo)2] (2) with ZrCl4 or HfCl4 in a CH2Cl2/THF/CH3CN mixture give thermally stable neutral heterobimetallic tetranuclear complexes [M3M′(μx‐O)(μ,η2‐thffo)6(Cl)6] (thffo=tetrahydrofurfuroxide; M/M′/x: 3, Zr/Mg/3; 4, Hf/Mg/3; 5, Zr/Ca/4; 6, Hf/Ca/4) as colorless crystals in 75–82 % yield. X‐ray diffraction studies show complexes 3–5 to contain oxo‐bridged M3 triangles that are capped by an alkaline earth metal‐containing moiety to form species of C3 symmetry. Reactions of ZrCl4 and HfCl4 with pure tetrahydrofurfuryl alcohol in EtOH and MeOH provide ionic complexes [M3(μ3‐O)(μ,η2‐thffo)3(L)3(Cl)6]Cl (M/L: 8, Zr/EtOH; 9, Hf/EtOH; 10, Zr/MeOH) in 66–79 % yield. Complexes 8–10 consist of M3 triangles that are analogous to those in 3–6 and possess similar overall symmetry, as shown by X‐ray crystallography. Changes in the reaction conditions afforded the asymmetric neutral dimer [Zr2(μ‐thffo)2(thffoH)(Cl)6] (7) and the homometallic [Zr3(μ3‐O)(μ,η2‐thp)3(thf)2(Cl)7] (11).
Differential responses of intracisternal injection of interleukin‐1 β to acute and inflammatory orofacial pain model in freely moving rats
Authors: Choi Hyo S. , Park Jae S. , Ahn Dong K.
Published: December 2002

The present study was performed to investigate the modulatory role of certain interleukin (IL)‐1β in nociception with a nociceptive jaw opening reflex and an orofacial formalin test in freely moving rats. In an acute pain model, 10 pg, 100 pg and 1 ng IL‐1β injected intracisternally did not change the digastric eletromyogram (dEMG). However, 10 ng IL‐1β suppressed dEMG to 76±8 % of control values. In an inflammatory pain model, 10 pg IL‐1β injected intracisternally did not change formalin‐induced noxious behavioral responses. However, 100 pg IL‐1β increased formalin‐induced noxious behavioral responses. At higher dose of 10 ng IL‐1β, it did not increase formalin‐induced behavioral responses. Pretreatment with IL‐1 receptor antagonist abolished hyperalgesic response of 100 pg IL‐1β. These results suggest that the intracisternal injection of IL‐1β modulate the transmission of nociceptive information in the orofacial area. The hypo/hyper‐algesic responses of central cytokines seem to depend on the pain model or dose related manner and the hyperalgesic action seems to be mediated by IL‐1 receptor.
Transplantation of a new composite of neural cells and marrow stromal cells into rat brain after stroke
Authors: Li Yi , Yang Xiaoyi , Chen Jieli , Wang Lei , Wang Ying , Zhang Chunling , Chen Xiaoguang , Katakowski Mark , Mikkelsen Tom , Lu Mei , Chopp Michael
Published: December 2002

We constructed a biologic material composed of fetal rat brain cells (neurospheres) and adult rat bone marrow stromal cells (MSCs), designated as NMCspheres. Adult rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo) and implanted with cultured prelabeled NMCspheres (n=6), neurospheres (n=5) or MSCs (n=6) into the ischemic penumbra at 24 hours after MCAo. Control adult rats (n=10) were subjected to MCAo alone. In vitro within the NMCspheres, MSCs rapidly formed a process network with intact neural cells compared with a necrotic core within neurospheres alone. An in vivo rat corneal assay demonstrated that NMCspheres enhanced angiogenesis compared to MSCs and neurospheres. Neurological functional recovery after stroke was enhanced in rats treated with NMCspheres, compared to rats with neurosphere or MSC treatments by day 7 and day 14 after transplantation. The NMCspheres are a new composite material that may be employed in the treatment of stroke.
Effects of low‐dose scopolamine on locomotor activity: No dissociation between cognitive and non‐effects
Authors: Poorheidari Gholamreza , Pratt Judith A. , Dehghani Nima
Published: December 2002

Attempts have been made to dissociate the cognitive effects of scopolamine from its non‐cognitive effects. It has been suggested that low doses of scopolamine may induce memory impairment without inducing significant non‐cognitive effects. We therefore tested changes in locomotor activity (as a non‐cognitive effect) in rats treated with low‐dose scopolamine (which is believed to induce cognitive effects only).

In this study, locomotor activity (as a non‐cognitive effect) induced by low doses of this drug was evaluated by using two methods and rat strains. In the first study (circular box method, an automated open‐field), scopolamine hydrobromide (HBr), scopolamine methylbromide (MeBr) or saline was injected subcutaneously into male Sprague‐Dawley rats. After 30 min, rats were put into an automated open‐field and locomotor activity was quantified by recording interruptions of infrared beams, with print‐outs every 2 min for 16 min. Locomotor activity was assessed by summing these recordings. In the second study (closed platform), scopolamine HBr or saline was injected intraperitoneally into male Long‐Evans rats. Twenty minutes later, the rats were placed in the center of a square‐shaped closed platform (with 3×3 divisions). Locomotor activity was defined as the sum of crossings (traversing of four paws of the rat from one area into another of nine) and rears, which were recorded every 5 min for 20 min.

Results from the circular box study showed that scopolamine HBr produced a marked increase in locomotor activity whereas scopolamine MeBr produced a non‐significant decrease in locomotor activity. The closed platform data also demonstrated that scopolamine HBr increased locomotor activity significantly.

These data show that scopolamine can induce non‐cognitive effects (such as increased locomotor activity), even at low doses. Our results also imply that the increase in locomotor activity is mediated centrally.
Resonant interaction of LO phonons with excited donor states in GaN
Authors: Wysmolek A. , Potemski M. , Stepniewski R. , Baranowski J. M. , Look D. C. , Lee S. K. , Han J. Y.
Published: December 2002

Magneto‐luminescence experiments performed on a thick, freestanding GaN layer in magnetic fields up to 28 T are presented. The photoluminescence spectrum of this material shows narrow emission lines due to neutral donor‐bound excitons (D0X). In addition to the principal recombination channel of D0X in which the donor is left in its ground state, two‐electron satellites (TES) involving different excited donor states, as well as LO phonon replica of the principal and satellite transitions are observed. For the magnetic field range in which internal donor excitations are tuned into resonance with the LO phonon excitations, the intensity of TES is strongly enhanced. A clear resonant interaction between TES corresponding to the highly excited donor states (n > 4) and LO phonon replica of D0X is observed. The observed effect is discussed in terms of electron–phonon interaction.
Oxidative stress in inborn errors of metabolism: Lessons from glutathione deficiency
Authors: Ristoff E. , Larsson A.
Published: December 2002

Oxidative stress has been thought to be involved in the pathogenesis of several inborn errors of metabolism, such as mitochondrial enzyme deficiencies, G6PD deficiency, methylmalonic acidaemia and PKU. The possible role of oxidative stress in the pathogenesis of inborn errors of metabolism is discussed in the light of inborn errors in the metabolism of glutathione.
DNA damage and its processing. Relation to human disease
Authors: Bohr V. A.
Published: December 2002

We are constantly exposed to sources of agents that directly damage the genetic material. This exposure comes from environmental sources but also from within our own organisms. DNA damage occurs at a high frequency due to metabolic processes and environmental factors such as various exposures and the intake of food and drugs. The stability and correct function of the DNA is necessary for normal cellular functions and there is good evidence that damage to the DNA can lead to cellular dysfunction, cancer and other diseases, or cell death. To avoid or minimize the damage to DNA we have evolved an elaborate set of DNA repair pathways that survey the DNA and fix the errors. There are several human diseases that are known to be defective in these repair pathways, and the accumulation of DNA damage with time in their genome may then be the cause of the associated high incidence of cancer or of an expedited ageing process. The prevention and/or repair of DNA damage thus represent major concerns in biology and medicine.
Complex I and the cAMP Cascade in Human Physiopathology
Authors: Papa S. , Scacco S. , Sardanelli A.M. , Petruzzella V. , Vergari R. , Signorile A. , Technikova-Dobrova Z.
Published: December 2002

A cAMP-dependent protein kinase (PKA) is localized in mammalian mitochondria with the catalytic site at the matrix side of the membrane where it phosphorylates a number of proteins. One of these is the 18 kDa(IP) subunit of the mammalian complex I of the respiratory chain, encoded by the nuclear NDUFS4 gene. Mitochondria have a Ca2+-inhibited phosphatase, which dephosphorylates the 18 kDa phosphoprotein of complex I. In fibroblast and myoblast cultures cAMP-dependent phosphorylation of the 18 kDa protein is associated with stimulation of complex I and overall respiratory activity with NAD-linked substrates. Mutations in the human NDUFS4 gene have been found, which in the homozygous state are associated with deficiency of complex I and fatal neurological syndrome.
Tetrahydrobiopterin responsiveness in a large series of phenylke tonuria patients
Authors: Weglage J. , Grenzebach M. , Teeffelen‐Heithoff A. v. , Marquardt T. , Feldmann R. , Denecke J. , Gödde D. , Koch H. G.
Published: December 2002

In a group of 87 consecutive patients with hyperphenylalaninaemia born since 1990, only 3 patients showed a (temporary) decrease of serum phenylalanine levels after tetrahydrobiopterin (BH4) loading in usual doses (20 mg/kg body weight).
A novel Y243S mutation in the pyruvate dehydrogenase E1 alpha gene subunit: Correlation with thiamine pyrophosphate interaction
Authors: Benelli C. , Fouque F. , Redonnet‐Vernhet I. , Malgat M. , Fontan D. , Marsac C. , Dey R.
Published: December 2002

We identified a new Y243S mutation in the X‐linked E1 α‐PDH gene in a patient with pyruvate dehydrogenase complex (PDHc) deficiency. The activity in cultured fibroblasts was very low even in the presence of high thiamine pyrophosphate (TPP) concentrations, indicating that the defect could be due to decreased affinity of PDHc for TPP.
Writing Effective Insurance Justification Letters for Cancer Genetic Testing: A Streamlined Approach
Authors: Shappell Heather L. , Matloff Ellen T.
Published: December 2002

The topic of insurance coverage and justification letters for cancer predisposition testing has been the subject of much discussion on the National Society of Genetic Counselors Cancer Special Interest Group (NSGC Cancer‐SIG) listserv. Some counselors have stated that they have had difficulty in obtaining insurance coverage for their patients, while others have indicated that they would appreciate seeing examples of successful letters. The purpose of this paper is to provide practical guidance in writing successful letters of justification and to share insurance success stories in the area of cancer genetic testing.
Designing supramolecular porphyrin arrays that self-organize into nanoscale optical and magnetic materials
Authors: Drain Charles Michael , Batteas James D. , Flynn George W. , Milic Tatjana , Chi Ning , Yablon Dalia G. , Sommers Heather
Published: December 2002

Tessellation of nine free-base porphyrins into a 3 × 3 array is accomplished by the self-assembly of 21 molecular entities of four different kinds, one central, four corner, and four side porphyrins with 12
trans
Pd(II) complexes, by specifically designed and targeted intermolecular interactions. Strikingly, the self-assembly of 30 components into a metalloporphyrin nonamer results from the addition of nine equivalents of a first-row transition metal to the above milieu. In this case each porphyrin in the nonameric array coordinates the same metal such as Mn(II), Ni(II), Co(II), or Zn(II). This feat is accomplished by taking advantage of the highly selective porphyrin complexation kinetics and thermodynamics for different metals. In a second, hierarchical self-assembly process, nonspecific intermolecular interactions can be exploited to form nanoscaled three-dimensional aggregates of the supramolecular porphyrin arrays. In solution, the size of the nanoscaled aggregate can be directed by fine-tuning the properties of the component macrocycles, by choice of metalloporphyrin, and the kinetics of the secondary self-assembly process. As precursors to device formation, nanoscale structures of the porphyrin arrays and aggregates of controlled size may be deposited on surfaces. Atomic force microscopy and scanning tunneling microscopy of these materials show that the choice of surface (gold, mica, glass, etc.) may be used to modulate the aggregate size and thus its photophysical properties. Once on the surface the materials are extremely robust.
Nanoscale surface chemistry
Authors: Madey Theodore E. , Pelhos Kalman , Wu Qifei , Barnes Robin , Ermanoski Ivan , Chen Wenhua , Kolodziej Jacek J. , Rowe John E.
Published: December 2002

We report evidence in several experiments for nanometer-size effects in surface chemistry. The evidence concerns bimetallic systems, monolayer films of Pt or Pd on W(111) surfaces. Pyramidal facets with {211} faces are formed on annealing on physical monolayer of Pt, Pd on a W(111) substrate, and facet sizes increase with annealing temperature. We used synchrotron radiation-based soft x-ray photoemission to show that monolayer films of Pt, Pd, on W “float” on the outer surface, whereas multilayer films form alloys on annealing. Acetylene reactions over bimetallic planar and faceted Pd/W surfaces exhibit size effects on the nanometer scale, that is, thermal desorption spectra of reactively formed benzene and ethylene (after acetylene adsorption) change systematically with facet size. In the second case, the decomposition of C
2
H
2
over planar and faceted Ir(210) surfaces also exhibits structure sensitivity; temperature programmed desorption of H
2
from C
2
H
2
dissociation depends on the nanoscale surface structure. Finally, we have characterized interactions of Cu with the highly ordered S(4 × 4)/W(111) surface. The substrate is a sulfur-induced nanoscale reconstruction of W(111) with (4 × 4) periodicity, having broad planar terraces (≈30 nm in width). Fractional monolayers of vapor-deposited Cu grow as threedimensional clusters on the S(4 × 4) surface over a wide coverage range. At low Cu coverage (≤ 0.1 ML), Cu nanoclusters nucleate preferentially at characteristic 3-fold hollow sites; we find a clear energetic preference for one type of site over others, and evidence for self-limiting growth of nanoclusters.
Platforms and methods for agent-based modeling
Authors: Gilbert Nigel , Bankes Steven
Published: December 2002

The range of tools designed to help build agent-based models is briefly reviewed. It is suggested that although progress has been made, there is much further design and development work to be done. Modelers have an important part to play, because the creation of tools and models using those tools proceed in a dialectical relationship.
Magnetic nanodots from atomic Fe: Can it be done?
Authors: te Sligte E. , Bosch R. C. M. , Smeets B. , van der Straten P. , Beijerinck H. C. W. , van Leeuwen K. A. H.
Published: December 2002

Laser focusing of Fe atoms offers the possibility of creating separate magnetic structures on a scale of 10 nm with exact periodicity. This can be done by using the parabolic minima of the potential generated by a standing light wave as focusing lenses. To achieve the desired 10-nm resolution, we need to suppress chromatic and spherical aberrations, as well as prevent structure broadening caused by the divergence of the incoming beam. Chromatic aberrations are suppressed by the development of a supersonic Fe beam source with speed ratio
S
= 11 ± 1. This beam has an intensity of 3 × 10
15
atoms sr
−1
s
−1
. The spherical aberrations of the standing light wave will be suppressed by aperturing with beam masks containing 100-nm slits at 744-nm intervals. The beam divergence can be reduced by application of laser cooling to reduce the transverse velocity. We have constructed a laser system capable of delivering over 500 mW of laser light at 372 nm, the wavelength of the
5
D
4
→
5
F
5
atomic transition of
56
Fe we intend to use for laser cooling. Application of polarization spectroscopy to a hollow cathode discharge results in a locking system holding the laser continuously within 2 MHz of the desired frequency.