bluuebunny/crossref_metadata_2025 huggingface dataset:
The novel bispecific diabody αCD40/αCD28 strengthens leukaemic dendritic cell‐induced T‐cell reactivity
Authors: Houtenbos Ilse , Santegoets Saskia , Westers Theresia M. , Waisfisz Quinten , Kipriyanov Sergey , Denkers Fedor , Scheper Rik J. , De Gruijl Tanja D. , Ossenkoppele Gert J. , Van De Loosdrecht Arjan A.
Published: May 2008

Dendritic cell (DC)‐based immunotherapy faces new challenges because the efficacy of DC vaccines in clinical trials has been inconsistent. Strategies to improve immune responses induced by DC are currently being explored. We have recently shown the feasibility of generating fully functional DC from acute myeloid leukaemic (AML) blasts, but with varying expression levels of the important costimulatory molecule CD86. To overcome this variability, we developed a novel bispecific diabody that simultaneously and agonistically targeted CD40 on AML‐DC and CD28 on naïve T cells. Beside optimization of CD28‐mediated signalling, the resulting cellular cross‐linking was also hypothesized to increase the strength and duration of T cell/AML‐DC interactions, thus increasing T‐cell responsiveness to AML antigens. The αCD40/αCD28‐bispecific diabody was found to bind to its target antigens and provoked increased T‐cell–DC cluster formation. The αCD40/αCD28 diabody is capable of increasing T‐cell proliferation induced by AML‐DC as well as the induction of DC maturation. Importantly, priming efficacy of tumour‐specific cytotoxic T cells can also be improved by cross‐linking AML‐DC and T cells with the αCD40/αCD28 diabody. We propose that the αCD40/αCD28‐bispecific diabody can serve as a potent therapeutic tool to effectively augment anti‐tumour T‐cell responses elicited by AML‐DC.
Thromboelastography in children with coagulation factor deficiencies
Authors: Chitlur Meera , Warrier Indira , Rajpurkar Madhvi , Hollon Wendy , Llanto Lolita , Wiseman Carol , Lusher Jeanne M.
Published: May 2008

Hemophilia is traditionally classified according to the levels of the deficient coagulation factor as Severe (<1%), Moderate (1–5%) or Mild (>5%). However, it is well known that the factor activity does not necessarily correspond to the clinical bleeding manifestations. As prophylactic therapy is the best method of prevention of serious complications such as hemophilic arthropathy, a test that may predict the bleeding pattern would be extremely beneficial. Thromboelastography (TEG) uses whole blood to determine clot formation characteristics, such as initiation, propagation as well as strength of the clot, and is now being extensively studied in bleeding and thrombophilia. This study attempted to determine the TEG characteristics in 47 children with moderate hemophilia (MH) and severe hemophilia with (SHI) and without inhibitors (SH) and tried to retrospectively correlate them to the clinical bleeding patterns. TEG showed evidence of faster and better clot formation, as evidenced by a higher maximum thrombin/fibrin generation, in those with mild bleeding manifestations compared to those with severe bleeding tendency, in addition to the expected prolongation in time to formation of clot related to factor deficiency. This may be a potentially useful tool to evaluate the bleeding tendency and determine need for prophylaxis in children with hemophilia.
Treosulfan‐containing regimens achieve high rates of engraftment associated with low transplant morbidity and mortality in children with non‐malignant disease and significant co‐morbidities
Authors: Greystoke Brigit , Bonanomi Sonia , Carr Trevor F. , Gharib Maged , Khalid Tasneem , Coussons Mary , Jagani Mamta , Naik Paru , Rao Kanchana , Goulden Nicholas , Amrolia Persis , Wynn Robert F. , Veys Paul A.
Published: May 2008

Treosulfan is an immuno‐suppressive and myeloablative alkylating agent that has been introduced as a conditioning agent in stem cell transplantation (SCT). Most studies have been performed in adult patients with malignancy where a low incidence of regimen‐related toxicity has been reported. We report the use of treosulfan in 32 consecutive children undergoing SCT for non‐malignant disease. Patients received a total treosulfan dose of 36 or 42 g/m2/patient given in three daily, divided doses. A range of other conditioning agents and serotherapy was administered to patients who underwent family donor SCT (n = 11), or unrelated donor SCT (n = 21). One patient (3%) died early. Transplant morbidity was limited and mucositis was only mild. Dermatological toxicity was frequent but mild. Twenty‐eight patients (87·5%) established donor cell engraftment. In 25 patients (78%) there was adequate, stable donor engraftment. Four patients have required additional transplant procedures to maintain adequate donor‐derived haemopoiesis. Twenty‐seven patients (84%) survive with a median follow up of 417 d. There were four late deaths due to progression of the underlying disease, graft‐versus‐host disease or infection. Treosulfan‐based conditioning regimens achieve excellent engraftment with reduced regimen‐related toxicity in children with non‐malignant disease at high risk for both regimen‐related toxicity and graft failure.
Ocular adnexal lymphoma: no evidence for bacterial DNA associated with lymphoma pathogenesis
Authors: Matthews Julie M. , Moreno Lilliana I. , Dennis Jeremy , Byrne Gerald E. , Ruiz Phillip , Dubovy Sander R. , Lossos Izidore S.
Published: May 2008

Ocular Adnexal Lymphomas (OALs) are the most common tumors of the eye, the majority being extranodal mucosa‐associated lymphoid tissue (MALT) lymphomas. Association with Chlamydia psittaci was described in some geographic areas. OAL response to antibiotic therapy was reported in cases not harboring Chlamydia psittaci DNA, suggesting that other bacterial infection might be implicated in the pathogenesis. We examined 49 MALT OALs for bacterial DNA using two distinct polymerase chain reaction techniques based on universal bacterial primers. No bacterial DNA that could be implicated in OAL pathogenesis was detected, suggesting that bacterial infection is not associated with OAL in South Florida.
TGF‐β receptor kinase inhibitor LY2109761 reverses the anti‐apoptotic effects of TGF‐β1 in myelo‐monocytic leukaemic cells co‐cultured with stromal cells
Authors: Xu Yuanyuan , Tabe Yoko , Jin Linhua , Watt Julie , McQueen Teresa , Ohsaka Akimichi , Andreeff Michael , Konopleva Marina
Published: May 2008

Transforming growth factor β1 (TGF‐β1) is an essential regulator of cell proliferation, survival and apoptosis, depending on the cellular context. TGF‐β1 is also known to affect cell‐to‐cell interactions between tumour cells and stromal cells. We investigated the role of TGF‐β1 in the survival of myelo‐monocytic leukaemia cell lines co‐cultured with bone marrow (BM)‐derived mesenchymal stem cells (MSC). Treatment with recombinant human (rh)TGF‐β1 inhibited spontaneous and cytarabine‐induced apoptosis in U937 cells, most prominently in U937 cells directly attached to MSCs. Conversely, the pro‐survival effects of TGF‐β1 were inhibited by LY2109761 or TGF‐β1 neutralizing antibody. rhTGF‐β1 increased pro‐survival phosphorylation of Akt, which was inhibited by LY2109761. The combination of rhTGF‐β1 and MSC co‐culture induced significant upregulation of C/EBPβ gene (CEBPB) and protein expression along with increased C/EBPβ liver‐enriched activating protein: liver‐enriched inhibitory protein ratio, suggesting the novel role of C/EBPβ in TGF‐β1‐mediated U937 cell survival in the context of stromal cell support. In summary, these results indicate that TGF‐β1 produced by BM stromal cells promotes the survival and chemoresistance of leukaemia cells under the direct cell‐to‐cell interactions. The blockade of TGF‐β signalling by LY2109761, which effectively inhibited the pro‐survival signalling, may enhance the efficacy of chemotherapy against myelo‐monocytic leukaemic cells in the BM microenvironment.
Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome
Authors: Rossi Davide , Cerri Michaela , Capello Daniela , Deambrogi Clara , Rossi Francesca Maria , Zucchetto Antonella , De Paoli Lorenzo , Cresta Stefania , Rasi Silvia , Spina Valeria , Franceschetti Silvia , Lunghi Monia , Vendramin Chiara , Bomben Riccardo , Ramponi Antonio , Monga Guido , Conconi Annarita , Magnani Corrado , Gattei Valter , Gaidano Gianluca
Published: May 2008

Predictors of chronic lymphocytic leukaemia (CLL) transformation to Richter syndrome (RS) are not established and were investigated in 185 consecutive CLL cases. Actuarial incidence of RS (n = 17; all diffuse large B‐cell lymphomas) at 10 years was 16·2% (95% confidence interval: 8·0–24·4%). At CLL diagnosis, prognosticators of RS by univariate analysis wereIGHVhomology ≥98% (P = 0·006),IGHV4‐39usage (P < 0·001), del13q14 absence (P = 0·004), expression of CD38 (P < 0·001) and ZAP70 (P = 0·004), size (P < 0·001) and number (P < 0·001) of lymph nodes, advanced Binet stage (P = 0·002), and lactate dehydrogenase (P < 0·001). Multivariate analysis, performed separately for biological and clinical variables, identified CD38 expression [Hazard ratio (HR) = 4·26;P = 0·018],IGHV4‐39usage (HR = 4·29;P = 0·018), and lymph node size ≥3 cm (HR = 9·07;P < 0·001) as independent RS prognosticators. A multivariate model simultaneously analysing biological and clinical variables identified lymph node size ≥3 cm (HR = 6·51;P = 0·001) and del13q14 absence (HR = 4·08;P = 0·031) as independent RS prognosticators. Risk factors of CLL transformation differed from risk factors of CLL progression. These results suggest that CD38 and del13q14 may identify biological subsets of CLL with different RS predisposition. Predominant nodal disease, CD38 expression,IGHV4‐39usage, and absence of del13q14 may help in predicting RS at CLL diagnosis. Close monitoring and a careful biopsy policy are needed in patients carrying transformation risk factors.
Splenic marginal zone lymphomas are characterized by loss of interstitial regions of chromosome 7q, 7q31.32 and 7q36.2 that include the protection of telomere 1 (POT1) and sonic hedgehog (SHH) genes
Authors: Vega Francisco , Cho‐Vega Jeong Hee , Lennon Patrick A. , Luthra Madan G. , Bailey Jaime , Breeden Megan , Jones Dan , Medeiros L. Jeffrey , Luthra Rajyalakshmi
Published: May 2008

To further characterize the genotypic features of splenic (S) and nodal (N) marginal zone lymphomas (MZL) we compared eight SMZL and five NMZL by array‐based comparative genomic hybridization (aCGH). Arbitrarily, aberrations were divided into major imbalances, defined as gains or losses involving five or more contiguous genetic loci, and minor imbalances, defined as those involving four or fewer loci. SMZL, but not NMZL, demonstrated major imbalances. These included deletions involving various lengths of 7q (three cases), and 14q23q24 (one case) and gains of 9p13p21 (one case), 13q21q33 (one case) and 16p13.1 (one case). Common minor imbalances in SMZL were: loss of sonic hedgehog gene (SHH) at 7q36.2 (four cases), loss of protection of telomere 1 gene (POT1) at 7q31.32 (three cases), and gain of glioma associated oncogene 1 (GLI1) at 12q13.2 (three cases). Common minor alterations in NMZL were: loss of the fas‐associated via death domain gene (FADD) at 11q13.2 (three cases) and gain of GLI1 (five cases). In conclusion, SMZL, but not NMZL, demonstrates large genomic imbalances and frequent loss of the 7q31.32 and 7q36.2 regions involving POT1 and SHH, respectively. In NMZL, loss of FADD and gain of GLI1 are frequent events.
Treosulfan and fludarabine low‐toxicity conditioning for allogeneic haematopoietic stem cell transplantation in chronic myeloid leukaemia
Authors: Holowiecki Jerzy , Giebel Sebastian , Wojnar Jerzy , Krawczyk‐Kulis Malgorzata , Markiewicz Miroslaw , Holowiecka‐Goral Aleksandra , Freund Mathias , Casper Jochen
Published: May 2008

Allogeneic haematopoietic stem cell transplantation (alloHSCT) is the only treatment of proven long‐term efficacy in chronic myeloid leukaemia (CML), although high non‐relapse mortality (NRM) observed after conventional myeloablative conditioning limits its applicability. This phase II trial evaluated the efficacy and toxicity of a new preparative regimen consisting of treosulfan 3 × 14 g/m2 and fludarabine 5 × 30 mg/m2, in patients with CML in chronic phase. Among the 40 patients included, 18 received alloHSCT from a sibling and 22 from an unrelated donor. All patients engrafted with 92·5% of cases achieving complete donor chimaerism by day +100. All but one patient had achieved complete cytogenetic remission on day +100. Grade III or IV non‐haematological toxicities included: neutropenic fever (10%), nausea/vomiting (10%), elevated liver enzymes (5%) and infection (2·5%). The incidence of grade II–IV acute graft‐versus‐host disease (GVHD) was 22·5% and extensive chronic GVHD, 14%. The 2‐year probability of overall survival, leukaemia‐free survival and NRM was 85%, 82·5% and 15% respectively. At 1 year post‐transplant, 85% of survivors had a Karnofsky index of 100%. We concluded that treosulfan and fludarabine conditioning is a low‐toxicity regimen with high anti‐leukaemic potential that seems feasible in CML patients referred for alloHSCT.
Status of minimal residual disease after induction predicts outcome in both standard and high‐risk Ph‐negative adult acute lymphoblastic leukaemia. The Polish Adult Leukemia Group ALL 4‐2002 MRD Study
Authors: Holowiecki Jerzy , Krawczyk‐Kulis Malgorzata , Giebel Sebastian , Jagoda Krystyna , Stella‐Holowiecka Beata , Piatkowska‐Jakubas Beata , Paluszewska Monika , Seferynska Ilona , Lewandowski Krzysztof , Kielbinski Marek , Czyz Anna , Balana‐Nowak Agnieszka , Król Maria , Skotnicki Aleksander B. , Jedrzejczak Wieslaw W. , Warzocha Krzysztof , Lange Andrzej , Hellmann Andrzej
Published: May 2008

The treatment of adults with Philadelphia‐negative acute lymphoblastic leukaemia (ALL) depends on the presence of risk factors including age, white blood cell count, immunophenotype and time to complete remission. In recent years, status of minimal residual disease (MRD) has been postulated as an additional risk criterion. This study prospectively evaluated the significance of MRD. Patients were treated with a uniform Polish Adult Leukemia Group (PALG) 4‐2002 protocol. MRD status was assessed after induction and consolidation by multiparametric flow cytometry. Out of 132 patients included (age, 17–60 years), 116 patients were suitable for analysis. MRD level ≥0·1% of bone marrow cells after induction was found to be a strong and independent predictor for relapse in the whole study population (P < 0·0001), as well as in the standard risk (SR,P = 0·0003) and high‐risk (P = 0·008) groups. The impact of MRD after consolidation on outcome was not significant. The combination of MRD status with conventional risk stratification system identified a subgroup of patients allocated to the SR group with MRD <0·1% after induction who had a very low risk of relapse of 9% at 3 years as opposed to 71% in the remaining subjects (P = 0·001). We conclude that MRD evaluation after induction should be considered with conventional risk criteria for treatment decisions in adult ALL.
Germinal center B (GCB) and non‐GCB cell‐like diffuse large B cell lymphomas have similar outcomes following autologous haematopoietic stem cell transplantation
Authors: Costa Luciano J. , Feldman Andrew L. , Micallef Ivana N. , Inwards David J. , Johnston Patrick B. , Porrata Luis F. , Ansell Stephen M.
Published: May 2008

Patients with germinal center B cell‐like (GCB) and non‐GCB diffuse large B cell lymphomas (DLBCL) receiving first line therapy have distinct prognosis. We explored the differences in outcome following salvage autologous hematopoietic stem cell (HSC) transplantation between patients with GCB and non‐GCB DLBCL. Forty‐four patients with relapsed and 15 patients with primary refractory chemosensitive disease undergoing BEAM (BCNU [carmustine], etoposide, cytarabine, melphalan) conditioning and autologous HSC were included. Immunohistochemical analysis was performed for CD10, BCL‐6, MUM1 (allowing classification into GCB and non‐GCB‐like DLBCL) and BCL‐2. Median follow‐up of survivors was 25 months; median age at the time of transplantation was 60 years (range 17–77). Thirty‐two patients (54%) were classified as having GCB and 27 (46%) as having non‐GCB‐like DLBCL. Patients with GCB and non‐GCB DLBCL did not differ in the risk of progression after HSC transplant (P = 0·78) or overall survival (P = 0·48). In multivariate analysis, only time to progression after initial treatment impacted overall survival. We conclude that patients with relapsed or primary refractory chemosensitive GCB and non‐GCB‐like DLBCL derive similar benefit from autologous HSC transplant.
Richter syndrome: a review of clinical, ocular, neurological and other manifestations
Authors: Omoti Caroline Edijana , Omoti Afekhide Ernest
Published: May 2008

Richter syndrome describes the development of high‐grade non‐Hodgkin lymphoma (NHL) or Hodgkin lymphoma in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Richter transformation occurs in 3·3 to 10·6% of patients with CLL. The large cell lymphoma clone occurs by transformation of the original CLL clone in the majority of patients, and as a separate and independent neoplasm in fewer cases. Richter transformation may be triggered by viral infections, such as Epstein‐Barr virus infection, which are common in immunosuppressed patients. Trisomy 12 and chromosome 11 abnormalities, as well as multiple genetic defects, have been described in patients with Richter syndrome. These abnormalities may cause CLL cells to proliferate and, by facilitating the acquisition of new genetic abnormalities, to transform into Richter syndrome cells. Presenting features typically include a rapid clinical deterioration with fever in the absence of infection, progressive lymph node enlargement, and an elevation in serum lactate dehydrogenase. Extranodal Richter syndrome has also been reported to occur in the central nervous system, eye, gastrointestinal system, nose, skin, face, bone and bronchus. The therapeutic options include cytoreductive therapy consisting of chemotherapy and immunotherapy, followed by allogeneic stem cell transplantation as postremission therapy.
Bland dyskaryosis: a new pitfall in liquid‐based cytology
Authors: Denton K. , Rana D. N. , Lynch M. A. , Desai M. S.
Published: May 2008

Objective:  To describe our experience in recognizing an unusual presentation of severe dyskaryosis at two large cytology centres using ThinPrep liquid‐based cytology (LBC). LBC has been introduced in England following successful pilot studies. It is clear that LBC improves visualization and preservation of cells, and that sensitivity for high‐grade dyskaryosis is at least as good as for conventional cytology, and may be better. Several variants of high‐grade dyskaryosis have been described on conventional cytology, including small and pale cell dyskaryosis. These are also seen on LBC.

We are reporting a new variant of dyskaryosis which in our experience is seen only in LBC specimens prepared by the Thinprep® method, which we have named bland dyskaryosis. This has not to our knowledge been previously described.

Bland dyskaryosis is characterized by cells with a high nuclear/cytoplasmic ratio, nuclear hyperchromasia and is present in groups with a chaotic architecture. The chromatin pattern appears bland at low power screening examination. On high power examination, however, the chromatin pattern can be seen to be subtly abnormal. Nuclear membranes are smooth. These changes mimic endocervical cells or immature squamous metaplasia at low power.

Method:  Identification and description of cytological appearances observed in routine practice and correlation with histological diagnosis.

Conclusion:  The features of bland dyskaryosis should be disseminated through teaching activities. Recognition of this previously undescribed variant will prevent false negative reporting of LBC samples.
Ecosystems: development, functions and consequences of disturbances, with special reference to the oral cavity
Authors: Midtvedt Tore
Published: May 2008

Abstract. Some general rules for the development and maintenance of microbial ecosystems are outlined. Studies on germ‐free animals have given valuable baselines concerning structures and functions in the host per se. The oral cavity represents several consortia of micro‐organisms, governed by factors deriving from the host, the diet and/or the micro‐organisms. Alterations in these factors, as well as intake of antibiotics, etc., may give disturbances, which can be analyzed according to general guidelines.
Antibiotics in periodontal therapy: advantages and disadvantages*
Authors: Slots Jørgen , Rams Thomas E.
Published: May 2008

Abstract. Antibiotic treatment of periodontitis aims at eradicating or controlling specific pathogens. Prime candidates for antibiotic therapy are patients with recently diagnosed active periodontitis or a history of recurrent disease who fail to stabilize following mechanical/surgical therapy. Since a variety of microbes with differing antimicrobial susceptibility profiles may cause periodontitis, selection of antimicrobial agents should be based on proper microbial diagnosis and sensitivity testing, as well as consideration of the patient's medical status. The risk of treating chemotherapeutically solely on the basis of clinical features, radiographic findings or a limited microbiological analysis, is failure to control the pathogens or overgrowth of new pathogens. A review of published papers reveals that appropriate systemic antibiotic therapy may enhance healing in patients with recent or high risk of periodontal breakdown. Systemic antibiotic therapy seems more predictable than topical administration in eradicating periodontal pathogens from deep periodontal pockets. Several promising antimicrobial agents for periodontitis treatment need testing in placebo‐controlled, double‐blind, randomized clinical trials.
Cardiovascular infections: bacterial endocarditis of oral origin. Pathogenesis and prophylaxis
Authors: Nord Carl Erik , Heimdahl Anders
Published: May 2008

Abstract. The diagnosis infective endocarditis describes infection of the endocardial surface of the heart and indicates the presence of micro‐organisms in the lesion. In most cases, the heart valves are affected, but the disease can also occur on septal defects or on the mural endocardium. The disease has been classified as acute or subacute based on the progression of the untreated disease. The acute form has a fulminant course with high fever and leukocytosis with death in less than 6 weeks. It is most often associated with infections caused by Staphylococcus aureus, Streptococcus pneumoniae or Streptococcus pyogenes. The subacute (death within 6 weeks to 3 months) and chronic (death more than 3 months) forms are mostly described together. These forms usually occur in patients with prior valvular disease and are characterized by a slow, indolent course with low‐grade fever, night sweats, and weight loss. This form is usually caused by the viridansstreptococci. The above mentioned classification does not include the nonbacterial forms of endocarditis and enterococci often give rise to a disease interrcediate between acute and subacute endocarditis. It is preferable to have a classification based on the micro‐organism responsible since this classification has implications for the course followed and the appropriate antimicrobial agent to use. The clinical manifestations of the disease are so varied that they may be encountered in most medical subspecialties. Successful management is also dependent on the close cooperation of medical and dental disciplines.
Vascular diseases and oral infections
Authors: Syrjänen Jaana
Published: May 2008

Abstract. Vascular diseases are multifactorial, and several risk factors, such as increasing age, male sex, hypertension, diabetes, dyslipidemias and smoking, are well‐known. In recent studies, associations have also been found between preceding infections and development of myocardial or cerebral infarction. Preceding acute respiratory infections are reported to be more common in patients with myocardial or cerebral infarction. Cerebral infarction may follow infective endocarditis, bacterial meningitis or any other bacteremic infection. Oral infections are common chronic bacterial infections. Although oral infections are local, they may lead to systemic infectious complications via stransient bacteremias, and there may also be other systemic effects, for instance, via immunologic or toxic mechanisms. Association between oral infections and vascular diseases has been studied in 2 Finnish case‐control studies concerning myocardial and cerebral infarction. In these case‐control studies, it was found that oral infections were more common in patients with myocardial or cerebral infarction than in their age‐ and sex‐matched community controls. There are many factors, such as diabetes, smoking and alcohol abuse, which may predispose to both development of infarction and oral infections. Therefore, the observed association between oral infections and vascular diseases may result from these common predisposing factors, and causality between them cannot be inferred. There are, however, several possible links between oral infections and infarction. Although causality between oral infections and infarction cannot be proven, patients who have poor oral health need health education, paying attention to those common risk factors of oral infections and vascular diseases. Furthermore, their oral infections should be treated, because they may predispose to infectious complications, which may lead to infarction.
Implants and infections with special reference to oral bacteria
Authors: Haanaes Hans R.
Published: May 2008

Abstract. Osseointegration or bony anchorage of oral implants was first described by Brånemark and coworkers. This type of connection between the titanium oxide layer and the bone gives stable long‐term results for the implants in function. Fibrous tissue interphase between implant and bone will allow mobility which will gradually increase and cause implant failure. The microbiota around stable versus failing implants seem to parallel the patterns around healthy versus diseased natural teeth. Infections most often develop around failing implants. This may create mostly localized, but sometimes even widespread serious infection problems. Metastatic infectious problems related to endo‐prosthesis replacing joints and cardiovascular structures are briefly discussed in connection with bacteremia caused by oral infections in general and surgical procedures.
Differences in hepatic cytochrome P450 activity correlate with the strain‐specific biotransformation of medetomidine in AX/JU and IIIVO/JU inbred rabbits
Authors: AVSAROGLU H. , BULL S. , MAAS‐BAKKER R. F. , SCHERPENISSE P. , VAN LITH H. A. , BERGWERFF A. A. , HELLEBREKERS L. J. , VAN ZUTPHEN L. F. M. , FINK‐GREMMELS J.
Published: May 2008

Medetomidine is an α2‐adrenoceptor agonist with sedative and analgesic properties. Previously we demonstrated significant differences in the response to medetomidine between two inbred rabbit strains, denoted IIIVO/JU and AX/JU. The aim of the present study was twofold: first, to compare the hepatic CYP450 enzyme activities between these rabbit strains [n = 13(6♂♂,7♀♀)/strain]. To this end, liver microsomes were incubated with known fluorescent substrates for the major drug‐metabolizing CYP450 isoforms. A comparison of the obtained results indicated significant gender differences as well as differences between the two rabbit inbred strains. Secondly, the biotransformation rate of medetomidine in liver microsomes of both rabbit strains was determined using liquid chromatography coupled to tandem mass spectrometry. The rate of hydroxymedetomidine and medetomidine carboxylic acid formation was found to be significantly higher in the AX/JU strain. Specific CYP2D and CYP2E inhibitors could decrease the formation of both metabolites. Significant correlations were found between the rate of biotransformation of medetomidine and the activities of CYP2D and CYP2E, as well as between CYP450 enzyme activities and the anaesthetic response to medetomidine.
Pharmacokinetics of ivermectin after maternal or fetal intravenous administration in sheep
Authors: PÉREZ R. , PALMA C. , NÚÑEZ M. J. , COX J.
Published: May 2008

In pregnant sheep at 120–130 days of gestational age, a study was undertaken in order to characterize the pharmacokinetics and transplacental exchange of Ivermectin after maternal or fetal intravenous administration.

Eight pregnant Suffolk Down sheep of 73.2 ± 3.7 kg body weight (bw) were surgically prepared in order to insert polyvinyl catheters in the fetal femoral artery and vein and amniotic sac. Following 48 h of recovery, the ewes were randomly assigned to two experimental groups. In group 1, (maternal injection) five ewes were treated with an intravenous bolus of 0.2 mg ivermectin/kg bw. In group 2, (fetal injection) three ewes were injected with an intravenous bolus of 1 mg of ivermectin to the fetus through a fetal femoral vein catheter. Maternal and fetal blood and amniotic fluid samples were taken before and after ivermectin administration for a period of 144 h post‐treatment. Samples were analyzed by liquid chromatography (HPLC). A computerized non‐compartmental pharmacokinetic analysis was performed and the results were compared by means of the Student t‐test.

The main pharmacokinetic changes observed in the maternal compartment were increases in the volume of distribution and in the half‐life of elimination (t½β). A limited maternal‐fetal transfer of ivermectin was evidenced by a low fetal Cmax (1.72 ± 0.6 ng/mL) and AUC (89.1 ± 11.4 ng·h/mL). While the fetal administration of ivermectin resulted in higher values of clearance (554.1 ± 177.9 mL/kg) and lower values of t½β(8.0 ± 1.4 h) and mean residence time (8.0 ± 2.9 h) indicating that fetal‐placental unit is highly efficient in eliminating the drug as well as limiting the transfer of ivermectin from the maternal to fetal compartment.
A novel nucleocytoplasmic traffic GTPase identified as a functional target of the bipartite geminivirus nuclear shuttle protein
Authors: Carvalho Claudine M. , Fontenelle Mariana R. , Florentino Lílian H. , Santos Anésia A. , Zerbini Francisco M. , Fontes Elizabeth P.B.
Published: May 2008

In contrast to the accumulated data on nuclear transport mechanisms of macromolecules, little is known concerning the regulated release of nuclear‐exported complexes and their subsequent trans‐cytoplasmic movement. The bipartite begomovirus nuclear shuttle protein (NSP) facilitates the nuclear export of viral DNA and cooperates with the movement protein (MP) to transport viral DNA across the plant cell wall. Here, we identified a cellular NSP‐interacting GTPase (NIG) with biochemical properties consistent with a nucleocytoplasmic transport role. We show that NIG is a cytosolic GTP‐binding protein that accumulates around the nuclear envelope and possesses intrinsic GTPase activity. NIG interacts with NSP in vitro and in vivo (under transient expression), and redirects the viral protein from the nucleus to the cytoplasm. We propose that NIG acts as a positive contributor to geminivirus infection by modulating NSP nucleocytoplasmic shuttling and hence facilitating MP–NSP interaction in the cortical cytoplasm. In support of this, overexpression of NIG in Arabidopsis enhances susceptibility to geminivirus infection. In addition to highlighting the relevance of NIG as a cellular co‐factor for NSP function, our findings also have implications for general nucleocytoplasmic trafficking of cellular macromolecules.
Hinokinin biosynthesis in Linum corymbulosum Reichenb.
Authors: Bayindir Ürün , Alfermann August Wilhelm , Fuss Elisabeth
Published: May 2008

Due to their peculiar stereochemistry and numerous biological activities, lignans are of widespread interest. As only a few biosynthetic steps have been clarified to date, we aimed to further resolve the molecular basis of lignan biosynthesis. To this end, we first established that the biologically active lignan (−)‐hinokinin could be isolated from in vitro cultures of Linum corymbulosum. Two hypothetical pathways were outlined for the biosynthesis of (−)‐hinokinin. In both pathways, (+)‐pinoresinol serves as the primary substrate. In the first pathway, pinoresinol is reduced via lariciresinol to secoisolariciresinol by a pinoresinol–lariciresinol reductase, and methylenedioxy bridges are formed later. In the second pathway, pinoresinol itself is the substrate for formation of the methylenedioxy bridges, resulting in consecutive production of piperitol and sesamin. To determine which of the proposed hypothetical pathways acts in vivo, we first isolated several cDNAs encoding one pinoresinol‐lariciresinol reductase (PLR‐Lc1), two phenylcoumaran benzylic ether reductases (PCBER‐Lc1 and PCBER‐Lc2), and two PCBER‐like proteins from a cDNA library of L. corymbulosum. PLR‐Lc1 was found to be enantiospecific for the conversion of (+)‐pinoresinol to (−)‐secoisolariciresinol, which can be further converted to give (−)‐hinokinin. Hairy root lines with significantly reduced expression levels of the plr‐Lc1 gene were established using RNAi technology. Hinokinin accumulation was reduced to non‐detectable levels in these lines. Our results strongly indicate that PLR‐Lc1 participates in (−)‐hinokinin biosynthesis in L. corymbulosum by the first of the two hypothetical pathways via (−)‐secoisolariciresinol.
Acceleration of plastoquinone pool reduction by alternative pathways precedes a decrease in photosynthetic CO2 assimilation in preheated barley leaves
Authors: Kaňa Radek , Kotabová Eva , Prášil Ondřej
Published: May 2008

Heat stress causes inhibition of photosynthetic CO2 assimilation, affects light photosynthetic reactions and accelerates alternative pathways of plastoquinone pool reduction (APPR). We have studied all these heat‐sensitive processes after preheating to a broad range of physiological temperatures (24–46°C) to explore a role of these alternative pathways during heat stress. Primarily, the effective quantum yield of PSII photochemistry was reduced (at 40°C). This PSII downregulation was accompanied by the stimulation of APPR and preceded reduction of photosynthetic CO2 assimilation by 2°; it occurred after preheating at 42°C because of inhibition in Rubisco (ribulose 1,5‐bisphosphate carboxylase/oxygenase) activation process. Thus, we suggest that the heat‐induced stimulation of APPR is not associated with the heat‐induced inhibition of Calvin cycle as it was reported for other types of stresses. A possible role of APPR in the compensation of PSII downregulation is briefly discussed.
Fish protein substrates can substitute effectively for poultry by‐product meal when incorporated in high‐quality senior dog diets
Authors: Zinn K. E. , Hernot D. C. , Fastinger N. D. , Karr‐Lilienthal L. K. , Bechtel P. J. , Swanson K. S. , Fahey G. C.
Published: May 2008

An experiment was conducted to analytically define several novel fish substrates and determine the effects of feeding diets containing these substrates on total tract nutrient digestibilities and on immune status of senior dogs. The control diet contained poultry by‐product meal while test diets contained 20% milt meal (MM), pink salmon hydrolysate (PSH) and white fish meal (WFM) added at the expense of poultry by‐product meal. Concentrations of lymphocytes positive for CD3, CD4, CD8α and CD21 cell‐surface markers and immunoglobulin concentrations were measured. Gene expression of cytokines tumour necrosis factor (TNF)‐α, interleukin (IL)‐6, interferon (IFN)‐γ, IL‐10 and transforming growth factor (TGF)‐β was determined by quantitative real‐time polymerase chain reaction. Major compositional differences were noted among fish substrates but apparent nutrient digestibility coefficients and immune indices were not affected by treatment. Fish protein substrates were found to be effective substitutes for poultry by‐product meal, providing diets of high nutritive value for senior dogs.
Modulation of apical Na+/Pi cotransporter type IIb expression in epithelial cells of goat mammary glands
Authors: Muscher A. , Breves G. , Huber K.
Published: May 2008

Recently, the type II sodium‐dependent phosphate cotransporter NaPi IIb, which mediates the intestinal phosphate transport, was detected in the apical membranes of caprine mammary gland epithelial cells. Regulatory influences of developmental stages, dietary phosphorus (P) supply and hormones like calcitriol are well described for the intestinal NaPi IIb. Therefore, it was the aim of this study to examine the influence of involution and dietary P restriction on the expression of mammary gland NaPi IIb and of vitamin D receptor (VDR). During involution both, NaPi IIb and VDR, showed an initial increase of expression. This resulted in a delayed response on protein level. Dietary P restriction resulted in a decrease of mRNA expression which was not reflected on protein level. Influenced expression pattern, at least on mRNA level, indicate that mammary gland NaPi IIb is a regulated phosphate transporter which might have an important role especially during involution. Coexpression pattern with VDR provides an indication that calcitriol could be the modulator of these adaptive responses to involution and dietary P restriction. Therefore, a physiological meaning of NaPi IIb in mammary gland epithelia during processes of cell regeneration has to be considered.
The impact of practical relevance on training transfer: evidence from a service quality training program for German bank clerks
Authors: Liebermann Susanne , Hoffmann Stefan
Published: May 2008

The management literature provides a variety of recommendations as to how workers’ customer orientation might be improved, including through training. Crucial factors in the process of transferring the contents of service quality training programs to practice, however, have not yet been sufficiently analysed. This study proposes and tests a model of transfer motivation and training transfer via structural equation modelling, validating Baldwin and Ford's framework and Kirkpatrick's levels of evaluation. Following the recommendation of Alliger et al., the present study analyses the relationship between Kirkpatrick's levels of evaluation, paying attention to the specificity of the measures at each level. The survey collects data from 213 German bank employees who attended a training program aimed at improving service quality. As hypothesized, the perceived practical relevance of the training was found to exert a strong influence on the reaction of the participants and had a substantial total effect on the motivation to transfer and on actual transfer. Subject to the limitations of the research methodology employed here, it is concluded that trainee satisfaction needs to be conceptually distinguished from perceived practical relevance and that the latter is the main driving force for transfer motivation and transfer.
Assessing the psychometric properties of the Dimensions of the Learning Organization Questionnaire in the Korean business context
Authors: Song Ji Hoon , Chermack Thomas J.
Published: May 2008

The primary purpose of this research is to adapt the Dimensions of the Learning Organization Questionnaire developed by Watkins and Marsick, and examine its validity and reliability in a Korean context. Although the concept of the learning organization is well established, there has not been rigorous validation of the application of the questionnaire in the Korean context. The present research sheds light on the reliability and validity of applying the learning organization concept to the Korean workforce. The results of confirmatory factor analysis and internal consistency tests indicate that the Korean version of the questionnaire produces valid and reliable psychometric properties of learning organization characteristics in a Korean cultural context. Several demographic variables were used to identify the differences in learning organization cultural perspectives. Conclusions and implications are set out and the limitations of the research stated.
Rethinking UK small employers' skills policies and the role of workplace learning
Authors: Kitching John
Published: May 2008

Small business employers in the UK are widely perceived as adopting a reactive, ad hoc approach to employee skill formation. Employer reliance on workplace learning is often treated, explicitly or implicitly, as evidence of such an approach. Small employers' approaches to skill creation are investigated using data from two employer samples. Three main conclusions challenging these arguments are presented. First, small employers' skills policies are highly diverse: strategic, tactical and restrictive policies are distinguished. Second, employers perceive particular benefits in enabling workplace learning; simplistic views that a reliance on workplace learning necessarily constitutes an inferior last resort for those employers unable to provide access to external training are rejected. Third, enabling workplace learning is important to strategic employers, as well as to those attaching a lower value to skills. For some employers, the workplace is the primary source of new knowledge and skills because they are unavailable elsewhere. The prevalence, diversity and significance of workplace learning in small businesses require a reappraisal of UK small employers' skills policies. The implications for research, practice and policy are discussed.
The Nordic advantage in child mental health: separating health differences from reporting style in a cross‐cultural comparison of psychopathology
Authors: Heiervang Einar , Goodman Anna , Goodman Robert
Published: May 2008

Background:  The use of similar standardised measures of psychopathology for population surveys permits cross‐cultural comparisons. However, interpretation of findings can be challenging because rating thresholds may differ across cultures. By combining questionnaire and interview data, we explore whether lower questionnaire scores in Norway as compared to Britain reflect genuine differences in child mental health, or simply different reporting thresholds.

Methods:  Information from the Strengths and Difficulties Questionnaire (SDQ) and the Development and Well‐Being Assessment (DAWBA) interview were compared across recent population surveys in Norway and Britain. The Norwegian study (2002–03) had questionnaire data for 6,658 and interview data for 1,024 8–10‐year‐old children. The British dataset included questionnaire and interview data for 4,898 children of the same age range from two independent surveys (1999 and 2004).

Results:  Norwegian children had lower SDQ scores on all problem scales (emotional, behavioural, hyperactive and peer relationship) according to parents as well as teachers. DAWBA information showed that the Norwegian prevalence of externalising disorders (behavioural and hyperactivity) was about half that found in Britain, whereas rates of emotional disorders were similar. Norwegian and British children with non‐emotional disorders had similar questionnaire scores and rates of problem‐recognition by parents and teachers. By contrast, questionnaire scores and problem‐recognition were all lower in Norwegian children with emotional disorders.

Conclusions:  Lower Norwegian questionnaire scores for externalising problems appear to reflect real and substantial differences between the two countries. By contrast, lower questionnaire scores for emotional problems seem to reflect under‐reporting/under‐recognition by Norwegian adults, and not a genuinely lower prevalence of emotional disorders. This illustrates that cross‐cultural differences in psychopathology based only on questionnaire data may be misleading. Nevertheless, careful use of questionnaire and interview data can focus mental health research on cross‐cultural variations likely to reflect genuine health differences.
Research Review: Williams syndrome: a critical review of the cognitive, behavioral, and neuroanatomical phenotype
Authors: Martens Marilee A. , Wilson Sarah J. , Reutens David C.
Published: May 2008

This review critically examines the research findings which characterize the cognitive, behavioral, and neuroanatomical features of Williams syndrome (WS). This article analyzes 178 published studies in the WS literature covering the following areas: 1) General intelligence, 2) Language skills, 3) Visuospatial and face processing skills, 4) Behavior patterns and hypersociability, 5) Musical abilities, and 6) Brain structure and function. We identify methodological issues relating to small sample size, use and type of control groups, and multiple measures of task performance. Previously described ‘peaks’ within the cognitive profile are closely examined to assess their veracity. This review highlights the need for methodologically sound studies that utilize multiple comparison groups, developmental trajectories, and longitudinal analyses to examine the WS phenotype, as well as those that link brain structure and function to the cognitive and behavioral phenotype of WS individuals.
A new symptom model for autism cross‐validated in an independent sample
Authors: Boomsma A. , Van Lang N.D.J. , De Jonge M.V. , De Bildt A.A. , Van Engeland H. , Minderaa R.B.
Published: May 2008

Background:  Results from several studies indicated that a symptom model other than the DSM triad might better describe symptom domains of autism. The present study focused on a) investigating the stability of a new symptom model for autism by cross‐validating it in an independent sample and b) examining the invariance of the model regarding three covariates: symptom severity, intelligence, and age.

Method:  The validity of the symptom model was examined in an independent sample of N = 263 children and adolescents with autism spectrum disorders, and model invariance was studied in a larger sample of N = 356 children and adolescents with autism spectrum disorders. The fit of the symptom model to the sample data was compared to that of alternative models (including the DSM triad), and the invariance of the new model was investigated for each covariate by multiple‐group comparisons.

Results:  The fit of the new symptom model was better than that of two alternative models. It could not be compared to that of the DSM triad, because the latter encountered empirical identification problems. There were no significant or substantive differences between the estimated model in each of the dichotomised groups for any of the three covariates, which indicated factorial invariance of both structural form and factor loadings.

Conclusions:  The symptom model appeared to be relatively stable: It could be cross‐validated in the independent sample and factorial invariance was shown between the dichotomised groups for each covariate. Further model validation with instruments other than the Autism Diagnostic Interview‐Revised (ADI‐R) is recommended.