bluuebunny/crossref_metadata_2025 huggingface dataset:
New criteria for impaired fasting glucose and screening for diabetes in cystic fibrosis: Fig. 1—
Authors: Mueller-Brandes C. , Holl R. W. , Nastoll M. , Ballmann M.
Published: March 2005

Cystic fibrosis-related diabetes mellitus (CFRD) is the most frequent comorbidity in cystic fibrosis. Its clinical relevance is stressed by the association with increased mortality, and decreased pulmonary and nutritional status. An annual oral glucose tolerance test (OGTT) is recommended as a screening test for CFRD, but this is often not realised because of its time- and resource-consuming nature. Therefore, alternative approaches are welcome.

In 2003, the American Diabetes Association (ADA) lowered the cut-off point separating normal from elevated fasting plasma glucose from <6.1 mmol·L−1to <5.6 mmol·L−1, suggesting the performance of an OGTT only in those with impaired fasting glucose (IFG; range 5.6–6.0 mmol·L−1). The current authors tested whether this approach was reliable for the early identification of patients with CFRD.

OGTTs from 1,128 patients (53% males; 47% females; median age 17.1 yrs) were available for analysis. A total of 101 (8.9%) OGTTs were classified as diabetic. The new ADA criteria for IFG increased the sensitivity to 82% (versus65%) and decreased the specificity to 70% (versus94%) compared with the old criteria used to identify patients with diabetic OGTTs.

In conclusion, the American Diabetes Association approach of using impaired fasting glucose as an indication for performing selective oral glucose tolerance tests is definitely unsuitable when aiming at the early identification of patients with cystic fibrosis-related diabetes mellitus, and it cannot replace annual oral glucose tolerance tests.
Relationship between pulmonary function and lung cancer surgical outcome
Authors: Win T. , Jackson A. , Sharples L. , Groves A. M. , Wells F. C. , Ritchie A. J. , Laroche C. M.
Published: March 2005

The British Thoracic Society and American College of Chest Physician guidelines outline criteria for investigating patients for lung cancer surgery. However, the guidelines are based on relatively old studies. Therefore, the relationship between pulmonary function test results and surgical outcome were studied prospectively in a large cohort of lung cancer patients.

From January 2001 to December 2003, 110 patients underwent surgery for lung cancer. All underwent full lung function testing in order to predict post-operative lung function.

The hospital mortality rate was 3% and major complication rate 22%. There was poor overall outcome in 13%. Mean pre-operative lung function values were: forced expiratory volume in one second (FEV1) 2.0 L (79.4% of the predicted value), and carbon monoxide diffusing capacity of the lung (DL,CO) 73.6% pred. The mean post-operative lung function values were: FEV11.4 L (55.6% pred), andDL,CO51.3% pred. All lung function values were better predictors of poor surgical outcome when expressed as a percentage of the predicted value. Using a threshold of pre-operative FEV1of 47% pred resulted in the most useful positive and negative predictive probabilities, 0.90 and 0.67, respectively.

Lung function values expressed as a percentage of the predicted value are more useful predictors of post-operative outcome than absolute values. The threshold of predicted forced expiratory volume in one second for surgical intervention could be lower (45–50% pred) than is currently accepted without increased mortality.
Low-dose inhaled corticosteroids and the risk of acute myocardial infarction in COPD
Authors: Huiart L. , Ernst P. , Ranouil X. , Suissa S.
Published: March 2005

Inflammation plays a major role in the development and complications of atherosclerosis. Here, the dose-related impact of inhaled corticosteroids (ICS), used for their anti-inflammatory properties, on the risk of acute myocardial infarction (AMI) is studied in a cohort of chronic obstructive pulmonary disease (COPD) patients.

Saskatchewan (Canada) health services databases were used to form a population-based cohort of 5,648 patients, ≥55 yrs, who received a first treatment for COPD between 1990 and 1997. A nested case-control analysis was conducted, where 371 cases presenting with a first AMI were matched with 1,864 controls, based on the date of cohort entry and age. A conditional logistic regression was used to estimate the effect of ICS, after adjusting for use of oral corticosteroids, severity of COPD, sex, systemic hypertension, diabetes and cardiovascular disease.

ICS were used in the prior year by 42.2% of cases and 46.4% of controls. Overall, current use of ICS was not associated with a significant decrease in the risk of AMI. However, a 32% reduction in the risk of AMI was observed for doses ranging 50–200 µg·day−1.

In conclusion, very low doses of inhaled corticosteroids may be associated with a reduction in the risk of acute myocardial infarction.
Analysis of the cues used by patients when making assessments of their asthma severity
Authors: Barley E. A. , Jones P. W.
Published: March 2005

This study measured the relative contribution of four cues: symptoms, effect on activities, emotions and social life, to patients' judgments of overall asthma severity.

Judgement analysis techniques were applied to patients' assessments of overall asthma severity using asthma states described in scenarios based on these cues.

Altogether, 40 patients, mean age 52 yrs, mean forced expiratory volume in one second 67% predicted, were studied. The relative importance of the cues varied widely between patients; symptoms contributed to 47% of the judgment of asthma severity (range 15–86%), activities 19% (1–73%), emotions 14% (0–43%), and social life 19% (2–57%). Some patients had difficulty with the judgment task, they tended to be older or have worse health. A total of 21 patients had consistent judgment policies. Cluster analysis identified two policy types. In one, symptoms were weighted heavily, in the other all cues were weighted similarly. Policies were not related to disease or demographic factors.

Symptoms are important cues for patients when assessing asthma severity, but other cues may be more important in some patients. Patients fall into two groups: those who rely on symptoms and those who use several cues.
CCR5 expression and CC chemokine levels in idiopathic pulmonary fibrosis
Authors: Capelli A. , Di Stefano A. , Gnemmi I. , Donner C. F.
Published: March 2005

CC chemokines play an important role in the pathogenetic mechanisms of interstitial lung disease, while a downregulation of CC chemokine receptor (CCR)5 in the fibrotic stages of sarcoidosis has been observed.

To evaluate the involvement of CC chemokines and the expression of CCR5 in idiopathic pulmonary fibrosis (IPF) and, more specifically, in usual interstitial pneumonia, 35 subjects were studied. CC chemokine ligand (CCL)2, CCL3 and CCL4 levels were measured in the bronchoalveolar lavage fluid (BALF) of 18 nonsmoker control subjects and 17 patients affected by IPF. CCR5 expression was evaluated in alveolar macrophages and lymphocytes.

The BALF levels of all chemokines were significantly increased in IPF: median (range) CCL3 1.6 (1.0–11.1)versus1.2 (0.0–3.8) pg·mL−1; CCL4 6.2 (1.3–96.0)versus3.4 (0.3–6.8) pg·mL−1; and CCL2 60.1 (16.7–251.3)versus4.6 (0.5–119.4) pg·mL−1. CCL2 levels correlated negatively with the carbon monoxide diffusing capacity of the lung (DL,CO) and arterial oxygen tension. CCR5 expression was significantly reduced in lymphocytes from IPF compared with controls.

The CC chemokines investigated are involved in the inflammatory mechanisms of idiopathic pulmonary fibrosis, and the results are in agreement with the hypothesis of a downregulation of the T-helper 1 immunological response in this disease.
Asthma during pregnancy: mechanisms and treatment implications
Authors: Murphy V. E. , Gibson P. G. , Smith R. , Clifton V. L.
Published: March 2005

Asthma is becoming increasingly prevalent worldwide. Numerous historical and prospective cohort studies have investigated the effects of maternal asthma on pregnancy outcome; however, the data has been conflicting and many studies have not used standard classifications for asthma severity. Overall, the literature suggests that asthmatic females are more at risk of low birth weight neonates, pre-term delivery and complications such as pre-eclampsia, especially in the absence of actively managed asthma treated with inhaled corticosteroids. Pregnancy with a female foetus may particularly increase the risk of these outcomes.

In addition, pregnancy has an effect on the course of asthma. The risk of an exacerbation requiring medical intervention may be as high as 50% in females with severe asthma and this may further increase the risk of poor outcomes, particularly low birth weight and pre-term delivery.

The mechanisms responsible for changes in asthma with pregnancy, or alterations in pregnancy outcomes due to asthma have not been thoroughly explored. Maternal inflammatory pathways may contribute to reduced foetal growth through alterations in placental function.

Asthma treatment, by reducing maternal inflammation and preventing exacerbations, is safe for use in pregnant females and contributes to improved outcomes for both mother and foetus.
Endothelial interactions of neutrophils under flow in chronic obstructive pulmonary disease
Authors: Woolhouse I. S. , Bayley D. L. , Lalor P. , Adams D. H. , Stockley R. A.
Published: March 2005

It is generally accepted that the neutrophil is central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Enhanced endothelial interactions of this cell may contribute to the susceptibility of smokers who develop the disease; however, these interactions have not previously been studied in COPD. The aim of the current study was to determine whether enhanced endothelial interactions of neutrophils from smokers are a predisposing factor for the development of COPD.

Endothelial interactions under flow and adhesion molecule expression of peripheral blood neutrophils were compared between seven never-smokers (NS), seven healthy smokers (HS), 11 COPD patients with severe α1-antitrypsin deficiency (PiZ) and neutrophils from 11 COPD patients without the deficiency (PiM).

Total adhesive and migratory responses (per mm2endothelium per 106neutrophils) were significantly greater in the PiM group (mean±se704.2±57.9versus509.3±48.8 in the PiZ group, 499.3±40.1 in the HS and 491.2±33.7 in the NS). This corresponded with increased macrophage antigen-1 (CD11b) expression on stimulated neutrophils in the PiM group compared with the PiZ group (mean±serelative fluorescence intensity 1.4±0.1versus1.1±0.1).

In conclusion, the enhanced endothelial interaction of neutrophils from smokers who have developed chronic obstructive pulmonary disease in the presence of normal levels of α1-antitrypsin deficiency, but not in those with severe α1-antitrypsin deficiency, suggests that this is a predisposing factor for the development of the disease, and upregulation of macrophage antigen-1 may be responsible.
Angiotensin II antagonism fails to ameliorate bleomycin-induced pulmonary fibrosis in mice
Authors: Keogh K. A. , Standing J. , Kane G. C. , Terzic A. , Limper A. H.
Published: March 2005

Based on current evidence, transforming growth factor (TGF)-β plays a central pathogenic role in the development of pulmonary fibrosis. There is growing evidence that angiotensin II can serve as a stimulus for TGF-β-mediated lung fibrosis. However, the role of angiotensin II in the pathobiology of pulmonary fibrosisin vivoremains unclear and the therapeutic potential for targeting angiotensin II in a bleomycin-induced pulmonary fibrosis model is not well known.

Therefore, the aim of this study was to test whether the angiotensin II antagonist, losartan, attenuated the development of bleomycin-induced pulmonary fibrosis in two distinct murine strains, C57/BL6 and Sv129. This was determined by histopathology and quantification of collagen content by hydroxyproline assay.

Despite demonstrable angiotensin II antagonismin vivoand a reduction in measures of acute lung injury, losartan therapy, at a dose shown to reduce renal and cardiac fibrosis in mice, failed to significantly ameliorate bleomycin-induced pulmonary fibrosis.

In conclusion, these data suggest that the pulmonary fibrotic disease processin vivois not solely dependent on angiotensin II activity and the potential for angiotensin II receptor blockers as a therapeutic strategy in patients with pulmonary fibrosis may be limited.
Interleukin-16 in tuberculous and malignant pleural effusions
Authors: Qin X-J. , Shi H-Z. , Huang Z-X. , Kang L-F. , Mo W-N. , Wu C.
Published: March 2005

The aim of this study was to explore the presence of interleukin (IL)-16 in pleural effusions, the correlation between IL-16 levels and cytological parameters, as well as the chemoattractant activity of IL-16 on CD4+ T-lymphocytes.

Total nucleated cell and differential counts, and IL-16 concentrations in the pleural effusion from 32 patients with tuberculous pleurisy and 30 patients with lung cancer were determined. Three-colour flow cytometry was performed to determine T-lymphocyte subsets in cell pellets of pleural effusion. The chemoattractant activity of IL-16 for CD4+ T-lymphocytes was also analysed.

The levels of IL-16 were significantly higher in tuberculous than in malignant effusions. However, IL-16 levels could not be used for diagnostic purposes due to significant overlap between the two groups. Positive correlations were found between the IL-16 levels and CD4+ T-cells, and pleural fluid was chemotactic for CD4+ T-cellsin vitro. Intrapleural administration of IL-16 to patients produced a marked progressive influx of CD4+ T-cells into the pleural space.

Compared with malignant pleural effusion, interleukin-16 appeared to be increased in tuberculous pleural effusion. Interleukin-16 levels were positively related to the numbers of CD4+ T-cells, and interleukin-16 could directly induce CD4+ T-cell infiltration into the pleural space.
Relationship between the inoculum dose ofStreptococcus pneumoniaeand pneumonia onset in a rabbit model
Authors: Yershov A. L. , Jordan B. S. , Guymon C. H. , Dubick M. A.
Published: March 2005

It is generally assumed that the development of bacterial pneumonia becomes possible when the dose of inhaled or aspirated pathogens overwhelms the respiratory tract host defence system, but this hypothesis has not yet been tested either clinically or experimentally.

This study evaluated inoculum dose in relation to onset of experimental pneumococcal pneumonia, and estimated the median effective dose resulting in pneumonia in healthy New Zealand White rabbits (mean±sd4.75±0.25 kg (n = 27)). Rabbits were endobronchially inoculated with increasing doses ofStreptococcus pneumoniaeand pneumonia onset was observed over the following 96 h. The diagnostic approach was based on the Clinical Pulmonary Infection Score, modified for use in rabbits.

Inoculation ofS. pneumoniaeat doses of >4.60 log10cfu made the development of pneumonia in rabbits more predictable (up to 90%). Lower doses of bacteria failed to cause pneumonia in 80% of inoculated animals. The median effective dose was estimated by means of logistical regression, probit analyses and the Reed–Muench method, and corresponded to 4.32, 4.38 and 4.67 log10cfu, respectively.

It is speculated that development of pneumococcal pneumonia becomes more likely when the inoculum dose exceeds a threshold of antibacterial protection, making inoculum dose a risk factor for disease onset.
Hypoxaemia in chronic obstructive pulmonary disease patients during a commercial flight
Authors: Akerø A. , Christensen C. C. , Edvardsen A. , Skjønsberg O. H.
Published: March 2005

The aim of the study was to investigate hypoxaemia in chronic obstructive pulmonary disease patients during a commercial flight.

The effect of a commercial flight, lasting 5 h 40 min, on arterial blood gas levels and symptoms in 18 chronic obstructive pulmonary disease patients with a pre-flight percutaneous oxygen saturation of ≥94% and self-reported ability to walk 50 m without severe dyspnoea was studied.

The arterial oxygen tension (Pa,O2) decreased from sea level to cruising altitude (10.3±1.2versus8.6±0.8 kPa), but, thereafter, except for one patient, remained stable throughout the flight. During light exercise, however, there was further desaturation (percutaneous oxygen saturation 90±4versus87±4%). After 4 h, a decrease in arterial carbon dioxide tension (5.0±0.4versus4.8±0.4 kPa) and an increase in cardiac frequency (87±13versus95±13 beats·min-1) were observed. A pre-flightPa,O2of >9.3 kPa did not secure an acceptable in-flightPa,O2. Aerobic capacity showed the strongest correlation with in-flightPa,O2.

In conclusion, following an initial decrease in arterial oxygen tension, chronic obstructive pulmonary disease patients in a stable state of their disease seem to maintain a stable arterial oxygen tension throughout a flight of intermediate duration, except when walking along the aisle. However, a decrease in arterial carbon dioxide tension, indicating compensatory hyperventilation, could imply a risk of respiratory fatigue during longer flights.
Decrease of vascular endothelial growth factor in macrophages from long-term smokers
Authors: Nagai K. , Betsuyaku T. , Ito Y. , Nasuhara Y. , Nishimura M.
Published: March 2005

Vascular endothelial growth factor (VEGF), a survival factor for endothelial cells and a promoter of angiogenesis, is reportedly expressed in alveolar macrophages (AMs).

To investigate whether long-term smoking with age affects VEGF expression in AMs, bronchoalveolar lavage (BAL) was performed on 18 young and 23 older volunteers with various smoking histories. The expressions of VEGF and its functional receptor, fms-like tyrosine kinase (Flt)-1, were quantified in AMs by real-time RT-PCR and, further, the level of VEGF in BAL fluid was determined by ELISA.

VEGF mRNA in AMs demonstrated a 1.8-fold reduction in current smokers compared with nonsmokers in older subjects and, furthermore, a 1.5-fold downregulation in those with emphysema, although there was no difference between current smokers and nonsmokers among the young subjects. The downregulation in total VEGF mRNA was supported by the substantial reduction of VEGF121 and VEGF165 isoforms. However, in contrast, Flt-1 mRNA did not differ within the older groups, whereas it was upregulated in young current smokers compared with age-matched nonsmokers. VEGF in BAL fluid is significantly decreased in current smokers compared with nonsmokers, regardless of their age.

In conclusion, these data imply that the biological availability of vascular endothelial growth factor in alveolar macrophages is impaired in older current smokers with long-term smoking histories.
Noninvasive assessment and monitoring of the pulmonary circulation
Authors: Vonk-Noordegraaf A. , van Wolferen S. A. , Marcus J. T. , Boonstra A. , Postmus P. E. , Peeters J. W. L. , Peacock A. J.
Published: March 2005

In pulmonary vascular disease, changes in the pulmonary vascular bed will lead to altered pulmonary haemodynamics. This review describes the application of several physiological principles to measure these changes noninvasively by means of novel techniques.

Flow characteristics of blood through the pulmonary vascular bed alter in pulmonary vascular disease. Recent developments in magnetic resonance imaging and computed tomography make it possible to visualise and quantify these abnormal flow patterns. Information regarding pulmonary perfusion can also be obtained by measuring the electrical impedance changes in the lung by electrical impedance tomography. A more indirect approach to measure the pulmonary blood flow is the measurement of the absorption of acetylene, a perfusion limited gas. Information on the pulmonary vascular bed can also be obtained by the measurement of exhaled products of the pulmonary vascular endothelium, such as nitric oxide.

Although all the techniques described offer new ways to diagnose or monitor pulmonary vascular disease, clinical data on these techniques are limited. Further improvement and evaluation of the clinical value of these techniques are therefore obligatory before they can be used in clinical practice.
Lung function in adults with cystic fibrosis at altitude: impact on air travel
Authors: Fischer R. , Lang S. M. , Brückner K. , Hoyer H-X. , Meyer S. , Griese M. , Huber R. M.
Published: March 2005

Current guidelines for air travel state that patients with chronic respiratory diseases are required to use oxygen if their in-flight arterial oxygen tensions (Pa,O2) drop below 6.6 kPa. This recommendation may not be strictly applicable to cystic fibrosis patients, who may tolerate lowerPa,O2for several hours without clinical symptoms.

Lung function, symptoms, blood gas levels and signs of pulmonary hypertension were studied in 36 cystic fibrosis patients at altitudes of 530 m and, after 7 h, 2,650 m. A hypoxia inhalation test (inspiratory oxygen fraction 0.15) was performed at low altitude in order to predict high-altitude hypoxaemia.

MedianPa,O2dropped from 9.8 kPa at low altitude to 7.0 kPa at high altitude. Mild exercise at a workload of 30 W further decreasedPa,O2. Two-thirds of all patients exhibitedPa,O2of <6.6 kPa during exercise and, except for one patient, were asymptomatic. Patients were significantly less obstructed at an altitude of 2,650 m. Low forced expiratory volume in one second at baseline was associated with a lowPa,O2at altitude.

It is concluded that cystic fibrosis patients with baseline arterial oxygen tensions of >8.0 kPa safely tolerate an altitude of 2,650 m for several hours under resting conditions. The risk assessment of low in-flight oxygenation should encompass the whole clinical situation of cystic fibrosis patients, with special attention being paid to the presence of severe airway obstruction.
Should tuberculosis treatment and control be addressed differently in HIV-infected and -uninfected individuals?
Authors: Dlodlo R. A. , Fujiwara P. I. , Enarson D. A.
Published: March 2005

Infection with HIV drives the tuberculosis epidemic, especially in sub-Saharan Africa, where up to 75% of individuals with tuberculosis are co-infected with HIV. This article reviews the epidemiological link between the conditions, how tuberculosis diagnosis and treatment differ between HIV-infectedversus-uninfected individuals and the span of additional measures required to prevent and control HIV-related tuberculosis.

Tuberculosis chemotherapy using standard short-course regimens is highly effective in both groups, and treatment follows the same principles. It differs in certain aspects, such as when antiretroviral treatment should be started in HIV-infected individuals with tuberculosis and consideration of drug–drug interactions between the rifamycins and certain antiretroviral drugs.

Control of HIV-related tuberculosis requires, fundamentally, control of HIV transmission. Meanwhile, it is necessary to make concentrated efforts to intensify high-quality tuberculosis services employing the directly observed treatment, short-course (DOTS) strategy, carry out extensive research towards an evidence-based model for the expanded scope of collaborative tuberculosis and HIV/AIDS interventions, and ensure efficient implementation of the findings and recommended policies.

The challenge is gigantic, and both robust within-country and international leadership and competent management capabilities will be required, in addition to substantial human and financial resources.
The de novo methylation activity of Dnmt3a is distinctly different than that of Dnmt1
Authors: Hsieh Chih-Lin
Published: March 2005

Background

Though Dnmt1 is considered the primary maintenance methyltransferase and Dnmt3a and Dnmt3b are considered de novo methyltransferases in mammals, these three enzymes may work together in maintaining as well as establishing DNA methylation patterns. It has been proposed that Dnmt1 may carry out de novo methylation at sites in the genome with transient single-stranded regions, such as replication origins, and then spread methylation from these nucleation sites in vivo, even though such activity has not been reported.

Results

In this study, we show that Dnmt3a does not act on single-stranded substrates in vitro, indicating that Dnmt3a is not likely to initiate DNA methylation at such proposed nucleation sites. Dnmt3a shows similar methylation activity on unmethylated and hemimethylated duplex DNA, though with some substrate preference. Unlike Dnmt1, pre-existing cytosine methylation at CpG sites or non-CpG sites does not stimulate Dnmt3a activity in vitro and in vivo.

Conclusion

The fact that Dnmt3a does not act on single stranded DNA and is not stimulated by pre-existing cytosine methylation indicates that the de novo methylation activity of Dnmt3a is quite different from that of Dnmt1. These findings are consistent with a model in which Dnmt3a initiates methylation on one of the DNA strands of duplex DNA, and these hemimethylated sites then stimulate Dnmt1 activity for further methylation.
A ring-like nucleoid is not necessary for radioresistance in the Deinococcaceae
Authors: Zimmerman Julie M , Battista John R
Published: March 2005

Background

Transmission electron microscopy images of Deinococcus radiodurans R1 suggest that the nucleoid of this species exists as a "ring-like" body, and have led to speculation that this structure contributes to the radioresistance of the species. Since extreme radioresistance is characteristic of six other species of Deinococcus, we have attempted to correlate nucleoid morphology and radioresistance by determining whether the genomic DNA of each of these species exhibit similar structures.

Results

The nucleoid morphologies of seven recognized species of Deinococcus, the radioresistant bacterium Rubrobacter radiotolerans, and the more radiosensitive deinococcal relative Thermus aquaticus were evaluated using epifluorescence and deconvolution techniques. Although the nucleoids of Deinococcus murrayi, Deinococcus proteolyticus, Deinococcus radiophilus, and Deinococcus grandis have structures similar to D. radiodurans, the majority of nucleoids found in Deinococcus radiopugnans and Deinococcus geothermalis lack any specific organization. The nucleoid of R. radiotolerans consists of multiple highly condensed spheres of DNA scattered throughout the cell. The genomic DNA of Thermus aquaticus is uniformly distributed throughout the cell.

Conclusion

There is no obvious relationship between the shape of a species' nucleoid and extreme radioresistance. However, the genomes of all extremely radioresistance species examined are highly condensed relative to more radiosensitive species. Whether DNA in this tightly packed configuration contributes to the radioresistance of these bacteria remains unknown, but this common structural feature appears to limit diffusion of fragments generated post-irradiation even in cells incapable of repairing strand breaks.
The GABBR1 locus and the G1465A variant is not associated with temporal lobe epilepsy preceded by febrile seizures
Authors: Ma Shaochun , Abou-Khalil Bassel , Sutcliffe James S , Haines Jonathan L , Hedera Peter
Published: March 2005

Background

Polymorphism G1465A in the GABBR1 gene has been suggested as a risk factor for non-lesional temporal lobe epilepsy (TLE); however, this genetic association study has not been independently replicated. We attempted to replicate this study in our cohort of patients with TLE. Furthermore, we also analyzed the coding sequence of this gene and searched for disease-causing mutations.

Methods

We included 120 unrelated individuals with TLE that was preceded by febrile seizures (FS) who did not have any evidence of structural lesions suggesting secondary epilepsy. 66 individuals had positive family history of TLE epilepsy and 54 were sporadic. Each patient was genotyped for the presence of G1465A polymorphism. All exons of the GABBR1 gene were screened by single strand confirmation polymorphism method. Genotypes were compared with two independent matched control groups.

Results

We detected two A alleles of the G1465A polymorphism in one homozygous control subject (0.87% of all alleles) and one A allele in a patient with TLE (0.45%, not significant). Other detected polymorphisms in coding regions had similar frequencies in epilepsy patients and control groups. No disease causing mutations in the GABBR1 gene were detected in patients with sporadic or familial TLE.

Conclusion

Our results indicate that TLE preceded by FS is not associated with the polymorphisms or mutations in the GABBR1 gene, including the G1465A polymorphism. The proportion of TLE patients with FS in the original study, reporting this positive association, did not differ between allele A negative and positive cases. Thus, our failure to reproduce this result is likely applicable to all non-lesional TLE epilepsies.
Hyperbolastic growth models: theory and application
Authors: Tabatabai Mohammad , Williams David Keith , Bursac Zoran
Published: March 2005

Background

Mathematical models describing growth kinetics are very important for predicting many biological phenomena such as tumor volume, speed of disease progression, and determination of an optimal radiation and/or chemotherapy schedule. Growth models such as logistic, Gompertz, Richards, and Weibull have been extensively studied and applied to a wide range of medical and biological studies. We introduce a class of three and four parameter models called "hyperbolastic models" for accurately predicting and analyzing self-limited growth behavior that occurs e.g. in tumors. To illustrate the application and utility of these models and to gain a more complete understanding of them, we apply them to two sets of data considered in previously published literature.

Results

The results indicate that volumetric tumor growth follows the principle of hyperbolastic growth model type III, and in both applications at least one of the newly proposed models provides a better fit to the data than the classical models used for comparison.

Conclusion

We have developed a new family of growth models that predict the volumetric growth behavior of multicellular tumor spheroids with a high degree of accuracy. We strongly believe that the family of hyperbolastic models can be a valuable predictive tool in many areas of biomedical and epidemiological research such as cancer or stem cell growth and infectious disease outbreaks.
Expression of the common heat-shock protein receptor CD91 is increased on monocytes of exposed yet HIV-1-seronegative subjects
Authors: Kebba Anthony , Stebbing Justin , Rowland Samantha , Ingram Rebecca , Agaba John , Patterson Steve , Kaleebu Pontiano , Imami Nesrina , Gotch Frances
Published: March 2005

The significantly higher surface expression of the surface heat-shock protein receptor CD91 on monocytes of human immunodeficiency virus type-1 (HIV-1)-infected, long-term nonprogressors suggests that HIV-1 antigen uptake and cross-presentation mediated by CD91 may contribute to host anti-HIV-1 defenses and play a role in protection against HIV-1 infection. To investigate this further, we performed phenotypic analysis to compare CD91 surface expression on CD14+ monocytes derived from a cohort of HIV-1-exposed seronegative (ESN) subjects, their seropositive (SP) partners, and healthy HIV-1-unexposed seronegative (USN) subjects. The median fluorescent intensity (MFI) of CD91 on CD14+ monocytes was significantly higher in ESN compared with SP (P=0.028) or USN (P=0.007), as well as in SP compared with USN subjects (P=0.018). CD91 MFI was not normalized in SP subjects on highly active antiretroviral therapy (HAART) despite sustainable, undetectable plasma viraemia. Data in three SP subjects experiencing viral rebounds following interruption of HAART showed low CD91 MFI comparable with levels in USN subjects. There was a significant positive correlation between CD91 MFI and CD8+ T cell counts in HAART-naïve SP subjects (r=0.7, P=0.015). Increased surface expression of CD91 on CD14+ monocytes is associated with the apparent HIV-1 resistance that is observed in ESN subjects.
Production of matrix metalloproteinase-9 by activated human monocytes involves a phosphatidylinositol-3 kinase/Akt/IKKα/NF-κB pathway
Authors: Lu Yunbiao , Wahl Larry M
Published: March 2005

Matrix metalloproteinase-9 (MMP-9) is considered to be an important component in the progression of inflammation. Monocytes/macrophages are prominent at inflammation sites, and activation of these cells by stimulants, such as lipopolysaccharide (LPS) or tumor necrosis factor α and granulocyte macrophage-colony stimulating factor, leads to the production of significant amounts of MMP-9. Here, we show that LPS stimulation of monocytes results in MMP-9 production through a phosphatidylinositol-3 kinase (PI-3K)/Akt/inhibitor of κB (IκB) kinase-α (IKKα)/nuclear factor (NF)-κB pathway. This new role for Akt in signaling leading to MMP-9 production was demonstrated by inhibitor and immunoprecipitation studies. LY294002 or wortmannin, inhibitors of PI-3K, suppressed LPS-induced Akt activity and MMP-9 production. Evidence for the participation of Akt in monocyte MMP-9 synthesis was demonstrated by the inhibition of MMP-9 by SH-5, a specific inhibitor of Akt. The mechanism by which Akt regulates MMP-9 is through the activation of NF-κB, as shown by coimmunoprecipitation of the phosphorylated form of IKKα and Akt as well as the SH-5 suppression of the dissociation of IκB from NF-κB and the activation of NF-κB p65. The role of NF-κB in regulation of MMP-9 was demonstrated further by the inhibition of MMP-9 production by proteasome inhibitors, lactacystin and MG-132, which prevented the ubiquitination and dissociation of IκB from NF-κB. This is the first demonstration that Akt is involved in the signaling pathway leading to the production of monocyte MMP-9 and provides an additional approach in the regulation of this enzyme in human primary monocytes.
Pathways to care and ethnicity. 1: Sample characteristics and compulsory admission
Authors: Morgan Craig , Mallett Rosemarie , Hutchinson Gerard , Bagalkote Hemant , Morgan Kevin , Fearon Paul , Dazzan Paola , Boydell Jane , McKenzie Kwame , Harrison Glynn , Murray Robin , Jones Peter , Craig Tom , Leff Julian
Published: March 2005

Background

Many studies have found high levels of compulsory admission to psychiatric hospital in the UK among African–Caribbean and Black African patients with a psychotic illness.

Aims

To establish whether African–Caribbean and Black African ethnicity is associated with compulsory admission in an epidemiological sample of patients with a first episode of psychosis drawn from two UK centres.

Method

All patients with a first episode of psychosis who made contact with psychiatric services over a 2-year period and were living in defined areas were included in the (ÆSOP) study. For this analysis we included all White British, other White, African–Caribbean and Black African patients from the ÆSOP sampling frame. Clinical, socio-demographic and pathways to care data were collected from patients, relatives and case notes.

Results

African–Caribbean patients were significantly more likely to be compulsorily admitted than White British patients, as were Black African patients. African–Caribbean men were the most likely to be compulsorily admitted.

Conclusions

These findings suggest that factors are operating at or prior to first presentation to increase the risk of compulsory admission among African–Caribbean and Black African patients.
Help-seeking behaviour in men and women with common mental health problems: cross-sectional study
Authors: Oliver Maria Isabel , Pearson Nicky , Coe Nicola , Gunnell David
Published: March 2005

Background

Many people with mental health problems do not seek professional help but their use of other sources of help is unclear.

Aims

To investigate patterns of lay and professional help-seeking in men and women aged 16–64 years in relation to severity of symptoms and sociodemographic variables.

Method

Postal questionnaire survey, including the 12-item General Health Questionnaire (GHQ–12), sent to a stratified random sample (n=15222) of the population of Somerset.

Results

The response rate was 76%. Only 28% of people with extremely high GHQ–12 scores (⩾8) had sought help from their general practitioner but most (78%) had sought some form of help. Males, young people and people living in affluent areas were the least likely to seek help.

Conclusions

Health promotion interventions to encourage appropriate help-seeking behaviour in young people, particularly in men, may lead to improvements in the mental health of this group of the population.
Assessing psychopathy in the UK: concerns about cross-cultural generalisability
Authors: Cooke David J. , Michie Christine , Hart Stephen D. , Clark Danny
Published: March 2005

Background

The diagnosis of psychopathy is important for violence risk assessment.

Aims

To investigate whether the syndromal structure of psychopathy, as measured by the Psychopathy Checklist – Revised (PCL–R), is the same in the UK and North America, and whether this measure yields scores that are equivalent in these two regions.

Method

Confirmatory factor analytic and item response theory methods were applied to large samples of PCL–R ratings.

Results

The syndromal structure of psychopathy was invariant across cultures, three distinct factors underpinning the superordinate syndrome of psychopathy. However, PCL–R scores were not equivalent across cultures: the same level of psychopathy was associated with lower PCL–R scores in the UK. Items that reflected affective symptoms had the highest cross-cultural stability.

Conclusions

Scores on the PCL–R obtained in the UK are not directly comparable with those obtained in North America. Care must be exercised when the PCL–R is used to make important clinical decisions in the UK.
Transference patterns in the psychotherapy of personality disorders: empirical investigation
Authors: Bradley Rebekah , Heim Amy Kegley , Westen Drew
Published: March 2005

Background

The concept of transference has broadened to a recognition that patients often express enduring relational patterns in the therapeutic relationship.

Aims

To examine the structure of patient relational patterns in psychotherapy and their relation with DSM–IV personality disorder symptoms.

Method

A random sample of psychologists and psychiatrists (n=181) completed a battery of instruments on a randomly selected patient in their care.

Results

Exploratory factor analysis identified five transference dimensions: angry/entitled, anxious/preoccupied, avoidant/counterdependent, secure/engaged and sexualised. These were associated in predictable ways with Axis II pathology; four mapped on to adult attachment styles. An aggregated portrait of transference patterns in narcissistic patients provided a clinically rich, empirically based description of transference processes that strongly resembled clinical theories.

Conclusions

The ways patients interact with their therapists can provide important data about their personality, attachment patterns and interpersonal functioning. These processes can be measured in clinically sophisticated and psychometrically sound ways. Such processes are relatively independent of clinicians' theoretical orientation.
New guidelines for prescribing injectable heroin in opiate addiction
Authors: Luty Jason
Published: March 2005

Few treatments are more controversial than the prescribing of injectable heroin (diamorphine) to heroin addicts. This practice is still banned in the USA and Australia, despite the serious drug problems in those countries. At present any UK doctor can prescribe injectable methadone for the treatment of heroin addiction; however, the prescribing of heroin requires a special licence from the Home Office. The National Treatment Agency for Substance Misuse is the statutory body currently responsible for advising purchasers (local drug action teams) in regard to specialist services for addictions. They have recently commissioned and published guidelines for the prescription of injectables in opiate addiction (National Treatment Agency for Substance Misuse, 2003). This follows the report of a Government committee, which stated:

‘If diamorphine treatment could be offered to all problematic users who do not successfully access other treatments, we believe it could play a useful part in managing the social problems generated by this group of people’ (House of Commons Home Affairs Committee, 2003).
Commentary on: New guidelines for prescribing injectable heroin in opiate addiction
Authors: Gilvarry Eilish
Published: March 2005

Until recently, the UK led the addiction field worldwide as the only country to prescribe diamorphine for the treatment of opiate drug dependence. However, the approach was inconsistent, with development conducted in a haphazard and arbitrary manner (Audit Commission, 2002), with variation in criteria, individualistic approaches and many doctors ‘inheriting’ patients on these long-term prescriptions from other doctors. There were relatively few restrictions once the doctor had been granted a licence by the Home Office.
The CARD-carrying caspase Dronc is essential for most, but not all,developmental cell death inDrosophila
Authors: Xu Dongbin , Li Ying , Arcaro Michael , Lackey Melinda , Bergmann Andreas
Published: March 2005

The initiator caspase Dronc is the only Drosophila caspase that contains a caspase activation and recruitment domain (CARD). Although Dronc has been implicated as an important effector of apoptosis, the genetic function of dronc in normal development is unclear because dronc mutants have not been available. In an EMS mutagenesis screen,we isolated four point mutations in dronc that recessively suppress the eye ablation phenotype caused by eye-specific overexpression of hid. Homozygous mutant dronc animals die during pupal stages; however, at a low frequency we obtained homozygous adult escapers. These escapers have additional cells in the eye and wings that are less transparent and slightly curved down. We determined that this is due to lack of apoptosis. Our analyses of dronc mutant embryos suggest that dronc is essential for most apoptotic cell death during Drosophila development, but they also imply the existence of a dronc-independent cell death pathway. We also constructed double mutant flies for dronc and the apoptosis inhibitor diap1. dronc mutants can rescue the ovarian degeneration phenotype caused by diap1 mutations, confirming that dronc acts genetically downstream of diap1.
The single AmphiTrk receptor highlights increased complexity of neurotrophin signalling in vertebrates and suggests an early role in developing sensory neuroepidermal cells
Authors: Benito-Gutiérrez Èlia , Nake Christian , Llovera Marta , Comella Joan X. , Garcia-Fernàndez Jordi
Published: March 2005

Neurotrophins (Nt) and their tyrosine kinase Trk receptors play an essential role in the development and maintenance of the complex vertebrate nervous system. Invertebrate genome sequencing projects have suggested that the Nt/Trk system is a vertebrate innovation. We describe the isolation and characterisation of the amphioxus Trk receptor, AmphiTrk. Its ancestral link to vertebrate Trk receptors is supported by phylogenetic analysis and domain characterisation. The genomic structure of AmphiTrk strongly suggests that a ProtoTrk gene emerged by means of exon-shuffling prior to the cephalochordate/vertebrate split. We also examined the physiological response of AmphiTrk to vertebrate neurotrophins,and found that despite 500 million years of divergence, AmphiTrk transduces signals mediated by NGF, BDNF, NT3 and NT4. Markedly, AmphiTrk is able to activate survival and differentiation pathways, but fails to activate the PLCγ pathway, which is involved in synaptic plasticity in higher vertebrates. AmphiTrk is expressed during amphioxus embryogenesis in sensory neural precursors in the epidermis, which possesses single migratory cells. We propose that the duplication and divergence of the Nt/Trk system, in tandem with recruitment of the PLCγ pathway, may have provided the genetic basis for a key aspect of vertebrate evolution: the complexity of the nervous system.
Valois, a component of the nuage and pole plasm, is involved in assembly of these structures, and binds to Tudor and the methyltransferase Capsuléen
Authors: Anne Joël , Mechler Bernard M.
Published: March 2005

Using the Capsuléen (Csul) methyltransferase as bait in the yeast two-hybrid system, we have identified a novel Drosophila protein containing multiple WD repeats and encoded by the valois(vsl) gene, which acts in pole plasm function. Vls is homologous to human MEP50, which forms a complex with the PRMT5 methyltransferase –the human homologue of Csul. We found that Vls localizes to the nuage in the nurse cells and to the pole plasm in the oocyte. Moreover vls is required for the synthesis and/or stability of Oskar and the localization of Tudor (Tud) in both the nuage and at the posterior pole of the oocyte. Furthermore, we show that Vls and a fragment of Tud interact directly in binding assay. As the PMRT5/MEP50 complex is involved in ribonucleoprotein complex assembly, we hypothesize that the Vls complex may play a similar function in assembling the nuage in nurse cells and the polar granules in the oocyte.
Propulsive force calculations in swimming frogs II. Application of a vortex ring model to DPIV data
Authors: Stamhuis Eize J. , Nauwelaerts Sandra
Published: March 2005

Frogs propel themselves by kicking water backwards using a synchronised extension of their hind limbs and webbed feet. To understand this propulsion process, we quantified the water movements and displacements resulting from swimming in the green frog Rana esculenta, applying digital particle image velocimetry (DPIV) to the frog's wake.

The wake showed two vortex rings left behind by the two feet. The rings appeared to be elliptic in planform, urging for correction of the observed ring radii. The rings' long and short axes (average ratio 1.75:1) were about the same size as the length and width of the propelling frog foot and the ellipsoid mass of water accelerated with it. Average thrust forces were derived from the vortex rings, assuming all propulsive energy to be compiled in the rings. The calculated average forces(Fav=0.10±0.04 N) were in close agreement with our parallel study applying a momentum–impulse approach to water displacements during the leg extension phase.

We did not find any support for previously assumed propulsion enhancement mechanisms. The feet do not clap together at the end of the power stroke and no `wedge-action' jetting is observed. Each foot accelerates its own water mantle, ending up in a separate vortex ring without interference by the other leg.