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1.  FOXA1 repression is associated with loss of BRCA1 and increased promoter methylation and chromatin silencing in breast cancer 
Oncogene  2014;34(39):5012-5024.
FOXA1 expression correlates with the breast cancer luminal subtype and patient survival. RNA and protein analysis of a panel of breast cancer cell lines revealed that BRCA1 deficiency is associated with the downregulation of FOXA1 expression. Knockdown of BRCA1 resulted in the downregulation of FOXA1 expression and enhancement of FOXA1 promoter methylation in MCF-7 breast cancer cells, whereas the reconstitution of BRCA1 in Brca1-deficent mouse mammary epithelial cells (MMECs) promoted Foxa1 expression and methylation. These data suggest that BRCA1 suppresses FOXA1 hypermethylation and silencing. Consistently, the treatment of MMECs with the DNA methylation inhibitor 5-aza-2′-deoxycitydine induced Foxa1 mRNA expression. Furthermore, treatment with GSK126, an inhibitor of EZH2 methyltransferase activity, induced FOXA1 expression in BRCA1-deficient but not in BRCA1-reconstituted MMECs. Likewise, the depletion of EZH2 by small interfering RNA enhanced FOXA1 mRNA expression. Chromatin immunoprecipitation (ChIP) analysis demonstrated that BRCA1, EZH2, DNA methyltransferases (DNMT)1/3a/3b and H3K27me3 are recruited to the endogenous FOXA1 promoter, further supporting the hypothesis that these proteins interact to modulate FOXA1 methylation and repression. Further co-immunoprecipitation and ChIP analysis showed that both BRCA1 and DNMT3b form complexes with EZH2 but not with each other, consistent with the notion that BRCA1 binds to EZH2 and negatively regulates its methyltransferase activity. We also found that EZH2 promotes and BRCA1 impairs the deposit of the gene silencing histone mark H3K27me3 on the FOXA1 promoter. These associations were validated in a familial breast cancer patient cohort. Integrated analysis of the global gene methylation and expression profiles of a set of 33 familial breast tumours revealed that FOXA1 promoter methylation is inversely correlated with the transcriptional expression of FOXA1 and that BRCA1 mutation breast cancer is significantly associated with FOXA1 methylation and downregulation of FOXA1 expression, providing physiological evidence to our findings that FOXA1 expression is regulated by methylation and chromatin silencing and that BRCA1 maintains FOXA1 expression through suppressing FOXA1 gene methylation in breast cancer.
PMCID: PMC4430311  PMID: 25531315
2.  Gene expression of INPP5F as an independent prognostic marker in fludarabine-based therapy of chronic lymphocytic leukemia 
Blood Cancer Journal  2015;5(10):e353-.
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease. Various disease-related and patient-related factors have been shown to influence the course of the disease. The aim of this study was to identify novel biomarkers of significant clinical relevance. Pretreatment CD19-separated lymphocytes (n=237; discovery set) and peripheral blood mononuclear cells (n=92; validation set) from the REACH trial, a randomized phase III trial in relapsed CLL comparing rituximab plus fludarabine plus cyclophosphamide with fludarabine plus cyclophosphamide alone, underwent gene expression profiling. By using Cox regression survival analysis on the discovery set, we identified inositol polyphosphate-5-phosphatase F (INPP5F) as a prognostic factor for progression-free survival (P<0.001; hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.35–1.98) and overall survival (P<0.001; HR, 1.47; 95% CI, 1.18–1.84), regardless of adjusting for known prognostic factors. These findings were confirmed on the validation set, suggesting that INPP5F may serve as a novel, easy-to-assess future prognostic biomarker for fludarabine-based therapy in CLL.
PMCID: PMC4635191  PMID: 26430724
3.  Meta-analysis of benzene exposure and non-Hodgkin lymphoma: biases could mask an important association 
Benzene is a widely recognised cause of leukaemia but its association with non-Hodgkin’s lymphoma (NHL) is less well established. The goal of this project is to review the current published literature on this association.
We performed a meta-analysis of cohort and case-control studies of benzene exposure and NHL and a meta-analysis of NHL and refinery work, a potential source of benzene exposure.
In 22 studies of benzene exposure, the summary relative risk for NHL was 1.22 (95% CI 1.02 to 1.47; one-sided p value = 0.01). When studies that likely included unexposed subjects in the “exposed” group were excluded, the summary relative risk increased to 1.49 (95% CI 1.12 to 1.97, n = 13), and when studies based solely on self-reported work history were excluded, the relative risk rose to 2.12 (95% CI 1.11 to 4.02, n = 6). In refinery workers, the summary relative risk for NHL in all 21 studies was 1.21 (95% CI 1.00 to 1.46; p = 0.02). When adjusted for the healthy worker effect, this relative risk estimate increased to 1.42 (95% CI 1.19 to 1.69).
The finding of elevated relative risks in studies of both benzene exposure and refinery work provides further evidence that benzene exposure causes NHL. In addition, the finding of increased relative risks after removing studies that included unexposed or lesser exposed workers in “exposed” cohorts, and increased relative risk estimates after adjusting for the healthy worker effect, suggest that effects of benzene on NHL might be missed in occupational studies if these biases are not accounted for.
PMCID: PMC4353490  PMID: 18417556
5.  Differential development of tolerance to the functional and behavioral effects of repeated baclofen treatment in rats 
Baclofen, a gamma-aminobutyric acid (GABA)B receptor agonist, has been used clinically to treat muscle spasticity, rigidity and pain. More recently, interest in the use of baclofen as an addiction medicine has grown, with promising preclinical cocaine and amphetamine data and demonstrated clinical benefit from alcohol and nicotine studies. Few preclinical investigations, however, have utilized chronic dosing of baclofen, which is important given that tolerance can occur to many of its effects. Thus the question of whether chronic treatment of baclofen maintains the efficacy of acute doses is imperative. The neural substrates that underlie the effects of baclofen, particularly those after chronic treatment, are also not known. In the present study, therefore, rats were treated with either a) vehicle, b) acute baclofen (5 mg/kg) or c) chronic baclofen (5 mg/kg, t.i.d. for 5 days). The effects of acute and chronic baclofen administration, compared to vehicle, were assessed using locomotor activity and changes in brain glucose metabolism (a measure of functional brain activity). Acute baclofen significantly reduced locomotor activity (horizontal and total distance traveled), while chronic baclofen failed to affect locomotor activity. Acute baclofen resulted in significantly lower rates of local cerebral glucose utilization throughout many areas of the brain, including the prefrontal cortex, caudate putamen, septum and hippocampus. The majority of these functional effects, with the exception of the caudate putamen and septum, were absent in animals chronically treated with baclofen. Despite the tolerance to the locomotor and functional effects of baclofen following repeated treatment, these persistent effects on functional activity in the caudate putamen and septum may provide insights into the way in which baclofen alters the reinforcing effects of abused substances such as cocaine, alcohol, and methamphetamine both in humans and animal models.
PMCID: PMC3717556  PMID: 23500188
2-[14C]-deoxyglucose; functional activity; locomotor activity; chronic baclofen; tolerance
6.  Genetic risk prediction and neurobiological understanding of alcoholism 
Translational Psychiatry  2014;4(5):e391-.
We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value SNPs in the top candidate genes discovered by CFG  (n=135 genes, 713 SNPs) was used to generate a genetic  risk prediction score (GRPS), which showed a trend towards significance (P=0.053) in separating  alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n=11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P=0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress-reactive animal model cross-validation. We also tested this small panel of genes in two other independent test cohorts from the United States, one with alcohol dependence (P=0.00012) and one with alcohol abuse (a less severe form of alcoholism; P=0.0094). SNCA by itself was able to separate alcoholics from controls in the alcohol-dependent cohort (P=0.000013) and the alcohol abuse cohort (P=0.023). So did eight other genes from the panel of 11 genes taken individually, albeit to a lesser extent and/or less broadly across cohorts. SNCA, GRM3 and MBP survived strict Bonferroni correction for multiple comparisons. Taken together, these results suggest that our stress-reactive DBP animal model helped to validate and prioritize from the CFG-discovered genes some of the key behaviorally relevant genes for alcoholism. These genes fall into a series of biological pathways involved in signal transduction, transmission of nerve impulse (including myelination) and cocaine addiction. Overall, our work provides leads towards a better understanding of illness, diagnostics and therapeutics, including treatment with omega-3 fatty acids. We also examined the overlap between the top candidate genes for alcoholism from this work and the top candidate genes for bipolar disorder, schizophrenia, anxiety from previous CFG analyses conducted by us, as well as cross-tested genetic risk predictions. This revealed the significant genetic overlap with other major psychiatric disorder domains, providing a basis for comorbidity and dual diagnosis, and placing alcohol use in the broader context of modulating the mental landscape.
PMCID: PMC4035721  PMID: 24844177
7.  Human Monoclonal Antibody MBL-HCV1 Delays HCV Viral Rebound Following Liver Transplantation: A Randomized Controlled Study 
Rapid allograft infection complicates liver transplantation (LT) in patients with hepatitis C virus (HCV). Pegylated interferon-α and ribavirin therapy after LT has significant toxicity and limited efficacy. The effect of a human monoclonal antibody targeting the HCV E2 glycoprotein (MBL-HCV1) on viral clearance was examined in a randomized, double-blind, placebo-controlled pilot study in patients infected with HCV genotype 1a undergoing LT. Subjects received 11 infusions of 50 mg/kg MBL-HCV1 (n=6) or placebo (n=5) intravenously with three infusions on day of transplant, a single infusion on days 1 through 7 and one infusion on day 14 after LT. MBL-HCV1 was well-tolerated and reduced viral load for a period ranging from 7 to 28 days. Median change in viral load (log10 IU/ml) from baseline was significantly greater (P=0.02) for the antibody-treated group (range −3.07 to −3.34) compared to placebo group (range −0.331 to −1.01) on days 3 through 6 post-transplant. MBL-HCV1 treatment significantly delayed median time to viral rebound compared to placebo treatment (18.7 days vs. 2.4 days, P <0.001). As with other HCV monotherapies, antibody-treated subjects had resistance-associated variants at the time of viral rebound. A combination study of MBL-HCV1 with a direct-acting antiviral is underway. Identifier: NCT01121185 funded by MassBiologics
PMCID: PMC3618536  PMID: 23356386
Hepatitis C virus; Monoclonal Antibody; HCV RNA titer; Liver Transplantation
8.  Eye casualty services in London 
Eye  2013;27(3):320-328.
The combined pressures of the European Working Time Directive, 4 h waiting time target, and growing rates of unplanned hospital attendances have forced a major consolidation of eye casualty departments across the country, with the remaining units seeing a rapid increase in demand. We examine the effect of these changes on the provision of emergency eye care in Central London, and see what wider lessons can be learned. We surveyed the managers responsible for each of London's 8 out-of-hours eye casualty services, analysed data on attendance numbers, and conducted detailed interviews with lead clinicians. At London's two largest units, Moorfields Eye Hospital and the Western Eye Hospital, annual attendance numbers have been rising at 7.9% per year (to 76 034 patients in 2010/11) and 9.6% per year (to 31 128 patients in 2010/11), respectively. Using Moorfields as a case study, we discuss methods to increase capacity and efficiency in response to this demand, and also examine some of the unintended consequences of service consolidation including patients travelling long distances to geographically inappropriate units, and confusion over responsibility for out-of-hours inpatient cover. We describe a novel ‘referral pathway' developed to minimise unnecessary travelling and delay for patients, and propose a forum for the strategic planning of London's eye casualty services in the future.
PMCID: PMC3597891  PMID: 23370420
eye casualty; paediatric eye casualty; ophthalmic accident and emergency
9.  New Insecticides for Management of Tomato Yellow Leaf Curl, a Virus Vectored by the Silverleaf Whitefly, Bemisia tabaci 
Journal of Insect Science  2014;14(1):183.
Greenhouse studies using a randomized complete block design were carried out to evaluate the effect of six insecticides on transmission of Tomato yellow leaf curl virus (TYLCV) by the silverleaf whitefly, Bemisia tabaci biotype B Gennadius (Hemiptera: Aleyrodidae) to tomato, Lycopersicon esculentum (Miller) (Solanales: Solanaceae), seedlings that were inoculated with whiteflies from a TYLCV colony in cages 3, 7, or 14 d after treatment with insecticide. The purpose was to reveal differences in residual efficacy of four materials that are nearing registration for use on tomato—cyazypyr, flupyradifurone, pyrafluquinazon, and sulfoxaflor—and to compare them with two established insecticides, pymetrozine and a zeta-cypermethrin/bifenthrin combination. Differences in efficacy were expected because these six materials represent five distinct modes of action and both contact and systemic materials. Percentage of tomato seedlings expressing virus symptoms tended to be lowest in seedlings treated with flupyradifurone. The zeta-cypermethrin/bifenthrin insecticide demonstrated comparable efficacy to flupyradifurone in some trials at 3 and 7 d after treatment inoculations, but not the 14 d after treatment inoculation. Pyrafluquinazon was not statistically different from cyazypyr or sulfoxaflor in percentage of plants with virus symptoms in any trial. Percentage virus in the cyazypyr and sulfoxaflor treatments was not statistically different in the 3 and 7 d after treatment inoculations. Among seedlings treated with insecticide, percentage with virus symptoms tended to be highest in the seedlings treated with pymetrozine.
PMCID: PMC4684678  PMID: 25368089
begomovirus; Bemisia tabaci; Geminiviridae; tomato yellow leaf curl virus; whitefly insecticidal control
10.  Associations between Accelerometer-derived Physical Activity and Regional Adiposity in Young Men and Women 
Obesity (Silver Spring, Md.)  2013;21(6):1299-1305.
Empirical evidence supports an inverse relationship between physical activity (PA) and adiposity, but studies using detailed measures of both are scarce. We described the relationship between regional adiposity and accelerometer-derived PA in men and women.
Design and Methods
Cross-sectional analysis included 253 participants from a weight loss study limited to ages 20–45 years and BMI 25–39.9 kg/m2. PA data were collected with accelerometers and expressed as total accelerometer counts and average amount of time per day accumulated in different intensity levels (sedentary, light-, and moderate- to vigorous- intensity PA (MVPA)). Accumulation of time spent above 100 counts was expressed as total active time. Computed tomography (CT) was used to measure abdominal and adipose tissue (AT). Multivariate linear regression analyses were used to assess the relationship between regional adiposity (dependent variable) and the various PA levels (independent variable), and were executed separately for men and women, adjusting for wear time, age, race, education, and BMI.
Among males light activity was inversely associated with total AT (β=−0.19; p=0.02) as well as visceral AT (VAT) (β=−0.30; p=0.03). Among females sedentary time was positively associated with VAT (β=0.11; p=0.04) and total active time was inversely associated with VAT (β=−0.12; p=0.04).
Findings from this study suggest that PA intensity level may influence regional adiposity differently in men and women. Additional research is needed in larger samples to clarify the difference in these associations by sex, create recommendations for the frequency, duration and intensity of PA needed to target fat deposits, and determine if these recommendations should differ by sex.
PMCID: PMC3716839  PMID: 23408709
11.  Patient-reported benefit from oculoplastic surgery 
Eye  2012;26(11):1418-1423.
It is vital that surgeons undertaking oculoplastic procedures are able to show that the surgery they perform is of benefit to their patients. Not only is this fundamental to patient-centred medicine but it is also important in demonstrating cost effectiveness. There are several ways in which benefit can be measured, including clinical scales, functional ability scales, and global quality-of-life scales. The Glasgow benefit inventory (GBI) is an example of a patient-reported, questionnaire-based, post-interventional quality-of-life scale that can be used to compare a range of different treatments for a variety of conditions.
A cross-sectional study was undertaken using the GBI to score patient benefit from four commonly performed oculoplastic procedures. It was completed for 66 entropion repairs, 50 ptosis repairs, 41 ectropion repairs, and 41 external dacryocystorhinostomies (DCR). The GBI generates a scale from −100 (maximal detriment) through zero (no change) to +100 (maximal benefit).
The total GBI scores of patients undergoing surgery for entropion, ptosis, ectropion, and external DCR were: +25.25 (95% CI 20.00–30.50, P<0.001), +24.89 (95% CI 20.04–29.73, P<0.001), +17.68 (95% CI 9.46–25.91, P<0.001), and +32.25 (95% CI 21.47–43.03, P<0.001), respectively, demonstrating a statistically significant benefit from all procedures.
Patients derived significant quality-of-life benefits from the four most commonly performed oculoplastic procedures.
PMCID: PMC3496101  PMID: 22975655
Glasgow benefit inventory; entropion; ectropion; ptosis; dacryocystorhinostomy
12.  Hunger can be taught: Hunger Recognition regulates eating and improves energy balance 
A set of spontaneous hunger sensations, Initial Hunger (IH), has been associated with low blood glucose concentration (BG). These sensations may arise pre-meal or can be elicited by delaying a meal. With self-measurement of BG, subjects can be trained to formally identify and remember these sensations (Hunger Recognition). Subjects can then be trained to ensure that IH is present pre-meal for most meals and that their pre-meal BG is therefore low consistently (IH Meal Pattern). IH includes the epigastric Empty Hollow Sensation (the most frequent and recognizable) as well as less specific sensations such as fatigue or light-headedness which is termed inanition. This report reviews the method for identifying IH and the effect of the IH Meal Pattern on energy balance. In adults, the IH Meal Pattern has been shown to significantly decrease energy intake by one-third, decrease preprandial BG, reduce glycosylated hemoglobin, and reduce insulin resistance and weight in those who are insulin resistant or overweight. Young children as well as adults can be trained in Hunger Recognition, giving them an elegant method for achieving energy balance without the stress of restraint-type dieting. The implications of improving insulin sensitivity through improved energy balance are as wide as improving immune activity.
Video abstract
PMCID: PMC3698025  PMID: 23825928
energy intake; hunger; energy balance; food intake regulation; prevention; insulin resistance; obesity; diabetes; inflammation; risks
13.  The Alaska Area Specimen Bank: a tribal–federal partnership to maintain and manage a resource for health research 
International Journal of Circumpolar Health  2013;72:10.3402/ijch.v72i0.20607.
Banked biospecimens from a defined population are a valuable resource that can be used to assess early markers for illness or to determine the prevalence of a disease to aid the development of intervention strategies to reduce morbidity and mortality. The Alaska Area Specimen Bank (AASB) currently contains 266,353 residual biologic specimens (serum, plasma, whole blood, tissue, bacterial cultures) from 83,841 persons who participated in research studies, public health investigations and clinical testing conducted by the U.S. Public Health Service and Alaska Native tribal health organisations dating back to 1961. The majority (95.7%) are serum specimens, 77% were collected between 1981 and 1994 and 85% were collected from Alaska Native people. Oversight of the specimen bank is provided by a working group with representation from tribal, state and federal health organisations, the Alaska Area IRB and a specimen bank committee which ensures the specimens are used in accordance with policies and procedures developed by the working group.
PMCID: PMC3629262  PMID: 23599909
Biobanking; policy and procedures; Tribal and Federal Management
14.  Small intestinal angiosarcoma masquerading as an appendiceal abscess 
Angiosarcomas of the small intestine are rare and present non-specifically. They usually manifest with abdominal discomfort, altered bowel habits, anaemia and gastrointestinal bleeding. Diagnosis is often challenging and occurs at an advanced tumour stage. We describe a case of a terminal ileum angiosarcoma masquerading as an appendiceal abscess, and discuss salient clinicopathological features in diagnosing and managing this disease.
PMCID: PMC3964668  PMID: 23317721
Angiosarcoma; Gastrointestinal; Tumour; Appendix; Abscess
15.  Group II metabotropic glutamate receptors in the striatum of non-human primates: dysregulation following chronic cocaine self-administration 
Neuroscience letters  2011;496(1):15-19.
A growing body of evidence has demonstrated a role for group II metabotropic glutamate receptors (mGluRs) in the reinforcing effects of cocaine. These receptors are important given their location in limbic-related areas, and their ability to control the release of glutamate and other neurotransmitters. They are also potential targets for novel pharmacotherapies for cocaine addiction. The present study investigated the impact of chronic cocaine self-administration (9.0 mg/kg/session for 100 sessions, 900 mg/kg total intake) on the densities of group II mGluRs, as assessed with in vitro receptor autoradiography, in the striatum of adult male rhesus monkeys. Binding of [3H]LY341495 to group II mGluRs in control animals was heterogeneous, with a medial to lateral gradient in binding density. Significant elevations in the density of group II mGluRs following chronic cocaine self-administration were measured in the dorsal, central and ventral portions of the caudate nucleus (P<0.05), compared to controls. No differences in receptor density were observed between the groups in either the putamen or nucleus accumbens. These data demonstrate that group II mGluRs in the dorsal striatum are more sensitive to the effects of chronic cocaine exposure than those in the ventral striatum. Cocaine-induced dysregulation of the glutamate system, and its consequent impact on plasticity and synaptic remodeling, will likely be an important consideration in the development of novel pharmacotherapies for cocaine addiction.
PMCID: PMC3110718  PMID: 21458540
cocaine self-administration; non-human primate; striatum; group II metabotropic glutamate receptors
16.  APOBEC-1 Complementation Factor (ACF) forms RNA-Dependent Multimers 
Limited proteolysis of APOBEC-1 Complementation Factor (ACF) and computational secondary structure modeling were used to guide the construction of a well-folded, truncation protein spanning residues 1-320 and containing three RNA Recognition Motifs (RRMs). ACF320 bound preferentially to apoB mRNA and supported APOBEC-1 dependent editing at 40% of the activity of full length ACF. Live cell FRET and immunoprecipitation assays revealed that ACF320 formed homomultimers in situ that were bridged by RNA. Our study predicted that the C to U editosome may be assembled on the mooring sequence of apoB mRNA as a dimer of ACF bound to a dimer of APOBEC-1.
PMCID: PMC2912146  PMID: 20541536
17.  Lung function in our aging population 
Aims of investigation
The chronological age of the Caucasian population and their anthropometrical data have significantly changed within the last five decades. Therefore the question arises whether or not the commonly used reference values of the European Community (ECCS) for lung function may still be accepted today. Since these values were obtained in the 1960s from subjects in a limited age range. For the elderly, the measured values are deduced by extrapolation beyond the range of reference equations which had been obtained in a different population. Therefore decisions concerning elderly and smaller subjects concerning remuneration due to impaired lung function after industrial exposure on the basis of EGKS values are questionable.
Lung function tests were performed by pneumotachography, recording static lung volumes and flow-volume-curves in 262 asymptomatic non smoking males, aged 20 to 90 years. Measurements were performed with the MasterLab, or Pneumo-Screen systems (CareFusion, Höchberg). Results were compared to the reference values of ECCS, SAPALDIA and LuftiBus.
For simplicity analysis of age and height dependence of investigated respiratory parameters (VC, FVC, FEV1, FEV1%FVC, PEF, MEF75,50,25) can be described by linear functions (y = a * height - b * age + c). The forced expiratory vital capacity, FVC, was calculated by FVC = 0.0615*H - 0.0308*A - 4.673; r = 0.78. Mean FVC for younger subjects was found to be 104.7 ± 10.7% of the ECCS reference values and 96.5 ± 11.8% in older subjects. For most parameters investigated linear regressions on age were steeper than described by the ECCS reference values. The regression of lung function to height largely follows the ECCS prescriptions.
Bochum lung function values of younger healthy subjects were higher compared to the reference values of the ECCS and showed a steeper age descent. The alternatively discussed reference values of the SAPALDIA-, or LuftiBus-Study are higher, but do not cover all necessary parameters and/or the age range. A multi centre study for contemporary reference values is recommended.
PMCID: PMC3352207  PMID: 21486723
Lung function testing; reference values; elderly males; spirometry; forced expiration
18.  Identification of Cryptosporidium Species and Genotypes in Scottish Raw and Drinking Waters during a One-Year Monitoring Period▿  
Applied and Environmental Microbiology  2010;76(17):5977-5986.
We analyzed 1,042 Cryptosporidium oocyst-positive slides (456 from raw waters and 586 from drinking waters) of which 55.7% contained 1 or 2 oocysts, to determine species/genotypes present in Scottish waters. Two nested PCR-restriction fragment length polymorphism (RFLP) assays targeting different loci (1 and 2) of the hypervariable region of the 18S rRNA gene were used for species identification, and 62.4% of samples were amplified with at least one of the PCR assays. More samples (577 slides; 48.7% from raw water and 51.3% from drinking water) were amplified at locus 1 than at locus 2 (419 slides; 50.1% from raw water and 49.9% from drinking water). PCR at loci 1 and 2 amplified 45.4% and 31.7% of samples containing 1 or 2 oocysts, respectively. We detected both human-infectious and non-human-infectious species/genotype oocysts in Scottish raw and drinking waters. Cryptosporidium andersoni, Cryptosporidium parvum, and the Cryptosporidium cervine genotype (now Cryptosporidium ubiquitum) were most commonly detected in both raw and drinking waters, with C. ubiquitum being most common in drinking waters (12.5%) followed by C. parvum (4.2%) and C. andersoni (4.0%). Numerous samples (16.6% total; 18.9% from drinking water) contained mixtures of two or more species/genotypes, and we describe strategies for unraveling their identity. Repetitive analysis for discriminating mixtures proved useful, but both template concentration and PCR assay influenced outcomes. Five novel Cryptosporidium spp. (SW1 to SW5) were identified by RFLP/sequencing, and Cryptosporidium sp. SW1 was the fourth most common contaminant of Scottish drinking water (3%).
PMCID: PMC2935041  PMID: 20639357
19.  Neoadjuvant chemotherapy in breast cancer-response evaluation and prediction of response to treatment using dynamic contrast-enhanced and diffusion-weighted MR imaging 
European Radiology  2010;21(6):1188-1199.
To explore the predictive value of MRI parameters and tumour characteristics before neoadjuvant chemotherapy (NAC) and to compare changes in tumour size and tumour apparent diffusion coefficient (ADC) during treatment, between patients who achieved pathological complete response (pCR) and those who did not.
Approval by the Regional Ethics Committee and written informed consent were obtained. Thirty-one patients with invasive breast carcinoma scheduled for NAC were enrolled (mean age, 50.7; range, 37–72). Study design included MRI before treatment (Tp0), after four cycles of NAC (Tp1) and before surgery (Tp2). Data in pCR versus non-pCR groups were compared and cut-off values for pCR prediction were evaluated.
Before NAC, HER2 overexpression was the single significant predictor of pCR (p = 0.006). At Tp1 ADC, tumour size and changes in tumour size were all significantly different in the pCR and non-pCR groups. Using 1.42 × 10−3 mm2/s as the cut-off value for ADC, pCR was predicted with sensitivity and specificity of 88% and 80%, respectively. Using a cut-off value of 83% for tumour volume reduction, sensitivity and specificity for pCR were 91% and 80%.
ADC, tumour size and tumour size reduction at Tp1 were strong independent predictors of pCR.
PMCID: PMC3088808  PMID: 21127880
Prediction; Breast cancer; DCE MRI; ADC; Neoadjuvant chemotherapy
20.  Relationship between disease course in the temporomandibular joints and mandibular growth rotation in patients with juvenile idiopathic arthritis followed from childhood to adulthood 
To investigate the relationship between radiographic JIA disease course in the TMJs and mandibular growth rotation, compared with growth in healthy individuals.
From a larger series of JIA patients followed from childhood to adulthood, 26 were included; 11 without and 15 with bilateral radiographic TMJ involvement. Joint morphology and function were assessed at baseline, 2-, 4-, 6- and 27 years follow-up. Mandibular growth rotation (anterior, posterior or none) was assessed from cephalometric evaluations at childhood and adulthood, with observations from 16 healthy individuals as controls. TMJ disease course and mandibular growth rotation were assessed independently and their relationship analysed. Non-parametric statistical methods were applied to test differences between groups.
In the normal TMJ group of JIA patients the joint morphology was similar at the follow-ups and all patients had good function both in childhood and in adulthood. The mandibular growth rotation was similar to that of healthy controls, i.e. predominantly in anterior direction. In the abnormal TMJ group different JIA TMJ disease courses were observed and associated with changes in the mandibular growth rotation (p = 0.007).
Progressing JIA TMJ disease course was related to posterior mandibular growth rotation and improving disease course to anterior mandibular growth rotation.
A relationship was found between JIA disease course in the TMJs and mandibular growth rotation, suggesting that a favourable growth could be regained in patients with improvement in TMJ morphology and/or TMJ function. To confirm this, further research on larger patient series is needed.
PMCID: PMC2867972  PMID: 20412568
21.  Effectiveness of five different approaches in management of urinary tract infection: randomised controlled trial 
Objective To assess the impact of different management strategies in urinary tract infections.
Design Randomised controlled trial.
Setting Primary care.
Participants 309 non-pregnant women aged 18-70 presenting with suspected urinary tract infection.
Intervention Patients were randomised to five management approaches: empirical antibiotics; empirical delayed (by 48 hours) antibiotics; or targeted antibiotics based on a symptom score (two or more of urine cloudiness, urine smell, nocturia, or dysuria), a dipstick result (nitrite or both leucocytes and blood), or a positive result on midstream urine analysis. Self help advice was controlled in each group.
Main outcome measures Symptom severity (days 2 to 4) and duration, and use of antibiotics.
Results Patients had 3.5 days of moderately bad symptoms if they took antibiotics immediately. There were no significant differences in duration or severity of symptoms (mean frequency of symptoms on a 0 to 6 scale: immediate antibiotics 2.15, midstream urine 2.08, dipstick 1.74, symptom score 1.77, delayed antibiotics 2.11; likelihood ratio test for the five groups P=0.177). There were differences in antibiotic use (immediate antibiotics 97%, midstream urine 81%, dipstick 80%, symptom score 90%, delayed antibiotics 77%; P=0.011) and in sending midstream urine samples (immediate antibiotics 23%, midstream urine 89%, dipstick 36%, symptom score 33%, delayed antibiotics 15%; P<0.001). Patients who waited at least 48 hours to start taking antibiotics reconsulted less (hazard ratio 0.57 (95% confidence interval 0.36 to 0.89), P=0.014) but on average had symptoms for 37% longer than those taking immediate antibiotics (incident rate ratio 1.37 (1.11 to 1.68), P=0.003), particularly the midstream urine group (73% longer, 22% to 140%; none of the other groups had more than 22% longer duration).
Conclusion All management strategies achieve similar symptom control. There is no advantage in routinely sending midstream urine samples for testing, and antibiotics targeted with dipstick tests with a delayed prescription as backup, or empirical delayed prescription, can help to reduce antibiotic use.
Study registration National Research Register N0484094184 ISRCTN: 03525333.
PMCID: PMC2817051  PMID: 20139214
22.  Presentation, pattern, and natural course of severe symptoms, and role of antibiotics and antibiotic resistance among patients presenting with suspected uncomplicated urinary tract infection in primary care: observational study 
Objective To assess the natural course and the important predictors of severe symptoms in urinary tract infection and the effect of antibiotics and antibiotic resistance.
Design Observational study.
Setting Primary care.
Participants 839 non-pregnant adult women aged 18-70 presenting with suspected urinary tract infection.
Main outcome measure Duration and severity of symptoms.
Results 684 women provided some information on symptoms; 511 had both laboratory results and complete symptom diaries. For women with infections sensitive to antibiotics, severe symptoms, rated as a moderately bad problem or worse, lasted 3.32 days on average. After adjustment for other predictors, moderately bad symptoms lasted 56% longer (incidence rate ratio 1.56, 95% confidence interval 1.22 to 1.99, P<0.001) in women with resistant infections; 62% longer (1.62, 1.13 to 2.31, P=0.008) when no antibiotics prescribed; and 33% longer (1.33, 1.14 to 1.56, P<0.001) in women with urethral syndrome. The duration of symptoms was shorter if the doctor was perceived to be positive about diagnosis and prognosis (continuous 7 point scale: 0.91, 0.84 to 0.99; P=0.021) and longer when the woman had frequent somatic symptoms (1.03, 1.01 to 1.05, P=0.002; for each symptom), a history of cystitis, urinary frequency, and more severe symptoms at baseline.
Conclusion Antibiotic resistance and not prescribing antibiotics are associated with a greater than 50% increase in the duration of more severe symptoms in women with uncomplicated urinary tract infection. Women with a history of cystitis, frequent somatic symptoms (high somatisation), and severe symptoms at baseline can be given realistic advice that they are likely to have severe symptoms lasting longer than three days.
PMCID: PMC2817050  PMID: 20139213
23.  Women’s views about management and cause of urinary tract infection: qualitative interview study 
Objectives To explore the views of women with urinary tract infection on the acceptability of different strategies for managing the infection, including delayed use of antibiotics, and the cause of infection.
Design Qualitative interview study with semistructured one to one interviews within a randomised controlled trial of different management strategies. Analysis drew on some of the principles of constant comparison to generate key themes grounded in reported experiences and understandings.
Setting Seven general practices across four counties in southern England.
Participants 21 women presenting to general practices who were taking part in the larger trial.
Results Women preferred not to take antibiotics and were open to alternative management approaches. With a strategy of “antibiotic delay” some women felt a lack of validation or that they were not listened to by their general practitioner. Women attributed urinary tract infection to lifestyle habits and behaviours, such as poor hygiene, general “negligence,” and even a “penalty of growing old.”
Conclusion A clear acknowledgment of women’s triggers to consult is needed. If women are asked to delay taking antibiotics, the clinician must address the particular worries that women might have and explain the rationale for not using antibiotics immediately.
PMCID: PMC2817049  PMID: 20139217
24.  Recognition of skin malignancy by general practitioners: observational study using data from a population-based randomised controlled trial 
British Journal of Cancer  2009;100(1):24-27.
Skin malignancy is an important cause of mortality in the United Kingdom and is rising in incidence every year. Most skin cancer presents in primary care, and an important determinant of outcome is initial recognition and management of the lesion. Here we present an observational study of interobserver agreement using data from a population-based randomised controlled trial of minor surgery. Trial participants comprised patients presenting in primary care and needing minor surgery in whom recruiting doctors felt to be able to offer treatment themselves or to be able to refer to a colleague in primary care. They are thus relatively unselected. The skin procedures undertaken in the randomised controlled trial generated 491 lesions with a traceable histology report: 36 lesions (7%) from 33 individuals were malignant or pre-malignant. Chance-corrected agreement (κ) between general practitioner (GP) diagnosis of malignancy and histology was 0.45 (0.36–0.54) for lesions and 0.41 (0.32–0.51) for individuals affected with malignancy. Sensitivity of GPs for the detection of malignant lesions was 66.7% (95% confidence interval (CI), 50.3–79.8) for lesions and 63.6% (95% CI, 46.7–77.8) for individuals affected with malignancy. The safety of patients is of paramount importance and it is unsafe to leave the diagnosis and treatment of potential skin malignancy in the hands of doctors who have limited training and experience. However, the capacity to undertake all of the minor surgical demand works demanded in hospitals does not exist. If the capacity to undertake it is present in primary care, then the increased costs associated with enhanced training for general medical practitioners (GPs) must be borne.
PMCID: PMC2634694  PMID: 19127264
skin malignancy; minor surgery; general practice
25.  Time for new reference values for ventilatory lung function 
European Journal of Medical Research  2009;14(Suppl 4):140-146.
The anthropometrical data of our aging population has significantly changed within the last five decades. Therefore the question arises whether or not the commonly used reference values of the European Community (ECCS) for lung function, may still be accepted today. Measured values for elderly are classified by extrapolation beyond the range of reference equations.
Materials and methods
Lung function was examined by pneumotachography for recording static lung volumes and flow-volume-curves in 257 asymptomatic non smoking males, aged 20-90 years. Results were compared to the reference values of ECCS, SAPALDIA, LuftiBus, and NHANES.
For analysis age and height dependence of investigated respiratory parameters (VC, FVC, FEV1, FEV1 %FVC, PEF, MEF75,50,25) can for simplicity be described by linear functions (y = a · height(H)-b · age (A)+c). The forced expiratory volume in one second, FEV1, was calculated by FEV1 = 0.0432 · H-0.0347 · A-2.114; where H - height, A - age; r = 0.78. Mean FEV1 for younger subjects was found to be 106.1 ± 11.2% of the ECCS reference values and 97.8 ± 11.7% in older subjects. For all parameters investigated linear regressions on age were steeper than described by the ECCS reference values. The regression of lung function to height largely follows the ECCS prescriptions.
Bochum lung function values of healthy subjects showed a steeper age descent compared to the reference values of the ECCS. The alternatively discussed reference values of the SAPALDIA-, NHANES- or LuftiBus-Study are higher, but do not cover all necessary parameters and/or the age range. A multi centre study for contemporary reference values is recommended.
PMCID: PMC3521331  PMID: 20156745
lung function; reference values; elderly males; spirometry; forced expiration

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