bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam
Authors: Shord Stacy S. , Chan Lingtak‐Neander , Camp Joseph R. , Vasquez Eva M. , Jeong Hyun‐Young , Molokie Robert E. , Baum Charles L. , Xie Hui
Published: October 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Clotrimazole troches are commonly used as prophylaxis for thrush that may develop in immunocompromised patients.

• Conflicting data suggest that clotrimazole may induce or inhibit cytochrome P450 (CYP) 3A4.

WHAT THIS STUDY ADDS?

• We have demonstrated that clotrimazole increased the area under the concentration–time curve and decreased the apparent oral clearance of midazolam following oral administration without affecting the pharmacokinetic properties of midazolam after intravenous administration.

• These data permit the suggestion that clotrimazole may cause clinically relevant changes in the pharmacokinetics or pharmacodynamics of concurrently administered oral CYP3A substrates that undergo significant first‐pass metabolism in this patient population.

AIMS

The aim of the study was to determine the effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam in the plasma.

METHODS

We conducted a randomized, open‐label, four‐way crossover study in 10 healthy volunteers. Each volunteer received oral midazolam 2 mg or intravenous midazolam 0.025 mg kg−1with and without oral clotrimazole troches 10 mg taken three times daily for 5 days. Each study period was separated by 14 days. Serial blood samples were collected up to 24 h after oral midazolam and 6 h after intravenous midazolam. Plasma concentrations for midazolam and its metabolite 1‐hydroxymidazolam were measured and fitted to a noncompartmental model to estimate the pharmacokinetic parameters.

RESULTS

Ten healthy volunteers aged 21–26 years provided written informed consent and were enrolled into the study. Clotrimazole decreased the apparent oral clearance of midazolam from 57 ± 13 l h−1[95% confidence interval 48, 66] to 36 ± 9.8 l h−1(95% confidence interval 29, 43) (P= 0.003). These changes were accompanied by a decrease in the area under the concentration–time curve (mean difference 22 µg h−1 l−1,P= 0.001) and bioavailability (mean difference 0.21,P= NS). There were no significant differences in the systemic clearance of midazolam with or without clotrimazole troches.

CONCLUSIONS

Oral clotrimazole troches decreased the apparent oral clearance of midazolam; no significant differences in the systemic clearance of midazolam were found.
Is there an anti‐inflammatory effect of statins in rheumatoid arthritis? Analysis of a large routinely collected claims database
Authors: Lodi Sara , Evans Stephen J. W. , Egger Peter , Carpenter James
Published: October 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The increasing evidence of the anti‐inflammatory action of statins has stimulated interest in whether these might be beneficial in disease management of rheumatoid arthritis (RA), a chronic diseases characterized by high levels of inflammation.

• The TARA trial (McCarey 2004) suggested a significant reduction in disease activity outcomes in RA patients randomized to atorvastatin compared with those assigned to the placebo harm.

• However, as the signal reported by the trial was small, more evidence is needed.

WHAT THIS PAPER ADDS

• We investigated the possible anti‐inflammatory effect of statins in a cohort of RA patients using a large health insurance claims database.

• To our knowledge, this is the largest study ever conducted on the anti‐inflammatory effects of statins.

• Our data do not show any beneficial effect of statins in reducing disease inflammation in RA patients.

AIM To investigate the possible anti‐inflammatory effect of statins in a cohort of rheumatoid arthritis (RA) patients.

METHODS We conducted a cohort study consisting of all patients with at least one claim for RA using LifeLink, a health insurance claims database. Initiation and cessation of oral steroid (OS) therapy were treated as surrogate for inflammatory flare‐up and controlled inflammation, respectively. We split the RA patients into two sub‐cohorts based on whether they were using OS within a specified time window of the RA index date (first recorded claim for RA in the database). Cox proportional hazard models were used to evaluate the association between time‐varying exposure to any statins and (i) initiation of OS therapy in the non‐users of OS at RA index date and (ii) cessation of OS therapy in the users of OS at RA index date controlling for potential confounders.

RESULTS We found 31 451 non‐users of OS at RA index date and 6026 users of OS within the time window at RA index date. The results on both sub‐cohorts were both consistent with no association of statin exposure with the risk of initiation/cessation of OS: the hazard ratio (HR) of initiating OS therapy was 0.96 (95% confidence interval 0.9, 1.01) in the sub‐cohort of non‐users and the HR of cessation of OS therapy was 0.95 (0.87, 1.05) in the sub‐cohort of users of OS therapy at RA diagnosis.

CONCLUSIONS These data do not show any beneficial effect of statins in reducing disease inflammation in RA patients.
Advances in the understanding of acquired haemophilia A: implications for clinical practice
Authors: Collins Peter W. , Percy Charles L.
Published: October 2009

Acquired haemophilia A is an auto‐immune disease caused by an inhibitory antibody to factor VIII. Patients with an acquired factor VIII inhibitor are at risk of life‐ and limb‐threatening bleeding until the inhibitor has been eradicated. Management relies on rapid and accurate diagnosis, control of bleeding episodes, investigation for a precipitating cause and eradication of the inhibitor by immunosuppression. Patients should always be managed jointly with a specialist centre even if they present without overt bleeding. Despite an extensive literature, few controlled data are available and management guidelines are predominantly based on case reports, retrospective cohorts and expert opinion. This paper reviews the current literature on incidence, pathogenesis, diagnosis, haemostatic therapy and inhibitor eradication strategies. Potential future developments are discussed.
Association between asthma control and bronchial hyperresponsiveness and airways inflammation: a cross‐sectional study in daily practice
Authors: Quaedvlieg V. , Sele J. , Henket M. , Louis R.
Published: October 2009

Background
The primary end‐point in the management of asthma is to obtain optimal control. The aim of this study was to assess the relationships between the markers of airway inflammation (sputum eosinophilia and exhaled nitric oxide), bronchial hyperresponsiveness (BHR) and asthma control.

Methods
One hundred and thirty‐four patients were recruited from our asthma clinic between January 2004 and September 2005 [mean age: 42 years, mean forced expiratory volume in 1 s (FEV1): 86% predicted]. Eighty‐six of them were treated by inhaled corticosteroids, 99 were atopic and 23 were current smokers. They all underwent detailed investigations including fractional‐exhaled nitric oxide (FENO) measurement, sputum induction and methacholine challenge when FEV1 was >70% predicted, and filled in a validated asthma control questionnaire (ACQ6 Juniper).

Results
When dividing patients into the three groups according to their level of asthma control determined by ACQ [well‐controlled asthma (ACQ score 0.75), borderline (0.75<ACQ score <1.5) and uncontrolled asthma (ACQ score 1.5)], it appeared that uncontrolled asthmatics had a greater BHR to methacholine and sputum eosinophilia than controlled asthma (P<0.05, P<0.001, respectively). By contrast, we failed to show significant differences in the FENO levels between the groups. With receiver‐operating characteristic curves for differentiating uncontrolled (ACQ1.5) from controlled and borderline (ACQ<1.5) asthma, sputum eosinophilia and methacholine responsiveness were found to be more accurate than FENO (area under the curve: 0.72, 0.72 and 0.59, respectively).

Conclusion
In a broad spectrum of asthmatics encountered in clinical practice, sputum eosinophilia and methacholine bronchial hyperresponsiveness, but not FENO, are associated with uncontrolled asthma.
Establishing the sequential progression of multiple allergic diagnoses in a UK birth cohort using the General Practice Research Database
Authors: Punekar Y. S. , Sheikh A.
Published: October 2009

Background
There is considerable international interest in understanding the sequential progression of multiple allergic conditions (also sometimes known as ‘the allergic march’).

Objectives
To study the sequential progression of multiple allergic conditions in a national birth cohort throughout childhood.

Methods
We constructed a birth cohort of 43 477 children born in 1990 and registered in UK general practices within a year of birth, using the national General Practice Research Database. Of these, 24 112 with complete follow‐up until the age of 18 years were studied in order to understand disease progression and to estimate the absolute and relative risks of developing second and third allergic diagnoses following an index allergic condition.

Results
52.1% of children were diagnosed with at least one condition at some point in childhood. We were able to describe 15 different disease trajectories. Eczema was the most likely index condition with 60.7% [95% confidence interval (CI): 59.8–61.6] of allergy sufferers being diagnosed with this condition first. For those with a diagnosis of eczema, the relative risks of being diagnosed with asthma followed by rhinitis and rhinitis followed by asthma were 1.59 (95% CI: 1.32–1.91; P<0.0001) and 0.54 (95% CI: 0.43–0.68; P<0.0001), respectively. For those diagnosed with asthma first, the relative risks of being diagnosed with eczema followed by rhinitis and rhinitis followed by eczema were 1.27 (95% CI: 0.96–1.68; P=0.095) and 0.27 (95% CI: 0.20–0.36; P<0.0001), respectively. For those diagnosed with rhinitis first, the relative risks of being diagnosed with eczema followed by asthma and asthma followed by eczema were 0.64 (95% CI: 0.42–0.95; P=0.025) and 0.47 (95% CI: 0.32–0.67; P<0.0001), respectively.

Conclusions
Among children diagnosed with multiple allergic diseases there is likely to be a number of variants of ‘the allergic march’. Of these, the diagnosis of eczema followed by asthma, which is in turn followed by rhinitis, is the most common trajectory. Surprisingly, some diagnoses indicate a possible strong protective effect of manifesting further likely allergic diagnoses.
Study of mutations in Jordanian patients with haemophilia A: identification of five novel mutations
Authors: AWIDI A. , RAMAHI M. , AlHATTAB D. , MEFLEH R. , DWEIRI M. , BSOUL N. , MAGABLAH A. , ARAFAT E. , BARQAWI M. , BISHTAWI M. , HADDADEEN E. , FALAH M. , TARAWNEH B. , SWAIDAN S. , FAUORI S.
Published: October 2009

Summary.  Haemophilia A (HA) is an X‐linked recessive bleeding disorder caused by mutations in the factor VIII gene (F8), which encodes factor VIII (FVIII) protein, a plasma glycoprotein, that plays an important role in the blood coagulation cascade. In the present study, our aim was to identify F8 gene mutations in HA patients from Jordan. One hundred and seventy‐five HA patients from 42 unrelated families were included in this study. Among these patients, 117 (67%) had severe HA, 13 (7%) had moderate HA and 45 (26%) had mild HA. Severe patients were first tested for intron‐22 inversion using long range polymerase chain reaction (PCR), then negative patients were tested for intron‐1 inversion using PCR. Sequencing for the entire F8 gene was performed for all severe HA patients who were found negative for intron‐22 and ‐1 inversions and it was also performed for moderate and mild HA patients. HA causative mutations were identified in all patients. Intron‐22 and ‐1 inversions were detected in 52% and 2% of families respectively. Beside these two mutations, 19 different mutations were identified, which include 15 missense and four frameshift mutations. Five novel mutations were identified including one frameshift and four missense mutations. No large deletions or nonsense mutations were detected in patients who participated in this study. Only 17 patients with severe HA were found positive for FVIII inhibitors. The data presented will play an important role for genetic counselling and health care of HA patients in Jordan.
Nitric oxide detection in cell culture exposed to LPS after Er:YAG laser irradiation
Authors: Rocha R. A. S. S. , Silva R. A. B. , Assed S. , Medeiros A. I. , Faccioli L. H. , Pécora J. D. , Nelson‐Filho P.
Published: October 2009

Aim  To evaluate in vitro the effect of calcium hydroxide [Ca(OH)2] and Er:YAG laser on bacterial endotoxin [also known as lipopolysaccharide (LPS)] as determined by nitric oxide (NO) detection in J774 murine macrophage cell line culture.

Methodology  Samples of LPS solution (50 μgmL−1), Ca(OH)2 suspension (25 mg mL−1) and LPS suspension with Ca(OH)2 were prepared. The studied groups were: I – LPS (control); II – LPS + Ca(OH)2; III – LPS + Er:YAG laser (15 Hz 140 mJ); IV – LPS + Er:YAG laser (15 Hz 200 mJ); V – LPS + Er:YAG laser (15 Hz 250 mJ), VI – Pyrogen‐free water; VII – Ca(OH)2. Murine macrophage J774 cells were plated and 10 μL of the samples were added to each well. The supernatants were collected for NO detection by the Griess reaction. Data were analysed statistically by one‐way anova and Tukey’s test at 5% significance level.

Results  The mean and SE (in μmol L−1) values of NO release were: I – 10.48 ± 0.58, II – 6.41 ± 0.90, III – 10.2 ± 0.60, IV – 8.35 ± 0.40, V – 10.40 ± 0.53, VI – 3.75 ± 0.70, VII – 6.44 ± 0.60; and the values for the same experiment repeated after 1 week were: I – 21.20 ± 1.50, II – 9.10 ± 0.60, III – 19.50 ± 1.00, IV – 18.50 ± 0.60, V – 21.30 ± 0.90, VI – 2.00± 0.20, VII – 6.80 ± 1.70. There was no significant difference (P > 0.05) between the control and the laser‐treated groups (III, IV and V), or comparing groups II, VI and VII to each other (P > 0.05). Group I had significantly higher NO release than group II (P < 0.05). Groups II and VI had similar NO release (P > 0.05).

Conclusions  Calcium hydroxide inactivated the bacterial endotoxin (LPS) whereas none of the Er:YAG laser parameter settings had the same effectiveness.
Rubber dam usage for endodontic treatment: a review
Authors: Ahmad I. A.
Published: October 2009

Rubber dam has been available to the dental profession for over 140 years. During this time, the use of rubber dam has been perfected, universally taught and recommended by professional organizations. Unfortunately, its consistent use has been rejected by many in the profession. The literature suggests that rubber dam is not used routinely by dental practitioners for root canal treatment. Many unfounded reasons have been cited for its lack of use, including concerns over patient acceptance, time required for application, cost of equipment and materials, insufficient training, difficulty in use and low treatment fees. Failure to use rubber dam has been shown to influence the choice of root canal irrigant, has a negative impact on treatment outcome and places the patient at risk of swallowing or aspirating materials and instruments. Methods to popularize rubber dam amongst general practitioners are discussed.
Body size–climate relationships of European spiders
Authors: Entling Wiebke , Schmidt‐Entling Martin H. , Bacher Sven , Brandl Roland , Nentwig Wolfgang
Published: October 2009

Aim  Geographic body size patterns of mammals and birds can be partly understood under the framework of Bergmann’s rule. Climatic influences on body size of invertebrates, however, appear highly variable and lack a comparable, generally applicable theoretical framework. We derived predictions for body size–climate relationships for spiders from the literature and tested them using three datasets of variable spatial extent and grain.

Location  Europe.

Methods  To distinguish climate from space, we compared clines in body size within three datasets with different degrees of co‐variation between latitude and climate. These datasets were: (1) regional spider faunas from 40 European countries and large islands; (2) local spider assemblages from standardized samples in 32 habitats across Europe; and (3) local spider assemblages from Central European habitats. In the latter dataset climatic conditions were determined more by habitat type than by geographic position, and therefore this dataset provided a non‐spatial gradient of various microclimates. Spider body size was studied in relation to latitude, temperature and water availability.

Results  In all three datasets the mean body size of spider assemblages increased from cool/moist to warm/dry environments. This increase could be accounted for by turnover from small‐bodied to large‐bodied spider families. Body size–climate relationships within families were inconsistent.

Main conclusions  Starvation resistance and accelerated maturation can be ruled out as explanations for the body size clines recorded, because they predict the inverse of the observed relationship between spider body size and temperature. The relationship between body size and climate was partly independent of geographic position. Thus, the restriction of large‐bodied spiders to their glacial refugia owing to dispersal limitations can be excluded. Our results are consistent with mechanisms invoking metabolic rate, desiccation resistance and community interactions to predict a decrease in body size from warm and dry to cool and moist conditions.
Cryptococcus neoformans Site‐2 protease is required for virulence and survival in the presence of azole drugs
Authors: Bien Clara M. , Chang Yun C. , Nes W. David , Kwon‐Chung Kyung J. , Espenshade Peter J.
Published: October 2009

In the human fungal pathogen Cryptococcus neoformans, the SREBP orthologue Sre1 is important for adaptation and growth in nutrient‐limiting host tissues. In this study, we characterize the C. neoformans serotype A Sre1 and its activating protease, Stp1. We demonstrate that Stp1 is a functionally conserved orthologue of the mammalian Site‐2 protease and that Stp1 cleaves Sre1 within its predicted first transmembrane segment. Gene expression analysis revealed that Stp1 is required for both Sre1‐dependent and Sre1‐independent gene transcription, indicating that other substrates of Stp1 may exist. Using gas chromatography, we showed that Sre1 and Stp1 are required for both normoxic and hypoxic ergosterol biosynthesis, and therefore cells lacking SRE1 or STP1 are defective for growth in the presence of low levels of the ergosterol biosynthesis inhibitors, itraconazole and 25‐thialanosterol. Importantly, our studies demonstrated fungicidal effects of itraconazole and 25‐thialanosterol towards sre1Δ and stp1Δ cells, demonstrating that the Sre1 pathway is required for both growth and survival in the presence of sterol biosynthesis‐inhibiting antifungal drugs. Given the need for fungicidal drugs, we propose that inhibitors of Stp1, Sre1, or other regulators of Sre1 function administered in combination with a sterol synthesis inhibitor could prove an effective anticryptococcal therapy.
A role for tungsten in the biology of Campylobacter jejuni: tungstate stimulates formate dehydrogenase activity and is transported via an ultra‐high affinity ABC system distinct from the molybdate transporter
Authors: Smart Jonathan P. , Cliff Matthew J. , Kelly David J.
Published: October 2009

The food‐borne pathogen Campylobacter jejuni possesses no known tungstoenzymes, yet encodes two ABC transporters (Cj0300–0303 and Cj1538–1540) homologous to bacterial molybdate (ModABC) uptake systems and the tungstate transporter (TupABC) of Eubacterium acidaminophilum respectively. The actual substrates and physiological role of these transporters were investigated. Tryptophan fluorescence spectroscopy and isothermal titration calorimetry of the purified periplasmic binding proteins of each system revealed that while Cj0303 is unable to discriminate between molybdate and tungstate (KD values for both ligands of 4–8 nM), Cj1540 binds tungstate with a KD of 1.0 ± 0.2 pM; 50 000‐fold more tightly than molybdate. Induction‐coupled plasma mass spectroscopy of single and double mutants showed that this large difference in affinity is reflected in a lower cellular tungsten content in a cj1540 (tupA) mutant compared with a cj0303c (modA) mutant. Surprisingly, formate dehydrogenase (FDH) activity was decreased ∼50% in the tupA strain, and supplementation of the growth medium with tungstate significantly increased FDH activity in the wild type, while inhibiting known molybdoenzymes. Our data suggest that C. jejuni possesses a specific, ultra‐high affinity tungstate transporter that supplies tungsten for incorporation into FDH. Furthermore, possession of two MoeA paralogues may explain the formation of both molybdopterin and tungstopterin in this bacterium.
Degradation of nitroaromatic compounds: a model to study evolution of metabolic pathways
Authors: Kivisaar Maia
Published: October 2009

Although many nitroaromatic compounds have been in nature for only a few decades, bacteria have already evolved the ability to metabolize them. Both horizontal transfer of genes and mutagenesis induced under stressful conditions might facilitate evolution of new catabolic pathways. Nitrotoluene degradation pathways are supposedly derived from an ancestral naphthalene degradation pathway. The 2‐nitrotoluene degradation genes in Acidovorax sp. strain JS42 are controlled by the transcriptional activator NtdR, which differs from NagR, the activator of the naphthalene degradation operon in Ralstonia sp. strain U2, by only five amino acids. Both regulators respond to salicylate, an intermediate of naphthalene degradation, but NtdR also recognizes a wide range of nitroaromatic compounds. In this issue of Molecular Microbiology, Ju et al. present results of site‐directed mutagenesis of NtdR and NagR and show how the nitrotoluene‐responsive regulator NtdR can be generated from a NagR‐like ancestor by only a few mutations. The reconstructed hypothetical pathway for the evolution of NtdR from NagR demonstrates stepwise broadening of the effector range of the evolving protein without loss of the original activity. These results provide strong evidence for the idea that promiscuity of proteins is an important step in the evolution of new functions.
An upstream activation element exerting differential transcriptional activation on an archaeal promoter
Authors: Peng Nan , Xia Qiu , Chen Zhengjun , Liang Yun Xiang , She Qunxin
Published: October 2009

Microorganisms can utilize different sugars as energy and carbon sources and the genes involved in sugar metabolism often exhibit highly regulated expression. To study cis‐acting elements controlling arabinose‐responsive expression in archaea, the promoter of the Sulfolobus solfataricus araS gene encoding an arabinose binding protein was characterized using an Sulfolobus islandicus reporter gene system. The minimal active araS promoter (ParaS) was found to be 59 nucleotides long and harboured four promoter elements: an ara‐box, an upstream transcription factor B‐responsive element (BRE), a TATA‐box and a proximal promoter element, each of which contained important nucleotides that either greatly decreased or completely abolished promoter activity upon mutagenesis. The basal araS promoter was virtually inactive due to intrinsically weak BRE element, and the upstream activating sequence (UAS) ara‐box activated the basal promoter by recruiting transcription factor B to its BRE. While this UAS ensured a general expression from an inactive or weak basal promoter in the presence of other tested carbon resources, it exhibited a strong arabinose‐responsive transcriptional activation. To our knowledge, this represents the first example of an archaeal UAS that exhibits differential activation to the expression on the same promoter in the presence of different carbon sources.
Replication fork collisions cause pathological chromosomal amplification in cells lacking RecG DNA translocase
Authors: Rudolph Christian J. , Upton Amy L. , Lloyd Robert G.
Published: October 2009

Duplication and transmission of chromosomes require precise control of chromosome replication and segregation. Here we present evidence that RecG is a major factor influencing these processes in bacteria. We show that the extensive DnaA‐independent stable DNA replication observed without RecG can lead to replication of any area of the chromosome. This replication is further elevated following irradiation with UV light and appears to be perpetuated by secondary events that continue long after the elimination of UV lesions. The resulting pathological cascade is associated with an increased number of replication forks traversing the chromosome, sometimes with extensive regional amplification of the chromosome, and with the accumulation of highly branched DNA intermediates containing few Holliday junctions. We propose that the cascade is triggered by replication fork collisions that generate 3′ single‐strand DNA flaps, providing sites for PriA to initiate re‐replication of the DNA and thus to generate linear duplexes that provoke recombination, allowing priming of even further replication. Our results shed light on why termination of replication in bacteria is normally limited to a single encounter of two forks and carefully orchestrated within a restricted area, and explain how a system of multiple forks and random termination can operate in eukaryotes.
Listeria monocytogenes CtaP is a multifunctional cysteine transport‐associated protein required for bacterial pathogenesis
Authors: Xayarath Bobbi , Marquis Hélène , Port Gary C. , Freitag Nancy E.
Published: October 2009

The bacterial pathogen Listeria monocytogenes survives under a myriad of conditions in the outside environment and within the human host where infections can result in severe disease. Bacterial life within the host requires the expression of genes with roles in nutrient acquisition as well as the biosynthesis of bacterial products required to support intracellular growth. A gene product identified as the substrate‐binding component of a novel oligopeptide transport system (encoded by lmo0135) was recently shown to be required for L. monocytogenes virulence. Here we demonstrate that lmo0135 encodes a multifunctional protein that is associated with cysteine transport, acid resistance, bacterial membrane integrity and adherence to host cells. The lmo0135 gene product (designated CtaP, for cysteine transport associated protein) was required for bacterial growth in the presence of low concentrations of cysteine in vitro, but was not required for bacterial replication within the host cytosol. Loss of CtaP increased membrane permeability and acid sensitivity, and reduced bacterial adherence to host cells. ctaP deletion mutants were severely attenuated following intragastric and intravenous inoculation of mice. Taken together, the data presented indicate that CtaP contributes to multiple facets of L. monocytogenes physiology, growth and survival both inside and outside of animal cells.
Cell elongation and branching are regulated by differential phosphorylation states of the nuclear Dbf2‐related kinase COT1 in Neurospora crassa
Authors: Ziv Carmit , Kra‐Oz Galia , Gorovits Rena , März Sabine , Seiler Stephan , Yarden Oded
Published: October 2009

Dysfunction of the Neurospora crassa nuclear Dbf2‐related kinase COT1 leads to cessation of tip extension and massive induction of new sites of growth. To determine the role phosphorylation plays in COT1 function, we mutated COT1 residues corresponding to positions of highly conserved nuclear Dbf2‐related phosphorylation sites. Analyses of the point‐mutation cot‐1 strains (mimicking non‐ and constitutively phosphorylated states) indicate the involvement of COT1 phosphorylation in the regulation of hyphal elongation and branching as well as asexual development by altering cell wall integrity and actin organization. Phosphorylation of COT1's activation segment (at Ser417) is required for proper in vitro kinase activity, but has only a limited effect on hyphal growth. In marked contrast, even though phosphorylation of the C‐terminal hydrophobic motif (at Thr589) is crucial for all COT1 functions in vivo, the lack of Thr589 phosphorylation did not significantly affect in vitro COT1 kinase activity. Nevertheless, its regulatory role has been made evident by the significant increase observed in COT1 kinase activity when this residue was substituted in a manner mimicking constitutive phosphorylation. We conclude that COT1 regulates elongation and branching in an independent manner, which is determined by its phosphorylation state.
Parasites as aetiological agents in chronic diseases. Epidemiological associations and potential mechanisms of pathogenesis
Authors: BROWN M.
Published: October 2009

The aetiological role of parasitic infection has been well established, through epidemiological studies, for many chronic diseases prevalent in the tropics. Examples include Schistosoma mansoni infection leading to portal hypertension, Schistosoma haematobium infection leading to obstructive uropathy and squamous cell carcinoma of the bladder, Clonorchis sinensis leading to cholangiocarcinoma, and Taenia solium infection leading to epilepsy. Our understanding of the pathogenesis of these associations, however, continues to evolve, with new insights from many fertile avenues in chronic disease research. There are also tenuous associations such as schizophrenia with toxoplasmosis, and the findings from observational studies that link malignancy and epilepsy with a range of helminthic infections. Imprecise case definitions, and the lack of good animal models, are limitations to the evidence for a causal role of parasitic infection in these diseases.
Assessment of need and capacity to benefit for people with a disability requiring aids, appliances and equipment
Authors: Masso Malcolm , Owen Alan , Stevermuer Tara , Williams Kathryn , Eagar Kathy
Published: October 2009

Aim:  To develop an equitable system for allocating equipment, aids and appliances to adults with disabilities based on assessment of need and capacity to benefit for use by occupational therapists, who are the main professional group involved in assessing and prioritising applications.

Methods:  An assessment tool was developed, pilot tested and field tested at four sites in New South Wales. Assessments were undertaken in parallel with existing systems. Feedback on use of the tool was obtained from those conducting the assessments and those making decisions to fund applications for equipment based on the assessments.

Results:  One hundred and six assessments were undertaken. Applications for bed, sleeping and seating equipment and equipment to assist with mobility, toileting, showering and transfers accounted for 94.2% of equipment requested. Provision of equipment was expected to have greatest impact on the physical effort and safety of carers and the safety and quality of life of applicants. Regression analysis identified assessment items that explain variation between applicants and that can avoid unnecessary data collection.

Conclusions:  The assessment tool provides a standardised method for assessing requests for equipment based on the twin concepts of need and capacity to benefit. The results support the use of both concepts as the foundation of the assessment process. Further development is required, particularly to move to the next stage of using the assessment tool as the basis for prioritising applications for equipment.
A model for play‐based intervention for children with ADHD
Authors: Cordier Reinie , Bundy Anita , Hocking Clare , Einfeld Stewart
Published: October 2009

Background/aim: The importance of play in the social development of children is undisputed. Even though children with attention‐deficit hyperactivity disorder (ADHD) experience serious social problems, there is limited research on their play. By integrating literature on ADHD with literature on play, we can postulate how play is influenced by the characteristics of ADHD. These postulations enabled us to propose a theoretical model (proposed model) to depict the interactive process between the characteristics of ADHD and factors that promote play. This paper presents the revised model and principles for intervention based on the results of a study investigating the play of children with ADHD (reported elsewhere).

Methods: We tested the proposed model in a study comparing two groups of children (n = 350) between the ages of 5 and 11 years. One group consisted of children diagnosed with ADHD (n = 112) paired with playmates (n = 112) who were typically developing; the control group consisted of typically developing children paired with typically developing playmates (n = 126). The Test of Playfulness was administered, and the model was revised in line with the findings.

Results and conclusions: The findings suggest difficulties in the social play and lack of interpersonal empathy in the play of children with ADHD. We draw on the revised model to propose preliminary principles for play‐based interventions for children with ADHD. The principles emphasise the importance of capturing the motivation of children with ADHD, counteracting the effects of lack of interpersonal empathy, and considerations for including playmates in the intervention process.
A novel device (SD‐101) with high accuracy for screening sleep apnoea‐hypopnoea syndrome
Authors: AGATSUMA Toshihiko , FUJIMOTO Keisaku , KOMATSU Yoshimichi , URUSHIHATA Kazuhisa , HONDA Takayuki , TSUKAHARA Teruomi , NOMIYAMA Tetsuo
Published: October 2009

Background and objective:  The SD‐101 is a non‐restrictive, sheet‐like medical device with an array of pressure sensors, to detect sleep‐disordered breathing by sensing gravitational alterations in the body corresponding to respiratory movements. This study evaluated the accuracy of the SD‐101 for screening sleep apnoea‐hypopnoea syndrome (SAHS) by comparison with polysomnography.

Methods:  Nocturnal polysomnography and SD‐101 monitoring were conducted simultaneously and compared in 201 patients with suspected SAHS (suspected SAHS group) and 165 male employees of a transport company (screening group).

Results:  Polysomnography revealed an AHI of <5, 5 ≤ AHI < 15, 15 ≤ AHI < 30, 30 ≤ AHI < 60 and AHI ≥ 60 events/h in 39, 35, 38, 68 and 21 subjects in the suspected SAHS group and 103, 34, 12, 12 and four subjects in the screening group, respectively. Central SAHS and obstructive SAHS were subsequently diagnosed in 11 (5.5%) and 135 (67.2%) of subjects in the suspected SAHS group and five (3.0%) and 39 (23.6%) of subjects in the screening group, respectively. Significant correlations were apparent between AHI and the respiratory disturbance index (RDI) measured with the SD‐101 in both the suspected SAHS group (r = 0.88) and screening group (r = 0.92). Receiver operating characteristic curve analysis revealed 89.5% sensitivity and 85.8% specificity in identifying SAHS, using an RDI of 14.0 events/h.

Conclusions:  These findings suggest that the SD‐101 is a useful device for screening SAHS.
Monoclonal anti‐vascular endothelial growth factor antibody reduces fluid volume in an experimental model of inflammatory pleural effusion
Authors: RIBEIRO Sabrina C.C. , VARGAS Francisco S. , ANTONANGELO Leila , MARCHI Evaldo , GENOFRE Eduardo H. , ACENCIO Milena M.P. , TEIXEIRA Lisete R.
Published: October 2009

Background and objective:  Vascular endothelial growth factor (VEGF) is known to increase vascular permeability and promote angiogenesis. It is expressed in most types of pleural effusions. However, the exact role of VEGF in the development of pleural effusions has yet to be determined. The anti‐VEGF mAb, bevacizumab, has been used in the treatment of cancer to reduce local angiogenesis and tumour progression. This study describes the acute effects of VEGF blockade on the expression of inflammatory cytokines and pleural fluid accumulation.

Methods:  One hundred and twelve New Zealand rabbits received intrapleural injections of either talc or silver nitrate. In each group, half the animals received an intravenous injection of bevacizumab, 30 min before the intrapleural agent was administered. Five animals from each subgroup were sacrificed 1, 2, 3, 4 or 7 days after the procedure. Twelve rabbits were used to evaluate vascular permeability using Evans's blue dye. Pleural fluid volume and cytokines were quantified.

Results:  Animals pretreated with anti‐VEGF antibody showed significant reductions in pleural fluid volumes after talc or silver nitrate injection. IL‐8 levels, vascular permeability and macroscopic pleural adhesion scores were also reduced in the groups that received bevacizumab.

Conclusions:  This study showed that bevacizumab interferes in the acute phase of pleural inflammation induced by silver nitrate or talc, reinforcing the role of VEGF as a key mediator in the production of pleural effusions. The results also suggest that bevacizumab should probably be avoided in patients requiring pleurodesis.
How to diagnose multiple sclerosis and what are the pitfalls
Authors: Shaw C. , Chapman C. , Butzkueven H.
Published: October 2009

The task of confirming a diagnosis of multiple sclerosis (MS), one of the commonest neurological disorders affecting young adults, has altered significantly in the magnetic resonance imaging era. Conversely, key principles, most notably objective documentation of neurological dissemination in time and space, remain fundamental to the process. Clinical acumen and experience are equally as crucial as an ability to interpret relevant investigations. Recognising typical clinical patterns, addressing potential ‘mimics’, and stratifying prognosis of a clinically isolated syndrome are just some of the challenges inherent in diagnosing MS.
Enhanced regenerative axon growth of multiple fibre populations in traumatic spinal cord injury following scar‐suppressing treatment
Authors: Schiwy Nora , Brazda Nicole , Müller Hans Werner
Published: October 2009

We analysed the effect of scar‐suppressing treatment (anti‐scarring treatment; AST) on augmenting axonal regeneration of various neuronal populations following spinal cord injury (SCI) in adult rat. AST included local iron chelator (2,2′‐dipyridine‐5,5′‐dicarboxylic acid) injection and 8‐bromo‐cyclic adenosine monophosphate application to the lesion core. In previous studies, this treatment promoted long‐distance regeneration of cut corticospinal tract axons, neuroprotection of projecting cortical neurons and functional improvement of treated rats [N. Klapka et al. (2005)Eur. J. Neurosci., 22, 3047–3058]. Treatment yielded significantly enhanced regrowth of descending serotonergic (5‐HT), catecholaminergic (tyrosine hydroxylase; TH), corticospinal and rubrospinal axons into the lesion zone, as assessed by anterograde tracing and immunohistochemistry followed by quantification of axon profiles at 5 and 12 weeks post‐injury. In addition, the determination of axons crossing the proximal borderline from uninjured tissue into fibrous scar area revealed a significant AST‐promoted increase of intersecting fibres for 5‐HT, TH and calcitonin gene‐related peptide containing ascending sensory fibres. For a prolonged time period after lesion, the delayed (secondary) scar developing in treated rats is significantly more permeable for all analysed axon tracts than the initial (primary) scar forming in injured control animals lacking treatment. Furthermore, enhanced outgrowth of descending axons from fibrous scar into distal healthy spinal tissue was achieved in treated animals, and is in line with previous functional studies [S. Hermanns et al. (2001) Restor. Neurol. Neurosci., 19,139–148; N. Klapka et al. (2005)Eur. J. Neurosci., 22, 3047–3058]. Our findings indicate that AST exerts a prolonged beneficial effect on fibrous scarring allowing enhanced axonal regrowth of different fibre tracts in SCI regardless of their distinct regenerative demands.
Pairing mild stress with increased serotonin‐1B receptor expression in the nucleus accumbens increases susceptibility to amphetamine
Authors: Ferguson Susan M. , Sandygren Nolan A. , Neumaier John F.
Published: October 2009

Both serotonin‐1B (5‐HT1B) receptors and stress modulate the behavioral and neurobiological effects of psychostimulant drugs. In order to examine how these factors interact to influence the development of behaviors associated with addiction, we used viral‐mediated gene transfer to transiently increase expression of 5‐HT1Breceptors in the nucleus accumbens (NAc) shell along with exposure to repeated mild stress (novelty + saline injection) in rats. Once the viral‐mediated increases in gene expression had dissipated, the resulting effects of this 5‐HT1B/stress pairing on the acute locomotor response to amphetamine and on the development of psychomotor sensitization were examined. We report that the increasing expression of 5‐HT1Breceptors on the terminals of NAc shell neurons that project to the ventral tegmental area and repeatedly exposing rats to mild stress subsequently enhance the acute locomotor‐activating effects of amphetamine. In addition, the development of psychomotor sensitization (both locomotor activity and stereotypy components) is facilitated. These results suggest that serotonin signaling through NAc 5‐HT1Bheteroreceptors can interact with stress to increase susceptibility to the enduring forms of drug‐induced plasticity that are associated with addiction.
‘Prostatic evasive anterior tumours’: the role of magnetic resonance imaging
Authors: Lawrentschuk Nathan , Haider Masoom A. , Daljeet Nikhil , Evans Andrew , Toi Ants , Finelli Antonio , Trachtenberg John , Zlotta Alexandre , Fleshner Neil
Published: October 2009

Study Type – Diagnosis (case series) Level of Evidence 4

OBJECTIVE

To review our experience and delineate the role of magnetic resonance imaging (MRI) in identifying patients presenting with a raised prostate‐specific antigen (PSA) level and clinical findings suggestive of anterior predominant tumours, which appear to be significant, particularly in those with a previous negative biopsy or low‐volume disease undergoing active surveillance.

PATIENTS AND METHODS

We retrospectively reviewed our database to identify patients with anteriorly predominant tumours on MRI whom had undergone prostate biopsy.

RESULTS

In all, 31 patients with anterior predominant tumours on MRI also had a positive biopsy (14 on active surveillance and 17 with previous negative biopsies). MRI was usually invoked by the presenting PSA level or PSA velocity. MRI had a positive predictive value for anterior tumours of 87% (27/31). The Gleason score distribution for the 27 men with cancer was 6 in 15; 3 + 4 in three, 4 + 3 in six and 8/9 in three. For prostatic cores, 44/85 (52%) samples from the anterior prostate had cancer. Thirteen patients had a radical prostatectomy (pT2 in three, pT3 in seven and pT4 in three); seven of the 13 had positive surgical margins and a third of them had a biochemical recurrence at the 1‐year follow‐up.

CONCLUSION

There is a subset of patients either having a negative biopsy or low‐volume disease and who are on active surveillance who should be considered for MRI and further biopsy, as their pathology might be aggressive. An entity might be emerging with anterior predominant tumours that are impalpable, and we believe the term ‘prostate evasive anterior tumour syndrome’ to be appropriate. This requires further analysis in a large prospective database with consideration for triggers for MRI and targeted biopsies.
Nerve growth factor and expression of its receptors in patients with diabetic neuropathy
Authors: Kim H. C. , Cho Y. J. , Ahn C. W. , Park K. S. , Kim J. C. , Nam J. S. , Im Y. S. , Lee J. E. , Lee S. C. , Lee H. K.
Published: October 2009

Aims  Low serum nerve growth factor (NGF) levels have been reported in patients with diabetic peripheral neuropathy (DPN), but the role of NGF in the development of neuropathy is unclear. Thus, we investigated the associations of serum NGF level and NGF receptor activity with the presence and severity of DPN.

Methods  One hundred and thirty‐six patients with Type 2 diabetes were included in this cross‐sectional study. Serum NGF levels were measured by ELISA. Expressions of NGF receptors (TrkA and p75NTR) were measured by immunohistochemical staining. The presence and severity of DPN were assessed by neuropathy disability score (NDS) and by corneal nerve fibre length (cNFL) and nerve branch density (cNBD) using in vivo confocal microscopy.

Results  Patients with DPN had higher serum NGF levels (56–451 pg/ml) than patients without DPN (4–54 pg/ml). However, in DPN patients, serum NGF was negatively associated with neuropathy severity (mild 222 ± 64 pg/ml; moderate 114 ± 17 pg/ml; severe 89 ± 20 pg/ml). This negative association was consistent in all severity indices (NDS, P < 0.001; cNFL, P < 0.001; cNBD P = 0.010) even after adjustment for age, sex, diabetes duration, insulin use, fasting glucose and glycated haemoglobin. Although NGF receptor activities had significantly (P < 0.05) negative associations with the presence and severity of neuropathy, these associations were not significant when adjusted for other factors.

Conclusions  Serum NGF level was positively associated with the presence of DPN but negatively associated with neuropathy severity in DPN patients. The change in serum NGF might be a consequence of, rather than a contributor to, the early development of DPN.
Does an advanced insulin education programme improve outcomes and health service use for people with Type 2 diabetes? A 5‐year follow‐up of the Newcastle Empowerment course
Authors: Lowe J. M. , Mensch M. , McElduff P. , Fitzgerald M. , Attia J.
Published: October 2009

Objective  To show that an advanced diabetes education programme delivers sustained benefits to people with diabetes prescribed insulin and healthcare providers over and above those provided by basic diabetes education.

Methods  An historical cohort study of 68 people with Type 1 and 51 people with Type 2 diabetes on insulin who attended the 4‐day Newcastle Empowerment programme in 2001 and 2002 compared with 71 people with Type 1 and 312 people with Type 2 diabetes who attended only the basic 4‐day insulin education programme over the same period, followed until 2007. Primary outcome was all hospital admissions and emergency visits; secondary outcomes were the composite of first cardiac event or death and readmission for diabetes complications. Cox‐proportional hazards regression was used to analyse Type 1 and Type 2 diabetes separately.

Results  The empowerment programme significantly delayed time to first hospital admission/visit for patients with Type 2 diabetes; the hazard ratio (HR) of 0.41 (P = 0.01) translates into a delay of almost 3 years; this was partly driven by a significant reduction in cardiovascular events and mortality (HR = 0.24, P = 0.01). These effects were not seen for people with Type 1 diabetes.

Conclusions  A one‐time, advanced diabetes education programme teaching intensive insulin self‐management with an empowerment style can lead to sustained improvement in patient outcomes and reduce use of hospital services for people with Type 2 diabetes on insulin.