bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetics of darbepoetin alfa in haemodialysis and peritoneal dialysis patients after intravenous administration
Authors: Takama Hirotaka , Tanaka Hideji , Nakashima Daisuke , Ogata Hiroyasu , Uchida Eiji , Akizawa Tadao , Koshikawa Shozo 
Published: August 2006

AimsTo characterize the pharmacokinetics of darbepoetin alfa and covariate relationships in haemodialysis (HD) and peritoneal dialysis (PD) patients.MethodsData were collected from 131 (63 HD and 68 PD) patients who received darbepoetin alfa intravenously. A total of 917 serum concentrations were available. The data were analysed by nonlinear mixed effect modelling using NONMEM with a model including endogenous erythropoietin production. In addition, the final model was evaluated using bootstrap resampling.ResultsThe selected basic model was a two‐compartment model with a combination of additive and the constant coefficient of variation error models. The significant covariates were weight (WT) for clearance (CL) and the volume of central compartment (V1), and the dialysis technique (DIA) for V1. The typical values of CL and V1 were 0.0807 l h−1 and 2.51 l, respectively. V1 in PD patients was 17% higher than in HD patients. With the introduction of WT in CL and WT and DIA in V1, interindividual variability decreased from 27.1% to 20.6% in CL and from 29.1% to 21.8% in V1. The mean parameter estimates from the bootstrap datasets were similar to those from the original dataset. Evaluation by bootstrapping showed that the final model was stable.ConclusionsThe results of the present analysis suggest no dosage regimen change is warranted for darbepoetin alfa in HD and PD patients over the range of distribution of covariates included in this study.
Recent insights into the pathogenesis of Diamond–Blackfan anaemia
Authors: Gazda Hanna T. , Sieff Colin A. 
Published: August 2006

SummaryDiamond–Blackfan anaemia (DBA) is a congenital anaemia and broad developmental disease that develops soon after birth. The anaemia is due to failure of erythropoiesis, with normal platelet and myeloid lineages, and it can be managed with steroids, blood transfusions, or stem cell transplantation. Normal erythropoiesis after transplantation shows that the defect is intrinsic to an erythroid precursor. DBA is inherited in about 10–20% of cases, and genetic studies have identified mutations in a ribosomal protein gene, RPS19, in 25% of cases; there is evidence for involvement of at least two other genes. In yeast, RPS19 deletion leads to a block in ribosomal RNA biogenesis. The critical question is how mutations in RPS19 lead to the failure of proliferation and differentiation of erythroid progenitors. While this question has not yet been answered, understanding the biology of DBA may provide insight not only into the defect in erythropoisis, but also into the other developmental abnormalities that are present in about 40% of patients, and into the cancer predisposition that is inherent to DBA.
Mycobacterium tuberculosis-susceptible I/St mice develop severe disease following infection with taxonomically distant bacteria,Salmonella entericaandChlamydia pneumoniae
Authors: Nesterenko L N , Balunets D V , Tomova A S , Romanova J M , Alyapkina J S , Zigangirova N A , Kapina M A , Kondratieva E V , Pichugin A V , Majorov K B , Apt A S 
Published: August 2006

SummaryMice of I/St strain develop severe lung inflammation and die shortly following infection with virulent mycobacteria. To find out whether tuberculosis (TB)-susceptible I/St mice are susceptible to other intracellular bacteria, we investigated two different taxonomically distant pathogens, Chlamydia pneumoniae and Salmonella enterica serovar Typhimurium. Comparison of I/St and TB-resistant A/Sn mice (both Nramp1r) demonstrated that the former are more susceptible to both salmonella and chlamydia, displaying a significantly shortened survival time following challenge. Lung pathology develops more rapidly in I/St compared to A/Sn mice following infection with chlamydia, despite their similar ability to control bacterial multiplication. Following infection with salmonella, substantial (∼ 3 log) but very short (second day post-infection) interstrain differences in bacterial loads were observed, accompanied by higher levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-α in the peritoneal cavities of I/St mice. I/St macrophages were more permissive for salmonella growth during the first 24 h following infection in vitro. Because the prominent differences in survival time did not correlate with permanent differences in bacterial multiplication, we suggest that both infections trigger fatal pathological processes whose dynamics depend strongly upon the host genetics.
High-dose intravenous immunoglobulin pulse therapy in patients with progressive immunoglobulin A nephropathy: a long-term follow-up
Authors: Rasche F M , Keller F , Lepper P M , Aymanns C , Karges W , Sailer L-C , von Müller L , Czock D 
Published: August 2006

Summary
In progressive immunoglobulin A nephropathy (IgAN), intravenous immunoglobulin (IVIg) treatment has been used to delay disease progression, but the long-term efficacy is largely unknown. We report the clinical outcomes after IVIg therapy in six male patients with progressive IgAN [median glomerular filtration rate (GFR) 31 ml/min per 1·73 m2] followed for a median observation period of 8 years. In this single-arm, non-randomized study, IVIg was given monthly at a dose of 2 g/kg body weight for 6 months. The course of renal function was assessed by linear regression analysis of GFR and proteinuria, and was compared to eight patients with IgAN (median GFR 29 ml/min per 1·73 m2) without IVIg as a contemporaneous control group. IgAN disease progression was delayed after IVIg therapy on average for 3 years. The mean loss of renal function decreased from − 1·05 ml/min per month to − 0·15 ml/min per month (P = 0·024) and proteinuria decreased from 2·4 g/l to 1·0 g/l (P = 0·015). The primary end-point (GFR &lt; 10 ml/min or relapse) occurred 5·2 years (median; range 0·4–8·8) after the first IVIg pulse, and after 1·3 years (median; range 0·8–2·4) in the control group (P = 0·043). In Kaplan–Meier analysis, the median renal survival time with IVIg was prolonged by 3·5 years (IVIg 4·7 years versus control 1·2 years; P = 0·006). IVIg pulse therapy may be considered as a treatment option to reduce the loss of renal function and improve proteinuria in patients with progressive IgAN.
Cellular autoreactivity against heat shock protein 60 in renal transplant patients: peripheral and graft-infiltrating responses
Authors: Caldas C , Luna E , Spadafora-Ferreira M , Porto G , Iwai L K , Oshiro S E , Monteiro S M , Fonseca J A , Lemos F , Hammer J , Ho P L , Kalil J , Coelho V 
Published: August 2006

SummaryAutoreactivity to heat shock protein 60 (Hsp60) has been implicated in the pathogenesis and regulation of chronic inflammation, especially in autoimmune diseases. In transplantation, there is a lack of information regarding the cytokine profile and specificity of cells that recognize self-Hsp60 as well as the kinetics of autoreactivity following transplantation. We studied the cellular reactivity of peripheral and graft-infiltrating lymphocytes against Hsp60 in renal transplant patients. Cytokine production induced by this protein in peripheral blood mononuclear cells indicated a predominance of interleukin (IL)-10 during the late post-transplantation period, mainly in response to intermediate and C-terminal peptides. Patients with chronic rejection presented reactivity to Hsp60 with a higher IL-10/interferon (IFN)-γ ratio compared to long-term clinically stable patients. Graft-infiltrating T cell lines, cocultured with antigen-presenting cells, preferentially produced IL-10 after Hsp60 stimulation. These results suggest that, besides its proinflammatory activity, autoreactivity to Hsp60 in transplantation may also have a regulatory role.
Complement membrane attack is required for endplate damage and clinical disease in passive experimental myasthenia gravis in Lewis rats
Authors: Chamberlain-Banoub J , Neal J W , Mizuno M , Harris C L , Morgan B P 
Published: August 2006

SummaryMyasthenia gravis (MG) is a debilitating and potentially fatal neuromuscular disease characterized by the generation of autoantibodies reactive with nicotinic acetylcholine receptors (AChR) that cause loss of AChR from the neuromuscular endplate with resultant failure of neuromuscular transmission. A role for complement (C) in the pathology of human MG has been suggested based upon identification of C activation products in plasma and deposited at the endplate in MG. In the rat model, experimental autoimmune MG (EAMG), C depletion or inhibition restricts clinical disease, further implicating C in pathology. The mechanisms by which C activation drives pathology in MG and EAMG are unclear. Here we provide further evidence implicating C and specifically the membrane attack complex (MAC) in the Lewis rat passive EAMG model of MG. Rats deficient in C6, an essential component of the MAC, were resistant to disease induction and endplate destruction was reduced markedly compared to C6-sufficient controls. After reconstitution with C6, disease severity and endplate destruction in the C6-deficient rats was equivalent to that in controls. The data confirm the essential role of the MAC in the destruction of the endplate in EAMG and raise the prospect of specific MAC inhibition as an alternative therapy in MG patients resistant to conventional treatments.
Hypoxia induces expression of connective tissue growth factor in scleroderma skin fibroblasts
Authors: Hong K-H , Yoo S-A , Kang S-S , Choi J-J , Kim W-U , Cho C-S 
Published: August 2006

SummaryConnective tissue growth factor (CTGF) plays a role in the fibrotic process of systemic sclerosis (SSc). Because hypoxia is associated with fibrosis in several profibrogenic conditions, we investigated whether CTGF expression in SSc fibroblasts is regulated by hypoxia. Dermal fibroblasts from patients with SSc and healthy controls were cultured in the presence of hypoxia or cobalt chloride (CoCl2), a chemical inducer of hypoxia-inducible factor (HIF)-1α. Expression of CTGF was evaluated by Northern and Western blot analyses. Dermal fibroblasts exposed to hypoxia (1% O2) or CoCl2 (1–100 µM) enhanced expression of CTGF mRNA. Skin fibroblasts transfected with HIF-1α showed the increased levels of CTGF protein and mRNA, as well as nuclear staining of HIF-1α, which was enhanced further by treatment of CoCl2. Simultaneous treatment of CoCl2 and transforming growth factor (TGF)-β additively increased CTGF mRNA in dermal fibroblasts. Interferon-γ inhibited the TGF-β-induced CTGF mRNA expression dose-dependently in dermal fibroblasts, but they failed to hamper the CoCl2-induced CTGF mRNA expression. In addition, CoCl2 treatment increased nuclear factor (NF)-κB binding activity for CTGF mRNA, while decreasing IκBα expression in dermal fibroblasts. Our data suggest that hypoxia, caused possibly by microvascular alterations, up-regulates CTGF expression through the activation of HIF-1α in dermal fibroblasts of SSc patients, and thereby contributes to the progression of skin fibrosis.
The testes‐specific bZip type transcription factor Tisp40 plays a role in ER stress responses and chromatin packaging during spermiogenesis
Authors: Nagamori Ippei , Yomogida Kentaro , Ikawa Masahito , Okabe Masaru , Yabuta Norikazu , Nojima Hiroshi 
Published: August 2006

We previously reported that the spermatid‐specific transcription factor Tisp40 functions through UPRE and CRE. To investigate Tisp40 function in vivo, we generated TISP40(–/–) mice. TISP40(–/–) mice were born at expected ratios, were healthy, and mutant males bred normally. However, the ER stress‐response protein Grp78/BiP accumulated in the TISP40(–/–) testis and RAMP4 (Ribosome‐associated membrane protein 4) mRNA level was up‐regulated. Disruption of TISP40 caused ER stress and activation of caspase 12 but not caspase 9, leading to apoptosis of meiotic/postmeiotic germ cells. On the other hand, DAPI staining and electron microscopy revealed that epididymal sperm nuclei were abnormally relaxed in the TISP40(–/–) testis, a phenotype that was independent of the expression and maturation of transition proteins and protamines but due to abnormally retained histones. Histones localized to the cytoplasm as well as to the nucleus and were also retained in epididymal sperm. Histones H2A and H4 were dramatically up‐regulated and the acetylation of H2A, H2B and H4 was also enhanced in the TISP40(–/–) testis. Taken together, we conclude that Tisp40 plays an important role in the unfolded protein response of the testis and in regulating the maturation of sperm head nuclei.
Ammonium transporter genes in the fission yeast Schizosaccharomyces pombe: role in ammonium uptake and a morphological transition
Authors: Mitsuzawa Hiroshi 
Published: August 2006

Ammonium is an important source of nitrogen for many microorganisms, including yeast, and its availability also has substantial effects on the nitrogen metabolism and development of yeast cells. Three ammonium transporter genes of the fission yeast Schizosaccharomyces pombe, named amt1, amt2, and amt3, were identified on the basis of amino acid sequence similarity to members of the ammonium transporter/methylammonium permease (Amt/Mep) family. A series of strains were constructed that carry all combinations of amt deletion (amtΔ) mutations, and tested for growth on low ammonium and resistance to the toxic ammonium analog methylammonium. The amt1Δ and amt2Δ single mutants had different growth defects, and the amt1Δamt2Δ double mutant displayed a much more severe growth defect on ≤ 5 mm ammonium. All single mutants exhibited methylammonium resistance but to different extents: amt2Δ was the most resistant and amt3Δ was the least. These results suggest that the amt genes encode functional transporters with distinct uptake properties. In response to ammonium limitation, the wild‐type strain isogenic to the amtΔ mutants underwent filamentous growth underneath the surface of solid medium. No such filamentous invasive growth, however, was observed for the amt1Δ mutant, indicating that Amt1 transporter is required for ammonium limitation‐induced filamentous invasive growth.
New reporter system for Per1 and Bmal1 expressions revealed self‐sustained circadian rhythms in peripheral tissues
Authors: Nishide Shin‐ya , Honma Sato , Nakajima Yoshihiro , Ikeda Masaaki , Baba Kenkichi , Ohmiya Yoshihiro , Honma Ken‐ichi 
Published: August 2006

A new reporter system for monitoring expressions of two clock genes, Per1 and Bmal1, from a single tissue in culture was developed in mice. Reporters are Vargula hilgendorfii luciferase (VL) and firefly luciferase (FL), whose activities are increased in parallel with Per1 and Bmal1 expressions, respectively. Formal properties of the circadian system in transgenic mice are indistinguishable from those in wild‐type animals. Circadian rhythms in Per1‐VL and Bmal1‐FL in the suprachiasmatic nucleus (SCN) were robust and anti‐phasic, although they were phase delayed by 4–8 h as compared with circadian rhythms in respective transcript levels in vivo. In peripheral tissues such as liver, circadian rhythms in Bmal1‐FL persisted for more than 3 weeks. In the course of prolonged culture, circadian rhythms apparently damped out, but were restored immediately by refreshment of the culture medium. Restoration of the circadian rhythm is unlikely to be due to resetting of desynchronized population oscillation, because peripheral circadian rhythms did not show a type 0 phase response curve (PRC) for medium refreshment, a requirement for instantaneous resetting of circadian oscillation. Long‐term persistence of circadian oscillation in spite of external perturbations supports an idea that circadian oscillations in peripheral tissues are self‐sustained.
Effect of water washing on the functional and rheological properties of proteins from threadfin bream (Nemipterus japonicus) meat
Authors: Karthikeyan M. , Dileep A.O. , Shamasundar B.A. 
Published: August 2006

SummaryThe effect of the number of water washing cycles on the proximate composition, physicochemical and functional properties of proteins from threadfin bream meat was studied. Contents of proteins, fat, ash and non‐protein nitrogen showed a significant (P < 0.05) decrease with the number of washing cycles. The removal of low molecular weight components and increase in the concentration of high molecular weight components was confirmed by gel filtration profile and sodium dodecyl sulphate polyacrylamide gel electrophoresis. The water absorption, fat absorption and emulsion capacity parameters showed a positive correlation with the number of washing cycles. The gel‐forming ability showed a marked improvement with the number of washing cycles. The dynamic viscoelastic behaviour of unwashed and washed meat showed a structure build‐up reaction and was more pronounced in once washed meat. The flow behaviour of total protein solution from unwashed and washed meat showed a pseudoplastic behaviour.
PBP3 inhibition elicits adaptive responses in Pseudomonas aeruginosa
Authors: Blázquez Jesús , Gómez‐Gómez José‐María , Oliver Antonio , Juan Carlos , Kapur Vivek , Martín Soledad 
Published: August 2006

SummaryAdaptive evolution depends on both the genetic variability in a population of organisms and the selection of the better adapted genotypes. However, for the fittest variants to be selected they must survive over a sufficient period under the new conditions. Bacteria are often exposed to different types of stress in nature, including antibiotics. We analysed the global expression profiles of the opportunistic pathogen Pseudomonas aeruginosa in response to ceftazidime, a PBP3 inhibitor, at different concentrations and times. PBP3 inhibition exerts a global impact on the transcription of a large number of genes. From an adaptive perspective, it is noteworthy the induction of several SOS genes, as well as adaptation, protection and antibiotic resistance genes. Intriguingly, transcription of pyocin genes, previously described as SOS‐regulated, was repressed upon PBP3 inhibition. Ciprofloxacin, an SOS inducer, produced transcriptional induction of pyocins. Our results indicate that: (i) the SOS responses resulting from treatments with these two antibiotics cause only partially overlapping transcription profiles; (ii) PBP3 and DNA‐gyrase inhibition produce opposite effects on transcription of pyocin genes. Consequently, ceftazidime decreases ciprofloxacin toxicity; (iii) error‐prone DNA‐polymerase DinB is induced by PBP3 inhibition but not by DNA‐gyrase inhibition; (iv) PBP3 inhibition causes induced mutagenesis; (v) ceftazidime upregulates several antibiotic‐resistance and adaptation genes; and (vi) ceftazidime concentrations thought previously to be lethal are not, as most cells treated with ceftazidime remain alive and recover their capacity to form colonies. Thus, transcriptional changes demonstrated in this work are likely to be adaptively relevant to cells that survive.
PfCRT and the trans‐vacuolar proton electrochemical gradient: regulating the access of chloroquine to ferriprotoporphyrin IX
Authors: Bray Patrick G. , Mungthin Mathirut , Hastings Ian M. , Biagini Giancarlo A. , Saidu Dauda K. , Lakshmanan Viswanathan , Johnson David J. , Hughes Ruth H. , Stocks Paul A. , O'Neill Paul M. , Fidock David A. , Warhurst David C. , Ward Stephen A. 
Published: August 2006

SummaryIt is accepted that resistance of Plasmodium falciparum to chloroquine (CQ) is caused primarily by mutations in the pfcrt gene. However, a consensus has not yet been reached on the mechanism by which resistance is achieved. CQ‐resistant (CQR) parasite lines accumulate less CQ than do CQ‐sensitive (CQS) parasites. The CQR phenotype is complex with a component of reduced energy‐dependent CQ uptake and an additional component that resembles energy‐dependent CQ efflux. Here we show that the required energy input is in the form of the proton electrochemical gradient across the digestive vacuole (DV) membrane. Collapsing the DV proton gradient (or starving the parasites of glucose) results in similar levels of CQ accumulation in CQS and CQR lines. Under these conditions the accumulation of CQ is stimulated in CQR parasite lines but is reduced in CQS lines. Energy deprivation has no effect on the rate of CQ efflux from CQR lines implying that mutant PfCRT does not function as an efflux pump or active carrier. Using pfcrt‐modified parasite lines we show that the entire CQ susceptibility phenotype is switched by the single K76T amino acid change in PfCRT. The efflux of CQ in CQR lines is not directly coupled to the energy supply, consistent with a model in which mutant PfCRT functions as a gated channel or pore, allowing charged CQ species to leak out of the DV.
Deletion of the gliP gene of Aspergillus fumigatus results in loss of gliotoxin production but has no effect on virulence of the fungus in a low‐dose mouse infection model
Authors: Kupfahl Claudio , Heinekamp Thorsten , Geginat Gernot , Ruppert Thomas , Härtl Albert , Hof Herbert , Brakhage Axel A. 
Published: August 2006

SummaryGliotoxin is a secondary metabolite produced by several fungi including the opportunistic human pathogen Aspergillus fumigatus. As gliotoxin exerts immunosuppressive effects in vitro and in vivo, a role as a virulence determinant in invasive aspergillosis has been discussed for a long time but evidence has not been provided until now. Here, by the use of different selection marker genes A. fumigatus knock‐out strains were generated that are deficient for the non‐ribosomal peptide synthetase GliP, the putative key enzyme of the gliotoxin biosynthesis. Deletion of the gliP gene resulted in loss of gliotoxin production, as analysed by high performance liquid chromatography and tandem mass spectrometry. No differences in morphology or growth kinetics between wild‐type and gliP‐deletion strains were observed. In vitro, the culture supernatant of the gliP‐deficient strains showed a reduced cytotoxic effect on both macrophage‐like cells and T cell lines. In a low‐dose murine infection model of invasive aspergillosis, gliotoxin was detected in the lung and absent when mice were infected with the gliP deletion strain. However, gliP deletion strains showed no difference in virulence compared with the corresponding wild‐type strains. Taken together, the non‐ribosomal peptide synthetase GliP is essential for gliotoxin production in A. fumigatus. Gliotoxin is not required for pathogenicity of the fungus in immunocompromised mice, despite the fact that a reduced cytotoxicity of the culture supernatant of gliP deletion strains was demonstrated.
Cutaneous squamous cell carcinoma of the lower limbs in Goiânia, Goiás, Brazil
Authors: Quinteiro Ribeiro Ana Maria , Curado Maria Paula , Benevides Santana Filho Jales 
Published: August 2006

AbstractBackground Cutaneous squamous cell carcinoma is a common malignant neoplasm that affects areas that are exposed to the sun in fair‐skinned people. It occurs less frequently on the lower limbs where other etiological factors are involved.Objective To determine the epidemiological aspects of cutaneous squamous cell carcinoma of the lower limbs in Goiânia.Methodology Forty‐three cases of cutaneous squamous cell carcinoma of the lower limbs from the Cancer Registry of the Population Base of Goiás, for the period between 1995 and 1999, were included in the study.Results Among the cases of cutaneous squamous cell carcinoma registered in this 5‐year interval, 43 (4.6%) represented cases affecting the lower limbs. Of these individuals, seven (16.3%) were male and 36 (83.7%) female (P < 0.001). Those in the age group of 60 years and above represented 90.7% of the cases (P < 0.001). None of the patients had metastasis.Conclusion Cutaneous squamous cell carcinomas on the lower limbs are more frequently seen in women older than 60 years of age, and they rarely metastasize.