bluuebunny/crossref_metadata_2025 huggingface dataset:
Characteristics of renal Rhbg as an NH4+ transporter
Authors: Nakhoul Nazih L. , DeJong Hendrik , Abdulnour-Nakhoul Solange M. , Boulpaep Emile L. , Hering-Smith Kathleen , Hamm L. Lee
Published: September 2004

Rhbg is one of two recently cloned nonerythroid glycoproteins belonging to the Rh antigen family. Rhbg is expressed in basolateral membranes of intercalated cells of the kidney cortical collecting duct and some other cell types of the distal nephron and may function as NH4+ transporters. The aim of this study was to characterize the role of Rhbg in transporting NH4+. To do so, we expressed Rhbg in Xenopus laevis oocytes. Two-electrode voltage-clamp and H+-selective microlectrodes were used to measure NH4+ currents, current-voltage plots, and intracellular pH (pHi). In oocytes expressing Rhbg, 5 mM NH4+ induced an inward current of 93 ± 7.7 nA ( n = 20) that was significantly larger than that in control oocytes of −29 ± 7.1 nA ( P < 0.005). Whole cell conductance, at all tested potentials (−60 to +60 mV), was significantly more in oocytes expressing Rhbg compared with H2O-injected oocytes. In Rhbg oocytes, 5 mM NH4+ depolarized the oocyte by 28 ± 3.6 mV and decreased pHi by 0.30 ± 0.04 at a rate of −20 ± 2.5 × 10−4 pH/s. In control oocytes, 5 mM NH4+ depolarized Vm by only 20 ± 5.8 mV and pHi decreased by 0.07 ± 0.01 at a rate of −2.7 ± 0.6 × 10−4 pH/s. Raising bath [NH4+] in increments from 1 to 20 mM elicited a proportionally larger decrease in pHi (ΔpHi), larger depolarization (Δ Vm), and a faster rate of pHi decrease. Bathing Rhbg oocytes in 20 mM NH4+ induced an inward current of 140 ± 7 nA that was not significantly different from 178 ± 23 nA induced in H2O-injected (control) oocytes. The rate of pHi decrease induced by increasing external [NH4+] was significantly faster in Rhbg than in H2O-injected oocytes at all external NH4+ concentrations. In oocytes expressing Rhbg, net NH4+ influx (estimated from NH4+-induced H+ influx) as a function of external [NH4+] saturated at higher [NH4+] with a Vmax of ∼30.8 and an apparent Km of 2.3 mM ( R2 = 0.99). These data strongly suggest that Rhbg is a specific electrogenic transporter of NH4+.
Different Inhibitory Inputs Onto Neostriatal Projection Neurons as Revealed by Field Stimulation
Authors: Tecuapetla Fatuel , Carrillo-Reid Luis , Guzmán Jaime N. , Galarraga Elvira , Bargas José
Published: September 2004

This work investigated if diverse properties could be ascribed to evoked inhibitory postsynaptic currents (IPSCs) recorded on rat neostriatal neurons when field stimulation was delivered at two different locations: the globus pallidus (GP) and the neostriatum (NS). Previous work stated that stimulation in the GP could antidromically excite projection axons from medium spiny neurons. This maneuver would predominantly activate the inhibitory synapses that interconnect spiny cells. In contrast, intrastriatal stimulation would preferentially activate inhibitory synapses provided by interneurons. This study shows that, in fact, intensity-amplitude experiments are able to reveal different properties for IPSCs evoked from these two locations (GP and NS). In addition, while all IPSCs evoked from the GP were always sensitive to ω-conotoxin GVIA (CaV2.22.2 or N-channel blocker), one-half of the inhibition evoked from the NS exhibited little sensitivity to ω-conotoxin GVIA. Characteristically, all ω-conotoxin GVIA–insensitive IPSCs exhibited strong paired pulse depression, whereas ω-conotoxin GVIA–sensitive IPSCs evoked from either the GP or the NS could exhibit short-time depression or facilitation. ω-Agatoxin TK (CaV2.12.1+ or P/Q-channel blocker) blocked IPSCs evoked from both locations. Therefore 1) distinct inhibitory inputs onto projection neostriatal cells can be differentially stimulated with field electrodes; 2) N-type Ca2+ channels are not equally expressed in inhibitory terminals activated in the NS; and 3) synapses that interconnect spiny neurons use both N- and P/Q-type Ca2+ channels.
Temporal and Spatial Expressions of Stanniocalcin mRNA in Mouse Brains
Authors: Yeung Ho Yee , Chan Daniel Kwong On , Wong Chris Kong Chu
Published: September 2004

In this study, a detailed mapping of stanniocalcin (STC) mRNA was conducted at various developmental stages of male and female mouse brains. The developmental profile of STC expression in mouse brains indicated that the transcripts were detectable on E12 and peaked on E16, and days 1 and 2 of postnatal stages and then declined slowly. There was no observable difference in the descending trends of STC expression in both male and female mouse brains at different postnatal periods (3, 5, 7, 9 and 11 weeks). As concerns the spatial distribution, the results indicated a differential expression of STC in the various regions of the brain; the highest level was detected in the striatum, followed by the hippocampus, parietal cortex, hypothalamus, frontal cortex, cerebellum and brain stem. Similar patterns of expression were observed in the mature rat brain. Our findings lend further support to the notion that STC is involved in distinct neural functions.
Overexpression of Interferon α/β Receptor β Chain in Fetal Down Syndrome Brain
Authors: Ferrando-Miguel Rosa , Shim Ki-Shuk , Cheon Myeong Sook , Gimona Mario , Furuse Mikio , Lubec Gert
Published: September 2004

Background: Down syndrome (DS; trisomy 21) is the most common chromosomal aberration, with an incidence of 1/700 live births, and presents with mental retardation, typical phenotype and a series of associated pathological conditions. Although overexpression of genes encoded on chromosome 21 was proposed to lead to the phenotype, this has not been fully addressed at the protein level. Aim: It was therefore the aim of our study to determine protein levels of several chromosome 21 gene products in fetal DS brain. We selected interferon (IFN) α/β receptor β chain (IFNAR2), glutamate receptor 5 (ionotropic kainate 1), h2 calponin, claudin-8 and oligodendrocyte transcription factor 1 for quantification in fetal brain of the early second trimester using immunoblotting. Results: We observed significant and about twofold overexpression of the 20-kD immunoreactive IFN receptor α/β band in the fetal cortex of DS brain (p = 0.0293), while the 70-kD immunoreactive band was overexpressed but did not reach statistical significance (p = 0.065). When data were normalized to the housekeeping protein β-actin, a significant increase in IFN receptor levels was observed. Levels of the aforementioned proteins were comparable between DS and controls. Conclusion: Overexpression of IFNAR2 in fetal DS brain may increase the responsiveness of DS cells, leading to altered neuronal excitability, neuronal growth and survival as well as cytoskeleton derangement.
Genetic, Environmental and Immunologic Factors in the Etiology of Autism Spectrum Disorders
Authors: Bölte Sven , Poustka Fritz
Published: September 2004

Autism spectrum disorders are early-onset chronic conditions of qualitatively impaired social interaction and reciprocal communication with an estimated prevalence rate of 0.6%. Autism is heterogeneous in phenotype and comorbidity. Its precise etiology remains largely an enigma, but twin and family studies indicate substantial hereditary fundamentals. In this report, we briefly review the progress of molecular genetic, environmental and (auto-)immunologic research in autism and similar conditions. At the present time, idiopathic autism is assumed to be an oligogenic epistatic disorder. In a minority of cases, some Mendelian syndromes and other medical conditions as well as exogenous and immune mechanisms may also cause or trigger autism. A standard epidemiologic vulnerability model has been proposed to integrate possible major and minor risks of different origin.
Topotecan, Ara-C, Cisplatin and Prednisolone (TOPOSHAP) for Patients with Refractory and Relapsing Lymphomas: Results of a Phase I Trial
Authors: Coutinho Fernando , Manhani Ana Rita , Velasquez William S. , del Giglio Auro
Published: September 2004

We designed a phase I trial to assess the feasibility of the combination of topotecan, Ara-C, cisplatin and solumedrol (TOPOSHAP) in patients with relapsed or primary refractory lymphomas. We included 9 patients with mesurable non-Hodgkin’s (n = 8) and Hodgkin’s (n = 1) lymphomas. Level 1 consisted of topotecan 1.0 mg/m2/day, i.v., given on days 1–3, cisplatin 25 mg/m2/day, i.v., on days 1–3, Ara-C 500 mg/m2, i.v., on day 4, methylprednisolone 250 mg, i.v., on days 1–4. The regimen was repeated every 3–4 weeks. The maximum tolerated dose was already reached at level 1. G-CSF was added systematically after the 5th patient was included. The most significant toxicity in this trial was hematologic (all had neutropenia WHO grade 4 and 7 had grade 4 thrombocytopenia). Three patients had neutropenic fever. We observed two instances of WHO grade 3 and one of grade 4 diarrhea. Two patients achieved a complete response and 6 a partial response. We conclude that TOPOSHAP with G-CSF support is feasible and should be further studied in phase II studies.
Lymphocyte Populations in Lymph Nodes in Different Histological Types of Hodgkin’s Disease in Children
Authors: Pituch-Noworolska Anna , Drabik Grażyna , Kacińska Ewa , Klekawka Tomasz
Published: September 2004

Proliferating Reed-Sternberg and Hodgkin’s cells within the lymph node in Hodgkin’s disease (HD) affect the surrounding cells, which results in alterations of the proportion between T and B lymphocytes and the activation of these cells. The purpose of this study was to assay the changes within lymphocyte populations in lymph nodes in different types of HD. The lymph nodes of 10 children with nonmalignant, reactive changes, and 31 children with HD of the following types: mixed cellularity (MC; 11 cases), nodular sclerosis (NS; 17 cases) and lymphocyte depletion (LD; 3 cases) were included in the study. The percentage of T lymphocytes (CD3+), B lymphocytes (CD22+), T cell (CD4+ and CD8+) and B cell subsets (kappa+ and lambda+ light chain) were assayed with flow cytometry. The ratio of T:B lymphocytes in reactive lymph nodes and in NS type of HD was similar. An increase of the T cell percentage (resembling an increase of the CD4+ subset) and a decrease of B cells resulted in a high ratio of T:B and was noted in the MC and LD types of HD. These HD types were associated with marked changes in lymphocytes within the lymph node, which suggested a different effect of proliferating Reed-Sternberg and Hodgkin cells in HD on the surrounding cells.
Stanford V Regimen plus Consolidative Radiotherapy Is an Effective Therapeutic Program for Bulky or Advanced-Stage Hodgkin’s Disease
Authors: Aversa Savina M.L. , Salvagno Luigi , Sorarù Mariella , Mazzarotto Renzo , Boso Caterina , Gaion Fernando , Chiarion-Sileni Vanna , De Franchis Giuseppe , Favaretto Adolfo G. , Crivellari Gino , Banna Giuseppe Luigi , Sotti Guido , Monfardini Silvio
Published: September 2004

Since September 1996, 48 untreated patients with bulky or advanced-stage Hodgkin’s disease received the 12-week Stanford V chemotherapy regimen followed by consolidation radiotherapy at a dose of 36 Gy to bulky mediastinal disease and 30.6 Gy to the initial sites of disease ≧3 cm in transverse diameter. After the combined therapy, 46 of 48 (96%) achieved complete remissions. With a median follow-up of 48 months, the 5-year overall survival was 95% and freedom from progression 86%.There were no treatment-related deaths. All but one premenopausal female patient (who received pelvic and inguinal irradiation) recovered normal menses. Until now no case of secondary leukemia or myelodysplasia was observed. Our results confirm that the Stanford V regimen with consolidation radiotherapy is safe and effective in patients with bulky or advanced-stage Hodgkin’s disease, achieving very high remission and overall 5-year survival rates. Longer follow-up is necessary to evaluate the extent of all complications.
Analysis of the Optimal Blood Sampling Conditions for Estimation of Hematopoietic Progenitor Cell Count by the SE-9000 Automated Hematolyzer
Authors: Nomura Tsutomu , Kubota Yoshitsugu , Baba Natsumi , Saigo Katsuyasu , Ohnishi Hiroaki , Kitanaka Akira , Taminato Tomohiko
Published: September 2004

We evaluated the optimal conditions for blood sampling for hematopoietic progenitor cells (HPCs) as estimated by the immature information program of the SE-9000 automated hematology analyzer. The HPC count was most stable when the blood samples were incubated at room temperature with ethylene-diaminetetraacetic acid dipotassium (EDTA-2K) as an anticoagulant. The HPC count should, however, be measured within 4 h after blood collection, even under optimal conditions. In contrast, the CD34+ cell count estimated by flow cytometric analysis was stable for at least 21 h after the blood samples were incubated with EDTA-2K at room temperature or 4°C. When appropriate blood samples were used, the HPC count in the peripheral blood significantly correlated with the CD34+ cell count in the peripheral blood and in the apheresis yields (r = 0.798 and 0.635, respectively); therefore, the HPC count is a reliable predictor for initiation of apheresis procedures to obtain sufficient HPCs for peripheral blood stem cell transplantation.
Severe Hypercalcemia in a Child with Acute Nonlymphocytic Leukemia: The Role of Parathyroid Hormone-Related Protein and Proinflammatory Cytokines
Authors: Kounami Shinji , Yoshiyama Megumi , Nakayama Keiko , Hiramatsu Chisako , Aoyagi Noriyuki , Yoshikawa Norishige
Published: September 2004

Among the hematological malignancies, hypercalcemia has often been reported in lymphoid malignancies such as multiple myeloma and adult T cell leukemia/lymphoma, but it has only rarely been described in acute nonlymphocytic leukemia. We describe here a 14-month-old girl with acute monocytic leukemia complicated by severe hypercalcemia (4.6 mmol/l) at presentation. A bone survey showed generalized bone resorption, but no localized osteolytic lesions. A search for the etiology of the hypercalcemia revealed that the serum levels of parathyroid hormone-related protein (PTHrP) and also proinflammatory cytokines with stimulatory effects on osteolytic bone resorption – TNF-α, IL-6 and M-CSF – were elevated. The patient achieved complete remission with induction chemotherapy, and the levels of PTHrP and the cytokines became normalized. In this case, PTHrP and cytokines might have acted cooperatively to exacerbate bone resorption, resulting in severe hypercalcemia.
A New Model for Olfactory Placode Development
Authors: Whitlock Kathleen E.
Published: September 2004

The peripheral nervous system of vertebrate animals arises primarily from the interaction of cranial neural crest and sensory placodes. Placodes are described as thickenings of ectoderm that arise through cell division during neural tube formation. The olfactory sensory system is one component of the peripheral nervous system that arises from paired sensory placodes during development. The olfactory placodes give rise to the primary sensory neurons, support cells and basal cells of the olfactory epithelium. Recent evidence from work in zebrafish and chick suggests that the olfactory and auditory placodes arise from large fields of cells that converge to form the sensory placode. The olfactory placodes arise from within the neural plate, and cell division is apparent only after the sensory placodes are morphologically distinct. As the olfactory placode is forming, its precursors must segregate from their neighboring fields which will give rise to the adenohypophyseal placode, cranial neural crest, and telencephalon. Analysis has shown that the endocrine cells thought to arise from the olfactory placode originate in the neighboring adenohypophyseal and cranial neural crest domains. The borders separating the domains are plastic, where cells sort as they move, and cell fate is dependent on the identity of neighbors once the cells have converged to form the sensory placode. Thus there is degeneracy built into the system such that cells accommodate changes in the environment until cell migrations controlling the formation of the sensory placodes are complete.
Oxidative Stress in Patients with End-Stage Renal Disease prior to the Start of Renal Replacement Therapy
Authors: Diepeveen Sabine H.A. , Verhoeven Gertie H.W.E. , van der Palen Job , Dikkeschei Bert L.D. , van Tits Lambertus J. , Kolsters Geert , Offerman Joop J.G. , Bilo Henk J.G. , Stalenhoef Anton F.H.
Published: September 2004

Background/Aim: In patients with end-stage renal disease (ESRD), cardiovascular complications are the main cause of death. Increased oxidative stress is one of the risk factors for enhanced atherosclerosis in this population. Literature data vary partially dependent on differences in methodology. The present study compares three different methods: plasma lipid peroxides, the newly developed measurement of circulating oxidized LDL (Ox-LDL) particles and the frequently used copper-induced LDL oxidation lag time. Methods: We assessed plasma lipid peroxides, circulating Ox-LDL and in vitro copper-induced LDL oxidation lag time in 47 non-diabetic patients with ESRD, at the start of renal replacement therapy, and compared these with 41 age- and sex-matched controls. Results: In ESRD, total cholesterol (4.6 ± 1.1 vs. 5.6 ± 0.9 mmol/l; p < 0.001), LDL cholesterol (2.8 ± 0.8 vs. 3.5 ± 0.7 mmol/l; p < 0.001) and HDL cholesterol (1.0 ± 0.3 vs. 1.4 ± 0.4 mmol/l; p < 0.001) were lower compared to controls. Plasma lipid peroxides were higher (1.1 ± 0.5 vs. 0.8 ± 0.5 µmol/l; p = 0.003) in ESRD. No differences were observed in plasma Ox-LDL (63.1 ± 62.0 vs. 55.3 ± 48.0 mg/l). However, due to the lower plasma LDL cholesterol in ESRD, LDL oxidation level was increased in ESRD (7.1 ± 0.1 vs. 4.2 ± 0.3%; p = 0.03). LDL lag time was slightly longer (89 ± 11 vs. 84 ± 11 min; p = 0.04) in ESRD. There were no significant differences regarding the amount and rate of dienes produced. Conclusions: Elevated levels of lipid peroxides and higher LDL oxidation levels support the theory that ESRD is associated with increased oxidative stress, which may explain the accelerated atherosclerosis. The measured amount of oxidative stress is not reflected by in vitro oxidizability of LDL.
Clinical Significance of Serum Oxidized Low-Density Lipoprotein/β2-Glycoprotein I Complexes in Patients with Chronic Renal Diseases
Authors: Kasahara Junko , Kobayashi Kazuko , Maeshima Yohei , Yamasaki Yasushi , Yasuda Tatsuji , Matsuura Eiji , Makino Hirofumi
Published: September 2004

Background: Peroxidation of low-density lipoprotein (LDL) plays an important role in the development of dyslipidemias associated with the progression of chronic renal disorders. We recently reported [J Lipid Res 2001;42:697, 2002;43:1486, 2003;44:716] that oxidized LDL (oxLDL) interacts with an endogenous plasma protein, β2-glycoprotein I (β2GPI), via specific ligands. In the present study, the prevalence and clinical significance of oxLDL/β2GPI complexes were evaluated in patients with chronic renal disorders. Methods: Serum levels of oxLDL/β2GPI complexes were measured by ELISA in patients with chronic renal disease and their association with clinical manifestations was assessed. Results: The serum levels of oxLDL/β2GPI complexes were significantly higher in patients with chronic renal failure (CRF), chronic nephritis (CN) and diabetes mellitus than those in healthy individuals. The presence of complexes in patients with CN was significantly associated with high dietary protein and sodium chloride intake, but not with lipid metabolic parameters. Malondialdehyde-modified LDL was significantly associated with total cholesterol and LDL cholesterol in all patient groups, but did not correlate with renal function parameters. Conclusions: Serum oxLDL/β2GPI complexes, generated by oxidative stress and associated with high dietary protein and salt intake, might be a novel risk factor and a diagnostic marker for the development of chronic renal diseases, especially IgA nephropathy.
Therapies to Slow Polycystic Kidney Disease
Authors: Torres Vicente E.
Published: September 2004

Advances in the understanding of cystogenesis and availability of animal models orthologous to human autosomal dominant polycystic kidney disease (ADPKD) and recessive polycystic kidney disease (ARPKD) will likely facilitate the development of treatments for these diseases. Proteins mutated in ADPKD and ARPKD, as well as in several animal models, are localized to renal primary cilia. These are thought to have a sensory function and contribute to the regulation of the intracellular calcium ([Ca2+]i). It seems likely that the maintenance of a differentiated renal epithelial phenotype, characterized by controlled fluid secretion and cell proliferation, requires precise functional coordination of cAMP and Ras/Raf/MEK/ERK signaling by [Ca2+]i. [Ca2+]i alterations, linked to genetic defects causing polycystic kidney disease, may hinder negative feedback mechanisms that control cAMP and Ras/Raf/MEK/ERK signaling, and result in increased fluid secretion and cell proliferation. cAMP levels, Raf kinase activities and ERK phosphorylation are increased in polycystic kidneys. There is also evidence of abnormal cross-talk between cAMP and MAPK pathways, that can be reproduced in wild-type cells by altering [Ca2+]i. While cAMP inhibits Ras–Raf-1-stimulated phosphorylation of ERK in normal kidney cells, it markedly increases B-Raf kinase activity and ERK phosphorylation in polycystic kidney cells. Treatment strategies should probably be aimed at increasing [Ca2+]i, inhibiting Ras/Raf/MEK/ERK signaling or lowering cAMP in the distal nephron and collecting duct. Vasopressin is the major adenylyl cyclase agonist in the collecting duct principal cells via a V2 receptor. OPC31260, a V2 receptor antagonist, lowers renal cAMP and markedly inhibits cystogenesis in four animal models of polycystic kidney disease, three of which are orthologous to human diseases (PCK rat, ARPKD; pcy mouse, adolescent nephronophthisis; Pkd2WS25/– mouse, ADPKD). The renal selectivity and safety profile of this class of drugs make it an excellent candidate for clinical trials.
Aggregated IgG Bind to Glomerular Epithelial Cells to Stimulate Urokinase Release through an Endocytosis-Independent Process
Authors: Haymann Jean-Philippe , Delarue Françoise , Baud Laurent , Sraer Jean-Daniel
Published: September 2004

Background: In membranous nephropathy, the development of glomerular lesions is related to the formation of immune complexes at subepithelial sites. These deposits are associated with modifications in the fibrinolytic activity of glomerular cells leading to the appearance of fibrin degradation products in the deposits and the urine. A previous study has shown that immune complexes interact with glomerular epithelial cells (GEC) through the neonatal Fc receptor (FcRn). We therefore determined whether this binding could be responsible for a modification in the fibrinolytic activity of GEC. Methods: Endocytosis of heat-aggregated immunoglobulins (AgIgG) in cultured human GEC was studied by immunofluorescence and confocal microscopy. The release of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI) by GEC or whole glomeruli was assessed by ELISA, fibrin zymography and Northern blot. Results: Human GEC in culture bound AgIgG that possess characteristics similar to soluble immune complexes and internalized them by 10 min. This process was mediated by FcRn since chicken aggregated IgG (AgIgY), that do not bind FcRn, did not colocalize with AgIgG in GEC. AgIgG but not AgIgY induced a decrease of FcRn expression at the membrane and within the cells. The binding of AgIgG to GEC elicited a dose- and time-dependent increase in the release of uPA activity, as in the uPA protein and mRNA expression without modification in the release of PAI. This process was not abrogated by agents inhibiting endocytosis and/or transcytosis such as cytochalasin B, suggesting an endocytosis-independent uPA regulation. Conclusion: GEC response to AgIgG overload comprises at least two sequential steps: (1) a FcRn-mediated endocytosis; (2) an endocytosis-independent fibrinolytic imbalance leading to plasmin generation which could favor in vivo AgIgG clearance and matrix remodeling.
Role of the B7RP-1/ICOS Pathway in Renal Tubular Epithelial Antigen Presentation to CD4+ Th1 and Th2 Cells
Authors: Wahl Patricia , Wüthrich Rudolf P.
Published: September 2004

Background: IFN-γ-stimulated renal tubular epithelial cells (TECs) can present foreign protein antigen to T cells when stimulated with IFN-γ. TECs normally do not express B7, the ligand for the classical T-cell costimulatory molecule CD28, but express B7RP-1, the ligand of the inducible costimulator (ICOS). Methods: Flow cytometry was used to demonstrate expression of B7RP-1 on TECs, and expression of ICOS on A.E7 (Th1 clone) and D10.G4 (Th2 clone) cells. Using gene arrays, ELISA, and protein arrays, we examined the cytokine response of Th1 and Th2 subsets of CD4+ T cells in antigen presentation by IFN-γ-stimulated murine primary TECs. Results: In the presence of a specific foreign protein antigen, MHC-II-positive TECs induced clustering and a marked production of IFN-γ (A.E7) or IL-4 (D10.G4) by T cells. Blockade of the B7RP-1/ICOS pathway with specific monoclonal antibodies (mAbs) lead to a further increase in IFN-γ production by A.E7 cells, and a further increase in IL-4 production by D10.G4 cells as detected by gene array and ELISA. Protein arrays demonstrated an increase in Th2 cytokine levels upon blockade of the B7RP-1/ICOS pathway. Conclusions: These data show that the B7RP-1/ICOS interaction inhibits Th1 and Th2 T-cell responses in the setting of foreign antigen presentation by renal TECs. This inhibitory pathway may therefore serve as a negative feedback mechanism to inhibit immune-mediated tubulointerstitial renal disease.
Isoforms of the Major Peanut Allergen Ara h 2: IgE Binding in Children with Peanut Allergy
Authors: Hales Belinda J. , Bosco Anthony , Mills Kristina L. , Hazell Lee A. , Loh Richard , Holt Patrick G. , Thomas Wayne R.
Published: September 2004

Background: The major peanut allergen Ara h 2 consists of two isoforms, namely Ara h 2.0101 and Ara h 2.0201. The recently identified Ara h 2.0201 isoform contains an extra 12 amino acids including an extra copy of the reported immunodominant epitope DPYSPS. This study aimed to evaluate the IgE binding of the two Ara h 2 isoforms. Methods: Ten clones of Ara h 2 were sequenced to assess the relative frequency of the Ara h 2 isoforms and to identify whether there was further variation in the Ara h 2 sequence. IgE binding to Ara h 2.0101 and Ara h 2.0201 was measured for 70 peanut-allergic children using an IgE DELFIATM assay to quantitate specific IgE binding. A competition assay was used to measure whether Ara h 2.0201 contained IgE epitopes other than those found for Ara h 2.0101. Results: The original Ara h 2.0101 sequence was found for 6/10 clones and Ara h 2.0201 was found for 2/10 clones. Ara h 2.0201 had the expected insertion of 12 amino acids as well as substitutions at positions 40 (40G) and 142 (142E). Two new isoforms were identified as different polymorphisms of position 142. One Ara h 2.01 clone (Ara h 2.0102) contained 142E and one Ara h 2.02 clone (Ara h 2.0202) contained 142D. A polymorphism that was previously identified by other investigators at position 77 (77Q or 77R) was not found for any of the 10 sequences. Although the level of IgE binding to Ara h 2.0201 of individual patients was frequently higher than the binding to Ara h 2.0101 (p < 0.01), there was a strong correlation in binding to both isoforms (r = 0.987, p < 0.0001) and when analyzed as a group the means were similar. Ara h 2.0101 was not as efficient at blocking reactivity to Ara h 2.0201 indicating there is an additional IgE specificity for the Ara h 2.0201 isoform. Conclusions: Ara h 2.0201 has similar but higher IgE binding than the originally sequenced Ara h 2.0101 isoform and contains other IgE specificities.
An Experimental Model of Allergic Asthma in Cats Sensitized to House Dust Mite or Bermuda Grass Allergen
Authors: Norris Reinero Carol R. , Decile Kendra C. , Berghaus Roy D. , Williams Kurt J. , Leutenegger Christian M. , Walby William F. , Schelegle Edward S. , Hyde Dallas M. , Gershwin Laurel J.
Published: September 2004

Background: Animal models are used to mimic human asthma, however, not all models replicate the major characteristics of the human disease. Spontaneous development of asthma with hallmark features similar to humans has been documented to occur with relative frequency in only one animal species, the cat. We hypothesized that we could develop an experimental model of feline asthma using clinically relevant aeroallergens identified from cases of naturally developing feline asthma, and characterize immunologic, physiologic, and pathologic changes over 1 year. Methods: House dust mite (HDMA) and Bermuda grass (BGA) allergen were selected by screening 10 privately owned pet cats with spontaneous asthma using a serum allergen-specific IgE ELISA. Parenteral sensitization and aerosol challenges were used to replicate the naturally developing disease in research cats. The asthmatic phenotype was characterized using intradermal skin testing, serum allergen-specific IgE ELISA, serum and bronchoalveolar lavage fluid (BALF) IgG and IgA ELISAs, airway hyperresponsiveness testing, BALF cytology, cytokine profiles using TaqMan PCR, and histopathologic evaluation. Results: Sensitization with HDMA or BGA in cats led to allergen-specific IgE production, allergen-specific serum and BALF IgG and IgA production, airway hyperreactivity, airway eosinophilia, an acute T helper 2 cytokine profile in peripheral blood mononuclear cells and BALF cells, and histologic evidence of airway remodeling. Conclusions: Using clinically relevant aeroallergens to sensitize and challenge the cat provides an additional animal model to study the immunopathophysiologic mechanisms of allergic asthma. Chronic exposure to allergen in the cat leads to a variety of immunologic, physiologic, and pathologic changes that mimic the features seen in human asthma.
Dietary Nucleic Acid and Intestinal Microbiota Synergistically Promote a Shift in the Th1/Th2 Balance toward Th1-Skewed Immunity
Authors: Sudo Nobuyuki , Aiba Yuji , Oyama Naomi , Yu Xiao-Nian , Matsunaga Masaji , Koga Yasuhiro , Kubo Chiharu
Published: September 2004

Background: Intestinal microbiota are known to play an important role in the establishment of oral tolerance, thereby protecting the organism from food allergies. Dietary intake of nucleic acid (NA) is also reported to have such an anti-allergic effect; however, one unsolved question is whether or not dietary NA would act through a process of toll-like receptor 9 signaling activated by DNA containing a CpG motif, a well-known sequence leading to immunostimulatory activity. In this study, we focused on the question of whether the addition of dietary NA lacking CpG motifs would allow continued modulation of the Th1/Th2 balance. Methods: Germ free (GF) and Bifidobacterium-infantis-monoassociated BALB/c mice were maintained on either an NA-free casein diet or on an NA-supplemented casein diet for 4 weeks. Thereafter, both the in vivo anti-casein antibody levels and in vitro splenocyte cytokine secretion pattern were evaluated. Results: Feeding with a casein diet elicited a substantial increase in the serum anti-casein-specific IgG1, IgG2a, and IgE levels of GF mice fed the NA free-diet. The in vitro cytokine production profile showed that enhanced IL-4 production in the GF mice fed the NA free-diet was markedly reduced by the supplementation with dietary NA in both the GF and B.-infantis-monoassociated mice. In addition, IFN-γ secretion increased in the B.-infantis-reconstituted mice fed the diet containing NA. Conclusions: These results suggest that dietary intake of NA devoid of CpG motifs may prevent the development of allergies via acceleration of Th1-dominant immunity.
Skin Reactivity to Histamine and Codeine in Unselected 9-Year-Old Children from Italy, Poland and Libya
Authors: Ronchetti Roberto , Villa Maria Pia , Bohmerova Zuzana , Martella Susy , Falasca Carlo , Barreto Mario , Lesiak-Bednarek Anna , Al-Bousafy Ahmed , Al-Tubuly Abdulhamid , Zakrzewski Jacek , Haluszka Janusz
Published: September 2004

Background: Previous studies have shown that histamine skin reactivity (the dimensions of a skin wheal elicited by a prick with histamine 10 mg/ml) in unselected school children has increased in Italy during the past two decades and is higher in Italy than in Poland. Hence this variable can probably be influenced by a changing or different lifestyle. The aim of this study was to compare skin reactivity to histamine and codeine (a marker of histamine releasability from mast cells) in schoolchildren from countries with different lifestyles. Methods: Six previously unstudied unselected populations of 9-year-old schoolchildren (two each from Poland, Italy, and Libya; n = 863 subjects; 49.0% males) were pricked with two concentrations of histamine (10 and 1 mg/ml) and codeine (90 and 9 mg/ml). Results: The higher concentrations of both pharmacologic agents tested yielded significantly different wheal areas in the three countries: Poland < Italy < Libya (histamine, 11.8, 16.1 and 20.7 mm2; codeine, 9.2, 13.2 and 16.2 mm2; p < 0.001 for all comparisons). The lower concentrations elicited almost matching results. Histamine wheal areas correlated closely with areas elicited by codeine in the same individual: angular coefficients of the histamine to codeine regression lines were 0.535, Italy; 0.551, Libya; 0.612, Poland; and 0.581 for the whole population. More histamine was needed to produce a wheal in Poland than in Libya: a 20-mm2 wheal required an injected histamine concentration of about 8.8 mg/ml in Libya, 29.5 mg/ml in Italy and 102.1 mg/ml in Poland. Conclusion: More studies are necessary to explain the observed international differences in skin histamine reactivity and their effect on the prevalence of positive allergen skin tests.
Serum Levels of Interleukin-18 Are Elevated in the Subacute Phase of Kawasaki Syndrome
Authors: Nomura Yuichi , Masuda Kiminori , Maeno Nobuaki , Yoshinaga Masao , Kawano Yoshifumi
Published: September 2004

Background: Elevations of various cytokines, including Th1 and Th2 cytokines, have been reported in the acute phase of Kawasaki syndrome (KS). As interleukin (IL)-18 plays an important role in the Th1 cell response, investigating the relevance of IL-18 in KS should be helpful in determining the pathophysiology of KS. Therefore, we examined the IL-18 values in KS. Methods: Serum IL-18 values were measured by an enzyme-linked immunosorbent assay. Samples were obtained from 41 patients in the acute and subacute phase of KS, 35 age-matched febrile controls and 13 afebrile controls. Results: No difference was observed in the values of white blood cell counts or C-reactive protein between acute-phase KS patients and febrile controls. On the contrary, acute-phase KS patients showed a significantly lower mean IL-18 value (398 ± 206 pg/ml) than that of febrile controls (584 ± 307 pg/ml) (p = 0.006). Subacute-phase KS patients showed a significantly elevated level of IL-18 (517 ± 276 pg/ml) compared to acute-phase patients (p = 0.0008). The IL-18 values in the subacute-phase patients showed a significant positive correlation with the duration of fever (r = 0.427, p = 0.0055) and also with the presence of coronary artery abnormalities (r = 0.332, p = 0.0340). The incidence of elevated IL-18 values in the subacute-phase patients was significantly higher than that in the afebrile controls (p = 0.048). Conclusions: Patients with KS showed normal IL-18 values in the acute phase and elevated values in the subacute phase. IL-18 pathways were activated in the subacute phase of KS, and subacute IL-18 values might be reflected in the severity of KS.
Bisphenol A Exerts Thyroid-Hormone-Like Effects on Mouse Oligodendrocyte Precursor Cells
Authors: Seiwa Chika , Nakahara Jin , Komiyama Takatsugu , Katsu Yoshinao , Iguchi Taisen , Asou Hiroaki
Published: September 2004

We report studies on the mechanism of action of bisphenol A (BPA) on the differentiation of oligodendrocyte precursor cells (OPCs). Our results show that: (1) BPA inhibits the differentiation of OPCs induced by exposure to thyroid hormone (T3). (2) The effect is mediated through various mechanisms via the thyroid hormone receptor (TRβ1) which is considered to be responsible for OPC differentiation. (3) The action of BPA on OPC differentiation does not involve the FcRγ-Fyn-myelin basic protein (MBP) cascade as an inducer of OPC differentiation nor does it suppress CREB phosphorylation, which is considered to be induced by the T3-TR complex. (4) The presence of MBP isoforms (21.5, 18.5, 17.0 and 14.0 kDa) was detected in OPCs, and the expression of exon 2-containing isoforms (i.e. 17.0 and 21.5 kDa) was upregulated upon treatment with T3. In contrast, expression of MBP was inhibited by BPA.
Social Hierarchy Affects Gene Expression for Catecholamine Biosynthetic Enzymes in Rat Adrenal Glands
Authors: Pohorecky Larissa A. , Blakley Gregory G. , Kubovcakova Lucia , Krizanova Olga , Patterson-Buckendahl Patricia , Kvetnansky Richard
Published: September 2004

Social stressors, like other stressors, are powerful activators of the sympathoadrenomedullary system. Differential housing (single vs. group) and social defeat of rats is known to alter the activity of catecholamine-synthesizing enzymes in the medulla. The present studies examined the effect of 70 days of triad (3 rats per large cage) and individual housing of male rats on adrenal mRNA levels of tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DBH) and phenylethanolamine-N-methyltransferase (PNMT) and on TH protein levels. Behavioral ratings carried out at the triad formation indicated that dominant rats exhibited mostly offensive aggressive behaviors. By contrast, subordinate rats expressed primarily defensive behaviors, while the subdominant rats displayed intermediate levels of these behaviors. Overall, compared with single housing, triad housing resulted in lower gene expression for TH, DBH and PNMT and lower TH protein in the adrenals. Within triads, gene expression for these enzymes and TH protein concentration were higher in subordinate compared with dominant and subdominant rats. The dominant rats tended to have the lowest gene expression of these enzymes. These data indicate that in rodents, individual housing and a subject’s social rank have a differential impact on the regulation of catecholamine biosynthesis already during the process of gene expression of catecholamine biosynthetic enzymes in the adrenals.
Surveillance for Hospitalizations with Infection-Related Diagnoses after Chemotherapy among Breast Cancer Patients Diagnosed before Age 65
Authors: Polednak Anthony P.
Published: September 2004

Background: The aim of this study was to assess the feasibility of population-based surveillance of the frequency of (and risk factors for) hospitalization with infection-related conditions potentially attributable to chemotherapy among breast cancer patients diagnosed before age 65 years in the USA, where a previous report was limited to older patients. Methods: This pilot study involved a sample of 675 Connecticut women diagnosed before the age of 65 years with early-stage breast cancer in 1999, who were identified from a population-based statewide cancer registry and were linked with a statewide inpatient hospital discharge database. Results: Hospitalization with an infection-related condition (neutropenia, fever, and/or infection/bacteremia) after diagnosis was found for 8.6% of 463 patients with chemotherapy vs. 2.8% of 212 without chemotherapy (p < 0.01). Such hospitalization was positively associated with lymph-node status and receipt of chemotherapy. Conclusion: Population-based surveillance appears feasible, but larger US studies are needed, with additional information (including use of antibiotics) as outlined by the European Surveillance of Infections in Cancer Patients (ESIC) study of risks and risk factors for serious adverse outcomes after cancer treatment.
Conditioning Regimens Including High-Dose Busulfan Cause a High Incidence of Transplant-Related Mortality after Myeloablative Stem Cell Transplantation
Authors: Nakamae Hirohisa , Yamane Takahisa , Aoyama Yasutaka , Yamamura Ryousuke , Ohta Kensuke , Hino Masayuki
Published: September 2004

Background: Transplant-related mortality (TRM) significantly decreases the long-term survival of patients with hematopoietic diseases who undergo hematopoietic stem cell transplantation (HSCT). Methods: We retrospectively evaluated the risk factors for TRM of 58 consecutive patients with hematopoietic disease who underwent allogeneic myeloablative HSCT between April 1994 and June 2002. Results: Thirty-one patients died after HSCT, 16 of whom were diagnosed as TRM. The actuarial incidence of TRM was 57.6 % in patients who received conditioning chemotherapies including high-dose busulfan and 19.4 % in those who did not (p = 0.008). Multivariate Cox model analysis revealed that disease status, graft versus host disease (GVHD) grades III–IV and the use of high-dose busulfan were significant and independent risk factors for TRM. Conclusion: These results suggest that high-dose busulfan as a conditioning therapy for allogeneic HSCT should be used cautiously, especially in patients with advanced disease.
Volume Flow Rate Evaluation in Patients with Obstructive Arteriosclerotic Disease
Authors: Doberenz Claudia , Paulus Walter , Reimers Carl D. , Eicke B. Martin
Published: September 2004

This study was performed to quantify the volumetric impact of extracranial arteriosclerotic lesions. We investigated patients with different degrees of carotid stenosis as defined by conventional velocity-based duplex criteria and different patterns of collateralization. We studied the volume flow rate (color duplex M-mode device) in 37 patients with symmetrical internal carotid artery (ICA) plaques (<50% stenosis) and compared these data to 43 patients with a unilateral 50–74% stenosis, 75–99% stenosis (n = 73) and occlusion of the ICA (n = 37). A 75–99% stenosis caused an ipsilateral flow reduction of 36% with a wide interindividual variability, and an occlusion of 51%. Collateralization via the ophthalmic artery only caused a nonsignificant ipsilateral volume flow increase, whereas the contralateral volume flow was significantly higher in patients with a patent anterior communicating artery. The increase was more pronounced in patients with an occluded vessel. Our data demonstrate a wide diversity of the hemodynamic impact of carotid stenosis as defined by ‘classical’ Doppler criteria. Collateral flow reflects a dynamic quantitative process.
Depressive Mixed State: A Feature of the Natural Course of Bipolar II (and Major Depressive) Disorder?
Authors: Benazzi Franco
Published: September 2004

Background: Depressive mixed state (DMX), i.e., a combination of hypomanic and depressive symptoms during the same episode, has recently seen a rebirth of studies after Kraepelin’s description. Kraepelin observed, in an inpatient sample, that DMX was related to the number of episodes and to duration of manic-depressive insanity (illness). Study Aim: The aim was to test Kraepelin’s observations in a very different sample. Methods: 563 consecutive outpatients with major depressive episode (MDE) – 320 with bipolar II disorder and 243 with major depressive disorder – were interviewed, in a private practice, by the Structured Clinical Interview for DSM-IV as modified by Benazzi and Akiskal (2003). Hypomanic symptoms during MDE were systematically assessed in patients while off psychoactive drugs. DMX was dimensionally defined, following Akiskal and Benazzi (2003), as an MDE plus 3 or more combined hypomanic symptoms. Kraepelin’s examples of DMX, i.e., agitated depression (MDE plus psychomotor agitation) and depression with flight of ideas (MDE plus racing thoughts) were also tested. Univariate and multivariate logistic regression was used to study associations. Results: DMX was present in 49.5% of the patients. Multiple logistic regression of DMX versus MDE recurrences and duration of illness, controlled for age, found a strong and significant association only between DMX and duration of illness. The same association was found between agitated depression and duration of illness (but not in depression with racing thoughts). Limitation: There was only a single interviewer. Discussion: The findings support Kraepelin’s observation of a link between DMX and durations of illness, but not that between DMX and recurrences. Onset of DMX could be more related to the natural course of manic-depressive illness than to a kindling process.
Psychopathy in Violent Female Offenders in Finland
Authors: Weizmann-Henelius Ghitta , Viemerö Vappu , Eronen Markku
Published: September 2004

Background: The base rate and construct of psychopathy in violent female offenders were examined. Sampling and Methods: More than half of all violent female offenders in Finland who where either hospitalised (n = 12) or incarcerated (n = 46) during the year of the study were assessed by the Hare Psychopathy Checklist-Revised (PCL-R), Structured Clinical Interview II for DSM-IV, Beck Anxiety Inventory, Beck Depression Inventory-II and Wechsler Adult Intelligence Scale-Revised. Results: PCL-R mean scores and a base rate of psychopathy were found to be in line with earlier studies, showing both lower values and prevalence in females. The PCL-R correlated with symptoms of cluster B personality disorders as well as with depressive personality disorder. Factor 2 was observed to positively correlate with anxiety and depression and negatively with verbal cognitive ability. Logistic regression analysis on the PCL-R items revealed that the items shallow affect, lack of remorse or guilt, conning/manipulation and lack of realistic goals seem to be important indicators of female psychopathy together with callous/lack of empathy, impulsivity and failure to accept responsibility for own actions. Conclusion: The finding indicates that the prevalence of psychopathy is lower among female offenders than among male offenders, but further research is needed to examine the base rate of psychopathy in women, and whether the symptoms of psychopathy are expressed differently in women than in men.
Bipolar Spectrum Disorder: A Pilot Study
Authors: Ghaemi S. Nassir , Hsu Douglas J. , Ko James Y. , Baldassano Claudia F. , Kontos Nicholas J. , Goodwin Frederick K.
Published: September 2004

Objective: To assess depressive features of a proposed definition of bipolar spectrum disorder (BSD). Methods: Thirty-six patients with bipolar disorder type I or II were compared to 37 patients with unipolar major depressive disorder through patient interview and chart review. Results: Univariate analysis suggests that 7 of 12 (recurrent major depressive episodes, brief major depressive episodes, atypical depressive symptoms, early age of onset, family history of bipolar disorder, antidepressant tolerance, and antidepressant-induced mania) features of major depressive episodes were more likely to occur in bipolar versus unipolar patients. After adjustment in a multivariable regression model, however, the five most powerful predictors of bipolar disorder were brief major depressive episodes, early age of onset, antidepressant- induced mania, postpartum depression, and atypical depressive symptoms. Conclusions: This preliminary study supports the idea that bipolar disorder is characterized by some depressive features less likely to be found in unipolar depression. Further prospective study needs to be conducted comparing BSD with unipolar depression.