bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of prostate weight on the outcomes of laparoscopic radical prostatectomy
Authors: Frota Rodrigo , Turna Burak , Santos Bruno Mello R. , Lin Yi‐Chia , Gill Inderbir S. , Aron Monish
Published: October 2007

Associate Editor

Ash Tewari

Editorial Board

Ralph Clayman, USA

Inderbir Gill, USA

Roger Kirby, UK

Mani Menon, USA

OBJECTIVE

To evaluate the effect of prostate weight on perioperative, functional and oncological outcomes after laparoscopic radical prostatectomy (LRP).

PATIENTS AND METHODS

Between January 2003 and January 2006, 327 patients had LRP by one surgeon, 193 of whom were available for analysis. Patients were stratified into three groups on the basis of pathological prostate weight, i.e. ≤30, 30–75 and ≥75 g. Perioperative, oncological and functional (continence and potency at 1 year) outcomes were compared among the three groups.

RESULTS

Of the 193 patients the prostate was ≤30 g in 18 (9%), 30–75 g in 131 (68%) and ≥75 g in 44 (23%); the mean prostate weight was 27, 49 and 98 g in the three subgroups, respectively. At presentation, 144 patients (75%) had T1c disease, 159 (82%) were potent and 187 (97%) were continent. Unilateral nerve‐sparing was done in 37 (19%) and bilateral in 114 (59%) patients. The three subgroups were comparable in age, body mass index, preoperative prostate‐specific antigen level, preoperative Gleason score, clinical stage, operative duration, length of hospital stay, duration of catheterization, biochemical recurrence and continence after LRP. In the patients with a prostate of ≤30 g there was a higher incidence of positive margins (39% vs 16% vs 27%; P = 0.03) and inferior 1‐year potency (47% vs 75% vs 79%; P =0.04), respectively. Estimated blood loss increased with increasing prostate size (204 vs 256 vs 340 mL; P = 0.01).

CONCLUSIONS

Prostate size has no effect on continence or biochemical recurrence at 1 year after LRP, but affects intraoperative blood loss, potency and surgical margins. More patients with a longer follow‐up are needed to confirm these findings.
Evaluation of costs and morbidity associated with laparoscopic radiofrequency ablation and laparoscopic partial nephrectomy for treating small renal tumours
Authors: Bensalah Karim , Zeltser Ilia , Tuncel Altug , Cadeddu Jeffrey , Lotan Yair
Published: October 2007

OBJECTIVE

To compare the costs and morbidity of laparoscopic radiofrequency ablation (LRFA) and laparoscopic partial nephrectomy (LPN) for treating small localized renal tumours.

PATIENTS AND METHODS

We retrospectively analysed the outcomes of 88 patients treated at our institution for a renal tumour either by LPN (50) or LRFA (38) between March 2000 and May 2006. Patients with multiple tumours, combined LRFA and LPN, and those who had other simultaneous surgical procedures were excluded. Clinical variables and outcomes were analysed for each patient. Direct cost data were available for 40 patients treated with LPN and 14 with LRFA. Continuous and categorical variables were compared using an independent t‐test and chi‐square test, respectively.

RESULTS

The tumour size was comparable in each group; patients in the LRFA group had more comorbidities (P = 0.01) and a higher overall mortality rate (P = 0.01) but no patient died from cancer. Operative duration, estimated blood loss and length of stay were significantly shorter in the LRFA group but there was no difference in complication rate. LRFA was less costly than LPN ($6103 vs $6808, P = 0.3) but not statistically significantly. The cost savings from the shorter operative duration and length of stay were reduced by the cost of probe. With a median follow‐up of 20 months there was no difference in oncological outcome.

CONCLUSION

Patients undergoing LRFA tend to be older and have more comorbidities than those treated with LPN. The cost is minimally lower for LRFA, secondary to the added cost of the probe. LRFA might be a good alternative treatment in patients at higher risk of surgical complications, but LPN provides good results when done by an experienced surgeon.
THE THIRD NOEL BUTLIN LECTURE: AUSTRALIAN EXCEPTIONALISM REVISITED
Authors: Irwin Douglas A.
Published: October 2007

In the late‐nineteenth century, Australia had one of the highest levels of income per capita in the world. Over the twentieth century, Australia's exceptional position declined as its high labour force participation rate and male‐skewed gender ratio gradually aligned with other countries. A similar reversion occurred in the other important components underlying Australia's high productivity, such as work hours. As the structure of the economy shifted away from a reliance on agricultural and towards manufacturing, Australia's protective attitude and restrictive business practices may have exacerbated its loss in productivity. Considerable research remains to be carried out to confirm these views.
COMMENTS ON FACTOR PRICES AND INCOME DISTRIBUTION IN LESS INDUSTRIALISED ECONOMIES, 1870–1939: REFOCUSING ON THE FRONTIER
Authors: Harley Knick
Published: October 2007

A great deal of the current research into nineteenth‐ and twentieth‐century globalisation has been focused through a neoclassical trade theory lens. Applying the Stopler‐Samuelson paradigm from Heckscher‐Ohlin trade theory, the result is an approach that sees price convergence as pivotal in defining, identifying, and measuring globalisation. This focus, however, obscures the implications of frontier incorporation and other insights achieved by viewing nineteenth‐century globalisation as a mechanism whereby peripheral economies were incorporated into the core of organised economic activity. A frontier‐centred perspective also reintroduces the role of economic institutions as a crucial element of economic growth and development.
THE NATURE AND DEVELOPMENT OF THE GENERAL INSURANCE INDUSTRY IN AUSTRALIA TO 1973
Authors: Keneley Monica , McDonald Tom
Published: October 2007

The development of the insurance industry in Australia in the twentieth century was fundamentally shaped by a collusive code of conduct called the tariff. This arrangement, established to overcome problems of uncertainty, initially benefited both tariff and non‐tariff firms by enhancing market stability. It also reduced competition. The collusive agreements gradually broke down, however, as new entrants and products entered the market in the 1950s. Self‐regulation gradually gave way as the ‘rules of the game’ changed. The result was a period of instability before new competitive practices, and more direct and specific regulatory requirements emerged in the 1970s.
AUSTRALASIAN ECONOMIC HISTORY: RESEARCH CHALLENGES AND BIG QUESTIONS
Authors: McLean Ian W. , Shanahan Martin P.
Published: October 2007

This paper reports a debate on the ‘big questions’ and ‘research challenges’ facing economic history in Australia and New Zealand. Noting the changes in research direction that occurred in the discipline over the past 50 years, and the resource challenges it currently faces, it identifies many areas of potentially fruitful research. These include the environment, market regulation and industry development, the interaction of peoples and culture, and the examination of units other than the national economy. While there is potential for exciting and diverse research, an immediate challenge is the training of the next generation of economic historians.
Worker Absenteeism in Search Equilibrium*
Authors: Engström Per , Holmlund Bertil
Published: October 2007

In this paper we introduce a general equilibrium model of search unemployment that incorporates absence from work as a distinct labor force state. Absenteeism is driven by random shocks to the value of leisure that are private information to the workers. Firms maximize profits while recognizing that the compensation package may affect the queue of job applicants and the absence rate. The analysis provides results concerning the effects of social insurance benefits and other determinants of workers' and firms' behavior. The normative analysis identifies externalities associated with firm‐provided sick pay and examines the welfare implications of alternative policies.
Inflation Adjustment and Labour Market Structures: Evidence from a Multi‐country Study*
Authors: Bowdler Christopher , Nunziata Luca
Published: October 2007

The impact of labour market structures on the response of inflation to macroeconomic shocks is analysed empirically. Results based on a 20‐country panel show that if labour market coordination is high, the effect on inflation of movements in unemployment, import prices, tax rates and productivity is dampened, both on impact and dynamically. In contrast, monopoly power in labour supply, measured by the percentage unionisation of the workforce, appears to amplify the response of inflation to its reduced‐form determinants. These findings are attributed to the behaviour of wages following movements in demand‐ and supply‐side conditions.
Taste response and poliomyelitis
Authors: BRAND N.
Published: October 2007

Taste threshold for phenylthiourea was measured in 115 paralytic poliomyelitis subjects and 120 healthy people of both sexes from 6 to 40 years of age originating from various countries (Israel, Europe, Asia and North Africa Jews).

A significant difference of non‐tasters frequency was found between paralytic poliomyelitis and healthy subjects, i.e. 31.3 and 16.7%, respectively.

It may be suggested that the non‐tasters of paralytic poliomyelitis patients are more susceptible to polio virus.

I wish to thank Prof. M. Makin, Director of the orthopedic hospital ‘Alyn’for crippled children in Jerusalem, Drs Mandel, Head of the Pediatric Department of the Government Hospital Sarafand, Goldman, Head of the Orthopedic Department of the Government Hospital Poriah for allowing me full access to their patients, and Dr A. Salamonovitsh, Head of the Health Centre Kiryath Shmonah for permission to examine school children.
An investigation into the fertility rates of mentally ill patients
Authors: MACSORLEY KATE
Published: October 2007

An investigation into celibacy and reproduction rates of 187 male and 203 female mentally ill patients has been described. Comparisons were made between patients and their sibs. Two control populations were used

1. Figures taken from the Registrar General's Reports.

2. An independent population drawn from the medical and surgical wards of Paddington General Hospital.

The mean ages of onset were calculated. The marital states and reproduction rates of all patients and controls were considered. It was found that the celibacy rate of patients was more than 50 % above that in the general population and almost as much above that of the independent control population, at least for the schizophrenic diseases. It was found that a fairly large group of patients (forty‐eight males and twenty females) designated as ‘Atypical’resembled the schizophrenic groups very closely in mean age of onset and low marriage and reproductive rates.

The number of children per marriage of patients was a good deal below, and the percentage of childless marriages a good deal above, that of the control population.

There was evidence of assortative mating.

I am grateful to the Medical Research Council for their financial support. I also wish to express my thanks to the Medical Superintendents of Horton, Paddington and St Bernard's Hospitals who permitted me to interview their patients. My special thanks are due to Drs B. A. J. C. Gregory, H. R. Rollin, L. W. Russell and P. J. F. Walsh who generously gave their time and opinions.
Distances which involve satellited chromosomes in metaphase preparations
Authors: MERRINGTON MAXINE , PENROSE L. S.
Published: October 2007

Investigations of distance measurements between centromeres of human chromosomes in metaphase photographs show that there is a general tendency for homologous pairs to lie closer to one another than would be expected on the hypothesis of random arrangement. In the present analysis no significant divergence from random arrangement of their distances was found for the specific pairs nos. 1, 2 and 3. However, there is strong evidence that the groups of large and small acrocentrics tend to lie closer to one another than would be expected on the random hypothesis. The distances between no. 1 and nos. 21 or 22 chromosomes were not found to be significantly less than expected.

The writers wish to thank Mr N. P. Bishun, Dr Joy D. A. Delhanty, Dr J. R. Ellis and Miss Ruth Marshall for supplying photographs of cells and Miss Patricia Jackson and Miss Katharine Solomon for assistance in measurement and standardization calculations.
Birth weight and some other factors in relation to infant survival. A study on an Indian sample
Authors: JAYANT K.
Published: October 2007

Effect of parity, maternal age, birth weight and sex of the child on infant survival have been studied in 3822 eases belonging to the upper socio‐economic group and the relationship of birth weight to survival in 2279 cases of a lower socio‐economic group have also been studied. It has been suggested that for the upper socio‐economic group a child with a birth weight of less than 5| lb., if it is a male, and 5 J lb., if it is a female, may be considered as premature whereas for the lower socio‐economic group the corresponding birth weight is 4J lb. for both males and females. In the latter group, the critical weight of 4½ lb. would have to be revised, if perinatal mortality rate improves.

I am indebted to the management of the Chamanlal Mehta Hospital for women for allowing me to collect the data from their hospital. I am grateful to Prof. M. C. Chakrabarti, University Department of Statistics for giving me all the facilities for the statistical analysis. I would like to record my gratitude to Miss Mary N. Karn, Galton Laboratory, London and to Dr A. M. Kshirsagar, University of Bombay for taking interest in this paper.

Grateful acknowledgement is due to Dr T. H. Rindani, the Dean, T.N. Medical College for permission to make use of outside resources for collection and analysis of the data and to Dr V. N. Panse, Professor, Department of Preventive and Social Medicine for his encouragement and advice.
Finger‐print patterns in mongolism
Authors: HOLT SARAH B.
Published: October 2007

The frequencies of arches, ulnar and radial loops and whorls on the fingers of 310 mongolian imbeciles and 1000 controls are given. In both sexes the mongols show a reduction in the frequencies of whorls, arches and radial loops, with a corresponding increase in the frequency of ulnar loops. In contrast with the controls, all the major pattern types occur with similar frequencies in both sexes.

Individuals with arches on all ten fingers are nearly seven times as common in mongols as in the control population.
Promyelocytic leukemia‐nuclear body formation is an early event leading to retinoic acid‐induced differentiation of neuroblastoma cells
Authors: Delaune A. , Corbière C. , Benjelloun F. D , Legrand E. , Vannier J. P. , Ripoll C. , Vasse M.
Published: October 2007

Neuroblastoma is one of the most common cancers in children. Neuroblastoma differentiation is linked to the presence of the promyelocytic leukemia (PML) protein. Retinoic acid, a powerful differentiation‐inducer in vitro, is a potent agent for the treatment of neuroblastoma. Using two different human neuroblastoma cell lines, SH‐SY5Y and LA‐N‐5, we show here that PML protein leads to the formation of nuclear bodies (PML‐NB) after only 1 h of retinoic acid treatment and that this formation is mediated by the extracellular signal‐regulated kinase (ERK) pathway. Inhibition of protein kinase C also leads to formation of PML‐NB via the ERK pathway. Both sumoylation and phosphorylation of PML in an ERK‐dependent pathway are also required for formation of PML‐NB. Finally, we show that PML‐NB formation in neuroblastoma cells is associated with neurite outgrowth. These results support the proposal that the formation of PML‐NB is correlated with the differentiation of neuroblastoma cells.
Gi‐coupled P2Y‐ADP receptor mediates GSK‐3 phosphorylation and β‐catenin nuclear translocation in granule neurons
Authors: Ortega Felipe , Pérez‐Sen Raquel , Miras‐Portugal MªTeresa
Published: October 2007

Glycogen synthase kinase‐3 (GSK‐3) is a multifaceted enzyme involved in development, neurogenesis, and survival at the CNS. We investigated nucleotides signaling to GSK‐3 in cerebellar granule neurons and found that the metabotropic agonist 2‐methyl‐thio‐ADP (2MeSADP) was able to induce GSK‐3 phosphorylation and inhibition of its catalytic activity. 2MeSADP could be acting through several P2Y‐ADP receptors expressed in granule neurons, as RT‐PCR expression was found for P2Y1, P2Y12, and P2Y13receptors, but the pharmacological data fitted well with a Gi‐coupled P2Y13receptor: the effect was sensitive to pertussis toxin, was unaffected by specific antagonists of P2Y1and P2Y12receptors, such as 2′‐deoxy‐N6‐methyl‐adenosine 3′,5′‐diphosphate and 2‐methyl‐thio‐AMP, respectively, and the EC50values for 2MeSADP and ADP were in the same low nanomolar range. 2MeSADP was able to phosphorylate and activate extracellular signal‐regulated kinase (ERK)‐1,2 and Akt proteins, but its effect on GSK‐3 phosphorylation was primarily dependent on the phosphatidyl inositol‐3 kinase (PI3‐K)/Akt pathway, as it was abolished by the PI3‐K inhibitor wortmannin. GSK‐3 inactivation by 2MeSADP in granule neurons resulted in nuclear translocation of its substrate β‐catenin, which functions as a transcriptional regulator, this effect being lost with wortmaninn. The present study first describes the coupling of a Gi‐coupled P2Y13‐like receptor to GSK‐3 and β‐catenin through PI3‐K/Akt signaling.
Arachidonic acid induces both Na+ and Ca2+ entry resulting in apoptosis
Authors: Fang Kwang‐Ming , Chang Wei‐Luen , Wang Su‐Mei , Su Ming‐Jai , Wu Mei‐Lin
Published: October 2007

Marked accumulation of arachidonic acid (AA) and intracellular Ca2+ and Na+ overloads are seen during brain ischemia. In this study, we show that, in neurons, AA induces cytosolic Na+ ([Na+]cyt) and Ca2+ ([Ca2+]cyt) overload via a non‐selective cation conductance (NSCC), resulting in mitochondrial [Na+]m and [Ca2+]m overload. Another two types of free fatty acids, including oleic acid and eicosapentaenoic acid, induced a smaller increase in the [Ca2+]i and [Na+]i. RU360, a selective inhibitor of the mitochondrial Ca2+ uniporter, inhibited the AA‐induced [Ca2+]m and [Na+]m overload, but not the [Ca2+]cyt and [Na+]cyt overload. The [Na+]m overload was also markedly inhibited by either Ca2+‐free medium or CGP3715, a selective inhibitor of the mitochondrial Na+cyt‐Ca2+m exchanger. Moreover, RU360, Ca2+‐free medium, Na+‐free medium, or cyclosporin A (CsA) largely prevented AA‐induced opening of the mitochondrial permeability transition pore, cytochrome c release, and caspase 3‐dependent neuronal apoptosis. Importantly, Na+‐ionophore/Ca2+‐free medium, which induced [Na+]m overload, but not [Ca2+]m overload, also caused cyclosporin A‐sensitive mitochondrial permeability transition pore opening, resulting in caspase 3‐dependent apoptosis, indicating that [Na+]m overload per se induced apoptosis. Our results therefore suggest that AA‐induced [Na+]m overload, acting via activation of the NSCC, is an important upstream signal in the mitochondrial‐mediated apoptotic pathway. The NSCC may therefore act as a potential neuronal death pore which is activated by AA accumulation under pathological conditions.
Physiological changes in GRK2 regulate CCL2‐induced signaling to ERK1/2 and Akt but not to MEK1/2 and calcium
Authors: Kleibeuker Wendy , Jurado‐Pueyo Maria , Murga Cristina , Eijkelkamp Niels , Mayor Jr Federico , Heijnen Cobi J. , Kavelaars Annemieke
Published: October 2007

G protein‐coupled receptor (GPCR) kinase 2 (GRK2) regulates G protein‐coupled receptor signaling via agonist‐induced receptor phosphorylation and desensitization. GRK2 can also modulate cellular activation by interacting with downstream signaling molecules. The intracellular GRK2 level changes during inflammatory conditions. We investigated how IL‐1β‐induced changes in endogenous GRK2 expression influence chemokine receptor signaling in primary astrocytes. Culturing astrocytes with IL‐1β for 24 h induced a 2–3‐fold increase in GRK2 and decreased C–C chemokine ligand 2 (CCL2)‐induced ERK1/2 activation. Conversely, the 45% decrease in GRK2 expression in astrocytes from GRK2+/− animals resulted in a more pronounced CCL2‐induced ERK1/2 phosphorylation. Increased GRK2 inhibited CCL2‐induced Akt phosphorylation at Thr308 and Ser473 as well as pPDK‐1 translocation. In contrast, altered GRK2 levels did not change the CCL2‐induced increase in intracellular calcium or MEK1/2 phosphorylation. These data suggest that altered GRK2 expression modulates chemokine signaling downstream of the receptor. We found that GRK2 kinase activity was not required to decrease chemokine‐induced ERK1/2 phosphorylation, whereas regulation of CCL2‐induced Akt phosphorylation did require an active GRK2 kinase domain. Collectively, these data suggest that changes in endogenous GRK2 expression in primary astrocytes regulate chemokine receptor signaling to ERK1/2 and to PDK‐1‐Akt downstream of receptor coupling via kinase‐dependent and kinase‐independent mechanisms, respectively.
Neural cell adhesion molecule‐180‐mediated homophilic binding induces epidermal growth factor receptor (EGFR) down‐regulation and uncouples the inhibitory function of EGFR in neurite outgrowth
Authors: Povlsen Gro Klitgaard , Berezin Vladimir , Bock Elisabeth
Published: October 2007

The neural cell adhesion molecule (NCAM) plays important roles in neuronal development, regeneration, and synaptic plasticity. NCAM homophilic binding mediates cell adhesion and induces intracellular signals, in which the fibroblast growth factor receptor plays a prominent role. Recent studies on axon guidance in Drosophila suggest that NCAM also regulates the epidermal growth factor receptor (EGFR) (Molecular and Cellular Neuroscience, 28, 2005, 141). A possible interaction between NCAM and EGFR in mammalian cells has not been investigated. The present study demonstrates for the first time a functional interaction between NCAM and EGFR in mammalian cells and investigates the molecular mechanisms underlying this interaction. First, NCAM and EGFR are shown to play opposite roles in neurite outgrowth regulation in cerebellar granular neurons. The data presented indicate that negative regulation of EGFR is one of the mechanisms underlying the neuritogenic effect of NCAM. Second, it is demonstrated that expression of the NCAM‐180 isoform induces EGFR down‐regulation in transfected cells and promotes EGFR down‐regulation induced by EGF stimulation. It is demonstrated that the mechanism underlying this NCAM‐180‐induced EGFR down‐regulation involves increased EGFR ubiquitination and lysosomal EGFR degradation. Furthermore, NCAM‐180‐mediated EGFR down‐regulation requires NCAM homophilic binding and interactions of the cytoplasmic domain of NCAM‐180 with intracellular interaction partners, but does not require NCAM‐mediated fibroblast growth factor receptor activation.
Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low‐density lipoprotein receptor family
Authors: Ambjørn Malene , Asmussen Johanne W. , Lindstam Mats , Gotfryd Kamil , Jacobsen Christian , Kiselyov Vladislav V. , Moestrup Søren K. , Penkowa Milena , Bock Elisabeth , Berezin Vladimir
Published: October 2007

Accumulating evidence suggests that metallothionein (MT)‐I and ‐II promote neuronal survival and regeneration in vivo. The present study investigated the molecular mechanisms underlying the differentiation and survival‐promoting effects of MT and a peptide modeled after MT, EmtinB. Both MT and EmtinB directly stimulated neurite outgrowth and promoted survival in vitro using primary cultures of cerebellar granule neurons. In addition, expression and surface localization of megalin, a known MT receptor, and the related lipoprotein receptor‐related protein‐1 (LRP) are demonstrated in cerebellar granule neurons. By means of surface plasmon resonance MT and EmtinB were found to bind to both megalin and LRP. The bindings were abrogated in the presence of receptor‐associated protein‐1, an antagonist of the low‐density lipoprotein receptor family, which also inhibited MT‐ and EmtinB‐induced neurite outgrowth and survival. MT‐mediated neurite outgrowth was furthermore inhibited by an anti‐megalin serum. EmtinB‐mediated inhibition of apoptosis occurred without a reduction of caspase‐3 activity, but was associated with reduced expression of the pro‐apoptotic B‐cell leukemia/lymphoma‐2 interacting member of cell death (BimS). Finally, evidence is provided that MT and EmtinB activate extracellular signal‐regulated kinase, protein kinase B, and cAMP response element binding protein. Altogether, these results strongly suggest that MT and EmtinB induce their neuronal effects through direct binding to surface receptors belonging to the low‐density lipoprotein receptor family, such as megalin and LRP, thereby activating signal transduction pathways resulting in neurite outgrowth and survival.
Netrin‐1‐independent adenosine A2b receptor activation regulates the response of axons to netrin‐1 by controlling cell surface levels of UNC5A receptors
Authors: McKenna William L. , Wong‐Staal Caroline , Kim Grace C. , Macias Hector , Hinck Lindsay , Bartoe Joseph L.
Published: October 2007

Growth cone response to the bifunctional guidance cue netrin‐1 is regulated by the activity of intracellular signaling intermediates such as protein kinase C‐alpha (PKCα) and adenylyl cyclase. Among the diverse cellular events these enzymes regulate is receptor trafficking. Netrin‐1, itself, may govern the activity of these signaling intermediates, thereby regulating axonal responses to itself. Alternatively, other ligands, such as activators of G protein‐coupled receptors, may regulate responses to netrin‐1 by governing these signaling intermediates. Here, we investigate the mechanisms controlling activation of PKCα and the subsequent downstream regulation of cell surface UNC5A receptors. We report that activation of adenosine receptors by adenosine analogs, or activation of the putative netrin‐1 receptor, the G protein‐coupled receptor adenosine A2b receptor (A2bR) results in PKCα‐dependent removal of UNC5A from the cell surface. This decrease in cell surface UNC5A reduces the number of growth cones that collapse in response to netrin‐1 and converts repulsion to attraction. We show these A2bR‐mediated alterations in axonal response are not because of netrin‐1 because netrin‐1 neither binds A2bR, as assayed by protein overlay, nor stimulates PKCα‐dependent UNC5A surface loss. Our results demonstrate that netrin‐1‐independent A2bR signaling governs the responsiveness of a neuron to netrin‐1 by regulating the levels of cell surface UNC5A receptor.
Widespread immunoreactivity for neuronal nuclei in cultured human and rodent astrocytes
Authors: Darlington Peter J. , Goldman Jen S. , Cui Qiao‐ling , Antel Jack P. , Kennedy Timothy E.
Published: October 2007

The monoclonal antibody (mAb) neuronal nuclei (NeuN) labels the nuclei of mature neurons in vivo in vertebrates. NeuN has also been used to define post‐mitotic neurons or differentiating neuronal precursors in vitro. In this study, we demonstrate that the NeuN mAb labels the nuclei of astrocytes cultured from fetal and adult human, newborn rat, and embryonic mouse brain tissue. A non‐neuronal fibroblast cell line (3T3) also displayed NeuN immunoreactivity. We confirmed that NeuN labels neurons but not astrocytes in sections of P10 rat brain. Western blot analysis of NeuN immunoreactive species revealed a distribution of bands in nucleus‐enriched fractions derived from the different cell lines that was similar, but not identical to adult rat brain homogenates. We then examined the hypothesis that the glial fibrillary acidic protein/NeuN‐double positive population of cells might correspond to neuronal precursors. Although the NeuN‐positive astrocytes were proliferating, no evidence of neurogenesis was detected. Furthermore, expression of additional neuronal precursor markers was not detected. Our results indicate that primary astrocytes derived from mouse, rat, and human brain express NeuN. Our findings are consistent with NeuN being a selective marker of neurons in vivo, but indicate that studies utilizing NeuN‐immunoreactivity as a definitive marker of post‐mitotic neurons in vitro should be interpreted with caution.
Selective enhancement of the activity of C‐terminally truncated, but not intact, acetylcholinesterase
Authors: Zimmermann Martina , Grösgen Sven , Westwell Martin S. , Greenfield Susan A.
Published: October 2007

Acetylcholinesterase (AChE) is one of the fastest enzymes approaching the catalytic limit of enzyme activity. The enzyme is involved in the terminal breakdown of the neurotransmitter acetylcholine, but non‐enzymatic roles have also been described for the entire AChE molecule and its isolated C‐terminal sequences. These non‐cholinergic functions have been attributed to both the developmental and degenerative situation: the major form of AChE present in these conditions is monomeric. Moreover, AChE has been shown to lose its typical characteristic of substrate inhibition in both development and degeneration. This study characterizes a form of AChE truncated after amino acid 548 (T548‐AChE), whose truncation site is homologue to that of a physiological form of T‐AChE detected in fetal bovine serum that has lost its C‐terminal moiety supposedly due to proteolytic cleavage. Peptide sequences covered by this C‐terminal sequence have been shown to be crucially involved in both developmental and degenerative mechanisms in vitro. Numerous studies have addressed the structure–function relationship of the AChE C‐terminus with T548‐AChE representing one of the most frequently studied forms of truncated AChE. In this study, we provide new insight into the understanding of the functional characteristics that T548‐AChE acquires in solution: T548‐AChE is incubated with agents of varying net charge and molecular weight. Together with kinetic studies and an analysis of different molecular forms and aggregation states of T548‐AChE, we show that the enzymatic activity of T548‐AChE, an enzyme verging at its catalytic limit is, nonetheless, apparently enhanced by up to 800%. We demonstrate, first, how the activity of T548‐AChE can be enhanced through agents that contain highly positive charged moieties. Moreover, the un‐competitive mechanism of activity enhancement most likely involves the peripheral anionic site of AChE that is reflected in delayed substrate inhibition being observed for activity enhanced T548‐AChE. The data provides evidence towards a mechanistic and functional link between the form of AChE unique to both development and degeneration and a C‐terminal peptide of T‐AChE acting under those conditions.
HUMAN RIGHTS AND THE REQUIREMENT FOR INTERNATIONAL MEDICAL AID
Authors: TOLCHIN BENJAMIN
Published: October 2007

Every year approximately 18 million people die prematurely from treatable medical conditions including infectious diseases and nutritional deficiencies. The deaths occur primarily amongst the poorest citizens of poor developing nations. Various groups and individuals have advanced plans for major international medical aid to avert many of these unnecessary deaths. For example, the World Health Organization's Commission on Macroeconomics and Health estimated that eight million premature deaths could be prevented annually by interventions costing roughly US$57 bn per year.

This essay advances an argument that human rights require high‐income nations to provide such aid. The essay briefly examines John Rawls’ obligations of justice and the reasons that their applicability to cases of international medical aid remains controversial. Regardless, the essay argues that purely humanitarian obligations bind the governments and citizens of high‐income liberal democracies at a minimum to provide major medical aid to avert premature deaths in poor nations. In refusing to undertake such medical relief efforts, developed nations fail to adequately protect a fundamental human right to life.
The Geometric Contribution to Gauge Factor of Patterned Lines on Substrates
Authors: Gouldstone C. , Wu Y. , Gouldstone A.
Published: October 2007

Abstract:  A semi‐analytical approach is taken to calculate the geometric contribution to gauge factor for patterned lines on substrates. A finite element model is presented in which a line section is strained along its length, and cross‐sectional dilatation is calculated for different line aspect ratios, and elastic properties of line and substrate. Results are bounded by analytical solutions for infinitely wide and tall lines. A simple experiment is posed for measuring Poisson's ratio and piezoresistivity of coatings, films or patterned structures.
Evaluation of Residual Stress in Flip Chip Using 3‐D Optical Interferometry/FEM Hybrid Technique
Authors: Su F. , Liu L. , Wang T.
Published: October 2007

Abstract:  The residual stress in flip chips was investigated by a hybrid technique of 3‐D finite element method (FEM) and 3‐D optical interferometry. The residual stress consists of two parts: the chemical shrinkage stress caused by underfill curing and the thermal stress caused by coefficient of thermal expansion (CTE) mismatch and cooling. Warpage and in‐plane deformation of the flip chip during the underfill curing and cooling procedure was real‐time characterised with an integrated 3‐D optical interferometry system. The measurement results were used to evaluate the chemical shrinkage stress and to verify/modify the FEM model for the analysis of thermal stress. It was found that the chemical shrinkage stress under isothermal curing condition is very small in average and negligible. As the difference between the simulated and measured thermal deformation falls within a limited scope, the accuracy of the simulated thermal stress can be guaranteed.
Periderm‐ and cortex‐based resistance to tuber‐feeding Phthorimaea operculella in two wild potato species
Authors: Horgan Finbarr G. , Quiring Dan T. , Lagnaoui Aziz , Salas Alberto R. , Pelletier Yvan
Published: October 2007

The trichome‐bearing wild potatoes Solanum berthaultii (Hawkes) and Solanum tarijense (Hawkes) (Solanaceae) have noted resistance to leaf‐feeding insect herbivores; however, little is known about their resistance to tuber‐feeding herbivores. This study evaluates resistance in tubers of these two species to attack by the potato tuber moth, Phthorimaea operculella (Zeller) (Lepidoptera: Gelechiidae). Tubers from a range of accessions were presented to recently emerged neonate tuber moth larvae. Resistance to neonates varied between accessions and was generally higher in accessions of S. tarijense. The contribution to observed resistance of periderm vs. cortex factors was assessed by perforating tuber periderm in paired‐tuber experiments. Across species and accessions, an average of 62% of resistance was attributed to periderm‐related factors. All larvae entered tubers through the eyes. Unidentified cortex‐related factors affected larval development time and pupal weight. Sprouting compromised resistance by reducing the protective value of the periderm. The degree of sprouting also decreased larval development times and increased pupal weights in one of two accessions examined. These results demonstrate the potential of S. berthaultii and S. tarijense as sources of tuber‐resistance and identify accessions of both species with notably high periderm‐based protection. Levels of periderm resistance were not correlated to levels of cortex resistance and represent an independent resistance source compatible with the food value of crop potato.
EHD1 Interacts with Retromer to Stabilize SNX1 Tubules and Facilitate Endosome‐to‐Golgi Retrieval
Authors: Gokool Suzanne , Tattersall Daniel , Seaman Matthew N. J.
Published: October 2007

Endosome‐to‐Golgi retrieval of the cation‐independent mannose 6‐phosphate receptor (CIMPR) requires the function of the retromer complex. Retromer is localized to endosomes and comprises two distinct sub complexes: the vacuolar protein sorting 35/29/26 sub complex that binds cargo and the sorting nexin (SNX)1/2 sub complex that tubulates endosomal membranes. To identify up‐ or down‐stream regulatory factors of retromer, a comparative proteomic strategy was employed. Protein profiles of endosomally enriched membranes, from either wild‐type or retromer‐deficient mouse cells, were compared to identify proteins with either elevated or reduced expression levels. Eps15 homology domain‐containing protein‐1 (EHD1) was identified in endosomally enriched membrane fractions from retromer‐deficient cells and was found to be approximately threefold upregulated in the absence of retromer. EHD1 is localized to tubular and vesicular endosomes, partially colocalizes with retromer and is associated with retromer in vivo. Mutation of the nucleotide‐binding P‐loop of EHD1 results in a dominant‐negative effect upon retromer localization and endosome‐to‐Golgi retrieval, while loss of EHD1 expression by RNA interference destabilizes SNX1‐positive tubules and inhibits endosome‐to‐Golgi retrieval. The interaction between EHD1 and retromer and the requirement for EHD1 to stabilize SNX1‐tubules establish EHD1 as a novel facilitating component of endosome‐to‐Golgi retrieval.
Polymorphisms in the Interleukin‐12/18 Genes and Recurrent Spontaneous Abortion
Authors: Ostojić Saša , Volk Marija , Medica Igor , Kapović Miljenko , Meden‐Vrtovec Helena , Peterlin Borut
Published: October 2007

Problem

Interleukin (IL) IL‐12/IL‐18 are involved in uterine NK cells control of uterine vascular development. Polymorphisms in the IL‐12/IL‐18 genes could modify the cytokine balance, which might result in an increased susceptibility to recurrent spontaneous abortion (RSA).

Method of Study

A case–control study was conducted to determine the association between the IL12 (I/D) and IL18 (−607C>A, −137G>C) gene polymorphisms and the risk of RSA in 125 women with RSA and in 136 controls.

Results

The frequencies of DD, ID, II for IL‐12 were, 25.6%, 52.8% and 21.6% respectively, in patients versus 21.3%, 51.5% and 27.2% respectively in controls; the frequencies of CC, CA, AA genotypes for IL‐18 (−607) were, 34.4%, 54.4% and 11.2% respectively in patients versus 30.1%, 58.1% and 11.8% respectively in controls; the frequencies of GG, GC, CC genotypes for IL‐18(−137) were 47.2%, 43.2% and 9.6% respectively in patients and 45.6%, 46.3% and 8.1% respectively in controls.

Conclusion

IL‐12B and IL‐18 promoter gene polymorphisms were not associated with RSA in our women.
Female Sex Steroid Hormones Modify Some Regulatory Properties of Monocyte‐Derived Dendritic Cells
Authors: Kyurkchiev Dobroslav , Ivanova‐Todorova Ekaterina , Hayrabedyan Soren , Altankova Iskra , Kyurkchiev Stanimir
Published: October 2007

Problem

Monocyte‐derived dendritic cells (mDCs) are present in human decidua during the first month of pregnancy where they experience the effect of the increased concentration of progesterone (Pg) and estradiol (Estr). The aim of our study was to assess the effect of these reproductive hormones on the immunomodulatory role of mDCs.

Methods of study

The mDCs cultured in vitro in the presence of sex steroid hormones and characterized for their apoptosis and secretion of cytokines by flow cytometry, enzyme linked immunosorbent assay and proteome profiler kit.

Results

Female sex steroid hormones enhance the life cycle of mDCs, thus increasing the maturation and apoptosis, they also increase the production of interleukin (IL)‐10 and IL‐27 but only Pg increases the production of IL‐13 and down regulates the secretion of IL‐23.

Conclusion

The Pg and Estr participate in the regulation of the immune response during pregnancy by influencing apoptosis and the cytokine profile of the mDCs.
Brain‐derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly
Authors: Miyajima F. , Ollier W. , Mayes A. , Jackson A. , Thacker N. , Rabbitt P. , Pendleton N. , Horan M. , Payton A.
Published: October 2007

A functional brain‐derived neurotrophic factor (BDNF) gene polymorphism (Val66Met) that alters activity‐dependent secretion has previously been reported to influence cognitive functioning. A large proportion of these reports suggest that the Met allele, which results in reduced secretion of BDNF, impairs long‐term memory as a direct consequence of its influence on hippocampal function but has little influence on working memory. In contrast, other studies have found that the Met allele can also play a protective role in certain neurological conditions and is associated with improved non‐verbal reasoning skills in the elderly suggesting effects that appear disease, domain and age specific. We have investigated six haplotype‐tagging single nucleotide polymorphisms (SNPs) using a cohort of 722 elderly individuals who have completed cognitive tests that measured the domains of fluid intelligence, processing speed and memory. We found that the presence of the Met allele reduced cognitive performance on all cognitive tests. This reached nominal significance for tests of processing speed (P = 0.001), delayed recall (P = 0.037) and general intelligence (g) (P = 0.008). No association was observed between cognitive tests and any other SNPs once the Val66Met was adjusted for. Our results support initial findings that the Met allele is associated with reduced cognitive functioning. We found no evidence that the Met allele plays a protective role in older non‐demented individuals. Magnetic resonance imaging data collected from a subgroup of 61 volunteers showed that the left and right hippocampus were 5.0% and 3.9% smaller, respectively, in those possessing the Met allele, although only a non‐significant trend was observed.
Ternary complex formation of pVHL, elongin B and elongin C visualized in living cells by a fluorescence resonance energy transfer–fluorescence lifetime imaging microscopy technique
Authors: Kinoshita Koshi , Goryo Kenji , Takada Mamiko , Tomokuni Yosuke , Aso Teijiro , Okuda Heiwa , Shuin Taro , Fukumura Hiroshi , Sogawa Kazuhiro
Published: October 2007

The tumor suppressor von Hippel–Lindau (VHL) gene product forms a complex with elongin B and elongin C, and acts as a recognition subunit of a ubiquitin E3 ligase. Interactions between components in the complex were investigated in living cells by fluorescence resonance energy transfer (FRET)–fluorescence lifetime imaging microscopy (FLIM). Elongin B–cerulean or cerulean–elongin B was coexpressed with elongin C‐citrine or citrine‐elongin C in CHO‐K1 cells. FRET signals were examined by measuring a change in the fluorescence lifetime of donors and by monitoring a corresponding fluorescence rise of acceptors. Clear FRET signals between elongin B and elongin C were observed in all combinations, except for the combination of elongin B‐cerulean and citrine‐elongin C. Although similar experiments to examine interaction between pVHL30 and elongin C linked to cerulean or citrine were performed, FRET signals were rarely observed among all the combinations. However, the signal was greatly increased by coexpression of elongin B. These results, together with results of coimmunoprecipitation experiment using pVHL, elongin C and elongin B, suggest that a conformational change of elongin C and/or pVHL was induced by binding of elongin B. The conformational change of elongin C was investigated by measuring changes in the intramolecular FRET signal of elongin C linked to cerulean and citrine at its N‐ and C‐terminus, respectively. A strong FRET signal was observed in the absence of elongin B, and this signal was modestly increased by coexpression of elongin B, demonstrating that a conformation change of elongin C was induced by the binding of elongin B.
Something from nothing − bridging the gap between constraint‐based and kinetic modelling
Authors: Smallbone Kieran , Simeonidis Evangelos , Broomhead David S. , Kell Douglas B.
Published: October 2007

Two divergent modelling methodologies have been adopted to increase our understanding of metabolism and its regulation. Constraint‐based modelling highlights the optimal path through a stoichiometric network within certain physicochemical constraints. Such an approach requires minimal biological data to make quantitative inferences about network behaviour; however, constraint‐based modelling is unable to give an insight into cellular substrate concentrations. In contrast, kinetic modelling aims to characterize fully the mechanics of each enzymatic reaction. This approach suffers because parameterizing mechanistic models is both costly and time‐consuming. In this paper, we outline a method for developing a kinetic model for a metabolic network, based solely on the knowledge of reaction stoichiometries. Fluxes through the system, estimated by flux balance analysis, are allowed to vary dynamically according to linlog kinetics. Elasticities are estimated from stoichiometric considerations. When compared to a popular branched model of yeast glycolysis, we observe an excellent agreement between the real and approximate models, despite the absence of (and indeed the requirement for) experimental data for kinetic constants. Moreover, using this particular methodology affords us analytical forms for steady state determination, stability analyses and studies of dynamical behaviour.
Effect of oxidative stress and involvement of poly(ADP‐ribose) polymerase (PARP) in Dictyostelium discoideum development
Authors: Rajawat Jyotika , Vohra Iqbal , Mir Hina A. , Gohel Dhaval , Begum Rasheedunnisa
Published: October 2007

Dictyostelium discoideum, a unicellular eukaryote, exhibits multicellularity upon nutrient starvation and is a good model system for developmental studies, and for the study of various signal transduction pathways. Reactive oxygen species at low doses act as signaling molecules; however, at high doses they are known to cause DNA damage that results in the activation of poly(ADP‐ribose) polymerase (PARP). We have earlier reported the high resistance of the unicellular stage of D. discoideum to oxidative stress, and we now show the response of this organism to oxidative stress and the role of PARP during development. We used hydroxylamine (HA) to induce in situ generation of H2O2 and monitored the effect of benzamide, a PARP inhibitor, on oxidative stress‐induced changes in D. discoideum development. Interestingly, oxidative stress resulted in PARP activation within 5 min that was inhibited by benzamide. Oxidative stress‐induced delay in developmental pattern was also partially restored by benzamide. We studied the long‐term effects of PARP inhibition under oxidative stress, and our results demonstrated that spores formed under HA stress exhibited significant delay in germination in comparison to benzamide‐pretreated HA‐stressed cells. However, second‐generation cells showed normal development, signifying that PARP inhibition has no deleterious effect on D. discoideum development under oxidative stress.