bluuebunny/crossref_metadata_2025 huggingface dataset:
A SOFTWARE RELIABILITY GROWTH MODEL WITH TESTING EFFORT DEPENDENT LEARNING FUNCTION FOR DISTRIBUTED SYSTEMS
Authors: KAPUR P. K. , GOSWAMI D. N. , GUPTA AMIT
Published: November 2004

Effective software process improvement will not start until management insists that product development work be planned and properly managed. This becomes even more challenging in an increasing number of major system developments made up from distributed sub-system software projects. These sub-systems are integrated and validated to provide the final system and product release. The need is growing to estimate, risk assess, plan and manage the development of these distributed sub-systems and the final full system release. In this paper, an attempt has been made to model the software reliability growth phenomenon with testing effort in a distributed development environment. Proposed Non Homogeneous Poisson Process (NHPP) based model assumes that the software system consists of a finite number of reused and newly developed sub-systems. The reused sub-systems do not consider the effect of severity of the faults on the software reliability growth phenomenon because they stabilize over a period of time i.e., the growth is uniform whereas, the newly developed sub-system do consider that. Fault removal phenomenon for reused and newly developed sub-systems have been modeled separately and is summed up to get the total fault removal phenomenon of the software system. The applicability of our model is shown by validating it on software failure data sets obtained from different real software development projects. The comparisons with established models in terms of goodness of fit, the Akaike Information Criterion (AIC), Mean of Squared Errors (MSE) have been presented.
FUZZY DYNAMIC RELIABILITY EVALUATION OF A DETERIORATING SYSTEM UNDER IMPERFECT REPAIR
Authors: VERMA A. K. , SRIVIDYA A. , GAONKAR RAJESH PRABHU
Published: November 2004

This paper presents the dynamic reliability evaluation of the deteriorating system using the concept of probist reliability as a fuzzy number. Triangular fuzzy number (TFN) has been used to represent the reliabilities. Initial reliability is determined using the expert's judgment and probabilistic improvement factor is considered to indicate the maintenance effectiveness of 1P maintenance activity. Deteriorating system is represented by PAR model and fuzzy dynamic reliability estimation procedure is demonstrated with appropriate illustration. Using this fuzzy dynamic reliability, fuzzy hazard rate is computed.
STRONGLY CORRELATED FUNCTIONS IN RELIABILITY—PHYSICAL APPROACH
Authors: RAWICZ ANDREW H.
Published: November 2004

A new approach to reliability called Strongly Correlated Functions is proposed in this paper based on the definition of reliability as a physical magnitude rather than as a probabilistic one. The reliability measure (e.g., life-length) of a component or a product treated as a physical/chemical parameter allows for the construction of analytic correlations between the reliability measure and other physical parameters such as electrical resistance, heat conductivity, or acoustic attenuation that can be nondestructively and quickly determined by a direct measurement. Examples of Strongly Correlated Functions applied to micro wire-joints are presented.
SYSTEM RELIABILITY GROWTH ANALYSIS USING COMPONENT FAILURE DATA
Authors: XIE M. , GOH T.N.
Published: November 2004

In this paper the problem of system-level reliability growth estimation using component-level failure data is studied. It is suggested that system failure data should be broken down into component, or subsystem, failure data when the above problems have occurred during the system testing phase. The proposed approach is especially useful when the system is not unchanged over the time, when some subsystems are improved more than others, or when the testing has been concentrated on different components at different time. These situations usually happen in practice and it may also be the case even if the system failure data is provided. Two sets of data are used to illustrate the simple approach; one is a set of component failure data for which all subsystems are available for testing at the same time and for the other set of data, the starting times are different for different subsystems.
AN OPTIMAL STATIC PESSIMISTIC SCHEME FOR FAULT TOLERANT DISTRIBUTED DATABASE SYSTEMS
Authors: PHAM HOANG , POTOSKI DAVID
Published: November 2004

A distributed database system often replicates data across its servers to provide a fault-resistant application, which maximizes server availability. Various replication control protocols have been developed to ensure data consistency. In this paper, we develop optimal design methods for the quorum-consensus replication protocol, which (1) maximizes availability of the distributed database systems and (2) minimizes the total system cost by calculating the optimal read quorum and the optimal number of system servers. Several numerical examples and applications are provided to illustrate the results.
CONFIDENCE INTERVAL FOR THE CRITICAL TIME OF INVERSE GAUSSIAN FAILURE RATE
Authors: TANG LOON CHING , CHANG DONG SHANG
Published: November 2004

Critical time is the point at which the failure rate attains its maximum and then decreases. For the inverse Gaussian distribution, the critical time always exists and can be used as a guide for conducting burn-in. In this paper, we use two different reparametrization schemes to establish monotonicity property of critical time. This property is then used to obtain exact confidence intervals for the critical time when either one of the parameters of the inverse Gaussian distribution is known. When both parameters are unknown we construct an analytically exact confidence interval for the critical time that guarentees the desired coverage probability. An approximate confidence interval, motivated by conservative nature of the above bound, is also proposed. Monte-Carlo simulation is conducted to investigate the performance of the two confidence intervals in terms of the their coverage probability and average width. Finally, a numerical example on repair time data is provided to illustrate the procedure.
Cytokine regulation of human sterol 12α-hydroxylase (CYP8B1) gene
Authors: Jahan Asmeen , Chiang John Y. L.
Published: November 2004

Sterol 12α-hydroxylase (CYP8B1) catalyzes cholic acid synthesis in the liver and is feedback inhibited by bile acids. In addition to activating farnesoid X receptor (nuclear receptor subfamily 1H4), bile acids also induce inflammatory cytokines in hepatocytes. The objective of this study was to investigate the mechanism by which inflammatory cytokines inhibit human CYP8B1 gene transcription. Real-time PCR assays revealed that both chenodeoxycholic acid (CDCA) and interleukin-1β (IL-1β) markedly reduced CYP8B1, cholesterol 7α-hydroxylase CYP7A1 and hepatic nuclear factor 4α (HNF4α) mRNA expression levels in human primary hepatocytes. However, CDCA induced, but IL-1β reduced, small heterodimer partner (SHP) mRNA expression. IL-1β inhibited human CYP8B1 reporter activity only in liver cells, and a c-Jun NH2-terminal kinase (JNK)-specific inhibitor-blocked IL-1β inhibition. Activated JNK1 or c-Jun inhibited, whereas their dominant negative forms blocked, IL-1β inhibition of CYP8B1 transcription. Mutagenesis analyses mapped an IL-1β response element to a previously identified bile acid response element, which contains an HNF4α binding site. A dominant negative HNF4α inhibited CYP8B1 gene transcription and ectopically expressed HNF4α blocked IL-1β inhibition. Furthermore, IL-1β inhibited HNF4α gene transcription, protein expression, and binding to the CYP8B1 gene. JNK1 phosphorylated HNF4α and a JNK-specific inhibitor blocked the IL-1β inhibition of HNF4α expression. These results suggest that IL-1β inhibits CYP8B1 gene transcription via a mitogen-activated protein kinase/JNK pathway that inhibits HNF4α gene expression and its DNA-binding ability. This mechanism may play an important role in the adaptive response to inflammatory cytokines and in the protection of the liver during cholestasis.
Components of intestinal epithelial hypoxia activate the virulence circuitry of Pseudomonas
Authors: Kohler Jonathan E. , Zaborina Olga , Wu Licheng , Wang Yingmin , Bethel Cindy , Chen Yimei , Shapiro James , Turner Jerrold R. , Alverdy John C.
Published: November 2004

We have previously shown that a lethal virulence trait in Pseudomonas aeruginosa, the PA-I lectin, is expressed by bacteria within the intestinal lumen of surgically stressed mice. The aim of this study was to determine whether intestinal epithelial hypoxia, a common response to surgical stress, could activate PA-I expression. A fusion construct was generated to express green fluorescent protein downstream of the PA-I gene, serving as a stable reporter strain for PA-I expression in P. aeruginosa. Polarized Caco-2 monolayers were exposed to ambient hypoxia (0.1–0.3% O2) for 1 h, with or without a recovery period of normoxia (21% O2) for 2 h, and then inoculated with P. aeruginosa containing the PA-I reporter construct. Hypoxic Caco-2 monolayers caused a significant increase in PA-I promoter activity relative to normoxic monolayers (165% at 1 h; P < 0.001). Similar activation of PA-I was also induced by cell-free apical, but not basal, media from hypoxic Caco-2 monolayers. PA-I promoter activation was preferentially enhanced in bacterial cells that physically interacted with hypoxic epithelia. We conclude that the virulence circuitry of P. aeruginosa is activated by both soluble and contact-mediated elements of the intestinal epithelium during hypoxia and normoxic recovery.
Inflammation induced changes in arachidonic acid metabolism in cat LES circular muscle
Authors: Cheng Ling , Cao Weibiao , Behar Jose , Biancani Piero , Harnett Karen M.
Published: November 2004

Myogenic lower esophageal sphincter (LES) tone is maintained by arachidonic acid metabolites, such as PGF2αand thromboxane A2/B2. Experimental esophagitis in cat reduces LES in vivo pressure and in vitro tone. Because IL-1β may mediate esophagitis-associated reduction in ACh release in esophagus, we examined whether IL-1β may also play a role in esophagitis-induced reduction of LES tone. A cat model of experimental esophagitis was obtained by repeated esophageal perfusion with HCl (Biancani P, Barwick K, Selling J, and McCallum R. Gastreonterology 87: 8–16, 1984 and Sohn UD, Harnett KM, Cao W, Rich H, Kim N, Behar J, and Biancani P. J Pharmacol Exp Ther 283: 1293–1304, 1997.). LES circular muscle strips were examined in muscle chambers as previously described (Biancani P, Billett G, Hillemeier C, Nissenshon M, Rhim BY, Sweczack S, and Behar J. Gastroenterology 103: 1199–1206, 1992). Levels of inflammatory mediators were measured. IL-1β levels were higher in esophagitis than in normal LES. IL-1β reduced normal LES tone, and the reduction was reversed by catalase, suggesting a role of H2O2. This was confirmed by IL-1β-induced production of H2O2in normal LES and elevated H2O2levels in esophagitis. H2O2by itself is sufficient to explain the changes that occur in the muscle, reducing its ability to contract. H2O2increased PGE2in normal LES, and PGE2levels were elevated in esophagitis LES, whereas PGF2αlevels were unchanged. H2O2also increased levels of 8-isoprostanes, stable prostaglandin-like compounds formed by free radical-induced peroxidation of arachidonic acid, and 8-isoprostane levels were elevated in esophagitis. The PGF2αanalog 8-iso-PGF2αcaused little contraction of LES strips but reduced PGF2αbinding and contraction of normal LES. In esophagitis, PGF2αbinding and contraction were reduced in LES, suggesting that isoprostanes may contribute to reduction in tone in esophagitis. The data suggest that, in esophagitis, IL-1β causes production of H2O2. H2O2increases PGE2, which relaxes the LES, and 8-iso-F2α, which blocks PGF2α-mediated contraction.
Cultured monolayers of the dog jejunum with the structural and functional properties resembling the normal epithelium
Authors: Weng Xing-He , Beyenbach Klaus W. , Quaroni Andrea
Published: November 2004

The development of a culture of the normal mammalian jejunum motivated this work. Isolated crypt cells of the dog jejunum were induced to form primary cultures on Snapwell filters. Up to seven subcultures were studied under the electron microscope and in Ussing chambers. Epithelial markers were identified by RT-PCR, Western blot, and immunofluorescent staining. Confluent monolayers exhibit a dense apical brush border, basolateral membrane infoldings, desmosomes, and tight junctions expressing zonula occludens-1, occludin-1, and claudin-3 and -4. In OptiMEM medium fortified with epidermal growth factor, hydrocortisone, and insulin, monolayer transepithelial voltage was −6.8 mV (apical side), transepithelial resistance was 1,050 Ω·cm2, and short-circuit current ( Isc) was 8.1 μA/cm2. Transcellular and paracellular resistances were estimated as 14.8 and 1.1 kΩ·cm2, respectively. Serosal ouabain reduced voltage and current toward zero, as did apical amiloride. The presence of mRNA of α-epithelial Na+channel (ENaC) was confirmed. Na-d-glucose cotransport was identified with an antibody to Na+-glucose cotransporter (SGLT) 1. The unidirectional mucosa-to-serosa Na+flux (19 nmol·min−1·cm−2) was two times as large as the reverse flux, and net transepithelial Na+flux was nearly double the amiloride-sensitive Isc. In plain Ringer solution, the amiloride-sensitive Iscwent toward zero. Under these conditions plus mucosal amiloride, serosal dibutyryl-cAMP elicited a Cl−-dependent Iscconsistent with the stimulation of transepithelial Cl−secretion. In conclusion, primary cultures and subcultures of the normal mammalian jejunum form polarized epithelial monolayers with 1) the properties of a leaky epithelium, 2) claudins specific to the jejunal tight junction, 3) transepithelial Na+absorption mediated in part by SGLT1 and ENaC, and 4) electrogenic Cl−secretion activated by cAMP.
Hypertrophic cardiomyopathy-related β-myosin mutations cause highly variable calcium sensitivity with functional imbalances among individual muscle cells
Authors: Kirschner Sebastian E. , Becker Edgar , Antognozzi Massimo , Kubis Hans-Peter , Francino Antonio , Navarro-López Francisco , Bit-Avragim Nana , Perrot Andreas , Mirrakhimov Mirsaid M. , Osterziel Karl-Josef , McKenna William J. , Brenner Bernhard , Kraft Theresia
Published: November 2004

Disease-causing mutations in cardiac myosin heavy chain (β-MHC) are identified in about one-third of families with hypertrophic cardiomyopathy (HCM). The effect of myosin mutations on calcium sensitivity of the myofilaments, however, is largely unknown. Because normal and mutant cardiac MHC are also expressed in slow-twitch skeletal muscle, which is more easily accessible and less subject to the adaptive responses seen in myocardium, we compared the calcium sensitivity (pCa50) and the steepness of force-pCa relations (cooperativity) of single soleus muscle fibers from healthy individuals and from HCM patients of three families with selected myosin mutations. Fibers with the Arg723Gly and Arg719Trp mutations showed a decrease in mean pCa50, whereas those with the Ile736Thr mutation showed slightly increased mean pCa50 with higher active forces at low calcium concentrations and residual active force even under relaxing conditions. In addition, there was a marked variability in pCa50 between individual fibers carrying the same mutation ranging from an almost normal response to highly significant differences that were not observed in controls. While changes in mean pCa50 may suggest specific pharmacological treatment (e.g., calcium antagonists), the observed large functional variability among individual muscle cells might negate such selective treatment. More importantly, the variability in pCa50 from fiber to fiber is likely to cause imbalances in force generation and be the primary cause for contractile dysfunction and development of disarray in the myocardium.
Endothelial dysfunction and hypercontractility of vascular myocytes are ameliorated by fluvastatin in obese Zucker rats
Authors: Nishimatsu Hiroaki , Suzuki Etsu , Satonaka Hiroshi , Takeda Ryo , Omata Masao , Fujita Toshiro , Nagai Ryozo , Kitamura Tadaichi , Hirata Yasunobu
Published: November 2004

To study the mechanisms of vascular dysfunction in diabetes mellitus, we examined the responses of the aorta to adrenomedullin (AM) and ANG II in obese Zucker (OZ), lean Zucker (LZ), and OZ rats administered fluvastatin (OZ + Flu). AM-induced endothelium-dependent vasorelaxation was impaired in OZ rats compared with LZ rats, and fluvastatin restored AM-induced, endothelium-dependent vasorelaxation (%Δtension at 10−7mol/l AM; LZ, −85.1 ± 3.1%; OZ, −50.7 ± 2.5%; OZ + Flu, −75.6 ± 2.7%). Expression of endothelial nitric oxide synthase (eNOS) and Akt phosphorylation in response to AM (10−7mol/l) were also diminished in OZ rats. Fluvastatin restored the eNOS expression and Akt phosphorylation [eNOS expression (relative intensity): LZ, 2.3 ± 0.4; OZ, 1.0 ± 0.2; OZ + Flu, 1.8 ± 0.3; Akt phosphorylation (relative intensity): LZ, 2.3 ± 0.2; OZ, 1.0 ± 0.3; OZ + Flu, 1.9 ± 0.2]. ANG II-induced vasoconstriction was enhanced in the aortic rings of OZ rats compared with LZ rats, and this enhanced vasoconstriction was partially normalized by fluvastatin and was abolished when the aorta of OZ rats was preincubated with the Rho kinase inhibitor Y-27632. GTPγS-induced contraction of permeabilized aortic smooth muscle cells, which is an indicator of the Rho-dependent Ca2+sensitization of contraction, was enhanced in OZ rats compared with LZ rats, and this enhanced contraction was suppressed in OZ + Flu rats. These results suggested that endothelium-dependent vasorelaxation was impaired, Ca2+sensitization of contraction was augmented in blood vessels of OZ rats and that fluvastatin restored vascular function by activating the Akt-dependent pathway and inhibiting the Rho-dependent pathway.
Reduced oxygen supply explains the negative force-frequency relation and the positive inotropic effect of adenosine in buffer-perfused hearts
Authors: Marin Rodrigo M. , Franchini Kleber G.
Published: November 2004

In isolated rat hearts perfused with HEPES and red blood cell-enriched buffers, we examined changes in left ventricular pressure induced by increases in heart rate or infusion of adenosine to investigate whether the negative force-frequency relation and the positive inotropic effect of adenosine are related to an inadequate oxygen supply provided by crystalloid perfusates. Hearts perfused with HEPES buffer at a constant flow demonstrated a negative force-frequency relation, whereas hearts perfused with red blood cell-enriched buffer exhibited a positive force-frequency relation. In contrast, HEPES buffer-perfused hearts showed a concentration-dependent increase in left ventricular systolic pressure [EC50 = 7.0 ± 1.2 nM, maximal effect (Emax) = 104 ± 2 and 84 ± 2 mmHg at 0.1 μM and baseline, respectively] in response to adenosine, whereas hearts perfused with red blood cell-enriched buffer showed no change in left ventricular pressure. The positive inotropic effect of adenosine correlated with the simultaneous reduction in heart rate ( r = 0.67, P < 0.01; EC50 = 3.8 ± 1.4 nM, baseline 228 ± 21 beats/min to a minimum of 183 ± 22 beats/min at 0.1 μM) and was abolished in isolated hearts paced to suppress the adenosine-induced bradycardia. In conclusion, these results indicate that the negative force-frequency relation and the positive inotropic effect of adenosine in the isolated rat heart are related to myocardial hypoxia, rather than functional peculiarities of the rat heart.
Surfactant phospholipids and proteins are increased in fetal sheep with pulmonary hypertension secondary to fetal systemic arteriovenous fistula
Authors: Benachi Alexandra , Jouannic Jean-Marie , Barlier-Mur Anne-Marie , Chailley-Heu Bernadette , Bourbon Jacques R.
Published: November 2004

To determine whether prenatal surfactant storage was altered in a model of systemic arteriovenous fistula (SAVF) with pulmonary hypertension, a fistula was created between the internal jugular vein and the carotid artery in 120-day fetal lambs, and surfactant material was explored at 134 days. Total phospholipids (TPL) and disaturated phosphatidylcholine (DSPC) were increased in whole lung tissue. Phospholipid analysis of isolated lamellar body fraction evidenced a specific increase of surfactant pool size: TPL and DSPC in this fraction were enhanced 1.9 and 2.9 times, respectively, when referred to DNA. Although the steady-state level of transcripts of surfactant protein (SP)-A and SP-B was not found to be changed at the time of death, semiquantitative Western blot analysis revealed elevated SP-A and SP-B protein contents three- and twofold, respectively. These findings indicate markedly enhanced accumulation of surfactant material in the presence of surgically induced prenatal pulmonary hypertension. Although total lung cell number was increased by 26%, SP-B immunolabeling indicated that increased surfactant amount did not result from an increased alveolar type II cell proportion, but rather from an increased rate of storage. Whether similar changes in surfactant are encountered in human neonates with persistent pulmonary hypertension is worthy of investigation.
Activation of slowly conducting medullary raphé-spinal neurons, including serotonergic neurons, increases cutaneous sympathetic vasomotor discharge in rabbit
Authors: Ootsuka Youichirou , Blessing William W.
Published: November 2004

Neurons in the rostral medullary raphé/parapyramidal region regulate cutaneous sympathetic nerve discharge. Using focal electrical stimulation at different dorsoventral raphé/parapyramidal sites in anesthetized rabbits, we have now demonstrated that increases in ear pinna cutaneous sympathetic nerve discharge can be elicited only from sites within 1 mm of the ventral surface of the medulla. By comparing the latency to sympathetic discharge following stimulation at the ventral raphé site with the corresponding latency following stimulation of the spinal cord [third thoracic (T3) dorsolateral funiculus] we determined that the axonal conduction velocity of raphé-spinal neurons exciting ear pinna sympathetic vasomotor nerves is 0.8 ± 0.1 m/s ( n = 6, range 0.6–1.1 m/s). Applications of the 5-hydroxytryptamine (HT)2A antagonist trans-4-((3 Z)3-[(2-dimethylaminoethyl)oxyimino]-3-(2-fluorophenyl)propen-1-yl)-phenol, hemifumarate (SR-46349B, 80 μg/kg in 0.8 ml) to the cerebrospinal fluid above thoracic spinal cord (T1-T7), but not the lumbar spinal cord (L2-L4), reduced raphé-evoked increases in ear pinna sympathetic vasomotor discharge from 43 ± 9 to 16 ± 6% ( P < 0.01, n = 8). Subsequent application of the excitatory amino acid (EAA) antagonist kynurenic acid (25 μmol in 0.5 ml) substantially reduced the remaining evoked discharge (22 ± 8 to 6 ± 6%, P < 0.05, n = 5). Our conduction velocity data demonstrate that only slowly conducting raphé-spinal axons, in the unmyelinated range, contribute to sympathetic cutaneous vasomotor discharge evoked by electrical stimulation of the medullary raphé/parapyramidal region. Our pharmacological data provide evidence that raphé-spinal neurons using 5-HT as a neurotransmitter contribute to excitation of sympathetic preganglionic neurons regulating cutaneous vasomotor discharge. Raphé-spinal neurons using an EAA, perhaps glutamate, make a substantial contribution to the ear sympathetic nerve discharge evoked by raphé stimulation.
Sensory or sympathetic white adipose tissue denervation differentially affects depot growth and cellularity
Authors: Shi Haifei , Song C. Kay , Giordano Antonio , Cinti Saverio , Bartness Timothy J.
Published: November 2004

Functional and histological evidence for the sympathetic nervous system (SNS) innervation of white adipose tissue (WAT) exists for several species; however, its sensory innervation has only been shown in laboratory rats, and its function is unclear. We tested the effects of sensory and SNS innervation of Siberian hamster epididymal and inguinal WAT (EWAT and IWAT) by assessing calcitonin gene-related peptide (CGRP)- and tyrosine hydroxylase-immunoreactivity (ir), respectively. Next, we tested the role of the sensory innervation of WAT on growth and cellularity because WAT surgical denervation increases pad mass via selective increases in fat cell number, an effect ascribed to SNS denervation but that could be due to the accompanying surgical disruption of WAT sensory innervation. Sensory denervation was accomplished via multiple local microinjections of capsaicin into WAT, and its effects were compared with those of surgical denervation. Surgically denervated IWAT and EWAT showed significantly decreased tyrosine hydroxylase-ir and CGRP-ir, whereas capsaicin-treated WAT had only significantly decreased CGRP-ir. Surgically denervated pad masses were significantly increased; this was accompanied by increased total fat cell number in IWAT, with no change in fat cell size. EWAT only showed a significant increase in the number of small- to medium-sized adipocytes (75–125 μm diameter). By contrast, sensory-denervated pad masses were unchanged, but IWAT showed significantly increased average fat cell size. Collectively, these data provide immunohistochemical evidence for sensory and SNS innervation of WAT in Siberian hamsters and differential control of WAT cellularity by these innervations, as well as the ability of locally applied capsaicin to selectively reduce WAT sensory innervation.
Social environment modulates photoperiodic immune and reproductive responses in adult male white-footed mice(Peromyscus leucopus)
Authors: Pyter Leah M. , Neigh Gretchen N. , Nelson Randy J.
Published: November 2004

Social cues may interact with photoperiod to regulate seasonal adaptations in photoperiod-responsive rodents. Specifically, photoperiod-induced adjustments (e.g., reproduction and immune function) may differ among individuals in heterosexual pairs, same-sex pairs, or isolation. Heterosexual cues may be more influential, based on their potential fitness value, than same-sex cues or no social cues. The present study examined the effects of pair (with a male or female) or individual housing on reproductive and immune responses in male white-footed mice ( Peromyscus leucopus) maintained in long or short photoperiods. Female pairing did not affect reproductive responses in short-day males. In long days, however, the presence of a female increased both testosterone concentrations and testes mass compared with individually housed and male-paired mice, respectively. Short-day, individually housed males enhanced delayed-type hypersensitivity (DTH) responses compared with single-housed mice in long days, but all paired groups decreased DTH responses regardless of photoperiod. The lack of enhanced DTH response in male mice paired with females coincided with reduced circulating corticosterone concentrations in both photoperiod treatments. Together, these results suggest that social environment may have important modulatory effects on photoperiod-regulated immune responses in male white-footed mice.
The Ischemic Penumbra: Identification, Evolution and Treatment Concepts
Authors: Fisher Marc
Published: November 2004

The concept of the ischemic penumbra is an important one for both basic investigators of cerebral ischemia and for clinicians who treat stroke patients. The ischemic penumbra has been defined in a variety of ways, but the most clinically relevant definition is that portion of the ischemic territory that is still potentially salvageable, if an appropriate treatment is given. Currently, three main challenges persist for those interested in the ischemic penumbra concept: how can this ischemic region be most accurately identified in stroke patients, what mechanisms of ischemic cell death are most important for progression from penumbra towards irreversible injury and what therapeutic modalities are most likely to impede the development of infarction? Much important information regarding each of these topics has become available recently and will be the focus of this paper.
Biochemical Changes and Inflammatory Response as Markers for Brain Ischaemia: Molecular Markers of Diagnostic Utility and Prognosis in Human Clinical Practice
Authors: Castillo José , Rodríguez Iria
Published: November 2004

The study of molecular markers associated with stroke has proved to be of considerable utility. We review the main biochemical changes of neurotoxicity and of inflammation and their usefulness as markers associated with early signs of ischaemia in the neuroimage, with early neurological deterioration, with the volume of the infarct, with haemorrhagic transformation, with the efficacy of thrombolytic treatment and with malignant ischaemic syndrome. Raised plasma concentrations of interleukin-6 (IL-6) are a powerful predictor of early neurological deterioration and the more important molecular marker associated with final volume of infarct. Levels of matrix metalloproteinases-9 (MMP-9) have a significant relationship with the efficacy of thrombolytic treatment and with the incidence and seriousness of haemorrhagic complications.
Internal Carotid Artery Stenting in Patients with Symptomatic Atheromatous Pseudo-Occlusion
Authors: Gil-Peralta Alberto , González Alejandro , González-Marcos José R. , Mayol Antonio , Boza Fernando , Ruano José , Cayuela Aurelio
Published: November 2004

Angioplasty and stenting of the atheromatous internal carotid artery (ICA), besides in patients with a high surgical risk, may be indicated in specific cases such as contralateral occlusion, acute stroke clinical signs, or atherosclerotic pseudo-occlusion (APO). APO of the ICA is an underrecognized condition due to diagnostic difficulties both with noninvasive methods and even with angiography. Once recognized, there is usually the opportunity for successful revascularization with carotid endarterectomy. However, as the natural history of the APO is poorly characterized, the management of patients remains controversial. While some authors advocate a surgical approach, others consider that APO patients are not at high risk of stroke, making any interventional approach unnecessary. The perioperative risk of stroke in patients with APO is not appreciably greater than in patients with lesser degrees of stenosis and clear recommendation of surgery, although at 2 years that risk seems to be considerably much higher than in the latter patients. Looking for safer interventional procedures is worthwhile. Results of angioplasty and stenting in patients with ICA-APO have not been published yet. We report the results and complications associated with this procedure to address the issue of appropriate management of patients with ICA-APO.
Increased Urinary Protein Excretion in Children from Families with Balkan Endemic Nephropathy
Authors: Stefanović Vladisav , Mitić-Zlatković Marina , Čukuranović Rade , Vlahović Predrag
Published: November 2004

Background: Balkan endemic nephropathy (BEN) has not been described in children, however some previous studies of children from families with BEN have revealed abnormalities of the urinary tract including an increased urinary protein excretion. Methods: In the present study, urinary excretion of total protein was studied in 703 healthy children, aged 9–13, from endemic and non-endemic settlements around the South Morava River. Since BEN is an environmentally induced disease, with possible seasonal variation of toxin(s), children were studied three times a year: in spring, autumn and winter, during a 3-year period. After a water load of 15 ml/kg body weight, a 3-hour urine sample was collected, from 7 to 10 a.m. Results: Protein excretion in urine was highest in children from families with BEN compared with the excretion in children from the city, non-endemic villages, and those from non-endemic families living in the same settlements. This was the case during all three periods investigated in the second year of the study. In the autumn term of all three years of the study, protein excretion was significantly higher in children from families with BEN than in children from the city and from non- endemic families living in the same settlements. If the upper limit of protein excretion is set at 34 mg/mmol creatinine, then increased protein excretion in autumn was found in the first year of study in 9/229 children from endemic settlements and in only 4/474 children from non-endemic areas (p = 0.004); in the second year in 5/229 and 3/474 children (p = 0.069), and in the third year in 10/229 and 4/474 children (p = 0.002), respectively. Conclusions: We have presented evidence that children from families with BEN and endemic villages consistently excreted significantly more protein in the autumn, and in three seasons (spring, autumn, winter) in 1 year of our study. These results are consistent with seasonal variations in exposure to an environmental toxin(s).
Calcitriol Increases Burst-Forming Unit-Erythroid Proliferation in Chronic Renal Failure
Authors: Aucella Filippo , Scalzulli Rosario Potito , Gatta Giuseppe , Vigilante Mimmo , Carella Angelo Michele , Stallone Carmine
Published: November 2004

Background: Calcitriol (C) improves anemia in chronic renal failure. This effect may be related to the suppression of iPTH release, or to a direct effect on erythropoiesis. Methods: Thirty-three patients with chronic renal failure were enrolled; among them, 24 were on chronic hemodialysis and 9 on conservative management. None had other chronic or hematological disease, aluminum levels were below 20 µg/l and DFO testing was negative. The iPTH range was 250–480 pg/l. None were treated with C or r-HuEpo. In vitro study: Samples were drawn for a basal erythroid precursor (burst forming unit-erythroid BFU-E) study: Mononuclear cells were incubated for 14 days with r-HuEpo 3U/ml (A), r-HuEpo 3U/l + C 30 pg (B), r-HuEpo 3U/ml + C 300 pg (C), or r-HuEpo 30 U/ml + C 300 pg (D). In vivo study: After the basal evaluation, 10 patients on chronic dialysis were treated with C (Calcijex-Abbott) 1 µg three times a week, and 4 patients served as controls. BFU-E studies were performed after 1, 2 and 4 months. Results: In vitro, culture B showed increased BFU-E proliferation vs. A (41 ± 23 vs. 27 ± 15, p < 0.02); in cultures C and D, proliferation was 61 ± 31 and 78 ± 42, respectively, p < 0.01 vs. A. There was no difference among patients with predialysis renal failure and those on dialysis. BFU-E proliferation was inversely related to basal Hb (p < 0.04) and CRP levels (p < 0.05). During the in vivo study, all cultures showed a progressive increase in proliferation without a plateau level (basal, after 1, 2 and 4 months, respectively) In A: 17 ± 8, 22 ± 13, 30.9 ± 14.9, 41.4 ± 20; in B: 27.3 ± 15, 35.6 ± 20, 45.5 ± 21, 57 ± 26; in C: 48.2 ± 20.6, 63.7 ± 32, 75.7 ± 37, 83 ± 40; in D: 72 ± 24, 91 ± 42, 106 ± 42, 110 ± 42.3 (all p < 0.001). Hb and Hct showed a significant increase (p < 0.03) in the treatment group. The decrease in iPTH was not related to BFU-E proliferation. Conclusions: In chronic uremia, C has a direct effect on erythroid precursors proliferation, as demonstrated both in vitro and in vivo, with a synergistic effect with r-HuEpo. C may be a useful adjuvant therapy to r-HuEpo treatment.
Effects of Atorvastatin on Lipid Profile and Non-Traditional Cardiovascular Risk Factors in Diabetic Patients on Hemodialysis
Authors: Navarro Juan F. , Mora Carmen , Muros Mercedes , García-Idoate Gabriela
Published: November 2004

Background/Aims: Dyslipidemia and non-traditional cardiovascular (CV) risk factors, such as lipoprotein(a) (Lp(a)), homocysteine, oxidative stress and inflammation, are important determinants in the increased CV risk of hemodialysis (HD) patients. The aim of our study was to evaluate the effects of atorvastatin on these parameters in one of the groups with the highest CV risk: diabetic patients with end-stage renal disease under HD therapy. Methods: Twenty maintenance HD diabetic patients (mean age 64 ± 10 years, mean time on HD 25 ± 11 months) with low-density lipoprotein cholesterol (LDL-C) >2.59 mmol/l received atorvastatin (10 mg/day) for 4 months. Lipid profile, including total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoproteins A1 and B (Apo-A and Apo-B), and the non-traditional risk factors Lp(a), homocysteine, autoantibodies against oxidized LDL-C (anti-LDLox), total antioxidant status (TAS), and high sensitive C-reactive protein (hs-CRP), were measured at baseline and at the end of the study. Safety was assessed by clinical and laboratory (liver and muscle enzymes) monitoring once a month. Results: Mean percent reductions for TC, LDL-C and TG were 18.5% (p < 0.001), 22% (p < 0.001) and 19% (p < 0.01), respectively. The ratios of TC/HDL-C and LDL-C/HDL-C decreased after treatment (p < 0.05), whereas the ratios of LDL-C/Apo-B (p < 0.01) and Apo-A/Apo-B (p < 0.001) increased. No significant changes were observed in HDL-C. Concerning the non-traditional risk factors, levels of homocysteine, Lp(a), anti-LDLox and TAS did not change significantly. However, hs-CRP decreased from 5.4 (range 0.9–67.8) to 2.3 mg/l (range 0.4–21) (p < 0.01), whereas a concomitant increase in serum albumin was observed (from 38 ± 2 to 40 ± 1.7 g/l, p < 0.01). At baseline, hs-CRP was inversely associated with HDL-C and Apo-A, and directly related to Lp(a). The change in hs-CRP was inversely associated with the change of HDL-C, whereas a direct correlation was found with the change of TG. Conclusions: Atorvastatin administration to diabetic patients on HD is associated with improvement of lipid profile and reduction of hs-CRP. These effects may be critical for the reduction of CV risk and mortality in HD population.
Intervention with Tranilast Attenuates Renal Pathology and Albuminuria in Advanced Experimental Diabetic Nephropathy
Authors: Mifsud Sally , Kelly Darren J. , Qi Weier , Zhang Yuan , Pollock Carol A. , Wilkinson-Berka Jennifer L. , Gilbert Richard E.
Published: November 2004

Background/Aims: Tubulointerstitial pathology with the accumulation of extracellular matrix are pathological hallmarks of diabetic nephropathy that are directly related to declining renal function. Tranilast (N-[3,4-dimethoxycinnamoyl]anthranilic acid), an inhibitor of transforming growth factor-β (TGF-β), used to treat hypertrophic scars has recently been shown in pilot studies to exert a beneficial effect in advanced diabetic nephropathy in humans. However, its effects on diabetic renal pathology are unknown. Methods: Studies were conducted using a transgenic model, the diabetic (mRen-2)27 rat, which develops many of the structural and functional characteristics of human diabetic nephropathy when diabetes is induced with streptozotocin (STZ). An experimental design was chosen to mimic, in part, the clinical context with drug therapy (tranilast 400 mg/kg/ day) initiated in established disease (8 weeks after STZ) and in the presence of persistent hyperglycaemia and hypertension. Results: At 16 weeks, diabetes was associated with progressive albuminuria, tubulointerstitial fibrosis and tubular atrophy. Without affecting blood pressure or blood glucose, tranilast treatment was associated with a 83% reduction in tubulointerstitial fibrosis (p < 0.001), a 58% reduction in tubular atrophy (p < 0.01) and near normalization of albuminuria (p < 0.05) in diabetic Ren-2 rats. In vitro studies in primary cultures of human renal cortical fibroblasts demonstrated a reduction in TGF-β-induced hydroxyproline incorporation and fibronectin synthesis with tranilast 100 µM. Conclusion: Tranilast, when administered during the course of experimental diabetic nephropathy, attenuates tubulointerstitial pathology and albuminuria. These findings are consistent with the antagonist effects of tranilast on TGF-β actions in the diabetic kidney.
Evaluation of the Role of Melanocortin 3 and 4 Receptors in Leptin-Stimulated and Spontaneous Growth Hormone Secretion in Rats
Authors: Watanobe Hajime , Yoneda Masashi
Published: November 2004

It has been reported that the melanocortin 4-receptor (MC4-R) may act downstream of leptin to mediate its effects on food intake and several neuroendocrine functions (the reproductive system, the hypothalamo-pituitary-thyroid axis, and prolactin secretion). However, no previous study examined whether MC4-R mediates leptin stimulatory actions on growth hormone (GH) secretion, or whether MC4-R signaling is involved in spontaneous pulsatile GH release in fed rats. Therefore in this study we examined the involvement of both MC3-R and MC4-R (the predominant MC-R subtypes expressed in the brain) in these two aspects of GH secretion in freely-moving male rats. In both fed and 3-day fasted rats, plasma GH levels were determined every 15 min over 5 h after single intracerebroventricular injections of the following substances or vehicle. Fasting diminished and leptin (0.3 nmol) reinstated the GH pulse amplitude without affecting the pulse frequency. Neither HS014 (1.0 nmol, a selective MC4-R antagonist) nor agouti-related peptide (1.0 nmol, a non-selective MC3/4-R antagonist) was effective in altering leptin-stimulated or spontaneous GH secretion. In addition, neither melanotan-II (1.0 nmol, a non-selective MC3/4-R agonist) nor γ1-melanocyte-stimulating hormone (10 nmol, a selective MC3-R agonist) affected significantly GH release in fasted rats. We have previously demonstrated that stimulation or blockade of MC4-R, achieved by the same drug dosage as in this study, significantly affect luteinizing hormone and prolactin secretion in rats. The present results thus suggest that neither MC4-R nor MC3-R is involved in leptin-stimulated or spontaneous GH secretion, or at least that the level of MC4-R involvement in GH secretion is much lower than that in luteinizing hormone and prolactin release regulation.
Lamivudine Therapy for Japanese Patients with Cirrhosis B
Authors: Okanoue Takeshi , Mori Kojiro , Kirishima Toshihiko , Kunimoto Koji , Yasui Kohichiroh , Itoh Yoshito , Minami Masahito
Published: November 2004

Objective: The aim of this study was to investigate the emergence of YMDD mutants in patients with chronic hepatitis B during lamivudine therapy and to compare the emergence patterns of YMDD mutants in cirrhotic and noncirrhotic patients. Methods: Eighteen cirrhotic and 37 noncirrhotic patients with chronic hepatitis B were studied. The emergence of YMDD mutants was determined before, as well as at 1, 3, 6, 9 and 12 months after treatment using a highly sensitive method based on polymerase chain reaction. Results: Although YMDD mutants were elicited early, the emergence of YMDD mutants was not always associated with breakthrough hepatitis. YMDD mutants appeared in cirrhotic and noncirrhotic patients: in 22 and 8% at 1 month, 13 and 21% at 3 months, 46 and 19% at 6 months, 30 and 19% at 9 months, and 83 and 27% at 12 months, respectively. Conclusion: YMDD mutants emerge more frequently in cirrhotic than noncirrhotic patients during the early period on lamivudine treatment. The highly sensitive method may be useful for monitoring the development of YMDD mutants in patients with chronic hepatitis B during lamivudine therapy.
Normal Bone Mineral Content in Young Adults with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency
Authors: Christiansen Peter , Mølgaard Christian , Müller Jørn
Published: November 2004

Objective: To assess bone mineral content (BMC) and body composition in adolescents and young adults with congenital adrenal hyperplasia. Methods: BMC, anteroposterior-projected bone area (BA), bone mineral density, and fat mass percentage were determined by dual-energy X-ray absorptiometry in 18 patients aged 18–33 years (8 females and 10 males) with 21-hydroxylase deficiency using a Hologic QDR 1000/W densitometer. Results: BMC and bone mineral density for age were significantly reduced at –1.2 standard deviation scores (SDS; range from –2.8 to +4.1) and –1.1 SDS (range from –3.2 to +2.6), respectively. The BA for height was significantly increased at +1.7 SDS (range from –0.5 to +4.8), and the BMC for BA was normal at 0.3 SDS (range from –2.0 to +3.6). The median final height was significantly reduced at –1.6 SDS (range from –5.6 to +0.3), and the fat mass percentage was significantly increased at +1.5 SDS (range from –1.0 to +5.0). Conclusion: Our study population of young adults with 21-hydroxylase deficiency had a short stature and broad bones with a normal BMC and had an increased fat mass percentage.
Validation of a Mathematical Model Predicting the Response to Growth Hormone Treatment in Prepubertal Children with Idiopathic Growth Hormone Deficiency
Authors: Vosahlo J. , Zidek T. , Lebl J. , Riedl S. , Frisch H.
Published: November 2004

Objective: To validate a mathematical model developed by Ranke et al. (J Clin Endocrinol Metab 1999;84:1174–7783) to predict the GH response during the first years of GH replacement therapy. Patients and Methods: 38 children with idiopathic GH deficiency (GHD) met all inclusion criteria for the prediction model, but the group differed in some characteristics from the cohort from which the model was derived. Results: Using the model for the 1st year including maximum GH after stimulation and the equation for the 6th year, the predicted value corresponded well with actual height gain. Differences were found when the growth response of the 1st year excluding maximum GH and that of the 2nd–5th year were calculated, resulting in a significant underestimation of actual height gain (–0.63 to –1.07 cm/year). Conclusion: The mathematical prediction model tended to underpredict the growth response to GH treatment in our patients with pronounced GHD. The severity of GHD seems to be an important parameter for the 1st year prediction.
Chloride Channel Blockade Attenuates the Effect of Angiotensin II on Tubuloglomerular Feedback in WKY but not Spontaneously Hypertensive Rats
Authors: Hashimoto Seiji , Kawata Tetsuya , Schnermann Jurgen , Koike Takao
Published: November 2004

Recent studies have shown that calcium-dependent chloride channels may play a crucial role in the modulation of the vascular effects of angiotensin II (ANG II). Thus, alterations in the function of these channels may be responsible for the enhanced renal vasoconstrictor and tubuloglomerular feedback (TGF) response to ANG II in spontaneously hypertensive rats (SHR). We investigated the effect of the calcium-dependent chloride channel blocker IAA-94 on renal hemodynamics and TGF responses. The renal interstitium was perfused with control solution, with ANG II, and with both ANG II and IAA-94. In Wistar Kyoto rats (WKY), perfusion with ANG II significantly increased renal vascular resistance (RVR), but the effect was significantly attenuated by perfusion with ANG II/IAA-94. In SHR, ANG II caused a significant elevation of RVR that was not altered by the simultaneous infusion of IAA-94. Proximal tubular stop flow pressure (Psf) was monitored during perfusion of peritubular capillaries with control solution, and subsequently with IAA-94, ANG II or both ANG II and IAA-94. TGF response magnitude of WKY rats was significantly augmented with ANG II, and this effect was suppressed by perfusion with ANG II /IAA-94. However, in SHR peritubular perfusion with ANG II/IAA-94 did not suppress the TGF response. We conclude that chloride channels susceptible to IAA-94 may play a significant role in modulating the effects of ANG II on renal hemodynamics, and that this modulation is absent in SHR.