bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional roles of social support within the stress and coping process: A theoretical and empirical overview
Authors: Schwarzer Ralf , Knoll Nina
Published: July 2007

This article reports four longitudinal field studies and one experimental study designed to shed light on the functional roles of social support within the stress and coping context. First, the enabling hypothesis is examined that assumes a facilitating effect of support on self‐efficacy, which, in turn, promotes coping with the aftermath of cardiac surgery. Second, we discuss the support cultivation hypothesis that regards support as a mediator between self‐efficacy and various outcomes, such as depressive mood, as illustrated by a finding on the experience of macrosocial stress during the East German transition. Third, support is highlighted as a coping resource by specifying provided partner support as a predictor of patients' coping with cancer. It was found that the direct effect of provided support on coping needs to be mediated by received support in order to become effective. Fourth, coping efforts of a target person are found to be predictive of support intentions of a potential provider. The better a victim appears to cope with various stigmas, the higher the likelihood that a significant other is willing to help. Fifth, in a dyadic study on coping with cancer, partners were found to provide high levels of support to patients, but received support was affected only at later points in time. Time‐lagged partner effects may characterize resource transfer in asymmetric social situations in which only one element of the dyad is under severe stress.
Usability, aesthetics and emotions in human–technology interaction
Authors: Thüring Manfred , Mahlke Sascha
Published: July 2007

In the past, research on human–technology interaction has almost exclusively concentrated on aspects of usefulness and usability. Despite the success of this line of research, its narrow perspective has recently become a target for criticism. To explain why people prefer some systems over others, factors such as aesthetic qualities and emotional experiences play an important role in addition to instrumental aspects. In the following, we report three experiments that illustrate the importance of such factors. In the first experiment, we study the role of emotions in human–technology interaction by using Scherer's (1984) component theory of emotions as a theoretical foundation. A combination of methods is derived from that theory and employed to measure subjective feelings, motor expressions, physiological reactions, cognitive appraisals, and behaviour. The results demonstrate that the manipulation of selected system properties may lead to differences in usability that affect emotional user reactions. The second experiment investigates the interplay of instrumental and non‐instrumental system qualities. The results show that users' overall appraisal of a technical device is influenced by both groups of qualities. In the third experiment, we join the approaches of the first two studies to analyse the influence of usability and aesthetics within a common design. The results indicate that systems differing in these aspects affect the perception of instrumental and non‐instrumental qualities as well as the users' emotional experience and their overall appraisal of the system. Summarizing our results, we present a model specifying three centralcomponents ofuserexperience and their interrelations (CUE‐Model). The model integrates the most important aspects of human–technology interaction and hints at a number of interesting issues for future research.
The Sep15 protein family: Roles in disulfide bond formation and quality control in the endoplasmic reticulum
Authors: Labunskyy Vyacheslav M. , Hatfield Dolph L. , Gladyshev Vadim N.
Published: July 2007

Disulfide bonds play an important role in the structure and function of membrane and secretory proteins. The formation of disulfide bonds in the endoplasmic reticulum (ER) of eukaryotic cells is catalyzed by a complex network of thiol‐disulfide oxidoreductases. Whereas a number of ER‐resident oxidoreductases have been identified, the function of only a few of them is firmly established. Recently, a selenocysteine‐containing oxidoreductase, Sep15, has been implicated in disulfide bond assisted protein folding, and a role in quality control for this selenoprotein has been proposed. This review summarizes up‐to‐date information on the Sep15 family proteins and highlights new insights into their physiological function.
IUBMB Life, 59: 1‐5, 2007
Defining the roles of T cell membrane proteinase and CD44 in type 1 diabetes
Authors: Savinov Alexei Y. , Strongin Alex Y.
Published: July 2007

Membrane type‐1 matrix metalloproteinase (MT1‐MMP) shedding of the signaling and adhesion CD44 receptor plays a significant role in stimulating cancer cells locomotion. Similarly, and unexpectedly, MT1‐MMP‐dependent shedding of CD44 plays an equally significant role in regulating the adhesion to the pancreatic vasculature and also in the concomitant transendothelial migration and intra‐islet homing of the diabetogenic, cytotoxic, T cells. Inactivation of the T cell MT1‐MMP functionality by clinically tested, synthetic inhibitors leads to an extended immobilization of the T killer cells on the pancreatic vasculature and, subsequently, to immunosuppression because of the cessation of the T cell transmigration and homing. Injections of insulin jointly with an MT1‐MMP inhibitor stimulated the regeneration of functional, insulin‐producing, β‐cells in acutely diseased non‐obese diabetic (NOD) mice. After insulin injections were suspended and inhibitor injections continued, diabetic NOD mice maintained mild hyperglycemia and did not require further insulin injections for survival. Overall, these data provide a substantive mechanistic rationale for clinical trials of the inhibitors of MT1‐MMP in human type 1 diabetes.
IUBMB Life, 59: 6‐13, 2007
Functional effects of mutations identified in patients with Multiminicore disease
Authors: Zorzato Francesco , Jungbluth Heinz , Zhou Haiyan , Muntoni Francesco , Treves Susan
Published: July 2007

Multiminicore disease is a recessive congenital myopathy characterized by the presence of small cores or areas lacking oxidative enzymes, in skeletal muscle fibres. From a clinical point of view, the condition is widely heterogeneous and at least four phenotypes have been identified; genetic analysis has revealed that most patients with the classical form of multiminicore characterized by rigidity of the spine, early onset and respiratory impairment harbour recessive mutations in the SEPN1 gene, whereas the majority of patients belonging to the other categories, including patients with ophthalmoplegia or patients with a phenotype similar to central core disease, carry recessive mutations in the RYR1. In the present review we discuss the most recent findings on the functional effect of mutations in SEPN1 and RYR1 and discuss how they may adversely affect muscle function and lead to the clinical phenotype.
IUBMB Life, 59: 14‐20, 2007
Role of glutathiolation in preservation, restoration and regulation of protein function
Authors: Hill Bradford G. , Bhatnagar Aruni
Published: July 2007

Glutathiolation has emerged as an important post‐translational modification that regulates protein function. Reduced glutathione remains bound to reactive cysteine side chains of several intracellular proteins even under basal conditions and the abundance of glutathiolated proteins increases upon oxidant challenge. Although protein glutathiolation was considered primarily to be a protective mechanism for preventing irreversible oxidation of protein thiols, recent evidence suggests that controlled glutathiolation reactions can also be used to modify protein structure and function. Several growth factors and cytokines promote protein glutathiolation and glutathiolated proteins have been shown to increase upon physiological stimulation of NO production. Given the high affinity of some nitrosylated proteins for glutathione, glutathiolation may also be a significant metabolic fate of nitrosylated proteins. Enzymatic pathways of protein de‐glutathiolation have also been described; indicating that both glutathiolation and de‐glutathiolation may be tightly regulated processes. In this review, we discuss the mechanisms of protein glutathiolation and how physiologic glutathiolation of specific proteins could regulate glucose metabolism, calcium homeostasis and changes in cell shape and contraction. We propose that glutathiolation represents a discrete sub‐state within complex thiol‐based redox circuits, relays and switches that regulate protein function basally and, upon oxidative stress, elicit adaptive responses or trigger cell death.
IUBMB Life, 59: 21‐26, 2007
A discourse on cancer cell chemotaxis: Where to from here?
Authors: Soon Lilian L.
Published: July 2007

The study of cancer cell chemotaxis on two‐dimensional surfaces in vitro has relevance to the diverse migratory behaviours exhibited in vivo that involve a directed path. These may include translocation along collagen fibres, invasion into the basement membrane and across stroma, intravasation and extravasation to arrive at a secondary destination designated for cancer cell colonization. Chemotaxis invariably denotes the ability of cells to sense gradients, polarize, adhere and deadhere to substrate, and translocate in the right direction. Amongst these, the sensing function is perhaps the unifying aspect of different migration styles, permitting the cells to resolve its orientation and path. This review examines the decision‐making processes that take place during chemotaxis and illustrates that a universal mechanism is involved. In various cell types from Dictyostelium to neutrophils, there are some unifying principles that dictate sensing and how the putative leading edge and trailing end of cells are determined. Some of these principles have recently been applied in the study of cancer cell chemotaxis albeit different pathways are substituted. In amoeboid‐like cancer cells, local excitation of the EGFR/PLCγ/cofilin pathway and parallel, global inhibition of cofilin by LIMK occur to promote the asymmetric distribution and amplification of these internal signals in response to an external EGF gradient.
IUBMB Life, 59: 60‐67, 2007
T‐armless tRNAs and elongated elongation factor Tu
Authors: Ohtsuki Takashi , Watanabe Yoh‐ichi
Published: July 2007

Most tRNAs share a common secondary structure containing a T arm, a D arm, an anticodon arm and an acceptor stem. However, there are some exceptions. Most nematode mitochondrial tRNAs and some animal mitochondrial tRNAs lack the T arm, which is necessary for binding to canonical elongation factor Tu (EF‐Tu). The mitochondria of the nematode Caenorhabditis elegans have a unique EF‐Tu, named EF‐Tu1, whose structure has supplied clues as to how truncated tRNAs can work in translation. EF‐Tu1 has a C‐terminal extension of about 60 aa that is absent in canonical EF‐Tu. Recent data from our laboratory strongly suggests that EF‐Tu1 recognizes the D‐arm instead of the T arm by a mechanism involving this C‐terminal region. Further biochemical analysis of mitochondrial tRNAs and EF‐Tu from the distantly related nematode Trichinella spp. and sequence information on nuclear and mitochondrial DNA in arthropods suggest that T‐armless tRNAs may have arisen as a result of duplication of the EF‐Tu gene. These studies provide valuable insights into the co‐evolution of RNA and RNA‐binding proteins.
IUBMB Life, 59: 68‐75, 2007
Protein oxidation, repair mechanisms and proteolysis in Saccharomyces cerevisiae
Authors: Costa Vitor , Quintanilha Alexandre , Moradas‐Ferreira Pedro
Published: July 2007

Reactive oxygen species, generated as normal by‐products of aerobic metabolism or due to cellular stress, oxidize molecules and cause cell death by apoptosis. The accumulation of oxidized proteins is a hallmark of aging and a number of aging diseases. Oxidation can impair protein function as the proteins are unfolded leading to an increase of protein hydrophobicity and often resulting in the formation of toxic aggregates. The yeast Saccharomyces cerevisiae has been used as a eukaryotic model system to analyze the molecular mechanisms of oxidative stress protection. This paper reviews how the identification in yeast of specific damaged proteins has provided new insights into mechanisms of cytotoxicity and highlights the role of repair and degradative processes, including vacuolar/lysosomal and proteasomal proteolysis, in housekeeping after protein oxidative damage.
IUBMB Life, 59: 293‐298, 2007
Zinc deficiency in neuronal biology
Authors: Mackenzie Gerardo G. , Zago M. Paola , Aimo Lucila , Oteiza Patricia I.
Published: July 2007

Adverse nutritional and environmental conditions during early development can irreversibly affect the nervous system. Zinc (Zn) deficiency associated with inadequate Zn intake and undernutrition is frequent throughout the world. Increasing evidence indicates that developmental Zn deficiency can lead to alterations in neonate and infant behavior, cognitive and motor performance that persist into adulthood. This review will address current knowledge on the events that are triggered in neuronal cells when Zn availability decreases and discuss their consequences on neuronal function and development. In neuronal cells, Zn deficiency induces oxidative stress, alters the normal structure and dynamics of the cytoskeleton, affects the modulation of transcription factors AP‐1, NF‐βB and NFAT and induces a decreased cell proliferation and increased apoptotic death. Thus, these closely associated events can affect neuronal function and critical developmental events (neuronal proliferation, differentiation, plasticity and survival) when Zn availability decreases.
IUBMB Life, 59: 299‐307, 2007
Plant polyphenols: How to translate their in vitro antioxidant actions to in vivo conditions
Authors: Fraga Cesar G.
Published: July 2007

Epidemiological evidence demonstrates that diets rich in fruit and vegetables promote health, and attenuate, or delay, the onset of various diseases, including cardiovascular disease, diabetes, certain cancers, and several other age‐related degenerative disorders. The chemical components and the physiological and molecular mechanisms by which fruit and vegetables reduce the risk for these pathophysiological conditions are matters of intense investigation. Regarding plant components, polyphenols are a group of phytochemicals that are gaining acceptance as responsible for the health benefits offered by fruit and vegetables. Because of their chemical structure, plant polyphenols are able to scavenge free radicals and inactivate other pro‐oxidants. The connection of these chemical properties to a physiological antioxidant action has triggered extensive research aimed to relate the consumption of plant polyphenols with human health. Although significant progress has been made, there are still some critical areas that need to be elucidated to arrive at definitive conclusions on the mechanisms linking plant polyphenol consumption, reduction in oxidative damage, and health improvement. Some of these topics will be discussed in this review of alternative molecular mechanisms, based on polyphenol‐membranes and polyphenol‐proteins interactions that develop in an antioxidant protection but are not directly related to free radical scavenging or metal chelating.
IUBMB Life, 59: 308‐315, 2007
Synaptotoxicity in Alzheimer's Disease: The Wnt Signaling Pathway as a Molecular Target
Authors: Inestrosa Nibaldo C. , Varela‐Nallar Lorena , Grabowski Catalina P. , Colombres Marcela
Published: July 2007

Recent evidence supports a role of the Wnt pathway in neurodegenerative disorders such as Alzheimer's disease (AD). A relationship between amyloid‐β‐peptide (Aβ)‐induced neurotoxicity and a decrease in the cytoplasmatic levels of β‐catenin has been proposed. Also, the inhibition of glycogen synthase kinase (GSK‐3β), a central modulator of the pathway, protects rat hippocampal neurons from Aβ‐induced damage. Interestingly, during the progression of AD, it has been described that active GSK‐3β is found in neuronal cell bodies and neurites, co‐localizing with pre‐neurofibrillary tangles observed in disease brains. Since Aβ oligomers are associated with the post‐synaptic region and we have found that the non‐canonical Wnt signaling modulates PSD‐95 and glutamate receptors, we propose that the synaptic target for Aβ oligomers in AD is the postsynaptic region and at the molecular level is the non‐canonical Wnt signaling pathway. Altogether, our evidence suggests that a sustained loss of Wnt signaling function may be involved in the Aβ‐dependent neurodegeneration observed in AD brains and that the activation of this signaling pathway could be of therapeutic interest in AD.
H+‐PPases: yesterday, today and tomorrow
Authors: Serrano Aurelio , Pérez‐Castiñeira José R. , Baltscheffsky Margareta , Baltscheffsky Herrick
Published: July 2007

Suggestions by Calvin about a role of inorganic pyrophosphate (PPi) in early photosynthesis and by Lipmann that PPi may have been the original energy‐rich phosphate donor in biological energy conversion, were followed in the mid‐1960s by experimental results with isolated chromatophore membranes from the purple photosynthetic bacterium Rhodospirillum rubrum. PPi was shown to be hydrolysed in an uncoupler stimulated reaction by a membrane‐bound inorganic pyrophosphatase (PPase), to be formed at the expense of light energy in photophosphorylation and to be utilized as an energy donor for various energy‐requiring reactions, as a first known alternative to ATP. This direct link between PPi and photosynthesis led to increasing attention concerning the role of PPi in both early and present biological energy transfer. In the 1970s, the PPase was shown to be a proton pump and to be present also in higher plants. In the 1990s, sequences of H+‐PPase genes were obtained from plants, protists, bacteria and archaea and two classes of H+‐PPases differing in K+ sensitivity were established. Over 200 H+‐PPase sequences have now been determined. Recent biochemical and biophysical results have led to new progress and questions regarding the H+‐PPase family, as well as the families of soluble PPases and the inorganic polyphosphatases, which hydrolyse inorganic linear high‐molecular‐weight polyphosphates (HMW‐polyP). Here we will focus attention on the H+‐PPases, their evolution and putative active site motifs, response to monovalent cations, genetic regulation and some very recent results, based on new methods for obtaining large quantities of purified protein, about their tertiary and quaternary structures.
IUBMB Life, 59: 76‐83, 2007
Regulation of glucose transporter type 4 isoform gene expression in muscle and adipocytes
Authors: Im Seung‐Soon , Kwon Sool‐Ki , Kim Tae‐Hyun , Kim Ha‐il , Ahn Yong‐Ho
Published: July 2007

The gene expression of glucose transporter type 4 isoform (GLUT4) is known to be controlled by metabolic, nutritional, or hormonal status. Understanding the molecular mechanisms governing GLUT4 gene expression is critical, because glucose disposal in the body depends on the activities of GLUT4 in the muscle and adipocytes. The GLUT4 activities are regulated by a variety of mechanisms. One of them is transcriptional regulation. GLUT4 gene expression is regulated by a variety of transcriptional factors in muscle and adipose tissue. These data are accumulating regarding the transcriptional factors regulating GLUT4 gene expression. These include MyoD, MEF2A, GEF, TNF‐α, TR‐1α, KLF15, SREBP‐1c, C/EBP‐α, O/E‐1, free fatty acids, PAPRγ, LXRα, NF‐1, etc. These factors are involved in the positive or negative regulation of GLUT4 gene expression. In addition, there is a complex interplay between these factors in transactivating GLUT4 promoter activity. Understanding the mechanisms controlling GLUT4 gene transcription in these tissues will greatly promote the potential therapeutic drug development for obesity and T2DM.
IUBMB Life, 59: 134‐145, 2007
The mAKAP signalosome and cardiac myocyte hypertrophy
Authors: Bauman Andrea L. , Michel Jennifer J. Carlisle , Henson Edward , Dodge‐Kafka Kimberly L. , Kapiloff Michael S.
Published: July 2007

Cardiac hypertrophy is regulated by a large intracellular signal transduction network. Each of the many signaling pathways in this network contributes uniquely to the control of cell growth. In the last few years, it has become apparent that multimolecular signaling complexes or 'signalosomes' are important for mediating crosstalk between different signaling pathways. These complexes integrate upstream signals and control downstream effectors. In the cardiac myocyte, the protein mAKAPβ serves as a scaffold for a large signalosome that is responsive to upstream cAMP, Ca2+, and mitogen‐activated protein kinase signaling. The mAKAPβ signalosome is important for the control of NFATc transcription factor activity and for the overall induction of myocyte hypertrophy.
IUBMB Life, 59: 163‐169, 2007
The pathogenesis of transaldolase deficiency
Authors: Perl Andras
Published: July 2007

The signaling networks that mediate cell growth, differentiation, and survival are dependent on complex metabolic and redox pathways. Metabolism of glucose through the pentose phosphate pathway (PPP) fulfills two unique functions: formation of ribose 5‐phosphate for the synthesis of nucleotides, RNA, and DNA in support cell growth and formation of NADPH for biosynthetic reactions and neutralization of reactive oxygen intermediates (ROI). Balancing of NADPH and ROI levels by the PPP enzyme transaldolase (TAL) regulates the mitochondrial trans‐membrane potential (Δψm), a critical checkpoint of ATP synthesis and cell survival. While complete deficiency of glucose 6‐phosphate dehydrogenase (G6PD) or transketolase (TK) is lethal, TAL‐deficient mice developed normally with the exception of male sterility due to structural and functional damage of sperm cell mitochondria. Recently, two cases of complete TAL deficiency have been reported in patients with liver cirrhosis which results from increased cell death of hepatocytes. Delineation of the cell type‐specific role that TAL plays in the PPP and cell death signal processing will be critical for understanding the pathogenesis of TAL deficiency.
iubmb Life, 59: 1‐9, 2007
Conformational stability and thermodynamic characterization of homotetrameric Plasmodium falciparum β‐ketoacyl‐ACP reductase
Authors: Karmodiya Krishanpal , Sajad Syed , Sinha Sharmistha , Maity Koustav , Suguna Kaza , Surolia Namita
Published: July 2007

The conformational stability of the homotetrameric Plasmodium falciparumβ‐ketoacyl‐ACP reductase (FabG) was determined by guanidinium chloride‐induced isothermal and thermal denaturation. The reversible unfolding transitions were monitored by intrinsic fluorescence, circular dichroism (CD) spectroscopy and by measuring the enzyme activity of FabG. The denaturation profiles were analyzed to obtain the thermodynamic parameters associated with unfolding of the protein. The data confirm the simple A4 ↔ 4A model of unfolding, based on the corroboration of CD data by fluorescence transition and similar ΔG estimation for denaturation curves obtained at four different concentration of the FabG. Denaturation is well described by the linear extrapolation model for denaturant‐protein interactions. In addition, the conformational stability (ΔGs) as well as the ΔCp for the protein unfolding is quite high, 22.68 kcal/mole and 5.83 kcal/(mole K), respectively, which may be a reflection of the relatively large size of the tetrameric molecule (Mr 120, 000) and a large buried hydrophobic core in the folded protein. This study provides a prototype for determining conformational stability of other members of the short‐chain alcohol dehydrogenase/reductase superfamily of proteins to which PfFabG belongs.
iubmb Life, 59: 441‐449, 2007
Experiences of prison among injecting drug users in England: A qualitative study
Authors: Tompkins Charlotte N. E. , Neale Joanne , Sheard Laura , Wright Nat M. J.
Published: July 2007

Imprisonment is common among drug users. However, historically healthcare for injecting drug users in prison in England and Wales has not been equivalent to that offered in community settings. Fiftyone injecting drug users who had a history of imprisonment were interviewed. Interviews focused on the experiences of drug‐related care and treatment in prison. The interviews were analysed using the Framework method. Accounts of prison drug treatment experiences provided valuable insights into drug treatment in the English prison. The participants’ accounts provided a historical perspective, many of which reflected the different practices of different prisons and prison staff and the changes in policy and practice that have occurred in prison healthcare over recent decades. Positive and negative experiences of healthcare and drug treatment in prison were discussed. Issues that affected levels of drug use inside prisons and their receipt of care, support and treatment in prison included prescribing policies, illicit drug availability and prison staff and doctor attitudes. Whilst negative experiences of prison and drug treatment prevailed, users identified that recent policy and practice changes had positively influenced healthcare provision for drug users in prison, particularly the provision of opiate maintenance therapy. Drug users often saw prison as an opportunity to detoxify and contemplate their drug use. Further work needs to build on the positive experiences identified to ensure that prison drug treatment in England and Wales is consistent, effective and efficient in the future.
Non-equilibrium steady states: fluctuations and large deviations of the density and of the
current
Authors: Derrida Bernard
Published: July 2007

These lecture notes give a short review of methods such as the matrix ansatz, the
additivity principle or the macroscopic fluctuation theory, developed recently in the
theory of non-equilibrium phenomena. They show how these methods allow us to
calculate the fluctuations and large deviations of the density and the current in
non-equilibrium steady states of systems like exclusion processes. The properties of these
fluctuations and large deviation functions in non-equilibrium steady states (for example,
non-Gaussian fluctuations of density or non-convexity of the large deviation function
which generalizes the notion of free energy) are compared with those of systems at
equilibrium.
Reducing the catch of small shrimps in the Gulf of Maine pink shrimp fishery with a size-sorting grid device
Authors: He Pingguo , Balzano Vincent
Published: July 2007

He, P., and Balzano, V. 2007. Reducing the catch of small shrimps in the Gulf of Maine pink shrimp fishery with a size-sorting grid device. – ICES Journal of Marine Science, 64: 1551–1557. Since implementation of the Nordmøre grid in the Gulf of Maine pink shrimp (Pandalus borealis) trawl fishery in the early 1990s, fish bycatch has been reduced drastically. However, the Nordmøre grid does not reduce the amount of small shrimps landed when the shrimps are on the fishing grounds. This paper reports on two designs of a new size-sorting grid system, one with a funnel and one without. The designs' main feature is the size-sorting grid's position, installed in front of the main Nordmøre grid. They were tested in the flume tank and at sea. Parallel tows involving two vessels and alternating tows using one vessel were made to compare the size-sorting grid system. Both size-sorting designs reduced the number of small shrimps in the catch significantly, by 38 and 45 kg−1 of catch, respectively. There was some reduction in shrimp catch rates, presumably from the release of small shrimps. There were no significant differences in the number or quantity of major bycatch species for the commercial grid and the two experimental grid designs. The designs were practical to operate and easy to install. Their application could reduce the catch of small shrimps in the pink shrimp fishery in the Gulf of Maine and in other areas.
Pharmacokinetics of lamivudine in subjects receiving peritoneal dialysis in end‐stage renal failure
Authors: Asari Ashwin , Iles‐Smith Heather , Chen Ya‐Chi , Naderer Odin J. , Johnson Mark A. , Yuen Geoffrey J. , Otto Vicky , Dunn John A. , Gokal Ram
Published: July 2007

What is already known about this subject

• Prior to the conduct of this study, information on the pharmacokinetics of lamivudine in subjects with renal impairment was limited to patients on haemodialysis. (Br J Clin Pharmacol 1998; 46: 21–7).

• No pharmacokinetic data were available on subjects receiving lamivudine who were concurrently receiving peritoneal dialysis.

• With increasing numbers of individuals opting for peritoneal dialysis, the need to establish if dose modification was necessary in this setting was important to ensure efficacious and safe drug exposures were being obtained.

What this study adds

• This study demonstrated that similar to patients receiving haemodialysis, dose modifications based on reductions in renal function (i.e. decreased CLCR), also applied to subjects on peritoneal dialysis.

Aims

To establish whether peritoneal dialysis (PD) requires dosing modification from the CLCR‐corrected lamivudine dose in end‐stage renal failure subjects.

Methods

This was an open‐label cohort study. A total of 12 subjects undergoing PD, six continuous ambulatory peritoneal dialysis (CAPD) and six automated peritoneal dialysis (APD), for at least 3 months received lamivudine 10 mg (5 mg ml −1 × 2 ml) daily for 8 consecutive days, followed by an intensive pharmacokinetic assessment. Urine and dialysate were collected from 0 to 24 h postdose on day 8 where possible. Pharmacokinetic parameters were calculated using noncompartmental techniques.

Results

The plasma pharmacokinetic results demonstrated that peritoneal dialysis clearance (CLD) of lamivudine was similar between APD and CAPD patients with median (range) of 0.19 l h−1 (0.14–0.25) and 0.1 l h−1 (0.09–0.25), respectively. CLD was approximately 1/15th to 1/30th of plasma clearance, demonstrating that peritoneal dialysis does not contribute significantly to overall lamivudine clearance in this patient population. The AUC(0,24 h) of lamivudine given 10 mg daily to APD and CAPD patients was 3430 ng ml−1 h and 3469 ng ml−1 h, respectively, similar to historical data obtained in patients with normal renal function administered at the normal dose of 100 mg daily (3781 ng ml−1 h). There were no clinically significant changes in any safety assessments that were attributable to lamivudine.

Conclusions

ESRD patients who receive CAPD or APD require no supplemental dosing. These patients should follow the standard dosing reduction for patients infected with HIV or HBV with renal dysfunction.
Pharmacokinetic and pharmacodynamic properties of oral L‐citrulline and L‐arginine: impact on nitric oxide metabolism
Authors: Schwedhelm Edzard , Maas Renke , Freese Ralf , Jung Donald , Lukacs Zoltan , Jambrecina Alen , Spickler William , Schulze Friedrich , Böger Rainer H.
Published: July 2007

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• L‐Arginine is a semiessential amino acid that is converted to nitric oxide (NO) by NO synthase (NOS).

• NO improves endothelial function by elevating cyclic guanosine monophosphate.

• However, oral L‐arginine treatment in humans is hampered by extensive metabolism.

WHAT THIS STUDY ADDS

• Oral L‐citrulline supplementation raises plasma L‐arginine concentration and augments NO‐dependent signalling in a dose‐dependent manner.

• L‐Citrulline may thus be an alternative to L‐arginine in patients with impaired NOS activity.

AIMS

Oral L‐arginine supplementation has been used in several studies to improve endothelium‐dependent, nitric oxide (NO)‐mediated vasodilation. L‐Arginine treatment is hampered by extensive presystemic elimination due to intestinal arginase activity. In contrast, L‐citrulline is readily absorbed and at least in part converted to L‐arginine. The aim of our study was to assess this metabolic conversion and its subsequent pharmacodynamic effects.

METHODS

In a double‐blind, randomized, placebo‐controlled cross‐over study, 20 healthy volunteers received six different dosing regimes of placebo, citrulline, and arginine. Pharmacokinetic parameters (Cmax, Tmax, Cmin, AUC) were calculated after 1 week of oral supplementation. The ratio of plasma L‐arginine over asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase (arginine/ADMA ratio), urinary cyclic guanosine monophosphate (cGMP) and nitrate excretion rates, and flow‐mediated vasodilation (FMD) was measured to assess pharmacodynamic effects.

RESULTS

L‐Citrulline dose‐dependently increased AUC and Cmax of plasma L‐arginine concentration more effectively than L‐arginine (P < 0.01). The highest dose of citrulline (3 g bid) increased the Cmin of plasma L‐arginine and improved the L‐arginine/ADMA ratio from 186 ± 8 (baseline) to 278 ± 14 [P < 0.01, 95% confidence interval (CI) 66, 121]. Moreover, urinary nitrate and cGMP were increased from 92 ± 10 to 125 ± 15 µmol mmol−1 creatinine (P = 0.01, 95% CI 8, 58) and from 38 ± 3.3 to 50 ± 6.7 nmol mmol−1 creatinine (P = 0.04, 95% CI 0.4, 24), respectively. No treatment improved FMD over baseline. However, pooled analysis of all FMD data revealed a correlation between the increase of arginine/ADMA ratio and improvement of FMD.

CONCLUSION

Our data show for the first time that oral L‐citrulline supplementation raises plasma L‐arginine concentration and augments NO‐dependent signalling in a dose‐dependent manner.
Developmental pharmacokinetics of ciclosporin – a population pharmacokinetic study in paediatric renal transplant candidates
Authors: Fanta S. , Jönsson S. , Backman J. T. , Karlsson M. O. , Hoppu K.
Published: July 2007

What is already known about this subject

• Ciclosporin is an immunosuppressant drug with a narrow therapeutic index and large variability in pharmacokinetics.

• It is likely that the inter‐ and intraindividual variability in ciclosporin pharmacokinetics and dose requirements is even larger in children than in adults as a result of variation in biological maturation status.

• However, data on the developmental pharmacokinetics of ciclosporin, as well as other CYP3A4 substrate drugs, in children are scarce.

What this study adds

• Adult CYP3A4 activity seems to be reached by the age of 6–12 months, and allometrically scaled body weight is a good predictor of the hepatic clearance of ciclosporin, a CYP3A4 substrate.

• Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age.

• These conclusions were reached using a robust modelling approach (NONMEM) with rich paediatric pharmacokinetic data collected after full i.v. and p.o. profiles.

Aims

To use population pharmacokinetic modelling to characterize the influence of developmental and demographic factors on the pharmacokinetic variability of ciclosporin.

Methods

Pharmacokinetic modelling was performed in NONMEM using a dataset comprising 162 pretransplant children, aged 0.36–17.5 years. Ciclosporin was given intravenously (3 mg kg−1) and orally (10 mg kg−1) on separate occasions followed by blood sampling for 24 h.

Results

A three‐compartment model with first‐order absorption without lag‐time best described the pharmacokinetics of ciclosporin. The most important covariate affecting systemic clearance (CL) and distribution volume (V) was body weight (BW; scaled allometrically), responsible for a fourfold difference in uncorrected ciclosporin CL and a sixfold difference in ciclosporin V. The other significant covariates, haematocrit, plasma cholesterol and creatinine, were estimated to explain 20–30% of interindividual differences in CL and V of ciclosporin. No age‐related changes in oral bioavailability or in BW‐normalized V were seen. The BW‐normalized CL (CL/BW) declined with age and prepubertal children (<8 years) had an approximately 25% higher CL/BW than did older children. Normalization of CL for allometric BW (BW3/4) removed its relationship to age.

Conclusion

The relationship between CL and allometric BW is consistent with a gradual reduction in relative liver size, until adult values, and a relatively constant CYP3A4 content in the liver from about 6–12 months of age to adulthood. Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age. These findings can enable better individualization of ciclosporin dosing in infants, children and adolescents.
Recommendations for the management of the haematological and onco‐haematological aspects of Gaucher disease1
Authors: Hughes Derralynn , Cappellini Maria Domenica , Berger Marc , Droogenbroeck Jan Van , De Fost Maaike , Janic Dragana , Marinakis Theodore , Rosenbaum Hanna , Villarubia Jesús , Zhukovskaya Elena , Hollak Carla
Published: July 2007

Current knowledge of the haematological and onco‐haematological complications of type 1 Gaucher disease has been reviewed with the aim of identifying best clinical practice for treatment and disease management. It was concluded that: (i) Awareness of typical patterns of cytopenia can help clinicians distinguish haematological co‐morbidities. (ii) Red blood cell studies and complete iron metabolism evaluation at baseline are recommended. (iii) Haemoglobin levels defining anaemia should be raised and used in Gaucher disease treatment and monitoring. (iv) Surgeons should be aware of potential bleeding complications during surgery in Gaucher patients.

The higher incidence of multiple myeloma in Gaucher disease suggests that Gaucher patients should have their immunoglobulin profile determined at diagnosis and monitored every 2 years (patients <50 years) or every year (patients >50 years). If monoclonal gammopathy of undetermined significance (MGUS) is found, general MGUS guidelines should be followed. Future studies should focus on the utility of early treatment to prevent immunoglobulin abnormalities and multiple myeloma.
Suppression of the asthmatic phenotype by ultraviolet B‐induced, antigen‐specific regulatory cells
Authors: McGlade J. P. , Gorman S. , Zosky G. R. , Larcombe A. N. , Sly P. D. , Finlay‐Jones J. J. , Turner D. J. , Hart P. H.
Published: July 2007

Background
Over recent decades, there has been a significant global increase in the prevalence of asthma, an inflammatory disease of the respiratory system. While ultraviolet radiation (UV) has been used successfully in the treatment of inflammatory conditions such as psoriasis, studies of UV‐induced regulation of allergic respiratory responses have been rare, and have not analysed in vivo measurements of airway hyperresponsiveness (AHR) or the antigen specificity of the UV‐induced effects.

Objective
To investigate the regulatory properties of erythemal ultraviolet B (UVB) irradiation of the skin and the induction of allergen‐induced airway immunity in a murine asthma model, and to examine the mechanisms involved.

Methods
BALB/c mice were exposed to a single erythemal dose of UV 3 days before intraperitonial sensitization (day 0) and boost (day 14) with the antigen, ovalbumin (OVA). Airway‐associated, asthma‐like responses to aerosolized OVA at day 21 were analysed including (a) AHR measured in vivo, (b) OVA‐specific proliferative responses and cytokine production by cells from the lung‐draining lymph nodes (LDLN), and (c) inflammatory cells and cytokines in the bronchoalveolar lavage fluid. To determine UVB‐induced mechanisms of regulation, LDLN cells from UVB irradiated, OVA‐sensitized mice were adoptively transferred into naïve BALB/c mice that were subsequently sensitized and challenged with OVA, or a non‐specific antigen.

Results
UVB irradiation of skin significantly suppressed AHR to methacholine and OVA‐specific responses in the LDLN and in the lung compartment. Reduced OVA‐specific responses by LDLN cells from both UVB irradiated mice and mice that received 5 × 106 LDLN cells from UVB irradiated, but not from non‐irradiated, OVA‐sensitized mice suggested that UVB‐induced regulatory cells are responsible for many of the asthma‐reducing effects of dorsal UVB exposure.

Conclusion
UVB irradiation of skin suppresses AHR and cellular responses of the airways to respiratory allergens. Further, this study implicates UVB or its downstream mediators as a potential approach to reducing the severity of asthma.
Exhaled nitric oxide and biomarkers in exhaled breath condensate indicate the presence, severity and control of childhood asthma
Authors: Robroeks C. M. H. H. T. , Van De Kant K. D. G. , Jöbsis Q. , Hendriks H. J. E. , Van Gent R. , Wouters E. F. M. , Damoiseaux J. G. M. C. , Bast A. , Wodzig W. K. W. H. , Dompeling E.
Published: July 2007

Background
Exhaled nitric oxide and inflammatory biomarkers in exhaled breath condensate may be useful to diagnose and monitor childhood asthma. Their ability to indicate an asthma diagnosis, and to assess asthma severity and control, is largely unknown.

Objective
To study (1) the ability of exhaled nitric oxide and inflammatory markers in exhaled breath condensate (nitrite, nitrate, hydrogen peroxide, 8‐isoprostane, IFN‐γ, TNF‐α, IL‐2, ‐4, ‐5, ‐10 and acidity) to discriminate between childhood asthma and controls. (2) The ability of these biomarkers to indicate asthma severity and control.

Methods
One‐hundred and fourteen children were included: 64 asthmatics (10.7±3.0 years, 67.2% atopic) and 50 controls (10.0±0.4 years). Condensate was collected using a glass condenser.

Results
Exhaled nitric oxide, IFN‐γ and IL‐4 in exhaled breath condensate differed significantly between asthma and controls. Multivariate backward logistic regression models demonstrated that IL‐4 (odds ratio 7.9, 95% confidence interval 1.2–51.0) was the only significant indicator of an asthma diagnosis. Asthma control was best assessed by exhaled nitric oxide, 8‐isoprostane, IFN‐γ and IL‐4 (sensitivity 82%, specificity 80%, P<0.05), whereas exhaled nitric oxide, 8‐isoprostane, nitrate and nitrite in condensate were the best indicators of asthma severity (sensitivity 89%, specificity 72%, P<0.05).

Conclusion
Different markers in condensate are of an additional value to exhaled nitric oxide, and are needed in non‐invasive inflammometry. They could be useful to diagnose asthma and to indicate asthma control and severity in childhood.
PX‐RICS, a novel splicing variant of RICS, is a main isoform expressed during neural development
Authors: Hayashi Tomoatsu , Okabe Toshio , Nasu‐Nishimura Yukiko , Sakaue Fumika , Ohwada Susumu , Matsuura Ken , Akiyama Tetsu , Nakamura Tsutomu
Published: July 2007

In our previous study, we identified RICS, a novel β‐catenin‐interacting protein with the GAP activity toward Cdc42 and Rac1, and found that RICS plays an important role in the regulation of neural functions, including postsynaptic NMDA signaling and neurite outgrowth. Here we report the characterization of an N‐terminal splicing variant of RICS, termed PX‐RICS, which has additional phox homology (PX) and src homology 3 (SH3) domains in its N‐terminal region. The PX domain of PX‐RICS interacted specifically with phosphatidylinositol 3‐phosphate [PtdIns(3)P], PtdIns(4)P and PtdIns(5)P. Consistent with this binding affinity, PX‐RICS was found to be localized at the endoplasmic reticulum (ER), Golgi and endosomes. We also found that wild‐type PX‐RICS possessed much lower GAP activity than RICS, whereas a mutant form of PX‐RICS whose PX domain lacks the binding ability to phosphoinositides (PIs) exhibited the GAP activity comparable to that of RICS. However, PX‐RICS and RICS exhibited similar inhibitory effects on neurite elongation of Neuro‐2a cells. Furthermore, we demonstrate that PX‐RICS is a main isoform expressed during neural development. Our results suggest that PX‐RICS is involved in early brain development including extension of axons and dendrites, and postnatal remodeling and fine‐tuning of neural circuits.
European Study on Orthopaedic Status of haemophilia patients with inhibitors
Authors: MORFINI M. , HAYA S. , TAGARIELLO G. , POLLMANN H. , QUINTANA M. , SIEGMUND B. , STIELTJES N. , DOLAN G. , TUSELL J.
Published: July 2007

Summary.   Development of inhibitors against factor VIII (FVIII) or factor IX (FIX) in haemophilia patients is one of the most serious complications of repeated exposure to replacement therapy and has major clinical and economic consequences. To evaluate the relationship between inhibitor status of haemophilia patients and their quality of life (QoL) and degree of arthropathy and to compare the orthopaedic status of patients with/without inhibitors. An observational, cross‐sectional, case control study enrolling: group A (n = 38), males aged 14–35 years, with severe congenital haemophilia A or B who had inhibitors against FVIII/FIX >5 years; group B (n = 41), as group A, but aged 36–65 years and group C (n = 49), as group A, but without inhibitors. Socio‐demographics: medical history, clinical characteristics and QoL were assessed. In groups A and B, 16% and 27% were hospitalized for orthopaedic procedures vs. 4% in group C. Patient mobility was also severely reduced in groups A and B, with 24% and 22% using wheelchairs vs. 4% in group C, and 50% and 51% needing a walking aid vs. 29% in group C. Significantly more joint pain was reported by patients in group A vs. those in group C; clinical/radiological orthopaedic scores were also worse in group A vs. group C. Significantly more joint abnormality was reported by patients in group A vs. group C. The burden of orthopaedic complications and the impact on QoL are more severe in haemophilia patients who have developed inhibitors than in those without inhibitors.
Incidence of factor FVIIIC deficiency in live male infants undergoing circumcision in South West, Nigeria
Authors: FAKUNLE E. E. , SHOKUNBI W. A. , SHITTU O. B.
Published: July 2007

Summary.  A prominent evidence of inherited bleeding disorder in newborn males is excessive postcircumcision bleeding. Male circumcision in Nigeria is the rule rather than the exception. Male siblings of some of the Nigerian haemophiliacs consequently died from severe postcircumcision bleeding. The aim was to determine the incidence of inherited factor VIIIc (FVIIIc) deficiencies in live male infants undergoing circumcision in South West, Nigeria. The study population was 244 male infants drawn from University College Hospital and Our lady of Apostles Catholic Hospital, Oluyoro, Ibadan. Precircumcision prothrombin time, activated partial thromboplastin time and FVIIIc levels were determined. Clinical features of inherited bleeding disorder particularly family history of bleeding diathesis, history of cephalhaematoma and bleeding from the umbilical stump in neonatal life were determined with the aid of a questionnaire. Only one of the mothers (0.4%) gave a family history of bleeding disorder. A history of excessive bleeding from the umbilical stump post delivery was obtained in three (2%) of the patients. Five (2%) other subjects had cephalhaematoma post delivery. Two of the subjects (0.8%) had prolonged activated partial thromboplastin time. The factor VIIIc level was between 31% and 49% in 16.1%, while 1.6% of the neonates had levels between 20% and 26%. This study detected four of the 244 (1.64%) neonates with FVIIIc deficiency, suggestive of either mild haemophilia or von Willebrand’s disease. A larger study (including family studies) will be required, so as to arrive at the exact incidence of both haemophilia A and vWD in live male infants in Nigeria.