bluuebunny/crossref_metadata_2025 huggingface dataset:
The N-formyl methionyl peptide, formyl-methionyl-leucyl phenylalanine (fMLF) increases the lateral diffusion of complement receptor 1 (CR1/CD35) in human neutrophils; a causative role for oxidative metabolites?
Authors: Rasmusson Birgitta J. , Carpentier Jean-Louis , Paccaud Jean-Pierre , Magnusson Karl-Eric
Published: February 2005

The effects of the N-formyl methionyl peptide, formyl-methionyl-leucyl phenylalanine (fMLF) on the lateral mobility of the complement receptor type 1 (CR1/CD35) in glass-adherent human neutrophils were investigated, using fluorescence recovery after photobleaching (FRAP) and confocal microscopy (CSLM). It was found that addition of 0.1–1 μM fMLF increased the diffusion constant (D) of CR1/CD35 to 167–278% of controls. No effect was observed on the receptor distribution or the mobile fraction of receptors. The effect of fMLF on the lateral diffusion of CR1/CD35 could be totally inhibited by addition of pertussis toxin (PT, 250 ng/ml) or of the free radical scavenger enzymes superoxide dismutase (SOD, 2000 U/ml) and catalase (CAT, 200 U/ml), added together the results show that oxidative metabolites produced by neutrophils in response to fMLF can modulate CR1/CD35 diffusion, and indicate a regulatory role for oxygen radicals in phagocytosis.
Effects of transforming growth factor β, tumor necrosis factor α and interferon γ on pancreatic islet β-cell responsiveness to transforming growth factor α
Authors: Sjöholm Åke
Published: February 2005

The insulin-producing pancreatic islet β-cell, characterized by low proliferative potential, is normally not responsive to the polypeptide epidermal growth factor (EGF) or its homolog transforming growth factor α (TGF-α). Since EGF receptors in other tissues can be up-regulated by other growth factors and by cytokines, we have in this paper investigated whether such a β-cell responsiveness to TGF-α, or EGF, can be conferred by co-culture with interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) or transforming growth factor β (TGF-β) in various combinations. To this end, fetal rat pancreatic islets enriched in β-cells were isolated and cultured for 3 days with or without 200 pM or 20 nM TGF-α. It was found that neither of these TGF-α concentrations affected β-cell mitogenesis, insulin content or insulin secretion. However, IFN-γ (1000 U/ml) evoked a modest stimulation of β-cell replication, while suppressing insulin secretion and leaving the islet insulin content unaltered. TNF-α (1000 U/ml), on the other hand, affected none of these parameters either alone or in any combination with TGF-α or IFN-γ. However, when TNF-α or IFN-γ, either alone or in combination, were combined with the cytokine interleukin-1β, this resulted in islet disintegration, whereas the latter cytokine alone did not exert any gross necrotic changes evident by light microscopy. TGF-β (500 pM) stimulated insulin secretion but did not influence islet insulin content or β-cell mitogenesis either alone or in combination with TGF-α (200 pM or 20 nM). In no instance could any mitogenic or secretory response to low or high concentrations of TGF-α be conferred by IFN-γ, TNF-α or TGF-β whether used alone or in combinations. Hence, responsiveness to TGF-α or EGF in the β-cell obviously cannot be achieved by any of these peptides.
A functional logic for higher level reasoning about computation
Authors: Staples John , Robinson Peter J. , Hazel Daniel
Published: February 2005

In many areas of computation and reasoning, the value of an expression may depend on an implicit parameter, which may for example represent a program state, or time, or a possible world. In this paper we describe a formal first order logic which captures a general notion of expressions which depend on an implicit parameter. Both semantics and syntax are discussed. An important application of the logic, used as a running example, is to provide a basis for unifying the Hoare logic of procedural programs with the mathematically powerful techniques of classical logic and set theory. It is, however, beyond the scope of this paper to develop this application fully.
A predicate transformer for the progress property ‘to-always’
Authors: Dijkstra Rutger M. , Sanders Beverly A.
Published: February 2005

The temporal property ‘to-always’ has been proposed for specifying progress properties of concurrent programs. Although the ‘to-always’ properties are a subset of the ‘leads-to’ properties for a given program, ‘to-always’ has more convenient proof rules and in some cases more accurately describes the desired system behavior. In this paper, we give a predicate transformer
wta
, derive some of its properties, and use it to define ‘to-always’. Proof rules for ‘to-always’ are derived from the properties of
wta
. We conclude by briefly describing two application areas, nondeterministic data flow networks and self-stabilizing systems where ‘to-always’ properties are useful.
Distributed maximum maintenance on hierarchically divided graphs
Authors: Lentfert P. J. A. , Swierstra S. D.
Published: February 2005

The design and verification of distributed and concurrent algorithms is highly complex, and thus error-prone. It is our experience that the intertwined use of an informal description as well as a formal method in designing and studying an algorithm, is a fruitful one. The advantage of the informal description is the ease with which algorithms can be produced, studied and discussed. In contrast with formal methods however, errors are easily made in informal arguments about programs that seem to be correct, but in fact are not.

In this paper we use an informal argument, carefully augmented with the use of the UNITY formalism, in the design of a distributed algorithm for maintaining the maximum value of a bag of frequently changing integers on a hierarchically divided network. The resulting algorithm is obtained by first designing an abstract algorithm on a virtual datastructure. Next, the abstract algorithm is transformed into the distributed algorithm.
Partial logics reconsidered: A conservative approach
Authors: Owe Olaf
Published: February 2005

Partial functions play an important role in computer science. In order to reason about partial functions one may extend classical logic to a logic supporting partial functions, a so-called partial logic. Usually such an extension necessitates side-conditions on classical proof rules in order to ensure consistency, and introduces non-classical proof rules in order to maintain completeness. These complications depend on the choice of consequence relation and non-monotonic operators. In computer science applications such complications are undesirable, because they affect (semi-) mechanical reasoning methods, and make manual reasoning difficult for computer scientists who are not logicians.

By carefully choosing the consequence relation and non-monotonic operators, a simple calculus for partial functions arises. The resulting logic is “healthy” in the sense that “meaningless” formulas (such as top(emptystack) > 1) cannot be concluded, except from contradictory or false assumptions, and a meaningless assumption provides no information. This requires all axioms to be healthy; and as a consequence the “excluded middle” (
a
V ¬a) must be weakened (to meaningful
a's
). All the well-known classical rules preserve healthiness and are therefore sound in the logic, provided substitutions are restricted to meaningful terms. This means that program reasoning methods based on classical logic usually can be adapted to the presented partial logic.
MetateM: An introduction
Authors: Barringer H. , Fisher M. , Gabbay D. , Gough G. , Owens R.
Published: February 2005

In this paper a methodology for the use of temporal logic as an executable imperative language is introduced. The approach, which provides a concrete framework, calledMetateM, for executing temporal formulae, is motivated and illustrated through examples. In addition, this introduction provides references to further, more detailed, work relating to theMetateMapproach to executable logics.
A model checker for linear time temporal logic
Authors: Fisher Michael
Published: February 2005

This report describes the design and implementation of a model checker for linear time temporal logic. The model checker uses a depth-first search algorithm that attempts to find a minimal satisfying model and uses as little space as possible during the checking procedure. The depth-first nature of the algorithm enables the model checker to be used where space is at a premium.
Communicating processes with value-passing and assignments
Authors: Hennessy M. , Ingólfsdóttir A.
Published: February 2005

A semantic theory of an imperative language which allows value-passing and assignments as a simple action prefixing is described. Three different semantic approaches are given: denotational based on the mathematical model Acceptance Trees, axiomatic based on inequations and behavioural in terms of testing. The equivalence of these different approaches is shown. The results are compared with similar results for other languages such as
CSP
and
Occam
.
A CCS-based investigation of deadlock in a multi-process electronic mail system
Authors: Brebner Gordon
Published: February 2005

The networking software for a VAX/VMS computer system had been implemented as a collection of communicating processes. One night, an unusually high load on the electronic mail component of the software caused deadlock to occur between two of the processes. This paper describes how the deadlock was analysed by modelling the software using the Calculus of Communicating Systems (CCS) and then by investigating the behaviour of the model using the Edinburgh Concurrency Workbench (CWB). The analysis suggested how the software should be restructured to prevent the problem recurring; the new set of processes was analysed, and shown to be deadlock-free.
On CCS with parametric relabelling
Authors: Hussak Walter
Published: February 2005

We present a concrete version of Astesiano and Zucca's CCS/PC, that permits parametric channels of a special form which are used in prefix expressions and in an extended way in relabelling functions. We report on the use of the calculus to describe nested process context in a parallel operating system.
The sliding-window protocol revisited
Authors: van de Snepscheut Jan L. A.
Published: February 2005

We give a correctness proof of the sliding-window protocol. Both safety and liveness properties are addressed. We show how faulty channels can be represented as nondeterministic programs. The correctness proof is given as a sequence of correctness-preserving transformations of a sequential program that satisfies the original specification, with the exception that it does not have any faulty channels. We work as long as possible with a sequential program, although the transformation steps are guided by the aim of going to a distributed program. The final transformation steps consist in distributing the actions of the sequential program over a number of processes.
Termination of rewrite systems by elementary interpretations
Authors: Lescanne Pierre
Published: February 2005

We focus on termination proofs of rewrite systems, especially of rewrite systems containing associative and commutative operators. We prove their termination by elementary interpretations, more specifically, by functions defined by addition, multiplication and exponentiation. We discuss a method based on polynomial interpretations and propose an implementation of a mechanisation of the comparison of expressions built with polynomials and exponentials.
VDM and Z: A comparative case study
Authors: Hayes Ian
Published: February 2005

The specification notations of VDM and Z are closely related. They both use model-based specification techniques and share a large part of their mathematical notation. However, the approaches taken to writing specifications differ in other, more subtle, ways.

We present a comparative case study of VDM and Z for specifying database systems. John Fitzgerald and Cliff Jones in their paper entitled “Modularising the formal description of a database system” in the proceedings of
VDM '90: VDM and Z
(LNCS Vol. 428, Springer-Verlag) provide the basis for the comparison. We present equivalent Z specifications to the VDM specifications contained in their paper.

The approach taken in writing the Z specifications is to reuse as much as possible of the Z mathematical toolkit and to build the system specification from specifications of components of the system.

In their paper, Fitzgerald and Jones emphasise their modularisation facilities. While the facilities for modularisation in Z are not as powerful, they are adequate for the specification of the database systems presented.
The imidazoline derivative calmidazolium inhibits voltage-gated Ca2+-channels and insulin release but has no effect on the phospholipase C system in insulin producing RINm5F-cells
Authors: Kindmark Henrik , Köhler Martin , Gerwins Pär , Larsson Olof , Khan Akhtar , Wahl Martin A. , Berggren Per-Olof
Published: February 2005

The present study shows that the calmodulin antagonist calmidazolium inhibited influx of Ca2+ through voltage-gated Ca2+-channels in clonal insulin producing RINm5F-cells. The mechanism of inhibition may involve both Ca2+-calmodulin-dependent protein kinases and direct binding of calmidazolium to the Ca2+-channel. Calmidazolium did not affect uptake of Ca2+ into intracellular Ca2+-pools, inositol 1,4,5-trisphosphate (InsP3) formation or action on intracellular Ca2+-pools. The calmodulin inhibitor also did not affect glucose utilization or oxidation in RINm5F-cells, speaking against an unspecific toxic effect of the compound. KCl-and ATP-stimulated insulin release from RINm5F-cells was attenuated by calmidazolium, whereas basal hormone secretion was unaffected.
Eating attitudes in a diverse sample of Israeli adolescent females: a comparison study
Authors: Latzer Y. , Tzischinsky O.
Published: February 2005

Objectives

To estimate the eating attitudes in Israeli Jewish female adolescents.

Methods: A representative sample of 1270 females in grades 7–12 from five different Israeli schools from five different residential areas were assessed by EAT‐26.

Results

Of the total sample, 19.5% were identified as having abnormal eating attitudes. In terms of age, the 16 year olds were found to have the significantly highest rate of total and positive EAT‐26 scores. As for school subgroups, the secular boarding schools had the significantly highest rate and the kibbutz had the lowest rate of positive EAT‐26 scores for the total and for all subscales.

Discussion

EAT‐26 was found to be a useful tool for screening and identifying at‐risk groups in a large adolescent Israeli population.
Regulation of divalent metal transporter expression in human intestinal epithelial cells following exposure to non‐haem iron
Authors: Johnson Deborah M. , Yamaji Sachie , Tennant Jason , Srai Surjit K. , Sharp Paul A.
Published: February 2005

A number of regulatory factors including dietary iron levels can dramatically alter the expression of the intestinal iron transporter DMT1. Here we show that Caco‐2 cells exposed to iron for 4 h exhibited a significant decrease in plasma membrane DMT1 protein, though total cellular DMT1 levels were unaltered. Following biotinylation of cell surface proteins, there was a significant increase in intracellular biotin‐labelled DMT1 in iron‐exposed cells. Furthermore, iron‐treatment increased levels of DMT1 co‐localised with LAMP1, suggesting that the initial response of intestinal epithelial cells to iron involves internalisation and targeting of DMT1 transporter protein towards a late endosomal/lysosomal compartment.
Dictyostelium discoideum requires an Alix/AIP1 homolog, DdAlix, for morphogenesis in alkaline environments
Authors: Ohkouchi Susumu , Saito Hajime , Aruga Fumika , Maeda Tatsuya , Shibata Hideki , Maki Masatoshi
Published: February 2005

Alix and its homologs are involved in various phenomena such as endosomal protein‐sorting and adaptation to stress conditions. In this study, we found that development of Dictyostelium discoideum Alix (DdAlix) deletion mutant (alx
−) cells was impaired in alkaline pH environments. The fruiting body formation efficiency of alx
− cells at pH 9.0 was significantly lower than that of wild‐type cells (6.8 ± 4.2% vs 93 ± 6.3%). The alkaline‐sensitive phenotype of alx
− cells was rescued by addition of salt. The phenotype was rescued by exogenous expression of human Alix as well as DdAlix but not by that of either Saccharomyces cerevisiae Alix homolog Rim20 or Bro1. DdAlix may be, structurally and functionally, more related to human Alix than to yeast Rim20 and Bro1.
Mitochondrial localization of Arabidopsis thaliana Isu Fe–S scaffold proteins
Authors: Léon Sébastien , Touraine Brigitte , Briat Jean-François , Lobréaux Stéphane
Published: February 2005

Isu are scaffold proteins involved in iron–sulfur cluster biogenesis and playing a key role in yeast mitochondria and Escherichia coli. In this work, we have characterized the Arabidopsis thaliana Isu gene family. AtIsu1,2,3 genes encode polypeptides closely related to their bacterial and eukaryotic counterparts. AtIsu expression in a Saccharomyces cerevisiae Δisu1Δnfu1 thermosensitive mutant led to the growth restoration of this strain at 37 °C. Using Isu‐GFP fusions expressed in leaf protoplasts and immunodetection in organelle extracts, we have shown that Arabidopsis Isu proteins are located only into mitochondria, supporting the existence of an Isu‐independent Fe–S assembly machinery in plant plastids.
The short time horizon in the Russian mind
Authors: Shlapentokh Vladimir
Published: February 2005

An individual’s vision of the future is an important factor that shapes his or her quality of life and behavior. The character and intensity of this factor varies from society to society, group to group, and from one moment to the next. Four actors are central to the analysis of the Russians’ perspective of the future: the leadership, political elites, business elites and the masses.

The members of each of these groups have their own ‘‘time horizon,’’ that is, the length of time in the future that influences their decisions, moods, and quality of life. The length of this period depends mostly on how they perceive the level of stability in society, now and in the future. As an actor’s pessimism about the future increases, the time horizon decreases. In extreme cases, the person’s time horizon can decline to the point where they disregard what may or may not happen tomorrow.

Another important factor is the power and readiness of the particular actor to influence the future of society and its institutions, not to mention their own lives. When people believe that it is impossible to change the future, or the fate of their nation, they become either fatalistic, or tend to violate social norms, resulting in crime, corruption and violence. The leadership and the elites in the country play an important role in influencing whether the masses believe that something can be done to change the nation for the better.
The physical constants as biosignature: an anthropic retrodiction of the Selfish Biocosm Hypothesis
Authors: Gardner James N.
Published: February 2005

Goal 7 of the NASA Astrobiology Roadmap states: ‘Determine how to recognize signatures of life on other worlds and on early Earth. Identify biosignatures that can reveal and characterize past or present life in ancient samples from Earth, extraterrestrial samples measured in situ, samples returned to Earth, remotely measured planetary atmospheres and surfaces, and other cosmic phenomena.’ The cryptic reference to ‘other cosmic phenomena’ would appear to be broad enough to include the possible identification of biosignatures embedded in the dimensionless constants of physics. The existence of such a set of biosignatures – a life-friendly suite of physical constants – is a retrodiction of the Selfish Biocosm (SB) hypothesis. This hypothesis offers an alternative to the weak anthropic explanation of our indisputably life-friendly cosmos favoured by (1) an emerging alliance of M-theory-inspired cosmologists and advocates of eternal inflation like Linde and Weinberg, and (2) supporters of the quantum theory-inspired sum-over-histories cosmological model offered by Hartle and Hawking. According to the SB hypothesis, the laws and constants of physics function as the cosmic equivalent of DNA, guiding a cosmologically extended evolutionary process and providing a blueprint for the replication of new life-friendly progeny universes.
Structural rearrangements in tubulin following microtubule formation
Authors: Krebs Angelika , Goldie Kenneth N , Hoenger Andreas
Published: February 2005

Microtubules are essential cytoskeletal structures that mediate several dynamic processes in a cell. To shed light on the structural processes relating to microtubule formation and dynamic instability, we investigated microtubules composed of 15 protofilaments using cryo‐electron microscopy, helical image reconstruction and computational modelling. Analysis of the configuration of the αβ‐tubulin heterodimer shows distinct structural differences in both subunits, and illustrates that the tubulin subunits have different roles in the microtubule lattice. Our modelling data suggest that after GTP hydrolysis microtubules, adopt a conformational state somewhere between a straight protofilament conformation—as found in zinc‐induced tubulin sheets—and an outward curved conformation—as found in tubulin–stathmin complexes. The tendency towards a curved conformation seems to be mediated mostly by β‐tubulin, whereas α‐tubulin resembles a state more related to the straight structure. Our data suggest a possible explanation of dynamic instability of microtubules, and for nucleotide‐sensitive microtubule‐binding properties of microtubule‐associated proteins and molecular motors.
High levels of variability in immune response using antigens from two reproductive proteins in brushtail possums
Authors: Deakin Janine E. , Belov Katherine , Curach Natalie C. , Green Peter , Cooper Desmond W.
Published: February 2005

Immune-based fertility control is being considered as an effective long-term approach for controlling the pest brushtail possum (Trichosurus vulpecula) population in New Zealand. This relies heavily on the immune response of each immunised possum. A strong and lasting immune response in the majority of individuals in a population is essential. In this study, possums and the model macropod species, the tammar wallaby (Macropus eugenii) were immunised with either a luteinising hormone or androgen receptor synthetic peptide coupled to the carrier molecule KLH (keyhole limpet haemocyanin). The antibody response of wallabies to the antigens was relatively uniform. In contrast, the possum immunoglobulin response to both synthetic peptides and KLH was variable. The apparent high level of variation in the immune response of possums raises questions about the feasibility of using these two antigens to control possum numbers in New Zealand.
Numerical model of self-propulsion in a fluid
Authors: Farnell D.J.J , David T , Barton D.C
Published: February 2005

We provide initial evidence that a structure formed from an articulated series of linked elements, where each element has a given stiffness, damping and driving term with respect to its neighbours, may ‘swim’ through a fluid under certain conditions. We derive a Lagrangian for this system and, in particular, we note that we allow the leading edge to move along thex-axis. We assume that no lateral displacement of the leading edge of the structure is possible, although head ‘yaw’ is allowed. The fluid is simulated using a computational fluid dynamics technique, and we are able to determine and solve Euler–Lagrange equations for the structure. These two calculations are solved simultaneously by using a weakly coupled solver. We illustrate our method by showing that we are able to induce both forward and backward swimming. A discussion of the relevance of these simulations to a slowly swimming body, such as a mechanical device or a fish, is given.
Context‐dependency of cue‐elicited urge to smoke
Authors: Thewissen Roy , Van Den Hout Marcel , Havermans Remco C. , Jansen Anita
Published: February 2005

Aims  Earlier studies have suggested that the cue‐induced urge to smoke depends on the expectation of the availability of smoking. The present study investigated whether a ‘room context’ change could undo the learned discrimination between two stimuli, respectively, predicting smoking availability or smoking unavailability.

Design  A 2 (smoking cue) × 2 (availability context cue) × 6 (trial) × 2 (room context change) within‐subjects design was used. Participants were repeatedly presented with a context cue predicting smoking availability (blue serving tray) and a context cue predicting unavailability (yellow serving tray) in one room and tested for an effect of context change in a different room.

Setting  Two distinct rooms located in different department buildings of Maastricht University.

Participants  Seventeen daily smokers who had smoked at least five cigarettes a day for at least 2 years.

Measurements  Self‐reported urge to smoke using a visual analogue scale (VAS).

Findings and conclusions  Results replicated the finding that a context cue that predicted smoking elicited greater urges to smoke than a context cue that predicted no smoking, irrespective of the presence of smoking cues. In addition, this study showed that this differential effect on the urge to smoke was generalized to a context other than the context in which learning took place. These findings are discussed in relation to the significance of a context change regarding the predictive value of smoking availability.
Does parental smoking cessation encourage their young adult children to quit smoking? A prospective study
Authors: Bricker Jonathan B. , Rajan K. Bharat , Andersen M. Robyn , Peterson Arthur V.
Published: February 2005

Aims  To investigate the extent to which parental early and late smoking cessation predicts their young adult children's smoking cessation.

Design  Parental early smoking cessation status was assessed when children were in 3rd grade, parental late smoking cessation was assessed when children were in 11th grade, and young adult children's smoking cessation was assessed 2 years after high school.

Setting  Forty Washington State school districts participated in the Hutchinson Smoking Prevention Project.

Participants and measurements  Participants were the 1553 families in which parents were ever regular smokers who had a young adult child smoking at least weekly at 12th grade who also reported their smoking status 2 years later. Questionnaire data were gathered on parents and their young adult children (49% female and 91% Caucasian) in a cohort with a 94% retention rate.

Findings  Parents who quit early had children with 1.8 (OR = 1.80; 95% CI = 1.22, 2.64) times higher odds of quitting smoking for at least 1 month in young adulthood compared to those whose parents did not quit early. In contrast, there was no association (OR = 0.84; 95% CI = 0.47, 1.51) between parents quitting late and their young adult children's smoking cessation.

Conclusions  Parental early smoking cessation is associated with increased odds of their young adult children's smoking cessation. Parents who smoke should be encouraged to quit when their children are young.
Associations between tobacco and cannabis use in remote indigenous populations in Northern Australia
Authors: Clough Alan R.
Published: February 2005

Aims  To assess whether cannabis use, recently taken up by many indigenous Australians in remote communities, has reinforced tobacco use.

Design  Cross‐sectional study.

Setting  Three eastern Arnhem Land communities (Northern Territory, NT); total population = 3384, in 2001.

Participants  From 1247 people aged 17–36 years, 190 (120 males, 70 females) were opportunistically recruited.

Measurements  Self‐reported life‐time and current tobacco, cannabis and other substance use were confirmed by local health workers and using clinic records. Participants reported level of substance use, frequency and duration (years used). Associations with tobacco use were calculated (odds ratios: OR) using logistic regression with age, sex, alcohol use and a history of petrol sniffing as confounders.

Findings  In univariate analyses current tobacco users were more likely than non‐users to be using cannabis (OR = 3.1, 1.5–6.2, P = 0.002) and this association remained in multivariate analyses (OR = 3.0, 1.4–6.8, P = 0.006). Tobacco use was associated with the number of years of cannabis use (P = 0.035). The likelihood that tobacco users were also cannabis users increased as quantity of cannabis used increased (P = 0.008). Current tobacco use was no more likely in those who initiated cannabis from 1998 onwards than in those who initiated cannabis before 1998 (OR = 1.1, 0.4–3.2, P = 0.881). One‐third of life‐time users of both tobacco and cannabis initiated their use at or near the same time, and very few of these (12%) had discontinued either cannabis or tobacco.

Conclusions  Cannabis appears to have influenced the continued use of tobacco in these populations with possible additional burdens for cardiovascular and respiratory diseases and challenges for interventions.
Retinoic acid increases tissue and plasma contents of nerve growth factor and prevents neuropathy in diabetic mice
Authors: Arrieta O. , García‐Navarrete R. , Zúñiga S. , Ordóñez G. , Ortiz A. , Palencia G. , Morales‐Espinosa D. , Hernández‐Pedro N. , Sotelo J.
Published: February 2005

Background  Decreased production of nerve growth factor (NGF) may contribute to diabetic neuropathy; however, exogenous administration of NGF induces only a modest benefit. Retinoic acid (RA) promotes the endogenous expression of nerve growth factor and its receptor. We studied the effects of RA on diabetic neuropathy in mice with streptozotocin‐induced diabetes.

Material and methods  One hundred and twenty National Institutes of Health (NIH) albino mice randomly separated into three groups (A, n = 30; B, n = 30; C, n = 60). Diabetes mellitus was induced with streptozotocin in groups A and B. Animals from group A received a subcutaneous injection of 25 µl of mineral oil daily for 90 days, while those from group B received a subcutaneous injection of 20 mg kg−1 of all trans RA. Animals from group C were taken as controls. At the end of the experiment, blood glucose and NGF levels (both in serum and sciatic nerve) were measured. Two behavioural tests were conducted in a blind fashion to detect abnormalities of thermal and nociceptive thresholds.

Results  Contents of NGF in healthy untreated mice were 1490 ± 190 pg mg−1 in nerve and 113 ± 67 pg mg−1 in serum; in diabetic untreated mice the values were 697 ± 219 pg mL−1 in nerve and 55 ± 41 pg mL−1 in serum; and in diabetic mice treated with RA the values were 2432 ± 80 pg mL−1 in nerve and 235 ± 133 pg mg−1 in serum (P < 0·002). Ultrastructural evidence of nerve regeneration and sensitivity tests improved in diabetic mice treated with RA as compared with nontreated diabetic mice.

Conclusion  Our findings indicate that administration of RA increases serum and nerve contents of NGF in diabetic mice and suggest a potential therapeutic role for retinoic acid in diabetic patients.
Circulating ADMA concentrations are elevated in hypopituitary adults with and without growth hormone deficiency
Authors: Krzyzanowska K. , Mittermayer F. , Schnack C. , Hofer M. , Wolzt M. , Schernthaner G.
Published: February 2005

Background  Cardiovascular mortality is increased in patients with hypopituitarism. Elevated concentrations of the endogenous NO synthase antagonist asymmetrical dimethylarginine (ADMA) may be related to the development of atherosclerosis and are associated with cardiovascular risk. We studied the concentrations of ADMA in hypopituitary patients with and without growth hormone deficiency (GHD) and in healthy subjects.

Materials and methods  Plasma from 44 patients with hypopituitarism with (n = 30) and without GHD (n = 14) and from 25 age‐ and sex‐matched healthy controls was taken for analysis of l‐arginine, ADMA, symmetrical dimethylarginine (SDMA) and clinical parameters. Further plasma from 10 hypopituitary patients was examined before and after treatment with 9 g of oral l‐arginine for 14 days.

Results  Asymmetrical dimethylarginine was significantly higher in the hypopituitary patients than in the controls (0·63 ± 0·12 vs. 0·51 ± 0·15 µmol L−1; P < 0·005). l‐arginine and the l‐arginine/ADMA ratios were lower in the subjects with hypopituitarism (53 ± 18 vs. 90 ± 29 µmol L−1 and 87 ± 31 vs. 185 ± 59; both P < 0·0001). Symmetrical dimethylarginine was comparable between the patients and the controls. l‐arginine and dimethylarginines were associated with 2‐h stimulated glucose levels in a glucose tolerance test (r = 0·33; P < 0·05), but not other cardiovascular risk factors. Oral l‐arginine supplementation normalized the reduced l‐arginine/ADMA ratio in the hypopituitary patients.

Conclusion  Asymmetrical dimethylarginine is elevated in patients with hypopituitarism independent of GHD and traditional risk factors. This might contribute to the increased cardiovascular morbidity in hypopituitary patients.
Glyc‐O‐genetics of Walker–Warburg syndrome
Authors: Van Reeuwijk J , Brunner HG , Van Bokhoven H
Published: February 2005

Walker–Warburg syndrome (WWS) is the most severe of a group of multiple congenital anomaly disorders known as the cobblestone lissencephalies. These are characterized by congenital muscular dystrophy in conjunction with severe brain malformation and ocular abnormalities. In the last 3 years, important progress has been made towards the elucidation of the genetic causes of these disorders. Mutations in three genes, POMT1, fukutin and FKRP, have been described for WWS, which together account for approximately 20% of patients with Walker–Warburg. It has become evident that some of the underlying genes may cause a broad spectrum of phenotypes, ranging from limb girdle muscular dystrophy type 2I to WWS. In some cases, a genotype–phenotype correlation can be recognized. In line with the known or proposed functions of the resolved genes, all patients with cobblestone lissencephaly show defects in the O‐linked glycosylation of the glycoprotein α‐dystroglycan. Perhaps, the missing genes underlying the remainder of the unexplained WWS patients have also to be sought in the pathways involved in O‐linked protein glycosylation.
Implementing evidence‐based guidelines: inpatient management of chronic obstructive pulmonary disease
Authors: Harvey P. A. , Murphy M. C. , Dornom E. , Berlowitz D. J. , Lim W. K. , Jackson B.
Published: February 2005

Background:  Evidence‐based guidelines exist to guide inpatient management of chronic obstructive pulmonary disease (COPD) exacerbations, but we do not know how well these recommendations are adhered to.

Aims:  The aims of this study were: (i) to examine concordance with evidence based guidelines for inpatient management of COPD and (ii) to address deficiencies in compliance with guidelines by feedback of audit results and distribution of an education package.

Methods:  Retrospective chart reviews were performed using a data collection tool based on current guidelines. Forty‐nine consecutive COPD admissions were audited, and results presented to medical staff. An education package was distributed directly after the presentation. One month later, 35 consecutive separations were reviewed. Concordance with recommendations supported by the highest level of evidence was calculated.

Results:  Data were complete for 84 cases. Concordance rates ranged from 0 to 100%. Apart from initiation of systemic steroids (80–83%) and avoidance of intravenous aminophylline (100%), concordance rates were less than 60%. The only significant improvement post‐intervention was for steroid duration (10 vs 29%, 95% confidence interval for difference (–36.2, –1.8)).

Conclusion:  Recommendations for steroid initiation and avoidance of aminophylline are well adhered to. Concordance rates for other recommendations were generally less than 60%. Concordance with recommendations for steroid duration was significantly improved by our intervention. The findings suggest that to facilitate evidence‐based practice, alternative interventions should be evaluated. (Intern Med J 2005; 35: 151–155)
Percutaneous carotid artery stenting: a strategy in evolution
Authors: Kovacic J. C. , Roy P. R. , Baron D. W. , Gunalingam B. , Muller D. W. M.
Published: February 2005

Background:  Carotid stenting was initially proposed as an alternative to surgical endarterectomy for selected high‐risk patients. More recently, patients of standard surgical risk are being considered for percutaneous treatment of their carotid disease.

Aims:  To describe the clinical outcomes of an initial consecutive cohort of patients treated by carotid stenting at one institution.

Methods:  Between December 1997 and July 2003, 111 patients underwent stenting of 118 carotid arteries. Peri‐procedural and long‐term outcome data were collected.

Results:  Most patients (>70%) were high‐risk candidates for endarterectomy. Stents were successfully placed in 117/118 carotid arteries (99.2%). Distal protection devices were used in 43/118 (36.4%). The peri‐procedural rate of death or disabling stroke was 3/118 (2.5%). Death or any stroke occurred in 11/118 (9.3%). However, only 7/118 (5.9%) procedures resulted in death or any persistent stroke (neurological deficit >1 week post‐procedure). No myocardial infarction occurred. Median length of post‐procedure hospitalization was 1 day. Long‐term follow up was possible for 101 patients (91.0%) over a mean period of 27.1 months. The Kaplan–Meier estimate of survival free of ipsilateral stroke 36 and 66 months after carotid stenting was 77.0 ± 9.5% and 68.2 ± 15.1%, respectively. The estimated survival free of any stroke or stent failure was 70.9 ± 10.7% and 60.7 ± 17.4%, respectively. The majority of late deaths (7/11) were due to cardiac disease.

Conclusion:  We conclude that stenting of carotid stenoses is feasible, with a high procedural success rate and low complication rate. Carotid stenting should be considered the procedure of choice for high‐risk patients. (Intern Med J 2005; 35: 143–150)
Enzyme replacement therapy for Gaucher disease in Australia
Authors: Goldblatt J. , Szer J. , Fletcher J. M. , McGill J. , Rowell J. A. , Wilson M.
Published: February 2005

Aim:  To study the effectiveness of a specific national programme of enzyme replacement therapy (ERT) for patients with severe forms of Gaucher disease, a disorder of sphingolipid metabolism resulting from an inherited deficiency of the lysosomal enzyme β‐Glucocerebrosidase.

Methods:  Prospective analysis of data submitted at entry and every 6 months on therapy. The responses of haemoglobin (Hb) and platelet (plt) concentrations, liver and spleen volumes were assessed.

Patients:  Forty‐eight patients were treated with ERT for a minimum of 6 months. Forty patients had Type 1 disease and eight had Type 3B. The age range was 1–70 years (median 24 years). Duration of therapy at the time of analysis was 6–114 months.

Results:  Thirty‐six per cent of patients started with a normal Hb increasing to 76% after 6 months. The mean improvement in Hb from baseline to the end of study period was 20 g/L, when the Hb was normal in 85% (41 patients). Thirty per cent of patients had a normal plt count at the start of therapy, with a more gradual increase in the count at 6 monthly intervals of 50, 91, 108 and 142% of starting value. Seventy‐five per cent of patients had a normal plt count at the end of study. Spleen volumes reduced by a mean of 56% in 33 evaluable patients, and the liver by 27% in 30 of 38 evaluable patients. Eight patients had an increase in liver volume of 28%.

Conclusion:  Enzyme replacement therapy produced a spectrum of beneficial responses in patients with Gaucher disease, but all had some evidence of reversal of haematological complications and/or reduction in visceromegaly. Future analyses will examine the effect of therapy on bone disease, prepubertal growth and quality of life. (Intern Med J 2005; 35: 156–161)
On not becoming a writer ...
Authors: Macdonald Graham
Published: February 2005

The two short articles on this page and the next arise from an acquaintance between two people interested in writing that began in first‐year medicine. Andrew Riemer went on to succeed as a writer. Graham Macdonald completed Medicine and became an academic nephrologist. These reflections on what they didn’t become contrast with accounts of careers and success we’re more used to in what's been called ‘success literature’. There may be a richer vein to be mined in the ‘changed my mind’ literature, given the diversity of stories behind these decisions.

Editor's Note
A novel thiol antioxidant that crosses the blood brain barrier protects dopaminergic neurons in experimental models of Parkinson's disease
Authors: Bahat‐Stroomza Merav , Gilgun‐Sherki Yossi , Offen Daniel , Panet Hana , Saada Ann , Krool‐Galron Nili , Barzilai Aari , Atlas Daphne , Melamed Eldad
Published: February 2005

It is believed that oxidative stress (OS) plays an important role in the loss of dopaminergic nigrostriatal neurons in Parkinson's disease (PD) and that treatment with antioxidants might be neuroprotective. However, most currently available antioxidants cannot readily penetrate the blood brain barrier after systemic administration. We now report that AD4, the novel low molecular weight thiol antioxidant and theN‐acytel cysteine (NAC) related compound, is capable of penetrating the brain and protects neurons in general and especially dopaminergic cells against various OS‐generating neurotoxins in tissue cultures. Moreover, we found that treatment with AD4 markedly decreased the damage of dopaminergic neurons in three experimental models of PD. AD4 suppressed amphetamine‐induced rotational behaviour in rats with unilateral 6‐OHDA‐induced nigral lesion. It attenuated the reduction in striatal dopamine levels in mice treated with 1‐methyl‐4‐phenyl‐1,2,3,6,‐tetrahydropyridine (MPTP). It also reduced the dopaminergic neuronal loss following chronic intrajugular administration of rotenone in rats. Our findings suggest that AD4 is a novel potential new neuroprotective drug that might be effective at slowing down nigral neuronal degeneration and illness progression in patients with PD.
Transient spatial deficit associated with bilateral lesions of the lateral mammillary nuclei
Authors: Vann Seralynne D.
Published: February 2005

The mammillary bodies have long been implicated in spatial memory, and lesions of this structure in rats can impair some spatial memory tasks. The mammillary bodies, however, comprise two main nuclei that have different electrophysiological and anatomical properties. It is therefore possible that they have different functions. The present study determined whether selective lesions of one of these components, the lateral mammillary nucleus, are sufficient to induce spatial memory deficits. While selective lateral mammillary nuclei lesions induced deficits on a working memory task in the water maze, this impairment was milder and not as persistent as that seen with complete mammillary body lesions. Furthermore, lateral mammillary nuclei lesions did not impair T‐maze alternation, which is sensitive to complete mammillary body lesions. From these results it appears that lesions confined to the lateral mammillary nuclei are sufficient to produce mild impairments when rapid, new spatial learning is at a premium. At the same time, the remaining mammillary nuclei also contribute to spatial learning, though this may be in a qualitatively different manner.
Vitamin A is a necessary factor for sympathetic‐ independent rhythmic activation of mitogen‐activated protein kinase in the rat pineal gland
Authors: Guillaumond F. , Giraudet F. , Becquet D. , Sage D. , Laforge‐Anglade G. , Bosler O. , François‐Bellan A. M.
Published: February 2005

The circadian clock in the suprachiasmatic nucleus (SCN) controls day‐to‐day physiology and behavior by sending timing messages to multiple peripheral oscillators. In the pineal gland, a major SCN target, circadian events are believed to be driven exclusively by the rhythmic release of norepinephrine from superior cervical ganglia (SCG) neurons relaying clock messages through a polysynaptic pathway. Here we show in rat an SCN‐driven daily rhythm of pineal MAPK activation that is not dependent on the SCG and whose maintenance requires vitamin A as a blood‐borne factor. This finding challenges the dogma that SCG‐released norepinephrine is an exclusive mediator of SCN–pineal communication and allows the assumption that humoral mechanisms are involved in pineal integration of temporal messages.
The N‐terminal active centre of human angiotensin‐converting enzyme degrades Alzheimer amyloid β‐peptide
Authors: Oba Ryutaro , Igarashi Akira , Kamata Makiko , Nagata Kinya , Takano Syoichi , Nakagawa Hachiro
Published: February 2005

We reported recently that angiotensin‐converting enzyme (ACE) significantly degraded amyloid β‐peptide (Aβ) to inhibit aggregation and cytotoxicity of Aβ in PC12h cells in vitro. On the other hand, others reported that ACE had two domains with highly homologous active centres, the N‐domain and C‐domain, but that they differed in their characteristics such as optimum chloride ion concentration, inhibition kinetics for various ACE inhibitors and rate of hydrolysis for many substrates. The aim of this study was to determine the specific ACE domain primarily responsible for degradation of Aβ. For this purpose, a series of ACE recombinant proteins, each containing only one intact domain, was constructed and expressed in COS7. Our results showed that all ACE recombinant proteins obtained were enzymatically active in terms of angiotensin I cleavage. However, inhibition of Aβ aggregation and cytotoxicity of the N‐domain were higher than those of the C‐domain. Reverse‐phase high‐performance liquid chromatography analyses confirmed that the N domain degraded Aβ. Our results indicate that the N domain of ACE is primarily responsible for the degradation of Aβ.
A new sampling formula for neutral biodiversity
Authors: Etienne Rampal S.
Published: February 2005

The neutral model of biodiversity, proposed by Hubbell (The Unified Neutral Theory of Biodiversity and Biogeography, Princeton University Press, Princeton, NJ, 2001) to explain the diversity of functionally equivalent species, has been subject of hot debate in community ecology. Whereas Hubbell studied the model mostly by simulations, recently analytical treatments have yielded expressions of the expected number of species of a particular abundance in a local community with dispersal limitation. Moreover, a formula has been offered for the joint likelihood of observing a given species‐abundance dataset in a local community with dispersal limitation, but this formula is too complicated to allow practical applications. Here, I present a much simplified expression that can be regarded as an enhanced version of the famous Ewens sampling formula. It can be used in maximum likelihood methods for quick estimation of the model parameters, using all information in the data, and for model comparison. I also show how to rapidly generate examples of species‐abundance distributions for a given set of model parameters and how to calculate Simpson's diversity index.