bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of class IA PI3Ks: is there a role for monomeric PI3K subunits?
Authors: Geering B. , Cutillas P.R. , Vanhaesebroeck B.
Published: March 2007

Class IA PI3Ks (phosphoinositide 3-kinases) consist of a p110 catalytic subunit bound to one of five regulatory subunits, known as p85s. Under unstimulated conditions, p85 stabilizes the labile p110 protein, while inhibiting its catalytic activity. Recruitment of the p85–p110 complex to receptors and adaptor proteins via the p85 SH2 (Src homology 2) domains alleviates this inhibition, leading to PI3K activation and production of PIP3 (phosphatidylinositol 3,4,5-trisphosphate). Four independent p85 KO (knockout) mouse lines have been generated. Remarkably, PI3K signalling in insulin-sensitive tissues of these mice is increased. The existence of p110-free p85 in insulin-responsive cells has been invoked to explain this observation. Such a monomeric p85 would compete with heterodimeric p85–p110 for pTyr (phosphotyrosine) recruitment, and thus repress PI3K activity. Reduction in the pool of p110-free p85 in p85 KO mice was thought to allow recruitment of functional heterodimeric p85–p110, leading to increased PI3K activity. However, recent results indicate that monomeric p85, like p110, is unstable in cells. Moreover, overexpressed free p85 does not necessarily compete with heterodimeric p85–p110 for receptor binding. Using a variety of approaches, we have observed a 1:1 ratio between the p85 and p110 subunits in murine cell lines and primary tissues. Alternative models to explain the increase in PI3K signalling in insulin-responsive cells of p85 KO mice, based on possible effects of p85 deletion on phosphatases acting on PIP3, are discussed.
Isoform-selective PI3K inhibitors as novel therapeutics for the treatment of acute myocardial infarction
Authors: Doukas J. , Wrasidlo W. , Noronha G. , Dneprovskaia E. , Hood J. , Soll R.
Published: March 2007

In the present paper, we review the preclinical development of TG100-115, a PI3K (phosphoinositide 3-kinase) γ/δ isoform-specific inhibitor currently in clinical trials for the reduction of acute MI (myocardial infarction). An overview is presented outlining the pathogenesis of acute MI and the rationale for clinical use of PI3K γ/δ-specific inhibitors in this indication. TG100-115's broad anti-inflammatory activities are described, as well as its ability to discriminate between cellular signalling pathways downstream of receptor tyrosine kinase ligands such as vascular endothelial growth factor. Finally, we review TG100-115's potent cardioprotective activities as revealed in rigorous animal models of acute MI, and, based on these data, this compound's potential for clinical utility.
Extracellular and subcellular regulation of the PI3K/Akt cassette: new mechanisms for controlling insulin and growth factor signalling
Authors: Wilson C. , Vereshchagina N. , Reynolds B. , Meredith D. , Boyd C.A.R. , Goberdhan D.C.I.
Published: March 2007

The PI3K (phosphoinositide 3-kinase)/Akt (also called protein kinase B) signalling cassette plays a central role in the response to growth factors, particularly insulin-like molecules, and its misregulation is a characteristic feature of diabetes and many forms of human cancer. Recent molecular genetic studies initiated in the fruitfly, Drosophila melanogaster, have highlighted two new cell-type-specific mechanisms regulating PI3K/Akt signalling and its downstream effects. First, the cellular response to this cassette is modulated by several classes of cell-surface transporters and sensors, suggesting an important role for extracellular nutrients in insulin-sensitivity. Secondly, various cell types show a markedly different subcellular distribution of the activated kinase Akt, influencing the cellular functions of this molecule. These findings reveal new mechanisms by which processes such as growth, lipogenesis and insulin resistance can be differentially regulated and may suggest novel strategies for treating insulin-linked diseases.
Resolution of Inflammatory Responses: a brief introduction
Authors: Adcock I. , Evans P.C.
Published: March 2007

Resolution of inflammatory responses is the regulatory process that prevents prolonged inflammation, thus avoiding diseases such as atherosclerosis, rheumatoid arthritis and transplant rejection. There are various different aspects to this process which are discussed briefly here and in the accompanying papers from this Focused Meeting.
IKKα in the regulation of inflammation and adaptive immunity
Authors: Lawrence T. , Bebien M.
Published: March 2007

Inflammation is a beneficial response to insult or injury which plays an important role in orchestrating the adaptive immune response. The resolution of acute inflammation is an active process that involves the release of anti-inflammatory mediators and the termination of pro-inflammatory signalling pathways coincident with leucocyte apoptosis and phagocytic clearance and the migration of antigen-presenting cells from the site of inflammation to the local lymphatic tissue. The latter process is required for the development of adaptive immunity and immunological memory. The NF-κB (nuclear factor κB) pathway is an important regulator of inflammation and immunity; NF-κB activation is controlled by IKK [IκB (inhibitor of NF-κB) kinase] complex, which regulates NF-κB activation in response to pro-inflammatory stimuli. The IKK complex has two catalytic subunits, IKKα and IKKβ; recent research shows that these highly homologous kinases have distinct roles in inflammation and adaptive immunity. Here, we discuss the emerging roles for IKKα in the tight regulation of inflammation and the development of adaptive immune responses.
Health Implications of Dietary Amines: an overview of COST Action 922 (2001–2006)
Authors: Wallace H.M.
Published: March 2007

The human diet contains significant amounts of amines and amine-related compounds that are present either naturally or as a result of food processing or storage. Some of these compounds are beneficial to health, while others are known to be hazardous or the dangers associated with them are poorly understood. Thus there is a need to bring together information from diverse scientific areas in order to evaluate the potential risks or benefits to human health of dietary amines.
Ornithine decarboxylase and S-adenosylmethionine decarboxylase in trypanosomatids
Authors: Persson L.
Published: March 2007

The production of polyamines has been shown to be an effective target for a drug against the West African form of sleeping sickness caused by Trypanosoma brucei gambiense. T. brucei belongs to the group of protozoan parasites classed as trypanosomatids. Parasitic species of this group are the causative agents of various tropical diseases besides African sleeping sickness, e.g. Chagas' disease (Trypanosoma cruzi), cutaneous (Lesihmania spp.) and visceral (Leishmania donovani) leishmaniasis. The metabolism of polyamines in the parasites is a potential target for the development of new drugs for treatment of these diseases. The key steps in polyamine synthesis are catalysed by ODC (ornithine decarboxylase) and AdoMetDC (S-adenosylmethionine decarboxylase). In the present paper, some of the available information on ODC and AdoMetDC in trypanosomatids will be described and discussed.
Impact of dietary amino acids and polyamines on intestinal carcinogenesis and chemoprevention in mouse models
Authors: Gerner E.W.
Published: March 2007

Colon cancer in humans is influenced by both genetic and dietary risk factors. The majority of colon cancers have somatic mutations in the APC (adenomatous polyposis coli) tumour-suppressor gene. Dietary arginine enhances the risk of APC-dependent colon carcinogenesis in mouse models by a mechanism involving NOS2 (nitric oxide synthase 2), as elimination of NOS2 alleles suppresses this phenotype. DFMO (difluoromethylornithine), a specific inhibitor of polyamine synthesis, also inhibits dietary arginine-induced colon carcinogenesis in C57BL/6J-ApcMin/J mice. The primary consequence of dietary arginine is to increase the adenoma grade in these mice. Either loss of NOS2 alleles or inhibition of polyamine synthesis suppresses the arginine-induced increase in adenoma grade. In addition to promoting intestinal carcinogenesis, polyamines can also reduce the efficacy of certain intestinal cancer chemopreventive agents. The NSAID (non-steroidal anti-inflammatory drug) sulindac is a potent inhibitor of intestinal carcinogenesis in the C57BL/6J-ApcMin/J mouse model and is used to treat humans with FAP (familial adenomatous polyposis). Dietary putrescine reduces the ability of sulindac to suppress intestinal tumorigenesis in the mouse model. These data suggest that reducing polyamine metabolism and dietary polyamine levels may enhance strategies for colon cancer chemoprevention.
Polyamine metabolism and tumorigenesis in the Apc
Min/+ mouse
Authors: Berger F.G. , Kramer D.L. , Porter C.W.
Published: March 2007

While polyamine homoeostasis is clearly important in maintenance of normal cell function, the roles of these cations, as well as the enzymes that regulate their metabolism, in the neoplastic process are not clear. In particular, the polyamine catabolic enzyme SSAT (spermidine/spermine N1-acetyltransferase) seems to have different roles in tumorigenesis, depending upon the particular system being analysed. In attempts to clarify the function of SSAT in tumour development, we have utilized the ApcMin/+ mouse, which carries a mutant allele of the Apc (adenomatous polyposis coli) gene, rendering it susceptible to the formation of multiple adenomas in the small intestine and colon. Using genetically engineered animals (i.e. transgenic and knockout mice), we have shown that SSAT acts as a tumour promoter in the ApcMin/+ model. Modulation of tumorigenesis is not associated with changes in tissue levels of either spermidine or spermine. These findings, along with those made in other animal models of cancer, have prompted us to propose that metabolic flux through the polyamine biosynthetic and catabolic pathways, and the consequent changes in levels of various metabolites within the cell (i.e. the metabolome), is critical to tumour development. The metabolic flux model represents a novel way of thinking about the role of polyamines in cell physiology and the neoplastic process.
Revival of 2-(difluoromethyl)ornithine (DFMO), an inhibitor of polyamine biosynthesis, as a cancer chemopreventive agent
Authors: Raul F.
Published: March 2007

ODC (ornithine decarboxylase), a key enzyme of polyamine biosynthesis, is an inducible enzyme exhibiting high activity in tumour cells, suggesting ODC as a target for antineoplastic therapy. Among the inhibitors of polyamine-related enzymes, the ODC inactivator DFMO [2-(difluoromethyl)ornithine] became the most well-known. The drug is usually cytostatic and its effects on growth are reversed by micromolar concentrations of polyamines in the cellular environment. ODC inactivation is associated with decreased transcription of the growth-related c-myc and c-fos genes. DFMO used as a single drug has only minor effects on tumour growth. The low efficacy of the drug is due to the use of exogenous (gastrointestinal) polyamines by the mammalian organism. Although it was disappointing in most therapeutic attempts, DFMO showed potential in cancer chemoprevention based on its ability to lower polyamine levels in colorectal mucosa at low dosages with no demonstrable toxicity over long periods of use. DFMO in combination with other drugs prevents and inhibits the development of a variety of chemically induced cancers in animals with doses far lower than those administered for therapy. Low doses of several NSAIDs (non-steroidal anti-inflammatory drugs) and DFMO administered in combination have been shown to be more effective in inhibiting chemically induced colon tumours in rats than are high doses of these agents given individually. This combination has gained further interest after findings suggesting that ODC polymorphism is a genetic marker for colon cancer risk and supporting the use of DFMO and aspirin or other NSAIDs in combination as a strategy for colon cancer prevention.
Novel approach to design an isosteric charge-deficient analogue of spermine and its biochemically important derivatives
Authors: Khomutov A.R. , Grigorenko N.A. , Skuridin S.G.
Published: March 2007

The design and synthesis of SpmTrien (1,12-diamino-3,6,9-triazadodecane), an isosteric and charge-deficient analogue of spermine with excellent chelating properties towards Cu2+ ions, as well as novel N1- and N12-Ac-SpmTriens and bis-Et-SpmTrien (N1,N12-diethyl-1,12-diamino-3,6,9-triazadodecane) are described. Possible applications of SpmTrien and its derivatives to the investigation of the enzymes of polyamine metabolism and spermine cellular functions, including interaction with DNA, are discussed.
Inhibition of agmatine transport in liver mitochondria by new charge-deficient agmatine analogues
Authors: Grillo M.A. , Battaglia V. , Colombatto S. , Rossi C.A. , Simonian A.R. , Salvi M. , Khomutov A.R. , Toninello A.
Published: March 2007

The charge of the agmatine analogues AO-Agm [N-(3-aminooxypropyl)guanidine], GAPA [N-(3-aminopropoxy)guanidine] and NGPG [N-(3-guanidinopropoxy)guanidine] is deficient as compared with that of agmatine and they are thus able to inhibit agmatine transport in liver mitochondria. The presence of the guanidine group is essential for an optimal effect, since AO-Agm and NGPG display competitive inhibition, whereas that of GAPA is non-competitive. NGPG is the most effective inhibitor (Ki=0.86 mM). The sequence in the inhibitory efficacy is not directly dependent on the degree of protonation of the molecules; in fact NGPG has almost the same charge as GAPA. When the importance of the guanidine group for agmatine uptake is taken into account, this observation suggests that the agmatine transporter is a single-binding, centre-gated pore rather than a channel.
The APP family of proteins: similarities and differences
Authors: Walsh D.M. , Minogue A.M. , Sala Frigerio C. , Fadeeva J.V. , Wasco W. , Selkoe D.J.
Published: March 2007

Overwhelming evidence indicates that the Aβ (amyloid β-peptide) plays a critical role in the pathogenesis of Alzheimer's disease. Aβ is derived from the APP (amyloid precursor protein) by the action of two aspartyl proteases (β- and γ-secretases) that are leading candidates for therapeutic intervention. APP is a member of a multigene family that includes APLP1 (amyloid precursor-like protein 1) and APLP2. Both APLPs are processed in a manner analogous to APP, with all three proteins subject to ectodomain shedding and subsequent cleavage by γ-secretase. Careful study of the APP family of proteins has already revealed important insights about APP. Here, we will review how knowledge of the similarities and differences between APP and the APLPs may prove useful for the development of novel disease-modifying therapeutics.
Apoptosis signalling pathways in seizure-induced neuronal death and epilepsy
Authors: Henshall D.C.
Published: March 2007

Delineating the molecular pathways underlying seizure-induced neuronal death may yield novel strategies for brain protection against prolonged or repetitive seizures. Glutamate-mediated excitotoxicity and necrosis is a primary contributing mechanism but seizures also activate programmed (apoptotic) cell death pathways. Apoptosis signalling pathways are typically initiated following perturbation of intracellular organelle function (intrinsic pathway) or by activated cell-surface-expressed death receptors (extrinsic pathway), with signalling cascades orchestrated in part by the Bcl-2 and caspase gene families. In this review, evidence for these pathways from experimental seizure modelling and clinical material from patients with intractable temporal lobe epilepsy is examined. Seizures cause mitochondrial dysfunction and activate intrinsic pathway components including pro-apoptotic Bcl-2 family proteins and caspases, processes that may be partly calcium-induced. The ER (endoplasmic reticulum) has emerged as a major intrinsic pathway trigger for apoptosis and its function may also be compromised following seizures and in epilepsy. The extrinsic, death-receptor-dependent pathway is also rapidly engaged following experimental seizures and in patient brain, supporting a previously unexpected apical role for a calcium-independent pathway. When considered alongside emerging functions of apoptosis-regulatory proteins in non-cell-death processes, including regulating intracellular calcium release and neuronal (re)structuring, apoptosis signalling pathways can be viewed as an important developing focus of research into how to obviate the deleterious impact of seizures on the brain.
Finite element analysis of four thread‐form configurations in a stepped screw implant
Authors: Geng J. P. , Ma Q. S. , Xu W. , Tan K. B. C. , Liu G.R.
Published: March 2007

summary  The purpose of this study was to determine the optimal thread form configuration for an experimental stepped screw implant. Two‐dimensional finite element analysis was applied to model the experimental stepped screw implant in a standard cross‐section of the posterior human mandible digitized from a CT‐generated patient data set. Four different thread form configurations: v‐thread (V), thin‐thread (T), and two square‐thread forms of 0·24 mm (S1) and 0·36 mm (S2) thread width were compared under oblique load in normal cortical bone condition. The support‐type constraint position changed from middle to the base of the bone segment. In middle support‐type constraint position only the thin‐thread (T) model demonstrated significantly different stress distribution from the other three models, however, in base support‐type constraint position T and S1 models demonstrated significantly different stress distribution from the other two models. The results implies that v‐thread (V) or large square‐thread (S2) are optimal thread form for the experimental stepped screw implant. While, minimal support constraints allow clearer differentiation of the stress picture between the different stepped screw types at the trabecular bone–implant interface.
Clinical evaluation of ferric oxalate in relieving dentine hypersensitivity
Authors: Gillam D. G. , Newman H. N. , Davies E. H. , Bulman J. S. , Troullos E. S. , Curro F. A.
Published: March 2007

summary  Previous in vitro permeability and scanning electron microscopic (SEM) studies have demonstrated the effectiveness of the oxalate ion in dentine permeability reduction and effective tubule occlusion. The aim of this randomized double‐blind, split mouth 4‐week clinical study, therefore was to determine whether a 1‐min application of ferric oxalate (Sensodyne Sealant) on exposed root dentine was effective in reducing dentine hypersensitivity (DH). Thirteen subjects [8F:5M, mean age 46·2 (s.d. 4·15) years] completed the study. The subjective response was evaluated by tactile, thermal and evaporative methods of assessment. Data were collected at baseline and post‐application at +5 min and 4 weeks. Analysis was based on paired t‐test (P=0·05) and Wilcoxon–Mann–Whitney tests. No statistically significant differences were noted between ferric oxalate and placebo preparations at +5 min and 4 weeks for any of the test stimuli. There was, however, a clear trend towards immediate reduction (+5 min) in DH reverting back to baseline values at 4 weeks with the exception of the Biomat Thermal Probe mean values, which maintained the reductions in DH compared with placebo. The results of the present study demonstrated that a 1‐min application of ferric oxalate is both rapid and effective in reducing DH although its long‐term effectiveness still needs to be determined.
Capacitance-voltage characterization of electron beam induced surface cross-linked functional monomers
Authors: Mahapatra Santosh , Bhoraskar V. N. , Gangal S. A. , Bodas Dhananjay
Published: March 2007

A metal-insulator-semiconductor (MIS) capacitor was fabricated using surface cross-linked functional monomers on silicon substrate. Functional monomer: multifunctional acrylates with 3:1 composition were spin coated and later cross-linked under the influence of keV electron irradiation on the surface of silicon to generate a surface-anchored cross-linked network bearing functional moieties. Capacitance-voltage (CV) measurements were carried out before and after electron irradiation. Doping concentration and bulk potential were calculated from the CV curve.
Sustaining Sustained Yield: Class, Politics, and Post-War Forest Regulation in British Columbia
Authors: Prudham Scott
Published: March 2007

In British Columbia, Canada, industrial sustained-yield forest regulation was embraced together with a system of forest tenures governing private access to public forest lands in the mid-19408. This approach has underpinned forest exploitation and regulation ever since, despite sometimes significant reforms over the years. Yet this approach to forest policy has also come under fire in recent years because of pervasive signs of economic, social, and environmental exhaustion. In this paper I analyze the political circumstances surrounding adoption of this particular approach to governing forest access and forest use in the province of British Columbia. In particular, I draw on historical documentation related to two key provincial Royal Commissions on Forestry conducted in the 1940s and 1950s. These commissions provided an arena for debating alternative approaches to forest regulation in the province, and resulted in a series of recommendations that were key influences on postwar forest policy. Drawing on the debate and particularly on the positions adopted by socialists and trade unionists, I link the politics of forest regulation to the politics of class struggle and class compromise in early postwar British Columbia. This serves the purpose of highlighting important, alternative ideas about forest use values and exchange values that contrast with those that underpin conventional, commodity-oriented forestry in the province, as well as with contemporary alternatives to mainstream forestry. It also serves the purpose of exploring the organization of political consent around industrial, sustained-yield forestry, treating this model of regulation not as something ‘natural’, but rather as something politically contingent and negotiated. And finally, I examine seldom explored links between the politics of producing and regulating nature, and the politics of class struggle under capitalism more generally.
Growth and development of the facultative root hemiparasite Rhinanthus minor after removal of its host
Authors: Jiang Fan , Timergalina Leila , Kudoyarova Guzel , Jeschke W. Dieter , Hartung Wolfram
Published: March 2007

Facultative plant hemiparasites exhibit optimal growth only when attached to a suitable host. After attachment, stomata of the parasite remain continuously open, thus, optimising the extraction of host xylem sap. When the host shoot was removed from the hemiparasitic Rhinanthus/barley association ~14 days after attachment, the resulting host-free attached Rhinanthus continued to grow and develop similarly well as the attached parasites. These plants, however, showed altered stomatal behaviour: their stomata were open at daytime and closed at night, whereas parasitising Rhinanthus has continuously open stomata all day and night and unattached single Rhinanthus has practically closed stomata throughout day and night. After removal of the host the root growth was strongly increased, thereby increasing the root-to-shoot ratio. Abscisic acid and cytokinin relationships became more ‘normal’ with the Rhinanthus roots becoming able to synthesise zeatin nucleotides and zeatin ribosides, thus, behaving much as non-parasitic plants in general. It is suggested that the degrading root system of the host plant produces signals that trigger this conversion. Two explanations for these changes are discussed, the supply of dissolved organic nitrogen by the degrading host root system and a possible strong growth of growth promoting soil microorganisms using the degrading host root system as a substrate.
Significant transpirational water loss occurs throughout the night in field-grown tomato
Authors: Caird Mairgareth A. , Richards James H. , Hsiao Theodore C.
Published: March 2007

Incomplete stomatal closure at night can result in substantial water loss at times when photosynthetic carbon gain is not occurring in C3 and C4 plant species. To investigate the magnitude of nighttime water loss for a crop species in the field, measurements of nighttime water loss by tomato (Lycopersicon esculentum Mill. cv. Heinz 8892) were made by three methods: a field-scale lysimeter and two leaf-level instruments, an automated viscous flow porometer and a portable photosynthesis system. The portable photosynthesis system indicated nighttime transpiration of 10% of maximal daytime transpiration and the viscous flow porometer demonstrated partially open stomata. Integrated crop water loss during the dark, non-photosynthetic hours measured on the lysimeter was 3–10.8% of total daily water loss. In the glasshouse, a survey of closely related wild and cultivated tomato species showed that under ambient conditions nighttime transpiration varied within and among species and was 8–33% of maximal daytime transpiration. Implications of such a substantial fraction of total daily crop water use occurring during the night are significant in agronomic, environmental, and economic terms. Further, variation within and among species in nighttime water loss has implications for breeding to improve crop water use efficiency.
Microfluidic immunoassays as rapid saliva-based clinical diagnostics
Authors: Herr Amy E. , Hatch Anson V. , Throckmorton Daniel J. , Tran Huu M. , Brennan James S. , Giannobile William V. , Singh Anup K.
Published: March 2007

At present, point-of-care (POC) diagnostics typically provide a binary indication of health status (e.g., home pregnancy test strip). Before anticipatory use of diagnostics for assessment of complex diseases becomes widespread, development of sophisticated bioassays capable of quantitatively measuring disease biomarkers is necessary. Successful translation of new bioassays into clinical settings demands the ability to monitor both the onset and progression of disease. Here we report on a clinical POC diagnostic that enables rapid quantitation of an oral disease biomarker in human saliva by using a monolithic disposable cartridge designed to operate in a compact analytical instrument. Our microfluidic method facilitates hands-free saliva analysis by integrating sample pretreatment (filtering, enrichment, mixing) with electrophoretic immunoassays to quickly measure analyte concentrations in minimally pretreated saliva samples. Using 20 μl of saliva, we demonstrate rapid (<10 min) measurement of the collagen-cleaving enzyme matrix metalloproteinase-8 (MMP-8) in saliva from healthy and periodontally diseased subjects. In addition to physiologically measurable indicators of periodontal disease, conventional measurements of salivary MMP-8 were used to validate the microfluidic assays described in this proof-of-principle study. The microchip-based POC diagnostic demonstrated is applicable to rapid, reliable measurement of proteinaceous disease biomarkers in biological fluids.
Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia
Authors: Parmar Kalindi , Mauch Peter , Vergilio Jo-Anne , Sackstein Robert , Down Julian D.
Published: March 2007

The interaction of stem cells with their bone marrow microenvironment is a critical process in maintaining normal hematopoiesis. We applied an approach to resolve the spatial organization that underlies these interactions by evaluating the distribution of hematopoietic cell subsets along an
in vivo
Hoechst 33342 (Ho) dye perfusion gradient. Cells isolated from different bone marrow regions according to Ho fluorescence intensity contained the highest concentration of hematopoietic stem cell (HSC) activity in the lowest end of the Ho gradient (i.e., in the regions reflecting diminished perfusion). Consistent with the ability of Ho perfusion to simulate the level of oxygenation, bone marrow fractions separately enriched for HSCs were found to be the most positive for the binding of the hypoxic marker pimonidazole. Moreover, the
in vivo
administration of the hypoxic cytotoxic agent tirapazamine exhibited selective toxicity to the primitive stem cell subset. These data collectively indicate that HSCs and the supporting cells of the stem cell niche are predominantly located at the lowest end of an oxygen gradient in the bone marrow with the implication that regionally defined hypoxia plays a fundamental role in regulating stem cell function.
Function, Homology, and Character Individuation
Authors: Griffiths Paul E.
Published: March 2007

I defend the view that many biological categories are defined by homology against a series of arguments designed to show that all biological categories are defined, at least in part, by selected function. I show that categories of homology are ‘abnormality inclusive’—something often alleged to be unique to selected function categories. I show that classifications by selected function are logically dependent on classifications by homology, but not vice-versa. Finally, I reject the view that biologists must use considerations of selected function to abstract away from variation and pathology to form a canonical description of a class of biological systems.
Outbreak of Varicella-Zoster Virus Infection Among Thai Healthcare Workers
Authors: Apisarnthanarak Anucha , Kitphati Rungrueng , Tawatsupha Pranee , Thongphubeth Kanokporn , Apisarnthanarak Piyaporn , Mundy Linda M.
Published: March 2007

Objective.

To evaluate the correlation between self-report of a prior history of chickenpox and results of varicella-zoster virus (VZV) immunoglobulin (Ig) G serologic test results in an outbreak of VZV infection among Thai healthcare workers (HCWs) and to conduct a cost-benefit analysis of establishing routine VZV immunization as part of an occupational health program on the basis of the outbreak data.

Methods.

All exposed patients received prophylaxis and the HCWs in our 3 intensive care units (ICUs) were prospectively evaluated. HCWs were assessed for disease history and serologic evidence of VZV IgG. A cost-benefit analysis was performed.

Results.

After 140 HCWs and 18 ICU patients were exposed to VZV, 10 HCWs (7%) with active VZV infection were relieved from work until skin lesions were crusted. Acyclovir (ACV) was prescribed to all 10 HCWs with active disease, and all 18 exposed patients received prophylaxis with ACV. Of 140 HCWs, 100 consented to longitudinal follow-up. Twenty-three (100%) of the HCWs who reported a history of chickenpox also had serologic test results that were postive for VZV IgG, compared with 30 (39%) of 77 HCWs who reported no prior history of chickenpox, yet had test results that were positive for VZV IgG. Reported history of chickenpox had a sensitivity of 43%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 61% with respect to VZV infection immunity. The total cost estimate for this outbreak investigation was $23,087.

Conclusions.

An HCWs reported history of chickenpox was a reliable predictor of immunity; a report of no prior history of chickenpox was unreliable. Our cost-benefit analysis suggests that the costs of an occupational health program that included VZV surveillance and immunization for the next 323 HCWs would be approximately equal to the excess costs of $17,227 for the ACV therapy, HCW furloughs, and staff overtime associated with this outbreak.
Predictive Factors for Pneumonia Onset After Cardiac Surgery in Rio de Janeiro, Brazil
Authors: Santos Marisa , Braga José Ueleres , Gomes Renato Vieira , Werneck Guilherme L.
Published: March 2007

Objective.

To develop a predictive system for the occurrence of nosocomial pneumonia in patients who had cardiac surgery performed.

Design.

Retrospective cohort study.

Setting.

Two cardiologic tertiary care hospitals in Rio de Janeiro, Brazil.

Patients.

Between June 2000 and August 2002, there were 1,158 consecutive patients who had complex heart surgery performed. Patients older than 18 years who survived the first 48 postoperative hours were included in the study. The occurrence of pneumonia was diagnosed through active surveillance by an infectious diseases specialist according to the following criteria: the presence of new infiltrate on a radiograph in association with purulent sputum and either fever or leukocytosis until day 10 after cardiac surgery. Predictive models were built on the basis of logistic regression analysis and classification and regression tree (CART) analysis. The original data set was divided randomly into 2 parts, one used to construct the models (ie, “test sample”) and the other used for validation (ie, “validation sample”).

Results.

The area under the receiver–operating characteristic (ROC) curve was 69% for the logistic regression model and 76% for the CART model. Considering a probability greater than 7% to be predictive of pneumonia for both models, sensitivity was higher for the logistic regression models, compared with the CART models (64% vs 56%). However, the CART models had a higher specificity (92% vs 70%) and global accuracy (90% vs 70%) than the logistic regression models. Both models showed good performance, based on the 2-graph ROC, considering that 84.6% and 84.3% of the predictions obtained by regression and CART analyses were regarded as valid.

Conclusion.

Although our findings are preliminary, the predictive models we created showed fairly good specificity and fair sensitivity.
Control of an Outbreak of Pandrug-Resistant Acinetobacter baumannii Colonization and Infection in a Neonatal Intensive Care Unit
Authors: Chan Pei-Chun , Huang Li-Min , Lin Hui-Chi , Chang Luan-Yin , Chen Mei-Ling , Lu Chun-Yi , Lee Ping-Ing , Chen Jung-Min , Lee Chin-Yun , Pan Hui-Jui , Wang Jann-Tay , Chang Shan-Chwen , Chen Yee-Chun
Published: March 2007

Objective.

To investigate the potential reservoir and mode of transmission of pandrug-resistant (PDR) Acinetobacter baumannii in a 7-day-old neonate who developed PDR A. baumannii bacteremia that was presumed to be the iceberg of a potential outbreak.

Design.

Outbreak investigation based on a program of prospective hospital-wide surveillance for nosocomial infection.

Setting.

A 24-bed neonatal intensive care unit in a 2,200-bed major teaching hospital in Taiwan that provides care for critically ill neonates born in this hospital and those transferred from other hospitals.

Interventions.

Samples from 33 healthcare workers' hands and 40 samples from the environment were cultured. Surveillance cultures of anal swab specimens and sputum samples were performed for neonates on admission to the neonatal intensive care unit and every 2 weeks until discharge. The PDR A. baumannii isolates, defined as isolates resistant to all currently available systemic antimicrobials except polymyxin B, were analyzed by pulsed-field gel electrophoresis. Control measures consisted of implementing contact isolation, reinforcing hand hygiene adherence, cohorting of nurses, and environmental cleaning.

Results.

One culture of an environmental sample and no cultures of samples from healthcare workers' hands grew PDR A. baumannii. The positive culture result involved a sample obtained from a ventilation tube used by the index patient. During the following 2 months, active surveillance identified PDR A. baumannii in 8 additional neonates, and isolates from 7 had the same electrokaryotype. Of the 9 neonates colonized or infected with PDR A. baumannii, 1 died from an unrelated condition. Reinforcement of infection control measures resulted in 100% adherence to proper hand hygiene protocol. The outbreak was stopped without compromising patient care.

Conclusions.

In the absence of environmental contamination, transient hand carriage by personnel who cared for neonates colonized or infected with PDR A. baumannii was suspected to be the mode of transmission. Vigilance, prompt intervention and strict adherence to hand hygiene protocol were the key factors that led to the successful control of this outbreak. Active surveillance appears to be an effective measure to identify potential transmitters and reservoirs of PDR A. baumannii.
Sharp-Device Injuries to Hospital Staff Nurses in 4 Countries
Authors: Clarke Sean P. , Schubert Maria , Körner Thorsten
Published: March 2007

Objective.

To compare sharp-device injury rates among hospital staff nurses in 4 Western countries.

Design.

Cross-sectional survey.

Setting.

Acute-care hospital nurses in the United States (Pennsylvania), Canada (Alberta, British Columbia, and Ontario), the United Kingdom (England and Scotland), and Germany.

Participants.

A total of 34,318 acute-care hospital staff nurses in 1998-1999.

Results.

Survey-based rates of retrospectively-reported needlestick injuries in the previous year for medical-surgical unit nurses ranged from 146 injuries per 1,000 full-time equivalent positions (FTEs) in the US sample to 488 injuries per 1,000 FTEs in Germany. In the United States and Canada, very high rates of sharp-device injury among nurses working in the operating room and/or perioperative care were observed (255 and 569 injuries per 1,000 FTEs per year, respectively). Reported use of safety-engineered sharp devices was considerably lower in Germany and Canada than it was in the United States. Some variation in injury rates was seen across nursing specialties among North American nurses, mostly in line with the frequency of risky procedures in the nurses' work.

Conclusions.

Studies conducted in the United States over the past 15 years suggest that the rates of sharp-device injuries to front-line nurses have fallen over the past decade, probably at least in part because of increased awareness and adoption of safer technologies, suggesting that regulatory strategies have improved nurse safety. The much higher injury rate in Germany may be due to slow adoption of safety devices. Wider diffusion of safer technologies, as well as introduction and stronger enforcement of occupational safety and health regulations, are likely to decrease sharp-device injury rates in various countries even further.
A Case of Healthcare-Associated, Multidrug-Resistant Tuberculosis in Austria: Reconsidering the Value of Cohorting of Patients with Culture-Positive Tuberculosis
Authors: Indra Alexander , Robl Barbara , Aumüller Ingrid , Magnet Eva , Meusburger Stefan , Allerberger Franz
Published: March 2007

Cohorting of patients with culture-positive tuberculosis is still widely practiced in Austria, a country where approximately 1% of Mycobacterium tuberculosis isolates are multidrug resistant. Cohorting of patients with tuberculosis prior to determination of drug susceptibility is unacceptable because M. tuberculosis superinfection can occur.
Non-cultural detection and molecular genotyping of Neisseria gonorrhoeae from a piece of clothing
Authors: Martin Iona M. C. , Foreman Ellie , Hall Vicky , Nesbitt Anne , Forster Greta , Ison Catherine A.
Published: March 2007

Isolation ofNeisseria gonorrhoeaeis currently the gold standard for the definitive diagnosis of gonorrhoea and for use in medico-legal cases in the UK. Molecular detection methods are used increasingly but are untested as evidence of infection in a court of law. An isolate ofN. gonorrhoeaewas obtained from a child and an article of clothing from an adult male who was suspected of sexual abuse of the child. Biochemical and immunological tests were used to confirm the isolate asN. gonorrhoeae. Amplification by PCR using two targets,cppBandompIII, was used both as further confirmation of the isolate and to detect the presence of gonococcal-specific DNA from the clothing. The relationship of the gonococcal DNA from the child and the adult was investigated using genotyping (N. gonorrhoeaemulti-antigen sequence typing; NG-MAST), including a nested PCR for theporgene. Both samples were indistinguishable by NG-MAST and shared the same sequence type, 403. This is the first report of molecular detection and genotyping ofN. gonorrhoeaeon an article of clothing, which resulted in conviction of the man for sexual assault.
Serotype distribution of Streptococcus mutans a pathogen of dental caries in cardiovascular specimens from Japanese patients
Authors: Nakano Kazuhiko , Nemoto Hirotoshi , Nomura Ryota , Homma Hiromi , Yoshioka Hideo , Shudo Yasuhiro , Hata Hiroki , Toda Koichi , Taniguchi Kazuhiro , Amano Atsuo , Ooshima Takashi
Published: March 2007

The involvement of oral bacteria in the pathogenesis of cardiovascular disease has been studied, with Streptococcus mutans, a pathogen of dental caries, detected in cardiovascular lesions at a high frequency. However, no information is available regarding the properties of S. mutans detected in those lesions. Heart valve specimens were collected from 52 patients and atheromatous plaque specimens from 50 patients, all of whom underwent cardiovascular operations, and dental plaque specimens were taken from 41 of those subjects prior to surgery. Furthermore, saliva samples were taken from 73 sets of healthy mothers (n=73) and their healthy children (n=78). Bacterial DNA was extracted from all specimens, then analysed by PCR with S. mutans-specific and serotype-specific primer sets. The detection rates of S. mutans in the heart valve and atheromatous plaque specimens were 63 and 64 %, respectively. Non-c serotypes were identified with a significantly higher frequency in both cardiovascular and dental plaque samples from the subjects who underwent surgery as compared to serotype c, which was detected in 70–75 % of the samples from the healthy subjects. The serotype distribution in cardiovascular patients was significantly different from that in healthy subjects, suggesting that S. mutans serotype may be related to cardiovascular disease.
Molecular evolution and radiation of dung beetles in Madagascar
Authors: Orsini Luisa , Koivulehto Helena , Hanski Ilkka
Published: March 2007

Madagascar is the world's fourth largest island and has a wide range of climates and ecosystems. Environmental diversity combined with long history of isolation (160 Myr) has generated a high level of endemism at different taxonomic levels, making Madagascar one of the hotspots of global biodiversity. Dung beetles, represented by the two tribes of Canthonini and Helictopleurini, exemplify a large insect taxon. Helictopleurini are completely endemic to Madagascar while Canthonini are endemic at generic level. Using data from mitochondrial and nuclear genes, phylogenetic relationships were investigated in a sample of 44 species. The phylogeny for Canthonini consists of several distinct clades, possibly reflecting multiple colonization of Madagascar. The phylogeny does not support the current taxonomy for all genera. The phylogeny for Helictopleurini lacks statistical support at supra‐specific level, and genetic divergence among the Helictopleurini species is comparable with that among species within genera in Canthonini. These results suggest that Helictopleurini has undergone rapid speciation and most likely more recently than Canthonini, consistent with the estimated radiation time based on mtDNA mutation rates in insects and with knowledge about the systematics and geographic distribution of dung beetles worldwide. A detailed analysis of sequence composition identified common patterns in Malagasy dung beetles and other insects.

© The Willi Hennig Society 2007.
The Relationship between Internal Audit and Senior Management: A Qualitative Analysis of Expectations and Perceptions
Authors: Sarens Gerrit , De Beelde Ignace
Published: March 2007

This study, based upon Belgian case studies, provides a qualitative assessment of the relationship between internal audit and senior management, analysing the expectations and perceptions of both parties. We found that senior management's expectations have a significant influence on internal audit and that internal audit, generally, is able to meet most of these expectations. Senior management wants internal audit to compensate for the loss of control they experience resulting from increased organisational complexity. Senior management expects internal audit to fulfil a supporting role in the monitoring and improvement of risk management and internal control, and wants them to monitor the corporate culture. Furthermore, they expect internal audit to be a training ground for future managers. On the other hand, internal audit expects senior management to take the first steps in the formalisation of the risk management system. They are looking for senior management support, as this benefits their overall acceptance.
Auditor Conservatism and Audit Quality: Evidence from IPO Earnings Forecasts
Authors: Lee Philip J. , Taylor Sarah J. , Taylor Stephen L.
Published: March 2007

We investigate the relation between a proxy for differential audit quality and both the (ex post) accuracy and conservatism of audited earnings forecasts provided in Australian initial public offering (IPO) prospectuses. For the period we examine, most Australian IPO prospectuses include an earnings forecast (i.e., disclosure is not ‘voluntary’), and the auditor must be satisfied prior to signing off on the prospectus. After controlling for other factors associated with forecast error, there is some evidence that forecasts audited by Big 6 auditors prove more accurate than those audited by a non‐Big 6 auditor, although this result is not robust across alternative measures of forecast accuracy. In contrast, our finding of significantly less optimistic bias for forecasts associated with Big 6 auditors is robust to alternative measures of forecast bias. We interpret these results as being consistent with the argument that the economic demand for differential audit quality reflects the same factors that underlie the demand for conservative financial reporting.
Genetic abnormalities involved in t(12;21) TEL–AML1 acute lymphoblastic leukemia: Analysis by means of array‐based comparative genomic hybridization
Authors: Tsuzuki Shinobu , Karnan Sivasundaram , Horibe Keizo , Matsumoto Kimikazu , Kato Koji , Inukai Takeshi , Goi Kumiko , Sugita Kanji , Nakazawa Shinpei , Kasugai Yumiko , Ueda Ryuzo , Seto Masao
Published: March 2007

The TEL (ETV6)–AML1 (RUNX1) chimeric gene fusion is the most common genetic abnormality in childhood acute lymphoblastic leukemias. Evidence suggests that this chimeric gene fusion constitutes an initiating mutation that is necessary but insufficient for the development of leukemia. In a search for additional genetic events that could be linked to the development of leukemia, we applied a genome‐wide array‐comparative genomic hybridization technique to 24 TEL–AML1 leukemia samples and two cell lines. It was found that at least two chromosomal imbalances were involved in all samples. Recurrent regions of chromosomal imbalance (>10% of cases) and representative involved genes were gain of chromosomes 10 (17%) and 21q (25%; RUNX1) and loss of 12p13.2 (87%; TEL), 9p21.3 (29%; p16INK4a/ARF), 9p13.2 (25%; PAX5), 12q21.3 (25%; BTG1), 3p21 (21%; LIMD1), 6q21 (17%; AIM1 and BLIMP1), 4q31.23 (17%; NR3C2), 11q22‐q23 (13%; ATM) and 19q13.11‐q13.12 (13%; PDCD5). Enforced expression of TEL and to a lesser extent BTG1, both single genes known to be located in their respective minimum common region of loss, inhibited proliferation of the TEL–AML1 cell line Reh. Together, these findings suggest that some of the genes identified as lost by array‐comparative genomic hybridization may partly account for the development of leukemia. (Cancer Sci 2007; 98: 698–706)