bluuebunny/crossref_metadata_2025 huggingface dataset:
Downregulation of neuropilin‐1 in patients with acute myeloid leukemia treated with thalidomide
Authors: Kreuter Michael , Steins Martin , Woelke Katja , Buechner Thomas , Berdel Wolfgang E. , Mesters Rolf M.
Published: October 2007

Objective:  Neuropilin‐1 (NRP‐1), a non‐tyrosine kinase receptor functioning as a mediator of angiogenesis and neuronal guidance, was recently found to be significantly overexpressed in newly diagnosed acute myeloid leukemia (AML) patients with significant correlation to survival. The role of NRP‐1 in refractory or relapsed AML patients and its regulation during anti‐angiogenic treatment remain to be elucidated.

Methods:  Bone marrow biopsies of 10 patients with refractory or relapsed AML were evaluated for NRP‐1 expression by immunohistochemical analysis, and NRP‐1 expression level was determined before and after start of thalidomide therapy and correlated to response and growth factor expression.

Results:  NRP‐1 expression was significantly increased in AML patients [median 7 arbitrary units (AU)] when compared with controls (n = 38, median 2.75 AU). Under thalidomide treatment, a marked difference in the course of NRP‐1 expression between responders and non‐responders was observed, however, without a statistical significance (P = 0.071) being reached. Additionally, a significant correlation of the NRP‐1 expression level to microvessel density could be detected under treatment with thalidomide (P = 0.018).

Conclusion:  Our data provide evidence of increased NRP‐1 expression in relapsed or refractory AML. Additionally, our results suggest that thalidomide‐induced antileukemic properties might at least in part be mediated by NRP‐1 downregulation.
Long‐term effects of idiotype vaccination on the specific T‐cell response in peripheral blood and bone marrow of multiple myeloma patients
Authors: Abdalla Amir Osman , Hansson Lotta , Eriksson Ingrid , Näsman‐Glaser Barbro , Mellstedt Håkan , Österborg Anders
Published: October 2007

Objectives:  To elucidate long‐term effects of idiotype (Id) vaccination on Id‐specific T cells of multiple myeloma (MM) patients and compare Id‐specific T‐cell responses of peripheral blood with those of bone marrow (BM).

Materials and methods:  Id‐specific T‐cell responses of peripheral blood mononuclear cells (PBMC) were compared with those of BM mononuclear cells (BMMC) in 10 MM patients vaccinated with the Id protein at a median time of 41 months since the last immunization. The PBMC responses at late follow‐up were also compared with those during active immunization. The responses were assessed by a proliferation assay, enzyme‐linked immunospot (ELISPOT) (γ‐interferon), cytometric bead array (CBA) for secreted cytokines and quantitative real‐time polymerase chain reaction (QRT‐PCR) for cytokine gene expression.

Results:  At the late testing time, an Id‐specific response was detected in PBMC of five patients (ELISPOT, CBA, QRT‐PCR) and in BMMC of four patients (CBA, QRT‐PCR). A response in both compartments was noted only in three patients. The cytokines gene profile was consistent with a predominance of Th2 cells [interleukin (IL)‐4, IL‐5, IL‐10]. Comparison of the Id‐specific responses of PBMC during active immunization with those at the late follow‐up showed that the frequency and magnitude of the responses had decreased significantly by time (proliferation/ELISPOT) (P < 0.02) and shifted at the gene level from a Th1 to a Th2 profile (P < 0.05).

Conclusion:  Id‐specific T cells may decline overtime and shift toward a Th2 response and may be found at a similar frequency of patients in blood and BM.
Oxidative stress in red blood cells, platelets and polymorphonuclear leukocytes from patients with myelodysplastic syndrome
Authors: Ghoti Hussam , Amer Johnny , Winder Asher , Rachmilewitz Eliezer , Fibach Eitan
Published: October 2007

Low‐risk myelodysplastic syndrome (MDS) is characterized by cytopenia, mainly anemia, because of ineffective hematopoiesis. Some of the patients with ineffective erythropoiesis, with or without ring sideroblasts in their bone marrow, develop severe anemia requiring frequent blood transfusions and consequently develop iron overload. Excess free iron in cells catalyses the generation of reactive oxygen species (ROS) that cause cell and tissue damage. Using flow cytometry techniques, we compared the oxidative status of red blood cells (RBC), platelets and neutrophils in 14 MDS patients with those of normal donors. The results show that ROS were higher while reduced glutathione (GSH) was lower in their RBC and platelets compared with normal cells. In neutrophils, no difference was found in ROS, while the GSH levels were lower. A correlation (r = 0.6) was found between serum ferritin levels of the patients and the ROS in their RBC and platelets. The oxidative stress was ameliorated by a short incubation with the iron‐chelators, the deferrioxamine and deferiprone or with antioxidants such as N‐acetylcysteine, suggesting that MDS patients might benefit from treatment with iron‐chelators and antioxidants.
Synchronous FIP1L1–PDGFRA‐positive chronic eosinophilic leukemia and T‐cell lymphoblastic lymphoma: a bilineal clonal malignancy
Authors: Capovilla Mathieu , Cayuela Jean‐Michel , Bilhou‐Nabera Chrystèle , Gardin Claude , Letestu Remi , Baran‐Marzak Fanny , Fenaux Pierre , Martin Antoine
Published: October 2007

Several reports of successful empirical treatment of idiopathic hypereosinophilic syndrome with imatinib led to the recent identification of the FIP1L1–PDGFRA fusion gene rearrangement, which characterizes a distinctive group of chronic eosinophilic leukemias. This fusion gene can be detected in eosinophils, neutrophils, mast cells, T cells, B cells and monocytes in FIP1L1–PDGFRA‐positive hypereosinophilic patients suggesting a multilineage involvement. Furthermore, the same FIP1L1–PDGFRA rearrangement was identified in patients with hypereosinophilia and atypical mast cell proliferations, raising the question of a disease with two concomitant lines of differentiation. In addition, a recent report noted two cases with the association of FIP1L1–PDGFRA‐positive chronic eosinophilic leukemia and T‐cell lymphoblastic lymphoma (T‐LBL). We report here the only third case of synchronous chronic eosinophilic leukemia and T‐LBL, both associated with a FIP1L1–PDGFRA fusion transcript, confirming the occurrence of such disease and suggesting a clonal proliferation with two lines of differentiation probably arising from a primitive multipotent medullary stem cell.
Evaluation of bone disease in multiple myeloma patients carrying the t(4;14) chromosomal translocation
Authors: Tosi Patrizia , Terragna Carolina , Testoni Nicoletta , Zamagni Elena , Renzulli Matteo , Tacchetti Paola , Montanari Elena , Perrone Giulia , Ceccolini Michela , Brioli Annamaria , Pallotti Maria C. , Tura Sante , Baccarani Michele , Cavo Michele
Published: October 2007

T(4;14) chromosomal abnormality is one of the most adverse prognostic factors predicting for poor outcome in multiple myeloma (MM) patients. It has been recently suggested that bone disease, as evaluated by spinal magnetic resonance imaging (MRI), is relatively infrequent in these patients. In the present study, we aimed at further testing this hypothesis by analyzing the extent of whole bone involvement in patients showing t(4;14) chromosomal translocation as compared with negative patients. For this purpose, 53 consecutive newly diagnosed MM patients (35M, 18F, median age = 55 yr) underwent evaluation of total skeletal X‐ray, whole spine MRI, and at the same time, quantification of markers of bone resorption (urinary N‐terminal telopeptide, pyridinoline, deoxypyridinoline, serum crosslaps), and bone formation (bone alkaline phosphatase and osteocalcin) was performed. The presence of IgH/MMSET fusion gene as a surrogate marker for t(4;14), was detected in 11 patients (20.7%), whose clinical characteristics were similar to those observed in t(4;14) negative patients. The type of marrow involvement at spinal MRI (diffuse vs. focal vs. negative) was the same in both groups of patients, even though overt vertebral fractures were more frequently found in t(4;14) positive cases (82% vs. 43%, P = 0.05); in line with this finding, skeletal lesions were more common in t(4;14) positive patients (mean skeletal score = 8.54 ± 1.36 SE, as compared with 3.42 ± 0.57 SE in t(4;14) negative cases, P = 0.000). These data were confirmed by the evaluation of serum crosslaps, that were significantly increased in patients with t(4;14) abnormality as compared with negative individuals (10 400 pmol/L ± 2160 SE vs. 5640 pmol/L ± 859 SE P = 0.02) Our results indicate that, at variance to what has been previously reported, bone resorption is more prominent in t(4;14) positive patients.
Profiling of diffuse large B‐cell lymphoma by immunohistochemistry: identification of prognostic subgroups
Authors: Sjö Lene Dissing , Poulsen Christian Bjørn , Hansen Mads , Møller Michael Boe , Ralfkiaer Elisabeth
Published: October 2007

Diffuse large B‐cell lymphoma (DLBCL) is a frequent lymphoma subtype with a heterogeneous behavior and a variable response to conventional chemotherapy. This clinical diversity is believed to reflect differences in the molecular pathways leading to lymphomagenesis. In this study, we have analyzed pretreatment, diagnostic samples from 108 DLBCL by immunohistology for expression of four markers linked to germinal center B‐cells (CD10, Bcl‐6), postgerminal center B‐cells (MUM1) and apoptosis (Bcl‐2). The results indicate that both CD10 and Bcl‐6 are favorable prognostic indicators, in contrast to Bcl‐2, which is an adverse parameter. Furthermore, using two algorithms for distinction between low‐ and high‐risk patients proposed by Hans et al. (Blood, 2004; 103:275) and Muris et al. (Journal of Pathology, 2006; 208:714), it is shown that both are useful for predicting outcome in DLBCL. However, in this report, the algorithm of Hans et al. was superior to that of Muris et al. These findings confirm and extend other studies and indicate that different prognostic subgroups of DLBCL can be distinguished by simple immunohistological investigations for a limited number of markers. Whether these groups are also relevant for individual treatment decisions will be important to investigate in prospective studies.
Inhibitors of protein kinase C sensitise multiple myeloma cells to common genotoxic drugs
Authors: Baumann Philipp , Armann Jakob , Mandl‐Weber Sonja , Grün Gabriel , Oduncu Fuat , Schmidmaier Ralf
Published: October 2007

Objectives:  Despite high dose treatment regimes multiple myeloma (MM) disease is still not curable. Patients become resistant to cytotoxic drugs and die of disease progression. Therefore, besides new cytotoxic compounds drug sensitisers are urgently needed.

Methods:  The MM cell lines U266, OPM‐2, RPMI‐8226 and NCI‐H929 were incubated with the common anti‐myeloma drugs like melphalan together with protein kinase C (PKC) inhibitors. Growth inhibition was measured using the water‐soluble tetrazolium salt 4‐[3‐(4‐iodophenyl)‐2‐(4‐nitrophenyl)‐2H‐5‐tetrazolio]‐1,3‐benzene disulfonate (WST‐1 assay), and apoptosis was determined by flow cytometry after staining with fluorescein isothiocyanate‐labeled annexin V (annexin‐V‐FITC) and propidium iodide. Intracellular signalling was shown by western blotting.

Results:  In this study we show that the combination of melphalan or doxorubicin with a PKC inhibitor, Gö6976 or enzastaurin, strongly increases cell toxicity. Increase of cytotoxicity is shown to be due to increased induction of apoptosis. Furthermore, we show that the protective effect of human bone marrow stromal cells (hBMSC) is abrogated by the PKC inhibitors. Finally, western blotting experiments revealed that incubation of myeloma cells with cytotoxic drugs like melphalan or doxorubicin leads to increased phosphorylation and therefore degradation of inhibitor of nuclear factor kappa B (IκB) and release of nuclear factor kappa B (NFκB). In contrast, enzastaurin inhibits phosphorylation of IκB.

Conclusions:  We conclude that the combination of conventional drugs and PKC inhibitors might be very effective and represents a new strategy in the treatment of MM.
Intracellular HMGB1 transactivates the human IL1B gene promoter through association with an Ets transcription factor PU.1
Authors: Mouri Fumihiko , Tsukada Junichi , Mizobe Takamitsu , Higashi Takehiro , Yoshida Yasuhiro , Minami Yasuhiro , Izumi Hiroto , Kominato Yoshihiko , Kohno Kimitoshi , Tanaka Yoshiya
Published: October 2007

High mobility group box 1 protein (HMGB1), originally described as a non‐histone, DNA binding protein, was recently identified as a late mediator of inflammation via its extracellular release from activated macrophages/monocytes. In the present study, we report that intracellular HMGB1 synergizes with a macrophage/monocyte‐specific E26 transformation‐specific sequence (Ets) transcription factor PU.1 to transactivate the promoter of the IL1B gene coding a 31‐kDa proIL‐1β protein. The −131 to +12 IL1B promoter, which possesses a PU.1 binding motif essential for its transactivation, was induced when HMGB1 expression vector was transfected into murine RAW264.7 macrophage cells. Our glutathione S‐transferase‐pulldown and coimmunoprecipitation assays demonstrated direct physical interaction of HMGB1 with PU.1. Deletion of the PU.1 winged helix‐turn‐helix DNA‐binding domain inhibited the association of the two proteins. In electrophoretic mobility shift assay using recombinant PU.1 protein, a ternary complex of PU.1, HMGB1 and PU.1‐binding element within the IL1B promoter was generated. The importance of PU.1 was further supported by our observation that induction of the IL1B promoter was obtained only after PU.1 expression in PU.1‐deficient murine EL4 thymoma cells. Thus, our data raise the possibility of a novel mechanism which sustains and amplifies inflammatory reactions through physical interaction of PU.1 with intracellular HMGB1 in macrophages/monocytes.
The impact of the regulatory design on the response of epidermal growth factor receptor‐mediated signal transduction towards oncogenic mutations
Authors: Wolf Jana , Dronov Serge , Tobin Frank , Goryanin Igor
Published: October 2007

Epidermal growth factor receptor (EGFR)‐mediated signal transduction is often hyperactivated in tumour cells and therefore considered a promising target for cancer therapy. A number of computational models have been developed which describe the pathway in great detail. These models are similar in their description of the activation events. The deactivation of the EGFR signalling seems to be cell type‐specific and is less understood. Deactivation via receptor internalization, feedback inhibition of son of sevenless (SOS) by double phosphorylated, extracellular signal‐regulated kinase (ERKPP) or transiently activated Ras‐GTPase activating protein (Ras‐GAP) proteins is discussed to play a role. In this study we address the question of to what extent the effect of oncogenic perturbations on EGFR signalling depend on the specific regulation structure. This is investigated using a detailed pathway model under two regulatory modes: the negative feedback via ERKPP to SOS and feed‐forward deactivation via transiently activated Ras‐GAP proteins. We show that the effect of receptor overexpression differs qualitatively under both regulations. In the system with transiently activated Ras‐GAP it may result in an attenuation of the ERK activation. Such a nonintuitive effect was also observed experimentally. In general we find the model with transiently activated Ras‐GAP to have a higher robustness towards receptor overexpression and Ras mutations. In particular, we demonstrate that this model can compensate for these oncogenic perturbations if the regulation is strong. The negative feedback can not protect the system against Ras mutations. A general sensitivity analysis, however, shows a higher robustness of the model under negative feedback, indicating the limited significance of such analyses for the prediction of specific oncogenic perturbations.
Molecular basis for specificities of reactivating factors for adenosylcobalamin‐dependent diol and glycerol dehydratases
Authors: Kajiura Hideki , Mori Koichi , Shibata Naoki , Toraya Tetsuo
Published: October 2007

Adenosylcobalamin‐dependent diol and glycerol dehydratases are isofunctional enzymes and undergo mechanism‐based inactivation by a physiological substrate glycerol during catalysis. Inactivated holoenzymes are reactivated by their own reactivating factors that mediate the ATP‐dependent exchange of an enzyme‐bound, damaged cofactor for free adenosylcobalamin through intermediary formation of apoenzyme. The reactivation takes place in two steps: (a) ADP‐dependent cobalamin release and (b) ATP‐dependent dissociation of the resulting apoenzyme–reactivating factor complexes. The in vitro experiments with purified proteins indicated that diol dehydratase‐reactivating factor (DDR) cross‐reactivates the inactivated glycerol dehydratase, whereas glycerol dehydratase‐reactivating factor (GDR) did not cross‐reactivate the inactivated diol dehydratase. We investigated the molecular basis of their specificities in vitro by using purified preparations of cognate and noncognate enzymes and reactivating factors. DDR mediated the exchange of glycerol dehydratase‐bound cyanocobalamin for free adeninylpentylcobalamin, whereas GDR cannot mediate the exchange of diol dehydratase‐bound cyanocobalamin for free adeninylpentylcobalamin. As judged by denaturing PAGE, the glycerol dehydratase–DDR complex was cross‐formed, although the diol dehydratase–GDR complex was not formed. There were no specificities of reactivating factors in the ATP‐dependent dissociation of enzyme–reactivating factor complexes. Thus, it is very likely that the specificities of reactivating factors are determined by the capability of reactivating factors to form complexes with apoenzymes. A modeling study based on the crystal structures of enzymes and reactivating factors also suggested why DDR cross‐forms a complex with glycerol dehydratase, and why GDR does not cross‐form a complex with diol dehydratase.
Stephen's Banded Snake envenomation treated with tiger snake antivenom
Authors: Hession Michael
Published: October 2007

Demonstration of the use of Tiger Snake Anti‐venom in Stephen's Banded Snake envenomation is described. The patient presented with a clear history of a bite and a mild headache. Subsequently, the patient developed defibrination coagulopathy. A swab of the bite site reacted to the Tiger anti‐venom on the Commonwealth Serum Laboratories anti‐venom detection kit. Two ampoules of anti‐venom were used. A mild allergic reaction to tiger snake antivenom developed. There was resolution of the coagulopathy.
Management and outcome of spontaneous pneumothoraces at three urban EDs
Authors: Paoloni Richard
Published: October 2007

Objective:  Spontaneous pneumothoraces predominantly affect young people. Substantial morbidity arises from the disease, invasive procedures and hospitalization. The literature is inconsistent regarding optimal management. This retrospective study aimed to define factors affecting the outcome of these patients.

Methods:  Patients were identified from databases at three EDs for explicit retrospective medical record review. Iatrogenic and traumatic pneumothoraces were excluded. Data collected included demographic details, treatment and outcome. The primary outcome was failure of initial treatment, defined as the need for a second treatment modality (including inpatient pleurodesis for persistent air leak) or re‐presentation within 5 days of treatment cessation. Associations with the primary outcome in primary spontaneous pneumothorax were assessed using logistic regression.

Results:  One hundred and twenty‐one spontaneous pneumothoraces were identified. There was poor correlation between clinician estimates and objective measurement of pneumothorax size. Pneumothorax size, measured using the average interpleural distance method, was the only independent predictor of treatment failure. Initial treatment modality demonstrated a confounder relationship with outcome. Subgroup analysis for patients treated with continuous pleural drainage compared small and large calibre drainage tubes, with no significant difference found.

Conclusions:  Objective measurement of pneumothorax size was the only independent predictor of treatment failure, with initial treatment modality having a confounding effect. Algorithms regarding initial treatment modalities are usually based on pneumothorax size and presence or absence of symptoms. The present study illustrates the importance of objective assessment of pneumothorax size in both clinical research and clinical practice.
Emergency medicine in a developing country: Experience from Kilimanjaro Christian Medical Centre, Tanzania, East Africa
Authors: Cox Megan , Shao John
Published: October 2007

Tanzania in East Africa has a population of over 36 million and is one of the poorest countries in the world. Life expectancy has declined and infant mortality rates are increasing. Four consultant specialist hospitals and 17 regional hospitals service the mainland. Kilimanjaro Christian Medical Centre is a major specialist teaching hospital with 500 beds, serving the entire north‐west of the country. There is a small ‘casualty’ ward with three cubicles and one resuscitation room. Malaria, HIV, respiratory infections and gastroenteritis are the chief causes of death in children. Changing lifestyle and Western influences have increased diabetes and vascular disease in adults, and large numbers of trauma deaths are increasingly encountered. Kilimanjaro Christian Medical Centre ‘Casualty’ admission data are presented, as well as an insight into the challenges of emergency medicine in this country.
Air bag‐associated burn
Authors: Sinha Vivek K , MacGill Kirstie A
Published: October 2007

Burns due to the deployment of air bags have been occasionally described in recent years. Most reports are about injuries in the USA. However, there have been few reports of this type of injury in Australia. This case report details such an injury that took place in a road traffic accident in Melbourne, Australia.
Effectiveness of monetary policy and limited asset market participation: Neoclassical versus Keynesian effects
Authors: Bartolomeo Giovanni Di , Rossi Lorenza
Published: October 2007

This paper investigates the effects of limited asset market participation on the effectiveness of monetary policy in a New Keynesian Dynamic Stochastic General Equilibrium model. Although an increase in consumers who cannot access financial markets reduces the effects of interest rate policies through consumption inter‐temporal allocation (neoclassical or permanent income effect), we find an opposite result: monetary policy becomes more effective as the degree of financial market participation falls. The reason has a very Keynesian flavor.
HLA class II similarities in Iranian Kurds and Azeris
Authors: Farjadian S. , Ghaderi A.
Published: October 2007

The genetic relationship between Kurds and Azeris of Iran was investigated based on human leukocyte antigen (HLA) class II profiles. HLA typing was performed using polymerase chain reaction/restriction fragment‐length polymorphism (PCR/RFLP) and PCR/sequence‐specific primer (PCR/SSP) methods in 100 Kurds and 100 Azeris. DRB1*1103/04, DQA1*0501 and DQB1*0301 were the most common alleles and DRB1*1103/04‐DQA1*0501‐DQB1*0301 was the most frequent haplotype in both populations. No significant difference was observed in HLA class II allele distribution between these populations except for DQB1*0503 which showed a higher frequency in Kurds. Neighbor‐joining tree based on Nei's genetic distances and correspondence analysis according to DRB1, DQA1 and DQB1 allele frequencies showed a strong genetic tie between Kurds and Azeris of Iran. The results of amova revealed no significant difference between these populations and other major ethnic groups of Iran. No close genetic relationship was observed between Azeris of Iran and the people of Turkey or Central Asians. According to the current results, present‐day Kurds and Azeris of Iran seem to belong to a common genetic pool.
Association of MCP‐1 and CCR2 polymorphisms with the risk of late acute rejection after renal transplantation in Korean patients
Authors: Kang S. W. , Park S. J. , Kim Y. W. , Kim Y. H. , Sohn H. S. , Yoon Y. C. , Joo H. , Jeong K. H. , Lee S. H. , Lee T. W. , Ihm C. G.
Published: October 2007

Among the factors modulating transplant rejection, chemokines and their respective receptors deserve special attention. Increased expression of monocyte chemoattractant protein‐1 (MCP‐1) and its corresponding receptor (chemokine receptor‐2, CCR2) has been implicated in renal transplant rejection. To determine the impact of the MCP‐1‐2518G and CCR2‐64I genotypes on renal allograft function, 167 Korean patients who underwent transplantation over a 25‐year period were evaluated. Genomic DNA was genotyped using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Fifty‐five (32.9%) patients were homozygous for the MCP‐1‐2518G polymorphism. Nine (5.4%) patients were homozygous for the CCR2‐64I polymorphism. None of the investigated polymorphism showed a significant shift in long‐term allograft survival. However, a significant increase was noted for the risk of late acute rejection in recipients who were homozygous for the MCP‐1‐2518G polymorphism (OR, 2.600; 95% CI, 1.125–6.012; P = 0.022). There was also an association between the MCP‐1‐2518G/G genotype and the number of late acute rejection episodes (P = 0.024). Although there was no difference in the incidence of rejection among recipients stratified by the CCR2‐V64I genotype, recipients with the CCR2‐V64I GG genotype in combination with the MCP‐1‐2518G/G genotype had a significantly higher risk of acute or late acute rejection among the receptor‐ligand combinations (P = 0.006, P = 0.008, respectively). The MCP‐1 variant may be a marker for risk of late acute rejection in Korean patients.
Autism Brain Tissue Banking
Authors: Haroutunian Vahram , Pickett Jane
Published: October 2007

One avenue of progress toward understanding the neurobiological basis of autism is through the detailed study of the post‐mortem brain from affected individuals. The primary purpose of autism brain tissue banking is to make well‐characterized and optimally preserved post‐mortem brain tissue available to the neuroscience research community. In this paper we discuss our current understanding of the criteria for optimal characterization and preservation of post‐mortem brain tissue; the pitfalls associated with inadequate clinical and neuropathological characterization and the advantages and disadvantages of post‐mortem studies of the brain. We then describe the current status of the brain tissue bank supported by the Autism Tissue Program, including the demographic characteristics of the tissue donors, post‐mortem interval, sex, age and the method of preservation. Finally, we provide information on the policies and procedures that govern the distribution of brain specimens by this bank and the nature of the studies that are currently being supported directly by this program.
The Neuropathology of Autism
Authors: Casanova Manuel F.
Published: October 2007

Autism is a brain disorder characterized by abnormalities in how a person relates and communicates to others. Both post‐mortem and neuroimaging studies indicate the presence of increased brain volume and, in some cases, an altered gray/white matter ratio. Contrary to established gross findings there is no recognized microscopic pathology to autism. Early studies provided multiple leads none of which have been validated. Clinicopathological associations have been difficult to sustain when considering possible variables such as use of medications, seizures, mental retardation and agonal/pre‐agonal conditions. Research findings suggest widespread cortical abnormalities, lack of a vascular component and an intact blood–brain barrier. Many of the previously mentioned findings can be explained in terms of a mini‐columnopathy. The significance of future controlled studies should be judged based on their explanatory powers; that is, how well do they relate to brain growth abnormalities and/or provide useful clinicopathological correlates.
Feminist Mentoring and Female Graduate Student Success: Challenging Gender Inequality in Higher Education
Authors: Dua Priya
Published: October 2007

There has been much research on gender inequality in higher education and the benefits of mentoring. However, since mentoring has been a predominantly male experience, most research with female students focuses on advising relationships. For women, there is a significant difference between experiences of advising and mentoring with problematic effects for them. Attrition rates are high for both men and women but the causes of female attrition are unique and possibly related to their mentoring experiences. Mentoring remains largely an informal activity in most graduate departments, and due to the patriarchal nature of graduate education, it has been a predominantly male experience (Lovitts 2001). In this paper, I provide an overview of the different types of advising/mentoring relationships for women in doctoral programs and the benefits of these for them. The paper concludes with a discussion of policy implications for graduate departments, suggestions for future research, and a call for developing and implementing feminist models of mentoring for all graduate students.
Modesty without Illusion
Authors: BRENNAN JASON
Published: October 2007

The common image of the fully virtuous person is of someone with perfect self‐command and self‐perception, who always makes correct evaluations. However, modesty appears to be a real virtue, and it seems contradictory for someone to believe that she is modest. Accordingly, traditional defenders of phronesis (the view that virtue involves practical wisdom) deny that modesty is a virtue, while defenders of modesty such as Julia Driver deny that phronesis is required for virtue. I offer a new theory of modesty—the two standards account—under which phronesis and modesty are reconciled. Additionally, since the two standards account involves reflection on moral ideals, I provide an account of the proper nature of moral ideals.
The Mere Addition Paradox, Parity and Vagueness*
Authors: QIZILBASH MOZAFFAR
Published: October 2007

Derek Parfit’s mere addition paradox has generated a large literature. This paper articulates one response to this paradox—which Parfit himself suggested—in terms of a formal account of the relation of parity. I term this response the ‘parity view’. It is consistent with transitivity of ‘at least as good as’, but implies incompleteness of this relation. The parity view is compatible with critical‐band utilitarianism if this is adjusted to allow for vagueness. John Broome argues against accounts which involve incompleteness. He thinks they are based on an intuition of ‘neutrality’, which is most naturally understood in terms of equality. There is no rationale, on Broome’s view, for seeing it as ‘incommensurateness’ which leads to incompleteness. Parity provides one. Broome’s worries that ‘incommensurateness’ makes neutrality implausibly ‘greedy’, and that ‘incommensurateness’ and vagueness are incompatible do not constitute a knock‐down case against the parity view. Similar worries arise for his preferred vagueness view.
Multifractal diversity‐area relationship at small scales in dune slack plant communities
Authors: Yakimov Basil N. , Bossuyt Beatrijs , Iudin Dmitry I. , Gelashviliy David B.
Published: October 2007

The species‐area relationship, SAR, is the first approximation to describe the spatial structure at the community level. This relation, however, takes only species richness into account and ignores interspecific differences in spatial patterns, such as dominance or rarity. The description of such patterns may be achieved via multifractal analysis, allowing the transition from SAR to the diversity‐area relation, DAR. This study analyzes the spatial structure of a dune slack plant community, which can be considered as a multifractal object, at a scale level between 25 cm and 2 m. We applied a complete multifractal analysis including both Rényi spectrum and multifractal spectrum, using confidence intervals. The results indicated that we succeeded for the first time deriving generalized Rényi dimensions’ spectrum without anomalies for diversity patterns in a plant community. We propose an interpretation of the multifractal spectrum in ecological terms as diversity patterns of subsets of species with a similar spatial distribution.
When is a maternal effect adaptive?
Authors: J. Marshall Dustin , Uller Tobias
Published: October 2007

Maternal effects have become an important field of study in evolutionary ecology and there is an ongoing debate regarding their adaptive significance. Some maternal effects can act to increase offspring fitness and are called ‘adaptive maternal effects’. However, other maternal effects decrease offspring fitness and there is confusion regarding whether certain maternal effects are indeed adaptive or merely physiological inevitabilities. Here we suggest that the focus on the consequences of maternal effects for offspring fitness only and the use of ‘snapshot’ estimates of fitness have misdirected our effort to understand the evolution of maternal effects. We suggest that selection typically acts on maternal effects to maximise maternal rather than (or in addition to) offspring fitness. We highlight the importance of considering how maternal effects influence maternal fitness across a mother's lifetime and describe four broad types of maternal effects using an outcome‐based approach. Overall, we suggest that many maternal effects will have an adaptive basis for mothers, regardless of whether these effects increase or decrease survival or reproductive success of individual offspring.
Flow Instability and Disk Vibration of Shrouded Corotating Disk System
Authors: Kanagai S. , Suzuki J. , Obi S. , Masuda S.
Published: October 2007

This paper focuses on the interaction between the flow unsteadiness and disk vibration of shrouded corotating disk system to identify the nature of the flow-induced vibration of disks in the wide range of rotation speed below critical. Special attention is paid to the role of the vortical flow structure on the disk vibration and vice versa. The water test rig for optical measurement and the air test rig for hot-wire and vibration measurements are employed, both being axisymmetric models of 3.5in. hard disk drive. Before investigating fluid-solid interaction, the velocity and vorticity fields between disks are examined by employing a particle image velocimetry, in order to check the flow within our own apparatus to have the same characteristics as those commonly accepted. In the course of this preliminary experiment, it is found that “vortical structures” reported in the previous papers based on the flow visualization are actually “vortices” in the sense that it exhibits closed streamlines with concentrated vorticity at its center when seen from an observer rotating with the structure itself. The measurements of out-of-plane displacement of the disk employing different disk materials reveal that disk vibration begins to occur even in low subcritical speed range, and amplitude of nonrepeatable run out (NRRO) can be uniquely correlated by using the ratio between the rotating speed and the critical speed. The power spectral densities of disk vibration showed that the disk vibrates as a free vibration triggered by, but not forced by, the flow unsteadiness even in the high subcritical speed range. The disk vibration has negligible effect on the vortical flow structure suggesting the soundness of the rigid disk assumption employed in the existing CFD. However, RRO has significant influence on the flow unsteadiness even if the disks are carefully manufactured and assembled. Since the RRO is unavoidable in the real disk system, the flat disk assumption should be considered more carefully.
On the Use of High-Order Accurate Solutions of PNS Schemes as Basic Flows for Stability Analysis of Hypersonic Axisymmetric Flows
Authors: Hejranfar Kazem , Esfahanian Vahid , Darian Hossein Mahmoodi
Published: October 2007

High-order accurate solutions of parabolized Navier–Stokes (PNS) schemes are used as basic flow models for stability analysis of hypersonic axisymmetric flows over blunt and sharp cones at Mach 8. Both the PNS and the globally iterated PNS (IPNS) schemes are utilized. The IPNS scheme can provide the basic flow field and stability results comparable with those of the thin-layer Navier–Stokes (TLNS) scheme. As a result, using the fourth-order compact IPNS scheme, a high-order accurate basic flow model suitable for stability analysis and transition prediction can be efficiently provided. The numerical solution of the PNS equations is based on an implicit algorithm with a shock fitting procedure in which the basic flow variables and their first and second derivatives required for the stability calculations are automatically obtained with the fourth-order accuracy. In addition, consistent with the solution of the basic flow, a fourth-order compact finite-difference scheme, which does not need higher derivatives of the basic flow, is efficiently implemented to solve the parallel-flow linear stability equations in intrinsic orthogonal coordinates. A sensitivity analysis is also conducted to evaluate the effects of numerical dissipation and grid size and also accuracy of computing the basic flow derivatives on the stability results. The present results demonstrate the efficiency and accuracy of using high-order compact solutions of the PNS schemes as basic flow models for stability and transition prediction in hypersonic flows. Moreover, indications are that high-order compact methods used for basic-flow computations are sensitive to the grid size and especially the numerical dissipation terms, and therefore, more careful attention must be kept to obtain an accurate solution of the stability and transition results.
Numerical Simulation of Vortex Shedding and Lock-in Characteristics for a Thin Cambered Blade
Authors: Zhu Baoshan , Lei Jun , Cao Shuliang
Published: October 2007

In this paper, vortex-shedding patterns and lock-in characteristics that vortex-shedding frequency synchronizes with the natural frequency of a thin cambered blade were numerically investigated. The numerical simulation was based on solving the vorticity-stream function equations with the fourth-order Runge–Kutta scheme in time and the Chakravaythy–Oscher total variation diminishing (TVD) scheme was used to discretize the convective term. The vortex-shedding patterns for different blade attack angles were simulated. In order to confirm whether the vortex shedding would induce blade self-oscillation, numerical simulation was also carried out for blade in a forced oscillation. By changing the pitching frequency and amplitude, the occurrence of lock-in at certain attack angles was determined. Inside the lock-in zone, phase differences between the blade’s pitching displacement and the torque acting on the blade were used to infer the probability of the blade self-oscillation.
Linear Instability of Entry Flow in a Pipe
Authors: Sahu Kirti Chandra , Govindarajan Rama
Published: October 2007

We show that flow in the entry region of a circular pipe is linearly unstable at a Reynolds number of 1000, a factor of 10 smaller than assumed hitherto. The implication that dynamics in this region could greatly hasten the transition to turbulence assumes relevance because in spite of major recent progress, the issue of how pipe flow becomes turbulent is far from settled. Being axisymmetric and close to the centerline, the present instability would be easily distinguishable in an experiment from other generators of turbulence.
Major Australian-Antarctic Plate Reorganization at Hawaiian-Emperor Bend Time
Authors: Whittaker J. M. , Müller R. D. , Leitchenkov G. , Stagg H. , Sdrolias M. , Gaina C. , Goncharov A.
Published: October 2007

A marked bend in the Hawaiian-Emperor seamount chain supposedly resulted from a recent major reorganization of the plate-mantle system there 50 million years ago. Although alternative mantle-driven and plate-shifting hypotheses have been proposed, no contemporaneous circum-Pacific plate events have been identified. We report reconstructions for Australia and Antarctica that reveal a major plate reorganization between 50 and 53 million years ago. Revised Pacific Ocean sea-floor reconstructions suggest that subduction of the Pacific-Izanagi spreading ridge and subsequent Marianas/Tonga-Kermadec subduction initiation may have been the ultimate causes of these events. Thus, these plate reconstructions solve long-standing continental fit problems and improve constraints on the motion between East and West Antarctica and global plate circuit closure.
Absence of Cooling in New Zealand and the Adjacent Ocean During the Younger Dryas Chronozone
Authors: Barrows Timothy T. , Lehman Scott J. , Fifield L. Keith , De Deckker Patrick
Published: October 2007

As the climate warmed at the end of the last glacial period, a rapid reversal in temperature, the Younger Dryas (YD) event, briefly returned much of the North Atlantic region to near full-glacial conditions. The event was associated with climate reversals in many other areas of the Northern Hemisphere and also with warming over and near Antarctica. However, the expression of the YD in the mid- to low latitudes of the Southern Hemisphere (and the southwest Pacific region in particular) is much more controversial. Here we show that the Waiho Loop advance of the Franz Josef Glacier in New Zealand was not a YD event, as previously thought, and that the adjacent ocean warmed throughout the YD.
Microbial Population Structures in the Deep Marine Biosphere
Authors: Huber Julie A. , Mark Welch David B. , Morrison Hilary G. , Huse Susan M. , Neal Phillip R. , Butterfield David A. , Sogin Mitchell L.
Published: October 2007

The analytical power of environmental DNA sequences for modeling microbial ecosystems depends on accurate assessments of population structure, including diversity (richness) and relative abundance (evenness). We investigated both aspects of population structure for microbial communities at two neighboring hydrothermal vents by examining the sequences of more than 900,000 microbial small-subunit ribosomal RNA amplicons. The two vent communities have different population structures that reflect local geochemical regimes. Descriptions of archaeal diversity were nearly exhaustive, but despite collecting an unparalleled number of sequences, statistical analyses indicated additional bacterial diversity at every taxonomic level. We predict that hundreds of thousands of sequences will be necessary to capture the vast diversity of microbial communities, and that different patterns of evenness for both high- and low-abundance taxa may be important in defining microbial ecosystem dynamics.
Methyl Salicylate Is a Critical Mobile Signal for Plant Systemic Acquired Resistance
Authors: Park Sang-Wook , Kaimoyo Evans , Kumar Dhirendra , Mosher Stephen , Klessig Daniel F.
Published: October 2007

In plants, the mobile signal for systemic acquired resistance (SAR), an organism-wide state of enhanced defense to subsequent infections, has been elusive. By stimulating immune responses in mosaic tobacco plants created by grafting different genetic backgrounds, we showed that the methyl salicylate (MeSA) esterase activity of salicylic acid–binding protein 2 (SABP2), which converts MeSA into salicylic acid (SA), is required for SAR signal perception in systemic tissue, the tissue that does not receive the primary (initial) infection. Moreover, in plants expressing mutant SABP2 with unregulated MeSA esterase activity in SAR signal–generating, primary infected leaves, SAR was compromised and the associated increase in MeSA levels was suppressed in primary infected leaves, their phloem exudates, and systemic leaves. SAR was also blocked when SA methyl transferase (which converts SA to MeSA) was silenced in primary infected leaves, and MeSA treatment of lower leaves induced SAR in upper untreated leaves. Therefore, we conclude that MeSA is a SAR signal in tobacco.
Life with Oxygen
Authors: Semenza Gregg L.
Published: October 2007

The survival of all metazoan organisms is dependent on the regulation of O
2
delivery and utilization to maintain a balance between the generation of energy and production of potentially toxic oxidants. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis and has essential roles in metazoan development, physiology, and disease pathogenesis. Remarkable progress has been made in delineating the molecular mechanisms whereby changes in cellular oxygenation are transduced to the nucleus as changes in gene transcription through the activity of HIF-1. Pharmacologic agents that activate or inhibit the hypoxia signal transduction pathway may be useful therapies for ischemic and neoplastic disorders, respectively, which are the major causes of mortality in industrialized societies.
Use of
Saccharomyces cerevisiae
-Expressed Recombinant Nucleocapsid Protein To Detect Hantaan Virus-Specific Immunoglobulin G (IgG) and IgM in Oral Fluid
Authors: Petraitytė Rasa , Jin Li , Hunjan Rashpal , Ražanskienė Aušra , Žvirblienė Aurelija , Sasnauskas Kęstutis
Published: October 2007

Hantaan virus is the causative agent of severe hemorrhagic fever with renal syndrome. Clinical surveillance for Hantaan virus infection is unreliable, and laboratory verification is essential. The detection of virus-specific immunoglobulin M (IgM) and IgG in serum is most commonly used for the diagnosis of hantavirus infection. Testing of oral fluid samples instead of serum offers many advantages for surveillance. However, commercial tests for hantavirus-specific antibodies are unavailable. For the detection of Hantaan virus in the oral fluid of humans, we have developed a monoclonal antibody-based capture enzyme-linked immunosorbent IgM assay (IgM capture ELISA) and indirect enzyme-linked immunosorbent IgG and IgM assays (indirect IgG and IgM ELISAs) for paired serum and oral fluid samples using the
Saccharomyces cerevisiae
yeast-expressed nucleocapsid protein of the Hantaan-Fojnica virus. The sensitivity and specificity of the oral fluid IgM capture ELISA in comparison with the results of the serum Hantaan virus IgM assay were 96.7% and of 94.9%, respectively. Thus, data on the overall performance of the oral fluid IgM capture ELISA are in close agreement with those of the serum IgM assay, and the method exhibits the potential to serve as an easily transferable tool for large-scale epidemiological studies. Data on the indirect IgM ELISA also showed close agreement with the serum IgM assay data; however, the indirect IgG ELISA displayed a lower sensitivity and a lower specificity. In conclusion, the IgM capture ELISA can be used with oral fluid instead of serum samples for the diagnosis of Hantaan virus infection.