Showing papers by "Leicester Royal Infirmary published in 2010"

The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation

Abstract: Defects in pancreatic beta cell turnover are implicated in the pathogenesis of type 2 diabetes by genetic markers for diabetes. Decreased beta cell neogenesis could contribute to diabetes. The longevity and turnover of human beta cells is unknown; in rodents 20 years) and remained constant thereafter. Human beta cells, unlike those of young rodents, are long-lived. LB proportions in type 2 diabetes and obesity suggest that little adaptive change occurs in the adult human beta cell population, which is largely established by age 20 years.

Mutations in the human laminin β2 (LAMB2) gene and the associated phenotypic spectrum

Abstract: Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin β2 which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin β2 function is the molecular basis of Pierson syndrome. While truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.

Can the Distress Thermometer be improved by additional mood domains? Part I. Initial validation of the Emotion Thermometers tool

Abstract: Purpose: To examine the value of a new screening instrument in a visual-analogue format. Methods: We report the design and validation of a new five-dimensional tool called the Emotion Thermometers (ET). This is a combination of five visual-analogue scales in the form of four predictor domains (distress, anxiety, depression, anger) and one outcome domain (need for help). Between March and August 2007, 130 patients attending the chemotherapy suite for their first chemotherapy treatment were asked to complete several questionnaires with validation for distress, anxiety and depression. Results: Of 81 with low distress on the Distress Thermometer (DT), 51% recorded emotional difficulties on the new ET tool, suggesting added value beyond the DT alone. Of those with a broadly defined emotional complication, 93.3% could be identified using the Anxiety Thermometer (AnxT) alone, compared with 54.4% who would be recognized using the DT alone. Using a cut-off of 3v4 on all thermometers against the total Hospital Anxiety and Depression Scale (HADS) score (cut-off 14v15), the optimal thermometer was the Anger Thermometer (sensitivity 61%, specificity 92%). Against HADS anxiety scale, the optimal thermometer was AnxT (sensitivity 92%, specificity 61%) and against the HADS depression scale, the optimal thermometer was the Depression Thermometer (DepT; sensitivity 60%, specificity 78%). Finally, against DSM-IV major depression, the optimal thermometer was the DepT (sensitivity 80%, specificity 79%). Further improvements may be possible by using a combination of thermometers or by repeating the screen. Conclusion: The diagnostic accuracy of the DT can be improved by the inclusion of simple addition linear domains without substantially increasing the time needed to apply the test. Copyright © 2009 John Wiley & Sons, Ltd.

A 24-Week, Randomized, Treat-to-Target Trial Comparing Initiation of Insulin Glargine Once-Daily With Insulin Detemir Twice-Daily in Patients With Type 2 Diabetes Inadequately Controlled on Oral Glucose-Lowering Drugs

Abstract: OBJECTIVE To determine whether glargine is noninferior to detemir regarding the percentage of patients reaching A1C RESEARCH DESIGN AND METHODS In this 24-week trial, 973 insulin-naive type 2 diabetic patients on stable oral glucose-lowering drugs with A1C 7.0–10.5% were randomized to glargine once daily or detemir twice daily. Insulin doses were systematically titrated. RESULTS 27.5 and 25.6% of patients reached the primary outcome with glargine and detemir, respectively, demonstrating the noninferiority of glargine. Improvements in A1C were −1.46 ± 1.09% for glargine and −1.54 ± 1.11% for detemir ( P = 0.149), with similar proportions of patients achieving A1C P = 0.254) but more detemir-treated patients reaching A1C P = 0.017). Hypoglycemia risk was similar. Weight gain was higher for glargine (difference: 0.77 kg, P P CONCLUSIONS In insulin-naive type 2 diabetic patients, glargine reached similar control as detemir, with more weight gain, but required significantly lower doses.

Testosterone treatment of HSDD in naturally menopausal women: the ADORE study.

Abstract: Objective To evaluate the efficacy and safety of a transdermal testosterone patch (TTP, 300 mg/day) in naturally menopausal women with hypoactive sexual desire disorder (HSDD). Methods A total of 272 naturally menopausal women, predominantly not using hormone therapy, were randomized in this 6-month, placebo-controlled, double-blind, multicenter study to receive twice weekly either TTP or an identical placebo. Efficacy endpoints measured were the 4-week frequency of satisfying sexual episodes (SSE) using the Sexual Activity Log, the sexual desire domain of the Profile of Female Sexual Function and distress by the Personal Distress Scale. Safety was assessed by adverse events, laboratory parameters and hormone levels. Results The TTP group demonstrated significant improvements in SSE (p ¼ 0.0089) as well as in sexual desire (p ¼ 0.0007) and reduced personal distress (p ¼ 0.0024) versus placebo at 6 months (intent-to-treat analysis, n ¼ 247). The results were significant for all three endpoints in the subgroup (n ¼ 199) not using hormone therapy. Similar numbers of women treated with placebo and TTP discontinued (n ¼ 39, 27.5% vs. n ¼ 26, 20%), reported adverse events (including application site reactions) (n ¼ 101, 71.1% vs. n ¼ 81, 62.3%) and withdrew due to adverse events (n ¼ 20, 14.1% vs. n ¼ 9, 6.9%). No clinically relevant changes were noted in laboratory parameters. Serum free and total testosterone levels increased from baseline in the TTP group (geometric means 5.65 pg/ml and 67.8 ng/dl, respectively, at week 24) within the physiological range; no changes were seen in estradiol and sex hormone binding globulin levels. Conclusions TTP was effective in treating HSDD and improving sexual function in this study of naturally menopausal women with and without concurrent hormone therapy.

Pharmacoeconomics: NICE's approach to decision-making.

Abstract: The National Institute for Health and Clinical Excellence (NICE) is a decision-maker Where NICE reaches a positive conclusion about the use of a particular health technology (such as a pharmaceutical product) in the National Health Service (NHS), there is a legal requirement for the service to make it available if a patient's physician considers it clinically appropriate [1] Although this legal obligation does not apply to technologies recommended in NICE's clinical guidelines, there is still a reasonable expectation by the Care Quality Commission for NHS healthcare professionals to use NICE's clinical guidelines as the basis, where appropriate, for their clinical practice NICE's independent advisory bodies (the Appraisal Committees, the Public Health Advisory Committee and Guideline Development Groups) are required to take account of both clinical and cost-effectiveness in reaching their conclusions about the use of health technologies generally and of pharmaceuticals in particular [2–4] These advisory bodies must fully assess the available evidence on benefits and costs in order to come to a decision as to whether the use of a technology is considered a cost-effective use of resources However, the scientific evidence underpinning any decision about the use of a particular health technology is never perfect Nor is it all-embracing Advisory bodies therefore need to use their experience to make judgements beyond the existing evidence These judgements are of two types [5]: Scientific value judgements are ones about what can be inferred from the available evidence base; and the extent to which imperfections in the evidence base should influence decisions Social value judgements are concerned with what is appropriate and acceptable for society in delivering healthcare across the NHS

Relative efficacy of drugs: an emerging issue between regulatory agencies and third-party payers

Abstract: Drug regulatory agencies have traditionally assessed the quality, safety and efficacy of drugs, and the current paradigm dictates that a new drug should be licensed when the benefits outweigh the risks. By contrast, third-party payers base their reimbursement decisions predominantly on the health benefits of the drug relative to existing treatment options (termed relative efficacy; RE). Over the past decade, the role of payers has become more prominent, and time-to-market no longer means time-to-licensing but time-to-reimbursement. Companies now have to satisfy the sometimes divergent needs of both regulators and payers, and to address RE during the pre-marketing stages. This article describes the current political background to the RE debate and presents the scientific and methodological challenges as they relate to RE assessment. In addition, we explain the impact of RE on drug development, and speculate on future developments and actions that are likely to be required from key players.

Pharmacological treatment of chronic pain – the need for CHANGE

Abstract: Background: Although chronic pain affects around 20% of adults in Europe and the USA, there is substantial evidence that it is inadequately treated. In June 2009, an international group of pain specialists met in Brussels to identify the reasons for this and to achieve consensus on strategies for improving pain management.

Xenon enhances hypothermic neuroprotection in asphyxiated newborn pigs.

Abstract: Objective To investigate whether inhaling 50% xenon during hypothermia (HT) offers better neuroprotection than xenon or HT alone. Methods Ninety-eight newborn pigs underwent a 45-minute global hypoxic-ischemic insult severe enough to cause permanent brain injury, and 12 pigs underwent sham protocol. Pigs then received intravenous anesthesia and were randomized to 6 treatment groups: (1) normothermia (NT; rectal temperature 38.5°C, n = 18); (2) 18 hours 50% xenon with NT (n = 12); (3) 12 hours HT (rectal temperature 33.5°C, n = 18); (4) 24 hours HT (rectal temperature 33.5°C, n = 17); (5) 18 hours 50% xenon with 12 hours HT (n = 18); and (6) 18 hours 50% xenon with 24 hours HT (n = 17). Fifty percent xenon was administered via a closed circle with 30% oxygen and 20% nitrogen. After 10 hours rewarming, cooled pigs remained normothermic until terminal perfusion fixation at 72 hours. Global and regional brain neuropathology and clinical neurological scores were performed. Results Xenon (p = 0.011) and 12 or 24 hours HT (p = 0.003) treatments offered significant histological global, and regional neuroprotection. Combining xenon with HT yielded an additive neuroprotective effect, as there was no interaction effect (p = 0.54). Combining Xenon with 24 hours HT offered 75% global histological neuroprotection with similarly improved regional neuroprotection: thalamus (100%), brainstem (100%), white matter (86%), basal ganglia (76%), cortical gray matter (74%), cerebellum (73%), and hippocampus (72%). Neurology scores improved in the 24-hour HT and combined xenon HT groups at 72 hours. Interpretation Combining xenon with HT is a promising therapy for severely encephalopathic infants, doubling the neuroprotection offered by HT alone. ANN NEUROL 2010

Diagnostic Testing of Patients Suspected of Primary Ciliary Dyskinesia

Abstract: Rationale: Electron microscopy (EM) of ciliated epithelium is widely used to diagnose primary ciliary dyskinesia (PCD). Ciliary beat frequency (CBF) has been used to screen samples to determine whether EM is indicated. Beat pattern analysis has been advocated as an additional diagnostic test. Neither has been subject to formal review.Objectives: To determine the ability of CBF and beat pattern analysis to predict EM-diagnosed PCD.Methods: CBF calculation and beat pattern analysis, using high-speed video microscopy, and EM were performed on nasal tissue from 371 patients consecutively referred to the Leicester Royal Infirmary for diagnostic assessment for PCD. With EM as the “gold standard,” receiver operating characteristic (ROC) curves were constructed and sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values were calculated for CBF less than 11 Hz, ciliary dyskinesia score equal to or exceeding 2, at least 90% of ciliated edges beating dyskinetically, and an immotility index ...

High prevalence of primary ciliary dyskinesia in a British Asian population

Abstract: Determining the prevalence of primary ciliary dyskinesia (PCD) in different populations has proved difficult, with estimates varying between one in 4000 to one in 40,000. The aim of this study was to determine the incidence of PCD in a well-defined highly consanguineous Asian population in the UK. Over a 15-year period all patients suspected of having PCD in the Asian population of Bradford, UK, were tested by measurement of ciliary beat pattern, frequency and electron microscopy. The prevalence of PCD in the population studied was one in 2265. 52% of the patients' parents were first cousins. All patients had a history of chronic cough and nasal symptoms from the first year of life. 73% had a history of neonatal respiratory distress. Clinical suspicion of PCD should be high in populations in which it is possible that high levels of consanguinity may result in an increase in those with PCD. In these communities the combination of chronic cough and nasal symptoms should prompt early diagnostic testing.

Cochrane review: Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants

Abstract: Background Neonatal extracorporeal membrane oxygenation (ECMO) is a complex procedure of life support used in severe but potentially reversible respiratory failure in term infants. Although the number of babies eligible for ECMO is small and the use of ECMO invasive and potentially expensive, its benefits may be high. Objectives To determine whether ECMO used for neonatal infants with severe respiratory failure is clinically and cost effective compared to conventional ventilatory support. Search strategy The Cochrane Neonatal Group Specialised Register, the Cochrane Controlled Trials Register, and MEDLINE were searched for 1974 to 2007. Selection criteria All randomised trials comparing neonatal ECMO to conventional ventilatory support. Data collection and analysis The authors independently evaluated the trials for methodological quality and appropriateness for inclusion in the Review (without consideration of their results) and independently extracted the data. Main results The four trials (three USA and one UK) recruited clinically similar groups of babies. Two trials excluded infants with congenital diaphragmatic hernias. In two trials, transfer for ECMO implied transport over long distances. Two trials had follow-up information. One study included economic evaluation. The three USA trials had very small numbers of patients. Two trials used conventional randomisation with low potential for bias. Two used less usual designs, which led to difficulties in their interpretation. All four trials showed strong benefit of ECMO on mortality (typical RR 0.44; 95% CI 0.31 to 0.61), especially for babies without congenital diaphragmatic hernia (typical RR 0.33, 95% CI 0.21 to 0.53). The UK trial provided follow up information about death or severe disability, and cost-effectiveness, and showed benefit of ECMO at one year (RR 0.56, 95% CI 0.40 to 0.78), four years (RR 0.62, 95% CI 0.45 to 0.86), and seven years (RR 0.64, 95% CI 0.47 to 0.86). Overall nearly half of the children recruited had died or were severely disabled by seven years of age, reflecting the severity of their underlying conditions. A policy of ECMO is as cost-effective as other intensive care technologies in common use. Authors' conclusions A policy of using ECMO in mature infants with severe but potentially reversible respiratory failure results in significantly improved survival without increased risk of severe disability. The benefit of ECMO for babies with diaphragmatic hernia is unclear. Further studies are needed to consider the optimal timing for introducing ECMO; to identify which infants are most likely to benefit; and to address the implications of neonatal ECMO during later childhood and adult life. Plain Language Summary Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants A complex life support procedure, called extracorporeal membrane oxygenation (ECMO), can be used in infants who are near term age to overcome severe, potentially reversible breathing problems. ECMO is similar to the technology used in cardiac bypass surgery. Blood is removed from the body of the patient, oxygen is added to the blood, and the blood is returned to the patient. Although the number of babies requiring ECMO is small, and ECMO is a very invasive and potentially expensive procedure, the benefits of this procedure are high. In this review, four randomized trials that compared the use of ECMO to the conventional approach to supporting these infants with severe breathing problems were identified. Overall, these trials showed a strong benefit for ECMO regarding survival at the time of hospital discharge. This is particularly true for infants without a specific problem of lung formation (congenital diaphragmatic hernia). The result implies that for every three babies with breathing problems and lung failure who were treated with ECMO rather than conventional ventilation, one more infant will survive. Although little information is available regarding long-term follow-up, one trial in the United Kingdom shows both benefits of ECMO and cost-effectiveness of the use of ECMO.

Which version of the geriatric depression scale is most useful in medical settings and nursing homes? Diagnostic validity meta-analysis.

Abstract: Background The Geriatric Depression Scale (GDS) has been evaluated in individual studies, but its validity and added value in medical settings and nursing homes is uncertain. Therefore, the authors conducted a meta-analysis, analyzing the diagnostic accuracy of long, short, and ultrashort versions of the GDS and stratified this into those with and without cognitive impairment. Methods A comprehensive search identified 69 studies that measured the diagnostic validity of the GDS against a semistructured psychiatric interview, and of these, 43 analyses (in 36 publications) took place in medical settings. Twenty-one studies examined the GDS 30 , 12 studies examined the GDS 15 , and 3 examined the GDS 4/5 . For comparison, the authors also summarized studies examining unassisted clinical judgment. Heterogeneity was moderate to high; therefore, random effects meta-analysis was used. Results Across all studies, the prevalence of late-life depression was 29.2% (95% confidence interval [CI] = 24.7%–33.9%), with no difference between inpatients, outpatients, and nursing homes. Diagnostic accuracy of the GDS 30 after meta-analytic weighting was given by a sensitivity of 81.9% (95% CI=76.4%–86.9%) and a specificity of 77.7% (95% CI=73.0%–82.1%). For the GDS 15 , sensitivity was 84.3% (95% CI=79.7%–88.4%) and specificity was 73.8% (95% CI=68.0%–79.2%). For the GDS 4/5 , the sensitivity and specificity were 92.5% (95% CI=85.5%–97.4%) and 77.2% (95% CI=66.6%–86.3%), respectively. Results were not significantly influenced by the presence of dementia. Concerning added value, when identification using the GDS was compared with routine clinicians' ability to diagnose late-life depressions, at a prevalence of 30%, of every 100 attendees, the GDS 30 would help correctly identify an additional 22 people as depressed but at a cost of 13 additional false positives. The GDS 15 performed the same as GDS 30 but with 15 false positives. The ultrashort form would help identify an additional 25 true positives with only 10 false positives. Thus, the best option when choosing between versions of the GDS seems to be the GDS 4/5 . Conclusion All versions of the GDS yield potential added value in medical settings, but the GDS 4/5 is the most efficient. In nursing homes, given an absence of data on the GDS 4/5 , the GDS 15 may be preferred until more studies are reported.

Patent ductus arteriosus and cerebral circulation in preterm infants.

Abstract: SUMMARY The diagnosis of patent ductus arteriosus (PDA) was determined by Doppler examinations of the descending aorta and/or main trunk of the pulmonary artery in a cohort of 120 preterm infants. 55 per cent of the infants had Doppler echocardiographic evidence of ductal patency on the first day of life and this proportion fell to 30 per cent on the second day and 21 per cent on the third day. The incidence remained constant for the rest of the first week. Infants with PDA were significantly more likely to develop periventricular leukomalacia (PVL) than infants without PDA, but the incidence of periventricular haemorrhage was not increased. The cerebral haemodynamic effects of ductal patency were evaluated. Infants with PVL were found to have a significantly higher incidence of retrograde flow in the anterior cerebral artery during diastole, but the study was unable to demonstrate any significant difference in cerebral blood flow velocity between the infants with and without PDA. RESUME Canal arteriel permeable et circulation cerebrale chez le premature Le diagnostic de canal arteriel permeable (PDA) fut porte par examen de Doppler de l'aorte descendante et/ou du tronc principal de l'artere pulmonaire dans un groupe de 120 prematures. Une evidence echocardiographique de canal arteriel permeable fut observee chez 55 prematures au premier jour de vie, la proportion tombant a 30 pour cent au deuxieme jour et 21 pour cent au troisieme. Une leucomalacie periventriculaire (PVL) se developpa significativement plus frequemment chez les nourrissons avec PDA que les nourrissons sans PDA mais l'incidence de l'hemorragie periventriculaire ne fut pas accrue. Les effets hemodynamiques cerebraux de la permeabilite du canal arteriel furent evalues. L'incidence d'un flux retrograde de l'artere cerebrale anterieure durant la diastole fut significativement plus elevee chez les nourrissons avec PVL mais les auteurs furent incapables de demontrer une difference significative de la vitesse du flux sanguin cerebral entre les nourrissons avec ou sans PDA. ZUSAMMENFASSUNG Offener Ductus arteriosus und Hirndurchblutung bei Fruhgeborenen Bei 120 Fruhgeborenen wurde die Diagnose eines offenen Ductus arteriosus (PDA) durch Doppler Untersuchungen der Aorta descendens und/oder des Hauptstamms der Arteria pulmonalis gestellt. Am ersten Lebenstag hatten 55 Prozent der Kinder im Doppler Echocardiogramm einen offenen Ductus, am zweiten 30 Prozent und am dritten 21 Prozent und dieser Wert blieb fur den Rest der ersten Woche konstant. Kinder mit PDA entwickelten eher eine periventrikulare Leukomalazie (PVL) als Kinder ohne PDA, die Haufigkeit der periventrikularen Blutungen war dagegen nicht erhoht. Es wurden die hamodynamischen Auswirkungen eines offenen Ductus auf das Gehirn untersucht. Kinder mit PVL hatten wahrend der Diastole signifikant haufiger einen retrograden Flus in der A, cerebri anterior, aber es ist uns nicht gelungen, irgendeinen signifikanten Unterschied der cerebralen Durchblutung bei Kindern mit und ohne PDA aufzuzeigen. RESUMEN Ductus arterioso patente y circulacion cerebral en lactantes pretermino El diagnostico de ductus arterioso patente (DAP) se determino por el examen con Doppler de la aorta descendente y/o del tronco principal de la arteria pulmonar en un grupo de 120 lactantes pretermino. El 55 por ciento de los ninos tenia una evidencia ecocardiografica con Doppler de un conducto permeable en el primer dia de la vida. Esta proporcion disminuyo al 30 por ciento en el segundo dia y al 21 por ciento al tercer dia. La incidencia permanecio constante durante el resto de la primera semana. Los lactantes con DAP tendian mas a desarrollar una leucomalacia periventricular (LPV) que los ninos sin DAP pero la incidencia de hemorragia periventricular no aumento. Los efectos hemodinamicos de la perma nencia del ductus fueron evaluados encontrandose que los ninos con LPV tenian una incidencia significativamente mas alta de flujo retrogrado en la arteria cerebral anterior, durante el diastole, pero no fue posible demonstrar ninguna diferencia significativa en el flujo sanguineo cerebral entre los ninos con o sin DAP.

Can the Distress Thermometer be improved by additional mood domains? Part II. What is the optimal combination of Emotion Thermometers?

Abstract: Purpose: To examine the added value of an algorithmic combination of visual-analogue thermometers compared with the Distress Thermometer (DT) when attempting to detect depression, anxiety or distress in early cancer Methods: We report Classification and Regression Tree and logistic regression analyses of the new five-domain Emotion Thermometers tool This is a combination of five visual-analogue scales in the form of four mood domains (distress, anxiety, depression, anger) as well as need for help 130 patients attending for their first chemotherapy treatment were assessed We calculated optimal accuracy for each domain alone and in combination against several criterion standards Results: When attempting to diagnose depression the Depression Thermometer (DepT) used alone was the optimal approach, but when attempting to detect broadly defined distress or anxiety then a combination of thermometers was most accurate The DepT was significantly more accurate in detecting depression than the DT For broadly defined distress a combination of depression, anger and help thermometers was more accurate than the DT alone For anxiety, while the anxiety thermometer (AnxT) improves upon the DT alone, a combination of the DepT and AnxT are optimal In each case the optimal strategy allowed the detection of at least an additional 9% of individuals However, combinations are more laborious to score In settings where the simplest possible option is preferred the most accurate single thermometer might be preferable as a first stage assessment Conclusion: The DT can be improved by specific combinations of simple thermometers that incorporate depression, anxiety, anger and help Copyright © 2009 John Wiley & Sons, Ltd

In vivo analysis of gut function and disease changes in a zebrafish larvae model of inflammatory bowel disease: a feasibility study

Abstract: Background: The aim of this study was to develop a model of inflammatory bowel disease (IBD) in zebrafish larvae, together with a method for the rapid assessment of gut morphology and function in vivo thereby enabling medium-throughput compound screening. Methods: Assays were performed using larval zebrafish from 3–8 days postfertilization (d.p.f.) in 96-well plates. Gut morphology and peristalsis were observed in vivo using fluorescent imaging following ingestion of fluorescent dyes. IBD was induced by addition of 2,4,6-trinitrobenzenesulfonic acid (TNBS) to the medium within the well. Pathology was assessed in vivo using fluorescent imaging and postmortem by histology, immunohistochemistry, and electron microscopy. Therapeutic compounds were evaluated by coadministration with TNBS. Results: A novel method of investigating gut architecture and peristalsis was devised using fluorescent imaging of live zebrafish larvae. Archetypal changes in gut architecture consistent with colitis were observed throughout the gut. Significant changes in goblet cell number and tumor necrosis factor alpha (TNF-α) antibody staining were used to quantify disease severity and rescue. Prednisolone and 5-amino salicylic acid treatment ameliorated the disease changes. Candidate therapeutic compounds (NOS inhibitors, thalidomide, and parthenolide) were assessed and a dissociation was observed between efficacy assessed using a single biochemical measure (TNF-α staining) versus an assessment of the entire disease state. Conclusions: Gut physiology and pathology relevant to human disease state can be rapidly modeled in zebrafish larvae. The model is suitable for medium-throughput chemical screens and is amenable to genetic manipulation, hence offers a powerful novel premammalian adjunct to the study of gastrointestinal disease. (Inflamm Bowel Dis 2010)

Changes in interleukin-1β and 6 after hepatic microwave tissue ablation compared with radiofrequency, cryotherapy and surgical resections.

Abstract: BACKGROUND: Cytokine changes after microwave tissue ablation (MTA) were compared with hepatic resection, cryotherapy (CRYO), and radiofrequency ablation (RFA). Cytokine production was measured at various ablation volumes for each modality and correlated with the transitional inflammatory zone produced by the ablation techniques. METHODS: Live rats underwent MTA, surgical resection, CRYO or RFA of 15%, 33%, or 66% of the total hepatic volume. Serum samples were collected preoperatively and at 1, 3, 6, 24, and 48 hours after surgery and analyzed for pro-inflammatory cytokines interleukin (IL)-1β and IL-6. RESULTS: Significantly higher levels of both cytokines were present after CRYO and RFA compared with MTA, hepatic resection, or controls (P < .001). All animals survived except those undergoing RFA or CRYO of 66% of the hepatic volume, which died within 6 hours. Transitional zones produced after RFA were larger than those after CRYO or MTA, but no correlation was present with the amount of cytokines. CONCLUSIONS: Large-volume MTA is associated with a significant decreased cytokine response and is well tolerated compared with RFA and CRYO.

Rationale and design of the ADDITION-Leicester study, a systematic screening programme and Randomised Controlled Trial of multi-factorial cardiovascular risk intervention in people with Type 2 Diabetes Mellitus detected by screening

Abstract: Earlier diagnosis followed by multi-factorial cardiovascular risk intervention may improve outcomes in Type 2 Diabetes Mellitus (T2DM). Latent phase identification through screening requires structured, appropriately targeted population-based approaches. Providers responsible for implementing screening policy await evidence of clinical and cost effectiveness from randomised intervention trials in screen-detected T2DM cases. UK South Asians are at particularly high risk of abnormal glucose tolerance and T2DM. To be effective national screening programmes must achieve good coverage across the population by identifying barriers to the detection of disease and adapting to the delivery of earlier care. Here we describe the rationale and methods of a systematic community screening programme and randomised controlled trial of cardiovascular risk management within a UK multiethnic setting (ADDITION-Leicester). A single-blind cluster randomised, parallel group trial among people with screen-detected T2DM comparing a protocol driven intensive multi-factorial treatment with conventional care. ADDITION-Leicester consists of community-based screening and intervention phases within 20 general practices coordinated from a single academic research centre. Screening adopts a universal diagnostic approach via repeated 75g-Oral Glucose Tolerance Tests within an eligible non-diabetic population of 66,320 individuals aged 40-75 years (25-75 years South Asian). Volunteers also provide detailed medical and family histories; complete health questionnaires, undergo anthropometric measures, lipid profiling and a proteinuria assessment. Primary outcome is reduction in modelled Coronary Heart Disease (UKPDS CHD) risk at five years. Seven thousand (30% of South Asian ethnic origin) volunteers over three years will be recruited to identify a screen-detected T2DM cohort (n = 285) powered to detected a 6% relative difference (80% power, alpha 0.05) between treatment groups at one year. Randomisation will occur at practice-level with newly diagnosed T2DM cases receiving either conventional (according to current national guidelines) or intensive (algorithmic target-driven multi-factorial cardiovascular risk intervention) treatments. ADDITION-Leicester is the largest multiethnic (targeting >30% South Asian recruitment) community T2DM and vascular risk screening programme in the UK. By assessing feasibility and efficacy of T2DM screening, it will inform national disease prevention policy and contribute significantly to our understanding of the health care needs of UK South Asians. Clinicaltrial.gov (NCT00318032).

Pathogenicity islands PAPI-1 and PAPI-2 contribute individually and synergistically to the virulence of Pseudomonas aeruginosa strain PA14.

Abstract: Pseudomonas aeruginosa is a leading cause of hospital-acquired pneumonia and severe chronic lung infections in cystic fibrosis patients. The reference strains PA14 and PAO1 have been studied extensively, revealing that PA14 is more virulent than PAO1 in diverse infection models. Among other factors, this may be due to two pathogenicity islands, PAPI-1 and PAPI-2, both present in PA14 but not in PAO1. We compared the global contributions to virulence of PAPI-1 and PAPI-2, rather than that of individual island-borne genes, using murine models of acute pneumonia and bacteremia. Three isogenic island-minus mutants (PAPI-1-minus, PAPI-2-minus, and PAPI-1-minus, PAPI-2-minus mutants) were compared with the wild-type parent strain PA14 and with PAO1. Our results showed that both islands contributed significantly to the virulence of PA14 in acute pneumonia and bacteremia models. However, in contrast to the results for the bacteremia model, where each island was found to contribute individually, loss of the 108-kb PAPI-1 island alone was insufficient to measurably attenuate the mutant in the acute pneumonia model. Nevertheless, the double mutant was substantially more attenuated, and exhibited a lesser degree of virulence, than even PAO1 in the acute pneumonia model. In particular, its ability to disseminate from the lungs to the bloodstream was markedly inhibited. We conclude that both PAPI-1 and PAPI-2 contribute directly and synergistically in a major way to the virulence of PA14, and we suggest that analysis of island-minus strains may be a more appropriate way than individual gene knockouts to assess the contributions to virulence of large, horizontally acquired segments of DNA.