bluuebunny/crossref_metadata_2025 huggingface dataset:
Band offsets for the epitaxial TiO2/SrTiO3/Si(001) system
Authors: Tuan A. C. , Kaspar T. C. , Droubay T. , Rogers J. W. , Chambers S. A.
Published: October 2003

We have used x-ray photoelectron spectroscopy with high energy resolution to determine band discontinuities at the two buried interfaces of the epitaxial TiO2 (anatase)/SrTiO3/Si(001) system. The valence band offsets are −2.1±0.1 eV and +0.2±0.1 eV at the SrTiO3/Si and TiO2/SrTiO3 heterojunctions, respectively. Assuming bulk band gaps for the SrTiO3 and TiO2 epitaxial films, the associated conduction band offsets are +0.1±0.1 eV and +0.1±0.1 eV. Si at the interface is in a flatband state, indicating a very low density of electronic states. These results suggest that spin-polarized electron injection from ferromagnetic Co-doped TiO2 anatase into Si should be facile.
Derepression of BDNF Transcription Involves Calcium-Dependent Phosphorylation of MeCP2
Authors: Chen Wen G. , Chang Qiang , Lin Yingxi , Meissner Alexander , West Anne E. , Griffith Eric C. , Jaenisch Rudolf , Greenberg Michael E.
Published: October 2003

Mutations in
MeCP2
, which encodes a protein that has been proposed to function as a global transcriptional repressor, are the cause of Rett syndrome (RT T), an X-linked progressive neurological disorder. Although the selective inactivation of MeCP2 in neurons is sufficient to confer a Rett-like phenotype in mice, the specific functions of MeCP2 in postmitotic neurons are not known. We find that MeCP2 binds selectively to
BDNF
promoter III and functions to repress expression of the
BDNF
gene. Membrane depolarization triggers the calcium-dependent phosphorylation and release of MeCP2 from
BDNF
promoter III, thereby facilitating transcription. These studies indicate that MeCP2 plays a key role in the control of neuronal activity–dependent gene regulation and suggest that the deregulation of this process may underlie the pathology of RT T.
Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor
Authors: Changelian Paul S. , Flanagan Mark E. , Ball Douglas J. , Kent Craig R. , Magnuson Kelly S. , Martin William H. , Rizzuti Bonnie J. , Sawyer Perry S. , Perry Bret D. , Brissette William H. , McCurdy Sandra P. , Kudlacz Elizabeth M. , Conklyn Maryrose J. , Elliott Eileen A. , Koslov Erika R. , Fisher Michael B. , Strelevitz Timothy J. , Yoon Kwansik , Whipple David A. , Sun Jianmin , Munchhof Michael J. , Doty John L. , Casavant Jeffrey M. , Blumenkopf Todd A. , Hines Michael , Brown Matthew F. , Lillie Brett M. , Subramanyam Chakrapani , Shang-Poa Chang , Milici Anthony J. , Beckius Gretchen E. , Moyer James D. , Su Chunyan , Woodworth Thasia G. , Gaweco Anderson S. , Beals Chan R. , Littman Bruce H. , Fisher Douglas A. , Smith James F. , Zagouras Panayiotis , Magna Holly A. , Saltarelli Mary J. , Johnson Kimberly S. , Nelms Linda F. , Des Etages Shelley G. , Hayes Lisa S. , Kawabata Thomas T. , Finco-Kent Deborah , Baker Deanna L. , Larson Michael , Si Ming-Sing , Paniagua Ricardo , Higgins John , Holm Bari , Reitz Bruce , Zhou Yong-Jie , Morris Randall E. , O'Shea John J. , Borie Dominic C.
Published: October 2003

Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolongedsurvival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associatedwith hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation andin other clinical settings.
Cyclic Dynamics in a Simple Vertebrate Predator-Prey Community
Authors: Gilg Olivier , Hanski Ilkka , Sittler Benoît
Published: October 2003

The collared lemming in the high-Arctic tundra in Greenland is preyed upon by four species of predators that show marked differences in the numbers of lemmings each consumes and in the dependence of their dynamics on lemming density. A predatorprey model based on the field-estimated predator responses robustly predicts 4-year periodicity in lemming dynamics, in agreement with long-term empirical data. There is no indication in the field that food or space limits lemming population growth, nor is there need in the model to consider those factors. The cyclic dynamics are driven by a 1-year delay in the numerical response of the stoat and stabilized by strongly density-dependent predation by the arctic fox, the snowy owl, and the long-tailed skua.
Molecular Pathways of Neurodegeneration in Parkinson's Disease
Authors: Dawson Ted M. , Dawson Valina L.
Published: October 2003

Parkinson's disease (PD) is a complex disorder with many different causes, yet they may intersect in common pathways, raising the possibility that neuroprotective agents may have broad applicability in the treatment of PD. Current evidence suggests that mitochondrial complex I inhibition may be the central cause of sporadic PD and that derangements in complex I cause α-synuclein aggregation, which contributes to the demise of dopamine neurons. Accumulation and aggregation of α-synuclein may further contribute to the death of dopamine neurons through impairments in protein handling and detoxification. Dysfunction of parkin (a ubiquitin E3 ligase) and DJ-1 could contribute to these deficits. Strategies aimed at restoring complex I activity, reducing oxidative stress and α-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.
Depleting Neuronal PrP in Prion Infection Prevents Disease and Reverses Spongiosis
Authors: Mallucci Giovanna , Dickinson Andrew , Linehan Jacqueline , Klöhn Peter-Christian , Brandner Sebastian , Collinge John
Published: October 2003

The mechanisms involved in prion neurotoxicity are unclear, and therapies preventing accumulation of PrP
Sc
, the disease-associated form of prion protein (PrP), do not significantly prolong survival in mice with central nervous system prion infection. We found that depleting endogenous neuronal PrP
c
in mice with established neuroinvasive prion infection reversed early spongiform change and prevented neuronal loss and progression to clinical disease. This occurred despite the accumulation of extraneuronal PrP
Sc
to levels seen in terminally ill wild-type animals. Thus, the propagation of nonneuronal PrP
Sc
is not pathogenic, but arresting the continued conversion of PrP
c
to PrP
Sc
within neurons during scrapie infection prevents prion neurotoxicity.
DNA Methylation-Related Chromatin Remodeling in Activity-Dependent
Bdnf
Gene Regulation
Authors: Martinowich Keri , Hattori Daisuke , Wu Hao , Fouse Shaun , He Fei , Hu Yan , Fan Guoping , Sun Yi E.
Published: October 2003

In conjunction with histone modifications, DNA methylation plays critical roles in gene silencing through chromatin remodeling. Changes in DNA methylation perturb neuronal function, and mutations in a methyl-CpG–binding protein, MeCP2, are associated with Rett syndrome. We report that increased synthesis of brain-derived neurotrophic factor (BDNF) in neurons after depolarization correlates with a decrease in CpG methylation within the regulatory region of the
Bdnf
gene. Moreover, increased
Bdnf
transcription involves dissociation of the MeCP2–histone deacetylase–mSin3A repression complex from its promoter. Our findings suggest that DNA methylation–related chromatin remodeling is important for activity-dependent gene regulation that may be critical for neural plasticity.
The Genetics of Adult-Onset Neuropsychiatric Disease: Complexities and Conundra?
Authors: Kennedy James L. , Farrer Lindsay A. , Andreasen Nancy C. , Mayeux Richard , St George-Hyslop Peter
Published: October 2003

Genetic factors play a major role in the etiology of adult-onset neurodegenerative and neuropsychiatric disorders. Several highly penetrant genes have been cloned for rare, autosomal-dominant, early-onset forms of neurodegenerative diseases. These genes have provided important insights into the mechanisms of these diseases (often altering neuronal protein processing). However, the genes associated with inherited susceptibility to late-onset neurodegenerative diseases, schizophrenia, and bipolar disorder appear to have smaller effects and are likely to interact with each other (and with nongenetic factors) to modulate susceptibility and/or disease phenotype. Several strategies have recently been applied to address this complexity, leading to the identification of a number of candidate susceptibility loci/genes.
Hematoprotection by Transfer of Drug-Resistance Genes
Authors: Flasshove Michael , Moritz Thomas , Bardenheuer Walter , Seeber Siegfried
Published: October 2003

Myelosuppression represents a major side effect of cytotoxic anti-cancer agents. Infection due to granulocytopenia and the risk of bleeding due to thrombocytopenia compromise the potential of curative and palliative chemotherapy. Considering the many chemotherapeutic agents for which drug resistance genes have been described, and the recent improvements in vector and transduction technology, it seems conceivable that drug resistance gene transfer into a patient’s autologous hematopoietic stem or progenitor cells will be able to reduce or abolish chemotherapy-induced myelosuppression.
Adoptive Immunotherapy in Chimeras with Donor Lymphocytes
Authors: Kolb Hans-Jochem , Schmid Christoph , Chen Xiao , Woiciechowski Anja , Roskrow Marie , Weber Martin , Guenther Wolfgang , Ledderose Georg , Schleuning Michael
Published: October 2003

Allogeneic stem cell transplantation has a well-defined indication in the treatment of hematological malignancies. The beneficial immune effect of allogeneic marrow transplantation has long been known, but only recently have methods been developed to separate the graft-versus-leukemia (GVL) effect from graft-versus-host disease (GVHD). Animal experiments have shown that lymphocytes from the marrow donor can be transfused without causing severe GVHD if stable chimerism and tolerance is established. First clinical studies have been preformed in patients with recurrent chronic myelogenous leukemia. In these patients complete molecular remissions were induced that persist without further maintenance treatment. These results have been confirmed in larger multicenter studies in Europe and the USA. The best results were obtained in chronic myelogenous leukemia (CML); repeated successes have been reported in relapsing acute myeloid leukemia (AML), myelodysplastic syndromes and multiple myeloma (MMY), and rare responses were reported for acute lymphoid leukemia. Contrary to animal experiments GVHD has been observed in human patients although to a lesser extent than expected in transplants not given immunosuppression. Secondly myelosuppression has been observed in patients treated with relapsing CML. In CML the incidence of GVHD could be reduced by depleting CD8+ T cells from the donor lymphocyte concentrate. Alternatively only small numbers of T lymphocytes can be transfused and in the case of failing responses, the numbers of donor lymphocytes may be increased. Results in recurrent AML have been improved by the use of low-dose cytosine arabinoside, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor mobilized blood cells as compared to lymphocytes only. In MMY the response rate is higher than in AML, but the remissions are of limited duration in most patients. Several protocols have been designed to include preemptive donor lymphocyte transfusion in patients with a high relapse risk after transplantation. Problems remain to avoid chronic GVHD and to circumvent the immune escape mechanisms of leukemia.
On Making Behavioral Genetics Truly Developmental
Authors: Gottlieb Gilbert
Published: October 2003

What will it take to make behavioral genetics truly developmental? In my opinion, the purely statistical population view will have to be abandoned in favor of the study of individuals: An analysis of the bi-directional relations from gene action to the external environment over the life course, including the prenatal period. I critically examine the somewhat vexed concept of ‘gene-environment interaction’, a crucial first step in correctly understanding the relational view of causality at the organism-environment level of analysis. I conclude by presenting a highly detailed psychobiological model for analyzing behavioral development, with special attention to the genetic level of analysis.
Ifosfamide in the Treatment of Head and Neck Cancer
Authors: Airoldi M. , Cortesina G. , Giordano C. , Pedani F. , Bumma C.
Published: October 2003

Ifosfamide (IFO) has demonstrated activity in recurrent/metastatic squamous cell head and neck carcinoma with an overall response rate of 24–26%. Better results are reported for chemotherapy-naive patients; in heavily pretreated cases results are poor and toxicity unacceptable. Cisplatin-IFO combination in stage III–IV is probably more active than IFO alone (ORR = 60–72 vs. 50%) but is indicated in patients who desire aggressive treatment and are physically able to tolerate the drugs. The carboplatin-IFO scheme is better tolerated than the cisplatin-IFO regimen with superimposable clinical results (ORR = 69%; CR = 15%). Carboplatin-taxol-IFO is one of the most active regimens in recurrent (ORR = 59%; CR = 17%) and in locally advanced (ORR = 81%; CR = 31%) head and neck cancer. Its role in the multidisciplinary treatment of advanced head and neck cancer is under investigation. In recurrent/metastatic undifferentiated nasopharygeal carcinoma, IFO combinations have proven to be effective as first- and second-line treatment.
Ifosfamide in Thymic Neoplasms
Authors: Daniele O. , Fornasiero A.
Published: October 2003

The role of systemic chemotherapy and optimal regimen in thymic neoplasms remains uncertain, because they are rare mediastinal tumors, frequently encapsulated or noninvasive at the time of presentation and surgical excision is adequate treatment. Chemotherapy is an essential treatment modality in advanced or recurrent disease and an increased number of publications on this aspect of management has appeared in the last 10 years. Both single-agent and combination chemotherapy have demonstrated activity in the adjuvant and neoadjuvant settings. There are little data concerning the activity of ifosfamide in thymoma and further investigation of the role of this drug in combination chemotherapy regimens, particularly as an alternative to the inclusion of cyclophosphamide, is warranted.
Ifosfamide in Non-Small Cell Lung Cancer
Authors: Boni C. , Zanelli F.
Published: October 2003

In recent years the role of chemotherapy in advanced non-small cell lung cancer (NSCLC) has been well established. Ifosfamide is an old drug still considered an effective cytostatic agent in the treatment of NSCLC. As a single agent, it has showed a response rate of 20–25%. These results are improved when it is used in combination with cisplatin and mitomycin C. Moreover, in recent years, several new drugs like gemcitabine, taxanes and vinorelbine have been identified, and combinations of two or three drugs have been tested in patients with advanced NSCLC. This paper reviews the main studies recently conducted for the treatment of NSCLC, considering the results obtained by ifosfamide alone and in combination. Three-drug regimens including first-generation cytostatic agents achieve a response rate of about 40% and median survival of 10 months. In combinations with new drugs, ifosfamide shows an improvement in response rate (50%) with a median survival of more than 1 year. Open questions in the treatment of NSCLC are whether three-drug are better than two-drug combinations, and whether cisplatin is still required.
Ifosfamide in the Treatment of Malignant Epithelial Ovarian Tumors
Authors: Lissoni A.A. , Fei F. , Rossi R. , Fruscio R. , Villa A. , Zani G.
Published: October 2003

Ifosfamide is one of the best-known alkylating agents. In advanced epithelial ovarian cancer, it has been tested in association with cisplatin, achieving results equal, if not better than cyclophosphamide, with acceptable toxicity. In second-line therapy, it shows remarkable activity, even in patients refractory to cisplatin already treated with cyclophosphamide, with more severe, but always manageable toxicity. In gynecological sarcomas, ifosfamide is, together with doxorubicin, the reference drug for chemotherapy.
Ifosfamide in Germ Cell Tumors
Authors: Einhorn L.H.
Published: October 2003

Ifosfamide has always had significant single-agent activity in patients with germ cell tumors. We first began studies of cisplatin + ifosfamide combination chemotherapy as salvage chemotherapy in 1982. The regimen of etoposide (VP-16) + ifosfamide + cisplatin (VIP) was initially utilized as third-line chemotherapy. Even in this refractory setting, we were able to cure a small cohort of patients. Ifosfamide-cisplatin combination chemotherapy then became a standard second-line chemotherapy program, and achieved a 25% cure rate. Subsequent phase III studies compared VIP to bleomycin + etoposide + cisplatin (BEP) as initial chemotherapy. Although the results of the ifosfamide-based regimen were slightly better, there was no statistically significant difference and BEP was less toxic. However, for individual patients with concern for bleomycin-induced pulmonary fibrosis, VIP remains an attractive first-line regimen.
Ifosfamide with Regional Hyperthermia in Soft-Tissue Sarcomas
Authors: Schlemmer M. , Wendtner C.M. , Issels R.D.
Published: October 2003

For high-risk soft tissue sarcomas (HR-STS) of adults, new treatment strategies are needed to improve outcome with regard to local control and overall survival. Therefore, systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. The combination with regional hyperthermia as a new treatment strategy seems to open a new therapeutic window.
Ifosfamide in the Adjuvant Therapy of Soft Tissue Sarcomas
Authors: Frustaci S. , De Paoli A. , Bidoli E. , La Mura N. , Berretta M. , Buonadonna A. , Boz G. , Gherlinzoni F.
Published: October 2003

Ifosfamide and anthracyclines are the only active agents in advanced soft tissue sarcomas. Doxorubicin was always used in sarcomas, whereas ifosfamide was reintroduced in the clinic after the discovery of mesna which prevents its typical dose-limiting toxicity: hemorrhagic cystitis. In the adjuvant setting, doxorubicin was used alone or in combination in the first-generation trials, whereas its parent compounds epirubicin and ifosfamide were employed in the second-generation adjuvant trials, which started in the early 90s. Other relevant aspects of the second-generation trials are the use of the hematopoietic growth factors and the increase of the dose intensity, the introduction of more restrictive selection criteria and the use of the two most active agents, ifosfamide and anthracyclines. Only the Italian cooperative trial has been concluded, and the results reported and updated. After a median follow-up of 89.6 months (range 56–119), the intention-to-treat analysis still reveals a difference in overall survival which, however, is not statistically significant. However, the 5-year overall survival estimate, which is a reasonable end point for the survival analysis of adjuvant treatment in soft tissue sarcomas, was 66.0 and 46.1% for the treatment and the control groups, respectively (p = 0.04).
Ifosfamide in Hematological Malignancies of Adults
Authors: Rodeghiero F. , Elice F.
Published: October 2003

Ifosfamide is an alkylating agent with a broad spectrum of activity in solid tumors and hematological malignancies. In this review we will illustrate its use in the treatment of lymphomas and Hodgkin’s disease and the results of the principal studies which have investigated ifosfamide-containing regimens. Ifosfamide has been mainly used, in combination with other drugs, as a component of salvage regimens for relapsed or primarily refractory lymphoma. These regimens induced a variable clinical response rate (complete remissions ranging from 6 up to 73% and overall response rate from 24 to 72%). High-dose ifosfamide, in combination with etoposide or mitoxantrone, showed a good potential for mobilization of peripheral stem cells while reducing the tumor burden. Ifosfamide-based regimens are also being evaluated in the treatment of newly diagnosed patients in sequential, response-based protocols, using many non-cross-resistant drugs.
Receptor-Mediated Biphasic Alteration of Hepatocellular Transport from Hepatocyte to Bile Canaliculi as Measured by Near-Infrared Spectroscopy: A Novel Test with Glucagon for Biliary Excretion
Authors: Tanaka A. , Shinohara H. , Yamaoka Y.
Published: October 2003

As glucagon is known to cause a receptor-mediated increase in intracellular calcium and cyclic AMP, we have developed a novel method of evaluating the integrity of the signal transduction and transport system using glucagon-induced changes in indocyanine green (ICG) excretion. The kinetics of the hepatocellular concentration of ICG at 4-second intervals was analyzed by near-infrared spectroscopy in vivo on the liver surface. After intravenous injection of 0.5 mg/kg ICG to rabbits, absorbance of ICG increased and then decreased according to the two-compartment model: ICG(t) = –Aexp(–αt) + Bexp(–βt), where α and β (min–1) indicate the time constants of uptake and excretion, respectively. During the excretion phase, 40 µg/kg glucagon was infused as a bolus via the portal vein. A biphasic acceleration and retardation of ICG excretion from the baseline exponential decay was observed in the controls. In order to perturb the glucagon response, colchicine, ouabain, wortmannin and an ischemia-reperfusion insult were employed. Colchicine, ouabain and wortmannin abolished the biphasic acceleration and retardation of ICG excretion. Glucagon response was absent upon the ischemia-reperfusion insult. The observed biphasic response to glucagon clearly indicates that glucagon modulates bile canalicular contraction and peristalsis via the two glucagon receptors and these second messengers. The glucagon response requires the integrity of signal transduction, cytoskeleton structure, myosin function, and bile canalicular pump.
Distance of Cecum Ligated Influences Mortality, Tumor Necrosis Factor-Alpha and Interleukin-6 Expression following Cecal Ligation and Puncture in the Rat
Authors: Singleton K.D. , Wischmeyer P.E.
Published: October 2003

Background/Aim: A mainstay of laboratory research into new therapies for sepsis has been the cecal ligation and puncture (CLP) model in rodents. Previous data indicate that the number of punctures made in the cecum and needle size utilized are primary determinants of mortality. Despite this, variability exists in mortality from this model, even when needle size is held constant. The aim of the present study was to evaluate the influence of the length of cecum ligated, independent of needle size, as a determinant of mortality. Materials and Methods: We evaluated this by ligating various cecal lengths in male Sprague-Dawley rats. A double puncture was then made with a 20-gauge needle, and mortality was analyzed. Plasma TNF-α and IL-6 expression was assessed at 6 h. Animals received no antibiotics, were not fasted, and fluid resuscitation was administered. Results: We determined that mortality does not begin to occur until a distance of >5% of cecal length is ligated. Further, our findings indicate that in this model, 90–100% mortality occurs 4 days following CLP when a distance of >30% is ligated. TNF-α and IL-6 expression is markedly increased with increasing length of cecum ligated. Conclusions: Our data demonstrate that the length of cecum ligated is a major determinant of mortality in the CLP model of sepsis. These findings indicate that investigators must rigorously control the distance of the cecum ligated in order to generate consistent mortality and inflammation data when utilizing the CLP model in rats. Further, the mortality from this model can be adjusted to fit the individual needs of a particular experiment.
Persistent Extracellular Matrix Remodelling at the Interface to Polymers Used for Hernia Repair
Authors: Junge K. , Rosch R. , Bialasinski L. , Klinge U. , Klosterhalfen B. , Schumpelick V.
Published: October 2003

On the one hand, recurrence rates and postoperative complications following hernia repair are supposed to be influenced by the kind of mesh material used. On the other hand, an impaired collagen metabolism and cleavage within connective tissue has been suggested as decisive factor in the pathogenesis of recurrent hernia formation. The aim of our study was, therefore, to analyze the impact of commonly used mesh materials on quality of collagen deposition, expression of collagenases (matrix metalloproteinases; MMP-1/MMP-13), and specific tissue inhibitors of MMPs (TIMPs) in an animal study. Four different mesh materials were used (Prolene® = polypropylene, Mersilene® = polyester, and Vypro® and Vypro II® = combinations of polypropylene and polyglactin) and implanted as abdominal wall replacement in 60 male Wistar rats. Mesh samples were explanted after 3, 21, and 90 days and investigated using immunohistochemistry (expression of MMP-1/MMP-13 and TIMP-1) and cross-polarization miscroscopy (percentage of collagen type III to overall collagen). Besides an insufficient collagen composition with an increased percentage of collagen type III, we found a complex expression of collagenases and their inhibitors combined with a persistent chronic foreign-body reaction even 90 days after implantation. Except for TIMP-1 expression, which was significantly related to a lowered amount of inflammatory (r = –0.980, p = 0.02) and connective tissue formation (r = –0.951, p = 0.049), there was no relation to the expression of collagenases (MMP-1/MMP-13) with regard to the amount of inflammarory and connective tissue formation despite partly significant differences between implanted polymers.
Electrocardiographic Changes during Hemodiafiltration with Different Potassium Removal Rates
Authors: Severi Stefano , Vecchietti Stefania , Cavalcanti Silvio , Mancini Elena , Santoro Antonio
Published: October 2003

Background/Aims: Sudden K removal is thought to be implicated in ECG alterations observed during hemodialysis (HD). The effects of the K removal rate on ECG-derived parameters have been investigated. Methods: Two different hemodiafiltration (HDF) schedules were used for 10 HD patients: the dialysate K concentration was kept constant in HDFst, while in HDFK it was decreased during the session in order to maintain a uniform plasma-dialysate K gradient. A 12-lead Holter monitor was used to acquire the ECG in the course of the treatments. Classical ECG parameters and overall indices for quantifying ventricular repolarization abnormalities were evaluated. Results: Several ECG parameters were affected by both HD therapies (ST depression, QRS amplitude and QT dispersion), but only indices of the homogeneity of repolarization (PCA-T, E1-T) were significantly affected by the K removal rate. Conclusion: The present study confirms the large impact of HD therapy on ECG. The analysis of the spatial T wave complexity points out the intrinsic arrhythmogenic implications of the K removal rate.
The Prognostic Role of Atrial Natriuretic Peptides in Hemodialysis Patients
Authors: Nakatani Tatuya , Naganuma Toshihide , Masuda Chikayoshi , Sugimura Takeshi , Uchida Junji , Takemoto Yoshiaki , Sugimura Kazunobu
Published: October 2003

Background: It is well known that plasma atrial natriuretic peptide (ANP) is an indicator of extracellular fluid volume expansion and that plasma ANP is considered to be a marker for setting the proper dry weight of HD patients. Although the plasma ANP is a prognostic predictor of cardiac death, the prognostic role of ANP in HD patients has yet to be elucidated. In this study, we investigated the prognostic role of ANP in HD patients. Methods: Plasma ANP concentrations were measured in 105 HD patients after HD. Multiple regression analysis was performed to determine the major factors causing increased plasma ANP concentrations. Cardiac mortality was monitored for 24 months after baseline analysis, and the prognostic role of ANP was examined by Cox proportional hazards regression analysis. Results: Multiple regression analysis showed that cardiovascular disease (CD) and age were independent factors for elevated ANP (R2 = 0.298, p < 0.0001). During a 24-month follow-up period, cardiac death occurred in 11 patients. Kaplan- Meier survival estimates of patients from varying plasma ANP levels (<50 and >50 pg/ml) differed between the two groups (p < 0.0001). The group with the higher ANP level (>50 pg/ml) had the lower survival. When compared with patients with ANP <50, the hazard ratios for cardiac death of patients with ANP of >50 pg/ml were 32.0 (95% confidence interval (CI) 4.1 to 252.4). Univariate Cox proportional hazards model showed that ANP, left ventricular ejection fraction (LVEF), LVMI, age, serum albumin and C-reactive protein (CRP) were significantly associated with the risk of cardiac mortality. By stepwise multivariate Cox proportional hazards analysis, only ANP, LVMI and CRP remained powerful independent predictors of cardiac death. The relative risk ratios were 3.483 (95% CI 1.640–7.397) for ln ANP, 1.023 (1.008–1.038) for LVMI, and 1.379 (1.115–1.705) for CRP. Conclusion: High plasma ANP level of post-HD were strongly associated with CD and age. Post-HD ANP level may be a reliable parameter for assessing the risk for cardiac death in HD patients by providing prognostic information independent of other variables previously reported.
Chronic, but Not Acute, Clomipramine or Fluoxetine Treatment Reduces the Spontaneous Firing Rate in the Mesoaccumbens Neurons of the Rat
Authors: Rodríguez-Landa Juan Francisco , Contreras Carlos M. , Gutiérrez-García Ana G. , Bernal-Morales Blandina
Published: October 2003

In the present study, single-unit extracellular recording was used in male Wistar rats to compare the effects of a single dose (acute treatment) and a 21-day regimen (long-term treatment) with clomipramine (2.5 mg/kg) and fluoxetine (1.0 mg/kg) on the spontaneous firing rate of nucleus accumbens (NAcc) neurons connected with the ventral tegmental area (VTA). A single injection of clomipramine or fluoxetine did not modify the firing rate of NAcc neurons as compared with the control group, whereas a 21-day regimen reduced the firing rate in comparison with a 21-day saline-treated group, specifically for NAcc neurons that were inhibited by VTA electrical stimulation. These results demonstrate that chronic, but not acute, clomipramine or fluoxetine treatment reduces the firing rate of mesoaccumbens neurons, probably by dopaminergic activation, supporting the hypothesis that the NAcc is involved in the actions of at least these antidepressants. However, additional experiments need to be performed in order to delineate the mechanisms by which chronic clomipramine and fluoxetine treatment reduces the firing rate of NAcc neurons in the rat.
Altered Cardiovascular Responses to Nitrosorbide in Alcohol Withdrawal
Authors: Kähkönen Seppo , Zvartau Edwin E.
Published: October 2003

The cardiovascular effects and pharmacokinetics of a single dose (20 mg sublingually) of isosorbide dinitrate (ISDN) were studied in 9 alcohol-dependent men during alcohol withdrawal syndrome (AW) on day 1 and after the resolution of AW on day 10. At the onset of AW, ISDN and its metabolites caused a hypotensive effect, which was increased on day 10, while no differences in ISDN-induced decrease in stroke volume were observed. Tachycardiac response to ISDN was more pronounced at onset of AW. On day 10, the AUC0–1.5 h, Cmax and t½ of ISDN were increased compared with day 1. The results of this study suggest that nitric oxide may modulate the cardiovascular system in AW.
EEG Alterations in Subjects at High Familial Risk for Alzheimer’s Disease
Authors: Ponomareva N.V. , Selesneva N.D. , Jarikov G.A.
Published: October 2003

Twenty first-order relatives of patients with early-onset Alzheimer’s disease (AD; mean age 43.7 ± 1.3 years), 20 patients with early-onset AD (mean age 65.7 ± 0.9 years) and age-matched normal controls for the relatives and the patients underwent quantitative EEG (qEEG) examinations. In AD patients, delta and theta relative power values were increased and alpha relative power was decreased compared with normal controls. The AD patients’ relatives had normal resting EEG parameters. Under hyperventilation in the AD relatives, synchronous high-voltage delta and theta activity and sharp waves were revealed, theta and delta relative powers were increased and alpha relative power was decreased compared with the resting EEG in the same persons. Moreover, under hyperventilation, the theta and delta relative powers in the EEG of the relatives were higher, and the alpha relative power was lower compared with the EEG of normal controls under the same conditions. It is suggested that the excitotoxic processes and oxidative stress underlie the EEG alterations in the AD patients’ relatives and that these alterations may be related to the further AD development.
Abnormal Umbilical Artery Doppler Waveforms and Cord Blood Inhibin A and Inhibin B Levels
Authors: Florio P. , Severi F.M. , Luisi S. , Ignacchiti E. , Calonaci G. , Bocchi C. , Petraglia F.
Published: October 2003

Inhibin A and inhibin B are glycoprotein hormones produced by human placenta and by several fetal organs during pregnancy. They are secreted in maternal circulation in increasing amounts from early until term pregnancy, and in umbilical cord blood levels are significantly lower than in maternal serum and do not differ from mid-pregnancy to term gestation. In the present study, we aimed to determine whether secretion of inhibin A and inhibin B into the fetal circulation is increased in pregnancies complicated by umbilical-placental vascular insufficiency. A group of women (n = 13) with abnormal Doppler umbilical artery flow velocimetry and a group of control women (n = 11) with uncomplicated term pregnancies and normal umbilical artery flow velocity waveforms were studied. In each woman, inhibin A and inhibin B concentrations were estimated in umbilical cord artery and vein. In the two groups of women, mean inhibin A levels did not differ between umbilical cord artery and vein. In addition, no difference was retrieved both in umbilical cord artery and vein values between healthy controls and patients with abnormal Doppler umbilical artery flow velocimetry. On the contrary, inhibin B levels were significantly higher in samples from umbilical cord vein than artery, in both groups of pregnant women (both p < 0.001). However, women with abnormal Doppler umbilical artery flow velocimetry had inhibin B levels significantly higher than healthy controls (p = 0.005) only in the umbilical cord artery, but not in the vein. In the presence of abnormal Doppler umbilical artery flow velocity, the concentrations of inhibin B are increased in the arterial umbilical circulation, suggesting that inhibin B is released from multiple fetal sources as a response to hypoxemic stress. As inhibins may affect the hypothalamus-pituitary-adrenal axis which plays an important role in the mechanisms of adaptations to the post-natal life, inhibin B in fetal circulation might then be beneficial to a fetus whose intrauterine survival is threatened by impaired umbilical-placental blood flow.
Vascular Endothelial Growth Factor and Angiogenin Levels during Fetal Development and in Maternal Diabetes
Authors: Lassus Patrik , Teramo Kari , Nupponen Irmeli , Markkanen Helene , Cederqvist Katariina , Andersson Sture
Published: October 2003

We evaluated the concentrations of vascular endothelial growth factor (VEGF) and angiogenin in the umbilical cord blood from 14 fetuses with erythroblastosis or alloimmune thrombocytopenia and at birth from 28 preterm fetuses, from 42 healthy term fetuses, and from 24 term fetuses born to mothers with insulin-treated diabetes. A correlation appeared between VEGF and angiogenin levels (r = 0.44, p = 0.038). The gestational age correlated with both VEGF (r = 0.38, p = 0.0008) and angiogenin levels (r = 0.80, p = 0.0001). The concentration of VEGF was lower in fetuses born to mothers with insulin-treated diabetes than in the healthy term fetuses (p = 0.0028), but this difference was absent for angiogenin (p > 0.05). In conclusion, in umbilical cord plasma, a developmental increase was evident in concentrations of VEGF and angiogenin during the last trimester of gestation. That the umbilical cord VEGF level was lower in term fetuses born to mothers with diabetes than in term fetuses of healthy mothers may be associated with an aberrant fetal vascular development in diabetic pregnancies.
LPS-Induced Changes in Myocardial Markers in Neonatal Rats
Authors: Ravindranath Thyyar M. , Goto Masakatsu , Bakr Soliman , Ramasamy Ravi
Published: October 2003

Lipopolysaccharide (LPS) produces varied systemic metabolic effects. We studied the effects of LPS on the cardiac fatty acid profile and its relationship to energy metabolism and inflammatory mediators that included TNF-α and nitric oxide synthase (NOS) in 10-day-old neonatal rat pups. Rat pups received an i.p. injection of LPS after a 4-hour starvation period, followed by collection of blood and cardiac tissue 4 h following LPS administration. Compared to controls, LPS induced significant hypoglycemia and hyperlactacidemia, suggesting the development of endotoxic shock. The result was a significant depression in total fatty acid levels as well as non-esterified fatty acid in the cardiac tissue of the LPS-treated pups. In addition, LPS-treated pups also showed a significant increase in TNF-α, NOS levels with a depressed redox state and energy metabolism in cardiac tissue. These observations suggest that endotoxic shock in 10-day-old rat pups induces a systemic inflammatory response with a depression in fatty acid metabolism that may contribute to myocardial failure.
Transgenesis and the Study of Expression, Cellular Targeting and Function of Oxytocin, Vasopressin and Their Receptors
Authors: Young, 3rd W. Scott , Gainer Harold
Published: October 2003

The neuropeptides oxytocin and vasopressin and the neurons in the hypothalamus that synthesize them have been a rich source for the exploration and understanding of both the brain and the endocrine system. Because of their large size and compact nuclear organization the magnocellular neurons of the hypothalamoneurohypophysial system have traditionally attracted scientists using state-of-the-art techniques, including the subject of this review, transgenesis. We discuss the role of transgenics in deciphering gene elements necessary for the appropriate expression of oxytocin and vasopressin and to deliver exogenous genes, such as green fluorescent protein, selectively to secretory granules in the neurons in the hypothalamoneurohypophysial system. Finally, we review the studies of mice whose genes for oxytocin and, most recently, for the oxytocin and vasopressin receptors have been knocked out through homologous recombination.
Critical Role for Estrogen Receptor alpha in Negative Feedback Regulation of Gonadotropin-Releasing Hormone mRNA Expression in the Female Mouse
Authors: Dorling Amber A. , Todman Martin G. , Korach Kenneth S. , Herbison Allan E.
Published: October 2003

Estrogen exerts an important regulatory influence upon the functioning of the gonadotropin-releasing hormone (GnRH) neurons. Whether this is mediated by estrogen receptor α (ERα) or ERβ or both ERs is presently unclear. Using female mice with targeted disruptions of ERα and ERβ (αERKO and βERKO, respectively) we have investigated the in vivo role of the two ERs in the negative feedback influence of estrogen upon GnRH mRNA expression. Compared with intact wild-type mice, plasma luteinizing hormone (LH) levels were substantially (p < 0.01) higher in intact αERKO females and increased modestly (p < 0.05) in intact βERKO mice. Three weeks after ovariectomy, LH concentrations were elevated significantly in wild-type (p < 0.01) and βERKO (p < 0.05) mice but not changed in αERKO females. Quantitative analysis of GnRH mRNA expression using in situ hybridization revealed that cellular GnRH mRNA content was greater (p < 0.05) in intact αERKO mice compared with intact wild-type and βERKO mice. Following ovariectomy, GnRH mRNA expression was elevated in wild-type (p = 0.06) and βERKO (p < 0.05) females but not αERKO mice. These data demonstrate that both ERα and ERβ are involved in inhibiting LH levels at times of estrogen-negative feedback in vivo. However, only ERα appears to be critical for the estrogen-negative feedback suppression of GnRH mRNA expression in the female mouse.
Sex Differences in the Stress-Induced Release of Acetylcholine in the Hippocampus and Corticosterone from the Adrenal Cortex in Rats
Authors: Mitsushima Dai , Masuda Junya , Kimura Fukuko
Published: October 2003

To assess sex differences in stress-induced acetylcholine (ACh) release in the hippocampus and corticosterone (CS) release from the adrenal cortex, an in vivo microdialysis study was performed in intact male (n = 6) and cycling female (diestrus 1, n = 5; proestrus, n = 6) rats. Dialysates and blood samples were taken from 11.00 to 16.00 h in freely moving rats, but restraint stress was applied from 12.00 to 13.00 h. Basal ACh release in the hippocampus was low without significant differences between groups. Although ACh release promptly increased with the onset of restraint stress in both sexes, the magnitude of the increase in males was significantly greater than in female rats during diestrus and proestrus (p < 0.01). Basal serum CS concentrations were significantly greater in proestrus than in diestrus (p < 0.01) or in male rats (p < 0.01). Serum CS concentrations significantly increased at the onset of restraint stress in both sexes (p < 0.01), but the magnitude of the increase was significantly greater in female than in male rats (p < 0.01). These results indicate that sex and/or gonadal steroid environment can affect the stress-induced ACh release in the hippocampus and CS release from the adrenal cortex.
Spontaneous Bacterial Peritonitis in a Patient with Myxedema Ascites
Authors: Alberti Laura E. , Lopez-Gomez Alfredo , Alberti-Flor Juan J.
Published: October 2003

Ascites is uncommon in patients with hypothyroidism. Herein we describe an 84-year-old female patient with myxedema ascites that resolved completely with thyroid replacement medication. Bacteriological studies of the ascitic fluid revealed gram-negative rods which eventually proved to be Klebsiella pneumoniae treated successfully with antibiotics. Our review of the literature failed to reveal a previous case of myxedema ascites with concomitant subclinical spontaneous bacterial peritonitis.
Gastrointestinal Symptoms in Type 1 Diabetic Patients, as Compared to a General Population
Authors: Mjörnheim Ann-Christine , Finizia Caterina , Blohmé Göran , Attvall Stig , Lundell Lars , Ruth Magnus
Published: October 2003

Objectives: To examine the prevalence of gastrointestinal (GI) symptoms in patients with type 1 diabetes as compared to age- and sex-matched controls. Method: 395 patients with type 1 diabetes, registered at the diabetes outpatient unit at the Sahlgrenska University Hospital, were studied by use of a GI symptom questionnaire. They were randomly selected within 10-year age intervals from 20 to 69 years. Age- and sex-matched controls (n = 242) were sampled from a cohort recruited from the general population. Results: While the study populations were well matched with regard to age, sex and body mass index (BMI), the diabetic population comprised more smokers and reported symptoms of respiratory and ischemic heart disease more frequently. Symptoms of heartburn, acid regurgitation, nausea and vomiting were significantly more frequent and intense in the diabetic cohort. The occurrence of GI symptoms co-varied with the presence of respiratory and cardiac symptoms but was not predicted by age, glycosylated haemoglobin (HbA1c) levels or the presence of peripheral neuropathy. Conclusion: Patients with diabetes type 1 had more frequent and intense upper and lower GI symptoms than age- and sex-matched controls, especially if only moderate and severe symptoms were considered. The presence of symptoms was related to lifestyle factors but not to the degree of diabetes control as expressed by the level of HbA1c and the presence of peripheral neuropathy.
Factors Involved in the Development of Hypertension Induced by a Low-Protein Diet in Rats with Renal Injury
Authors: Endoh Michiyo , Odamaki Mari , Ikegaya Naoki , Kumagai Hiromichi
Published: October 2003

Background/Aims: While a low-protein diet (LPD) has been reported to increase blood pressure, the mechanism for its increase has not yet been clarified. We investigated the factors involved in the development of hypertension induced by LPD in rats with post-cyclosporine (CsA) nephropathy, and determined the appropriate composition for LPD that is to be utilized for renal research. Methods: The rats were divided into 4 groups, each group being fed either a normal-protein diet (NPD), LPD with a low sucrose content as the main component of carbohydrate, LPD with a high-sucrose content, or LPD with low sucrose plus 2% L-arginine (Arg) for 12 weeks, and the blood pressure, urinary nitric oxide (NO) metabolite (NOx) excretion, renal NO-generating capacity and renal Arg content were compared among these groups. CsA was administered for the first 5 weeks to all groups. Results: The blood pressure was significantly higher in the high-sucrose LPD rats than in the NPD and the low-sucrose LPD rats. The supplement of Arg significantly decreased the blood pressure in the low-sucrose LPD rats. Urinary NOx, renal NO-generating capacity and the renal Arg content were significantly lower in the low-sucrose LPD rats than in the NPD rats. Arg supplementation to the LPD rats returned these values to the level of the NPD rats. Conclusion: The increase in blood pressure by LPD was associated with the higher amount of sucrose contained in LPD and the decrease in NO generation caused by the Arg depletion in rats with post-CsA nephropathy. For animal experiments we recommend that sucrose should not be used in LPD to balance the energy intake between LPD and NPD, and that a small amount of Arg be supplemented to LPD.