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1.  Sedentary time and markers of inflammation in people with newly diagnosed type 2 diabetes 
Background and aims
We investigated whether objectively measured sedentary time was associated with markers of inflammation in adults with newly diagnosed type 2 diabetes.
Methods and results
We studied 285 adults (184 men, 101 women, mean age 59.0 ± 9.7) who had been recruited to the Early ACTivity in Diabetes (Early ACTID) randomised controlled trial. C-reactive protein (CRP), adiponectin, soluble intracellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), and accelerometer-determined sedentary time and moderate-vigorous physical activity (MVPA) were measured at baseline and after six-months. Linear regression analysis was used to investigate the independent cross-sectional and longitudinal associations of sedentary time with markers of inflammation.
At baseline, associations between sedentary time and IL-6 were observed in men and women, an association that was attenuated following adjustment for waist circumference. After 6 months of follow-up, sedentary time was reduced by 0.4 ± 1.2 h per day in women, with the change in sedentary time predicting CRP at follow-up. Every hour decrease in sedentary time between baseline and six-months was associated with 24% (1, 48) lower CRP. No changes in sedentary time between baseline and 6 months were seen in men.
Conclusions
Higher sedentary time is associated with IL-6 in men and women with type 2 diabetes, and reducing sedentary time is associated with improved levels of CRP in women. Interventions to reduce sedentary time may help to reduce inflammation in women with type 2 diabetes.
Highlights
•Sedentary time is associated with inflammation in adults with type 2 diabetes.•Reducing sedentary time in women improved C-reactive protein.•Interventions to reduce sedentary time may reduce cardiovascular risk in women.
doi:10.1016/j.numecd.2014.03.009
PMCID: PMC4154448  PMID: 24925122
Sedentary time; Type 2 diabetes; Breaks in sedentary time; Inflammation
2.  Parental inconsistency, impulsive choice and neural value representations in healthy adolescents 
Translational Psychiatry  2014;4(4):e382-.
A well-characterized potential marker for addiction is impulsive choice, stably measured by delay discounting (DD) paradigms. While genetic influences partly account for inter-individual variance in impulsivity, environmental factors such as parenting practices may have an important role. The present study investigates how inconsistent fulfillment of delayed reward promises impacts on DD. A combined correlational and experimental functional magnetic resonance imaging (fMRI) design was performed in a sample of 48 healthy adolescents (13–15 years). More specifically, neural activation during a DD task was investigated at two assessment points (T0 and T1). Adolescents' self-reports of parenting and substance use were assessed at T0. Between assessment points, we experimentally varied the reliability of delayed reward promises, measuring the impact of this intervention on DD and neural value processing at T1. In the correlational part, same-sex parent reward inconsistency was associated with steeper DD and an attenuated subjective value (SV) representation in the nucleus accumbens (NAcc) and ventromedial prefrontal cortex (vmPFC). Steeper DD was in turn associated with alcohol use during the past year. In the experimental part, the reward inconsistency manipulation resulted in an attenuation of the NAcc SV representation, similar to the parental inconsistency effect. Together, our correlational and experimental findings raise new light on how parents may influence their children's degree of impulsivity, making parenting a potential target in addiction prevention.
doi:10.1038/tp.2014.20
PMCID: PMC4012284  PMID: 24736798
3.  Rasmussen's encephalitis presenting as focal cortical dysplasia 
Rasmussen's encephalitis is a rare syndrome characterized by intractable seizures, often associated with epilepsia partialis continua and symptoms of progressive hemispheric dysfunction. Seizures are usually the hallmark of presentation, but antiepileptic drug treatment fails in most patients and is ineffective against epilepsia partialis continua, which often requires surgical intervention. Co-occurrence of focal cortical dysplasia has only rarely been described and may have implications regarding pathophysiology and management. We describe a rare case of dual pathology of Rasmussen's encephalitis presenting as a focal cortical dysplasia (FCD) and discuss the literature on this topic.
doi:10.1016/j.ebcr.2014.01.009
PMCID: PMC4307873  PMID: 25667877
Rasmussen's encephalitis; Focal cortical dysplasia
4.  Activation of Sonic hedgehog signaling in neural progenitor cells promotes glioma development in the zebrafish optic pathway 
Oncogenesis  2014;3(3):e96-.
Dysregulation of Sonic hedgehog (Shh) signaling has been implicated in glioma pathogenesis. Yet, the role of this pathway in gliomagenesis remains controversial because of the lack of relevant animal models. Using the cytokeratin 5 promoter, we ectopically expressed a constitutively active zebrafish Smoothened (Smoa1) in neural progenitor cells and analyzed tumorigenic capacity of activated Shh signaling in both transient and stable transgenic fish. Transient transgenic fish overexpressing Smoa1 developed retinal and brain tumors, suggesting smoa1 is oncogenic in the zebrafish central nervous system (CNS). We further established stable transgenic lines that simultaneously developed optic pathway glioma (OPG) and various retinal tumors. In one of these lines, up to 80% of F1 and F2 fish developed tumors within 1 year of age. Microarray analysis of tumor samples showed upregulated expression of genes involved in the cell cycle, cancer signaling and Shh downstream targets ptc1, gli1 and gli2a. Tumors also exhibited specific gene signatures characteristic of radial glia and progenitor cells as transcriptions of radial glia genes cyp19a1b, s100β, blbp, gfap and the stem/progenitor genes nestin and sox2 were significantly upregulated. Overexpression of GFAP, S100β, BLBP and Sox2 was confirmed by immunofluorescence. We also detected overexpression of Mdm2 throughout the optic pathway in fish with OPG, therefore implicating the Mdm2–Tp53 pathway in glioma pathogenesis. In conclusion, we demonstrate that activated Shh signaling initiates tumorigenesis in the zebrafish CNS and provide the first OPG model not associated with neurofibromatosis 1.
doi:10.1038/oncsis.2014.10
PMCID: PMC4038393  PMID: 24686726
zebrafish; Sonic hedgehog (Shh) pathway; activated Smoothened (Smoa1); optic pathway glioma (OPG)
5.  The risk of oesophago-gastric cancer in symptomatic patients in primary care: a large case–control study using electronic records 
British Journal of Cancer  2012;108(1):25-31.
Background:
Over 15 000 new oesophago-gastric cancers are diagnosed annually in the United Kingdom, with most being advanced disease. We identified and quantified features of this cancer in primary care.
Methods:
Case–control study using electronic primary-care records of the UK patients aged ⩾40 years was performed. Cases with primary oesophago-gastric cancer were matched to controls on age, sex and practice. Putative features of cancer were identified in the year before diagnosis. Odds ratios (ORs) were calculated for these features using conditional logistic regression, and positive predictive values (PPVs) were calculated.
Results:
A total of 7471 cases and 32 877 controls were studied. Sixteen features were independently associated with oesophago-gastric cancer (all P<0.001): dysphagia, OR 139 (95% confidence interval 112–173); reflux, 5.7 (4.8–6.8); abdominal pain, 2.6 (2.3–3.0); epigastric pain, 8.8 (7.0–11.0); dyspepsia, 6 (5.1–7.1); nausea and/or vomiting, 4.9 (4.0–6.0); constipation, 1.5 (1.2–1.7); chest pain, 1.6 (1.4–1.9); weight loss, 8.9 (7.1–11.2); thrombocytosis, 2.4 (2.0–2.9); low haemoglobin, 2.4 (2.1–2.7); low MCV, 5.2 (4.2–6.4); high inflammatory markers, 1.7 (1.4–2.0); raised hepatic enzymes, 1.3 (1.2–1.5); high white cell count, 1.4 (1.2–1.7); and high cholesterol, 0.8 (0.7–0.8). The only PPV >5% in patients ⩾55 years was for dysphagia. In patients <55 years, all PPVs were <1%.
Conclusion:
Symptoms of oesophago-gastric cancer reported in secondary care were also important in primary care. The results should inform guidance and commissioning policy for upper GI endoscopy.
doi:10.1038/bjc.2012.551
PMCID: PMC3553533  PMID: 23257895
oesophago-gastric cancer; primary care; symptoms; diagnosis; positive predictive values
6.  The risk of pancreatic cancer in symptomatic patients in primary care: a large case–control study using electronic records 
British Journal of Cancer  2012;106(12):1940-1944.
Background:
Over 8000 new pancreatic cancers are diagnosed annually in the UK; most at an advanced stage, with only 3% 5-year survival. We aimed to identify and quantify the risk of pancreatic cancer for features in primary care.
Methods:
A case–control study using electronic primary care records identified and quantified the features of pancreatic cancer. Cases, aged ⩾40 in the General Practice Research Database, UK, with primary pancreatic cancer were matched with controls on age, sex and practice. Putative features of pancreatic cancer were identified in the year before diagnosis. Odds ratios (OR) were calculated for features of cancer using conditional logistic regression. Positive predictive values (PPV) were calculated for consulting patients.
Results:
In all, 3635 cases and 16 459 controls were studied. Nine features were associated with pancreatic cancer (all P<0.001 except for back pain, P=0.004); jaundice, OR 1000 (95% confidence interval (CI) 4 302 500); abdominal pain, 5 (4.4, 5.6); nausea/vomiting, 4.5 (3.5, 5.7); back pain, 1.4 (1.1, 1.7); constipation, 2.2 (1.7, 2.8); diarrhoea, 1.9 (1.5, 2.5); weight loss, 15 (11, 22); malaise, 2.4 (1.6, 3.5); new-onset diabetes 2.1 (1.7, 2.5). Positive predictive values for patients aged ⩾60 were <1%, apart from jaundice at 22% (95% CI 14, 52), though several pairs of symptoms had PPVs >1%.
Conclusion:
Most previously reported symptoms of pancreatic cancer were also relevant in primary care. Although predictive values were small – apart from jaundice – they provide a basis for selection of patients for investigation, especially with multiple symptoms.
doi:10.1038/bjc.2012.190
PMCID: PMC3388562  PMID: 22617126
pancreatic cancer; primary care; symptoms; diagnosis; positive predictive values
7.  Stand-alone performance of a computer-assisted detection prototype for detection of acute pulmonary embolism: a multi-institutional comparison 
The British Journal of Radiology  2012;85(1014):758-764.
Objective
To assess whether the performance of a computer-assisted detection (CAD) algorithm for acute pulmonary embolism (PE) differs in pulmonary CT angiographies acquired at various institutions.
Methods
In this retrospective study, we included 40 consecutive scans with and 40 without PE from 3 institutions (n=240) using 64-slice scanners made by different manufacturers (General Electric; Philips; Siemens). CAD markers were classified as true or false positive (FP) using independent evaluation by two readers and consultation of a third chest radiologist in discordant cases. Image quality parameters were subjectively scored using 4/5-point scales. Image noise and vascular enhancement were measured. Statistical analysis was done to correlate image quality of the three institutions with CAD stand-alone performance.
Results
Patient groups were comparable with respect to age (p=0.22), accompanying lung disease (p=0.12) and inpatient/outpatient ratio (p=0.67). The sensitivity was 100% (34/34), 97% (37/38) and 92% (33/36), and the specificity was 18% (8/44), 15% (6/41) and 13% (5/39). Neither significantly differed between the institutions (p=0.21 and p=0.820, respectively). The mean number of FP findings (4.5, 6.2 and 3.7) significantly varied (p=0.02 and p=0.03), but median numbers (2, 3 and 3) were comparable. Image quality parameters were significantly associated with the number of FP findings (p<0.05) but not with sensitivity. After correcting for noise and vascular enhancement, the number of FPs did not significantly differ between the three institutions (p=0.43).
Conclusions
CAD stand-alone performance is independent of scanner type but strongly related to image quality and thus scanning protocols.
doi:10.1259/bjr/26769569
PMCID: PMC3474087  PMID: 22167514
8.  Early thalamic lesions in patients with sleep-potentiated epileptiform activity 
Neurology  2012;78(22):1721-1727.
Objective:
To compare the prevalence and type of early developmental lesions in patients with a clinical presentation consistent with electrical status epilepticus in sleep either with or without prominent sleep-potentiated epileptiform activity (PSPEA).
Methods:
We performed a case-control study and enrolled patients with 1) clinical features consistent with electrical status epilepticus in sleep, 2) ≥1 brain MRI scan, and 3) ≥1 overnight EEG recording. We quantified epileptiform activity using spike percentage, the percentage of 1-second bins in the EEG tracing containing at least 1 spike. PSPEA was present when spike percentage during non-REM sleep was ≥50% than spike percentage during wakefulness.
Results:
One hundred patients with PSPEA (cases) and 47 patients without PSPEA (controls) met the inclusion criteria during a 14-year period. Both groups were comparable in terms of clinical and epidemiologic features. Early developmental lesions were more frequent in cases (48% vs 19.2%, p = 0.002). Thalamic lesions were more frequent in cases (14% vs 2.1%, p = 0.037). The main types of early developmental lesions found in cases were vascular lesions (14%), periventricular leukomalacia (9%), and malformation of cortical development (5%). Vascular lesions were the only type of early developmental lesions that were more frequent in cases (14% vs 0%, p = 0.005).
Conclusions:
Patients with PSPEA have a higher frequency of early developmental lesions and thalamic lesions than a comparable population of patients without PSPEA. Vascular lesions were the type of early developmental lesions most related to PSPEA.
doi:10.1212/WNL.0b013e3182582ff8
PMCID: PMC3359583  PMID: 22539569
9.  Evaluation of cell death mechanisms induced by the vascular disrupting agent OXi4503 during a phase I clinical trial 
British Journal of Cancer  2012;106(11):1766-1771.
Background:
OXi4503 is a tubulin-binding vascular disrupting agent that has recently completed a Cancer Research UK-sponsored phase I trial. Preclinical studies demonstrated early drug-induced apoptosis in tumour endothelial cells at 1–3 h and secondary tumour cell necrosis between 6 and 72 h.
Methods:
To capture both possible outcomes of OXi4503 treatment on cell death, plasma samples for analysis by M30 and M65 ELISAs, which measure different circulating forms of cytokeratin 18 as biomarkers of apoptosis and necrosis, respectively, were collected from patients entered into the trial at early (4/6 h) and later time points (24 h, day 8 and day 15).
Results:
OXi4503 induced a selective dose-dependent elevation in M30 antigen levels (apoptosis) at 4/6 h and a similar elevation in M65 antigen levels at 24 h (necrosis) consistent with its preclinical cell death profile. For the purposes of investigating potential biomarker relationships to patient characteristics, the trial population was divided into three groups based on radiological and clinical response: (a) early progression, (b) progressive disease and (c) stable disease (SD)/partial response. A significant increase in antigen concentrations was measured by M65 at 24 h in the SD group compared with the two other groups (P=0.015, mean increase 30.9%).
Conclusion:
These results provide pharmacodynamic evidence of drug mechanism of action in cancer patients and highlight the M65 ELISA as a potentially useful biomarker assay of response to OXi4503.
doi:10.1038/bjc.2012.165
PMCID: PMC3364117  PMID: 22538971
OXi4503; vascular disrupting agent; phase I trial; cell death mechanisms; M30 ELISA; M65 ELISA
10.  Distinct Proteasome Subpopulations in the Alveolar Space of Patients with the Acute Respiratory Distress Syndrome 
Mediators of Inflammation  2012;2012:204250.
There is increasing evidence that proteasomes have a biological role in the extracellular alveolar space, but inflammation could change their composition. We tested whether immunoproteasome protein-containing subpopulations are present in the alveolar space of patients with lung inflammation evoking the acute respiratory distress syndrome (ARDS). Bronchoalveolar lavage (BAL) supernatants and cell pellet lysate from ARDS patients (n = 28) and healthy subjects (n = 10) were analyzed for the presence of immunoproteasome proteins (LMP2 and LMP7) and proteasome subtypes by western blot, chromatographic purification, and 2D-dimensional gelelectrophoresis. In all ARDS patients but not in healthy subjects LMP7 and LMP2 were observed in BAL supernatants. Proteasomes purified from pooled ARDS BAL supernatant showed an altered enzyme activity ratio. Chromatography revealed a distinct pattern with 7 proteasome subtype peaks in BAL supernatant of ARDS patients that differed from healthy subjects. Total proteasome concentration in BAL supernatant was increased in ARDS (971 ng/mL ± 1116 versus 59 ± 25; P < 0.001), and all fluorogenic substrates were hydrolyzed, albeit to a lesser extent, with inhibition by epoxomicin (P = 0.0001). Thus, we identified for the first time immunoproteasome proteins and a distinct proteasomal subtype pattern in the alveolar space of ARDS patients, presumably in response to inflammation.
doi:10.1155/2012/204250
PMCID: PMC3272875  PMID: 22363101
12.  Comparison of cardiac index: LiDCOrapid and PiCCOplus in the ICU 
Critical Care  2011;15(Suppl 1):P62.
doi:10.1186/cc9482
PMCID: PMC3061692
13.  The safety and efficacy of sunitinib before planned nephrectomy in metastatic clear cell renal cancer 
Annals of Oncology  2011;22(5):1041-1047.
Background: The safety and efficacy of upfront sunitinib, before nephrectomy in metastatic clear cell renal cancer (mCRC), has not been prospectively evaluated.
Methods: Two prospective single-arm phase II studies investigated either two cycles (study A: n = 19) or three cycles (study B: n = 33) of sunitinib before nephrectomy in mCRC.
Results: Overall, 38 of 52 (73%) of patients obtained clinical benefit (by RECIST) before surgery. The partial response rate of the primary tumour was 6% [median reduction in longest diameter of 12% (range 8%−35%)]. No patients became ineligible due to local progression of disease. A nephrectomy was carried out in 37 (71%) of patients. Necrosis (>50%) was a prominent feature at nephrectomy in 49%. Surgical complications (Clavien–Dindo classification) occurred in 10 (27%) patients, including one death (3%). The median blood loss and surgical time were 725 (90–4200) ml and 189 (70–420) min, respectively. The median progression-free survival was 8 months (95% confidence interval 6–15 months). A comparison of two versus three pre-surgery cycles showed no significant difference in terms of surgical complications or efficacy.
Conclusions: Nephrectomy after upfront sunitinib can be carried out safely. It obtains control of disease. Randomised studies are required to address if this approach is beneficial.
doi:10.1093/annonc/mdq564
PMCID: PMC3082157  PMID: 21242586
metastatic renal cancer; nephrectomy; sunitinib
14.  Re-evaluation of the diagnosis of porphyria cutanea tarda in Admiral Sir Francis Beaufort 
JRSM Short Reports  2010;1(1):13.
Objectives
Two biographies of Admiral Francis Beaufort (1774–1857) have stated that, aged 20–25 years, he suffered from porphyria cutanea tarda (PCT) that was ‘cured’ following severe blood loss during a naval skirmish. We have examined the evidence concerning the nature of his skin disease.
Design
Primary records, most notably Beaufort's correspondence with his family, his journals and his father's diaries were sought out and analysed.
Setting
This case report is discussed in the context of 18th-century naval medicine and concepts and treatment of skin disease.
Results
The description of his lesions, their age of onset, their progression and response to treatment, particularly topical tar and associated features are quite inconsistent with a diagnosis of PCT. His mother, Mary Waller Beaufort (1739–1821), consulted Dr Robert Darwin in 1803 about a painful skin disease affecting her legs. Detailed description of the lesions and a contemporary diagnosis are not available but possible diagnoses include chronic psoriasis and stasis eczema.
Conclusions
A more tenable diagnosis is that Francis Beaufort had chronic plaque psoriasis remitted by bed rest and convalescence in the sunny Mediterranean climate with cessation of alcohol consumption and improved nutrition as well as topical and oral medications.
doi:10.1258/shorts.2009.090366
PMCID: PMC2984337  PMID: 21103105
15.  Recurrent In-Stent Restenosis in a Symptomatic Nonatherosclerotic M1 Plaque 
Clinical Neuroradiology  2010;20(3):165-169.
doi:10.1007/s00062-010-0012-y
PMCID: PMC2933851  PMID: 20512301
16.  Peroxisome proliferator activated receptor γ in colonic epithelial cells protects against experimental inflammatory bowel disease 
Gut  2006;55(8):1104-1113.
Introduction
Peroxisome proliferator activated receptor γ (PPARγ) is expressed in epithelial cells, macrophage, and T and B lymphocytes. Ligand induced activation of PPARγ was reported to attenuate colitis activity but it is not clear whether this protection is mediated by epithelial or leucocyte PPARγ.
Methods
Mice with targeted disruption of the PPARγ gene in intestinal epithelial cells, generated using a villin‐Cre transgene and floxed PPARγ allele and designated PPARγΔIEpC, were compared with littermate mice having only the PPARγ floxed allele with no Cre transgene that expressed PPARγ in the gut, designated PPARγF/F. Colitis was induced by administering dextran sodium sulphate (DSS) and the two mouse lines compared for typical symptoms of disease and expression of inflammatory cytokines.
Results
PPARγΔIEpC mice displayed reduced expression of the PPARγ target genes ADRP and FABP in the gut but were otherwise normal. Increased susceptibility to DSS induced colitis, as defined by body weight loss, colon length, diarrhoea, bleeding score, and altered histology, was found in PPARγΔIEpC mice in comparison with PPARγF/F mice. Interleukin (IL)‐6, IL‐1β, and tumour necrosis factor α mRNA levels in colons of PPARγΔIEpC mice treated with DSS were higher than in similarly treated PPARγF/F mice. The PPARγ ligand rosiglitazone decreased the severity of DSS induced colitis and suppressed cytokine production in both PPARγF/F and PPARγΔIEpC mice.
Conclusions
These studies reveal that PPARγ expressed in the colonic epithelium has an endogenous role in protection against DSS induced colitis and that rosiglitazone may act through a PPARγ independent pathway to suppress inflammation.
doi:10.1136/gut.2005.081745
PMCID: PMC1513267  PMID: 16547072
peroxisome proliferator activated receptor γ; colitis; cytokines; inflammatory bile disease; rosiglitazone
17.  Computed tomography in a patient after percutaneous left atrial appendage transcatheter occlusion (PLAATO) 
Heart  2006;92(4):486.
doi:10.1136/hrt.2005.071704
PMCID: PMC1860868  PMID: 16537763
Images in cardiology
18.  Evaluation of survival and ischaemic and thromboembolic event rates in patients with non‐valvar atrial fibrillation in the general population when treated and untreated with warfarin 
Heart  2005;92(2):196-200.
Objective
To compare survival and adverse outcome of patients with non‐valvar atrial fibrillation (NVAF) treated with or without warfarin.
Design
Record linkage method to identify patients with a previous hospital diagnosis of atrial fibrillation and to link these patients to international normalised ratio (INR) test results and mortality data.
Setting
Cardiff and the Vale of Glamorgan, Wales.
Main outcome measures
Mortality, specifically from ischaemic and thromboembolic events.
Results
6108 patients were identified with NVAF, of whom 36.4% received warfarin. Mean survival in the warfarin and non‐warfarin groups was 52.0 months and 38.2 months, respectively (p < 0.001), and 14.4 months (p < 0.001) after adjustment for confounding factors. Warfarin treated patients in the upper quartile of INR control had significantly longer survival (57.5 months) than did those in the lowest quartile of control (38.1 months, p < 0.001). The risk of stroke in the warfarin group when treated was lower than that in the non‐warfarin group (relative rate (RR) 0.74, p < 0.001). The risk of death from ischaemic stroke was lower in the warfarin group (RR 0.43, p < 0.001). The risk of all ischaemic and embolic events in the warfarin group was lower when they were taking warfarin (RR 0.74, p < 0.001). The risk of bleeding in the warfarin group when treated was greater (RR 1.78, p  =  0.001).
Conclusions
Patients with NVAF within the recommended target INR range of 2.0–3.0 survive longer and have reduced morbidity. Probably too few people are anticoagulated with warfarin in NVAF.
doi:10.1136/hrt.2004.058339
PMCID: PMC1860757  PMID: 15883133
atrial fibrillation; warfarin; anticoagulation; stroke
19.  The importance of anaemia in diagnosing colorectal cancer: a case–control study using electronic primary care records 
British Journal of Cancer  2008;98(2):323-327.
Although anaemia is recognised as a feature of colorectal cancer, the precise risk is unknown. We performed a case–control study using electronic primary care records from the Health Improvement Network database, UK. A total of 6442 patients had a diagnosis of colorectal cancer, and were matched to 45 066 controls on age, sex, and practice. We calculated likelihood ratios and positive predictive values for colorectal cancer in both sexes across 1 g dl−1 haemoglobin and 10-year age bands, and examined the features of iron deficiency.In men, 178 (5.2%) of 3421 cases and 47 (0.2%) of 23 928 controls had a haemoglobin <9.0 g dl−1, giving a likelihood ratio (95% confidence interval) of 27 (19, 36). In women, the corresponding figures were 227 (7.5%) of 3021 cases and 58 (0.3%) of 21 138 controls, a likelihood ratio of 41 (30, 61). Positive predictive values increased with age and for each 1 g dl−1 reduction in haemoglobin. The risk of cancer for current referral guidance was quantified. For men over 60 years with a haemoglobin <11 g dl−1 and features of iron deficiency, the positive predictive value was 13.3% (9.7, 18) and for women with a haemoglobin <10 g dl−1 and iron deficiency, the positive predictive value was 7.7% (5.7, 11). Current guidance for urgent investigation of anaemia misses some patients with a moderate risk of cancer, particularly men.
doi:10.1038/sj.bjc.6604165
PMCID: PMC2361444  PMID: 18219289
anaemia; colorectal cancer; diagnosis; primary health care
20.  New sources and instrumentation for neutrons in biology 
Chemical physics  2008;345(2-3):133-151.
Neutron radiation offers significant advantages for the study of biological molecular structure and dynamics. A broad and significant effort towards instrumental and methodological development to facilitate biology experiments at neutron sources worldwide is reviewed.
doi:10.1016/j.chemphys.2008.02.030
PMCID: PMC2614686  PMID: 19132140
Neutron scattering; Neutron crystallography; Small angle neutron scattering; Reflectometry; Inelastic neutron scattering; Quasi-elastic neutron scattering; Proteins; Membranes; Macromolecular structure and dynamics
21.  Reducing inequalities in access to health care: developing a toolkit through action research 
Quality & safety in health care  2005;14(5):336-339.


Problem: Healthcare organisations are expected both to monitor inequalities in access to health services and also to act to improve access and increase equity in service provision.
Design: Locally developed action research projects with an explicit objective of reducing inequalities in access.
Setting: Eight different health care services in the Yorkshire and Humber region, including community based palliative care, general practice asthma care, hospital based cardiology clinics, and termination of pregnancy services.
Key measures for improvement: Changes in service provision, increasing attendance rates in targeted groups.
Strategies for change: Local teams identified the population concerned and appropriate interventions using both published and grey literature. Where change to service provision was achieved, local data were collected to monitor the impact of service change.
Effects of change: A number of evidence based changes to service provision were proposed and implemented with variable success. Service uptake increased in some of the targeted populations.
Lessons learnt: Interventions to improve access must be sensitive to local settings and need both practical and managerial support to succeed. It is particularly difficult to improve access effectively if services are already struggling to meet current demand. Key elements for successful interventions included effective local leadership, identification of an intervention which is both evidence based and locally practicable, and identification of additional resources to support increased activity. A "toolkit" has been developed to support the identification and implementation of appropriate changes.
doi:10.1136/qshc.2005.013821
PMCID: PMC1744068  PMID: 16195566
22.  Leptin Analog Antagonizes Leptin Effects on Food Intake and Body Weight but Mimics Leptin-Induced Vagal Afferent Activation 
Endocrinology  2007;148(6):2878-2885.
A recombinantly produced murine leptin analog (MLA) antagonizes leptin-induced signaling in cell lines that express the long form of the leptin receptor. However, the effects of MLA on the activity of leptin-sensitive neurons and on central neural controls of food intake have not been reported. Here we report effects of MLA on food intake and body weight in adult rats and on the activity of cultured rat vagal afferent neurons. Daily intracerebroventricular coinjection of MLA with exogenous leptin significantly attenuated leptin-induced reduction of 48-h food intake and body weight. Coinjection of MLA with leptin also reduced leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in the hypothalamus. In addition, chronic intracerebroventricular MLA infusion over 14 d via osmotic minipumps significantly increased daily food intake, rate of body weight gain, fat-pad mass, and circulating plasma leptin concentrations. Surprisingly, however, MLA did not antagonize leptin-evoked increases in cytosolic calcium concentrations in vagal afferent neurons in primary culture. Rather, MLA itself produced acute activation selectively in leptin-responsive vagal afferent neurons. These data suggest that MLA is an antagonist for the central effects of leptin on food intake and body weight but an agonist at sites where leptin induces acute neuronal activation. This mixed antagonist/agonist action suggests either 1) that the coupling of a single leptin receptor (ObRb) to acute activation of neurons occurs by a signaling mechanism different from those that mediate centrally evoked reductions in food intake and body weight or 2) that acute neuronal activation and centrally induced reductions of food intake and body weight are mediated by different leptin receptor subtypes.
doi:10.1210/en.2006-1320
PMCID: PMC2509585  PMID: 17363463
23.  Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population 
Heart  2005;91(4):472-477.
Objective: To evaluate how well patients with non-valvar atrial fibrillation (NVAF) were maintained within the recommended international normalised ratio (INR) target of 2.0–3.0 and to explore the relation between achieved INR control and clinical outcomes.
Design: Record linkage study of routine activity records and INR measurements.
Setting: Cardiff and the Vale of Glamorgan, South Wales, UK.
Participants: 2223 patients with NVAF, no history of heart valve replacement, and with at least five INR measurements.
Main outcome measures: Mortality, ischaemic stroke, all thromboembolic events, bleeding events, hospitalisation, and patterns of INR monitoring.
Results: Patients treated with warfarin were outside the INR target range 32.1% of the time, with 15.4% INR values > 3.0 and 16.7% INR values < 2.0. However, the quartile with worst control spent 71.6% of their time out of target range compared with only 16.3% out of range in the best controlled quartile. The median period between INR tests was 16 days. Time spent outside the target range decreased as the duration of INR monitoring increased, from 52% in the first three months of monitoring to 30% after two years. A multivariate logistic regression model showed that a 10% increase in time out of range was associated with an increased risk of mortality (odds ratio (OR) 1.29, p < 0.001) and of an ischaemic stroke (OR 1.10, p  =  0.006) and other thromboembolic events (OR 1.12, p < 0.001). The rate of hospitalisation was higher when INR was outside the target range.
Conclusions: Suboptimal anticoagulation was associated with poor clinical outcomes, even in a well controlled population. However, good control was difficult to achieve and maintain. New measures are needed to improve maintenance anticoagulation in patients with NVAF.
doi:10.1136/hrt.2004.042465
PMCID: PMC1768813  PMID: 15772203
24.  The mortality of colorectal cancer in relation to the initial symptom at presentation to primary care and to the duration of symptoms: a cohort study using medical records 
British Journal of Cancer  2006;95(10):1321-1325.
The association between the staging of colorectal cancer and mortality is well known. Much less researched is the relationship between the duration of symptoms and outcome, and whether particular initial symptoms carry a different prognosis. We performed a cohort study of 349 patients with primary colorectal cancer in whom all their prediagnostic symptoms and investigation results were known. Survival data for 3–8 years after diagnosis were taken from the cancer registry. Six features were studied: rectal bleeding, abdominal pain, diarrhoea, constipation, weight loss, and anaemia. Two of these were significantly associated with different staging and mortality. Rectal bleeding as an initial symptom was associated with less advanced staging (odds ratio from one Duke's stage to the next 0.50, 95% confidence interval 0.31, 0.79; P=0.003) and with reduced mortality (Cox's proportional hazard ratio (HR) 0.56 (0.41, 0.79); P=0.001. Mild anaemia, with a haemoglobin of 10.0–12.9 g dl−1, was associated with more advanced staging (odds ratio 2.2 (1.2, 4.3); P=0.021) and worse mortality (HR 1.5 (0.98, 2.3): P=0.064). When corrected for emergency admission, sex, and the site of the tumour, the HR for mild anaemia was 1.7 (1.1, 2.6); P=0.015. No relationship was found between the duration of symptoms and staging or mortality.
doi:10.1038/sj.bjc.6603439
PMCID: PMC2360591  PMID: 17060933
colorectal cancer; primary health care; diagnosis; mortality

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