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A 57-year-old man with a history of metastatic melanoma and sclerotic bone lesions seen on CT was referred for F NaF PET/CT evaluation of active skeletal metastases. While the bone lesions had no uptake and were therefore thought to represent sequela of previously treated disease, an unexpected area of F NaF uptake was identified in the left temporal lobe. Concurrent contrast-enhanced brain MRI re-demonstrated a large metastasis, also seen on previous MRI scans done at another institution.

Background: Cardiopulmonary exercise testing (CPET) assessed "poorer" fitness correlates with poorer outcomes in blinded studies. Whether this correlation will persist when CPET is utilized to stratify care as part of a multi-modal enhanced recovery after surgery (ERAS) program is unclear. This study examined whether CPET variables were associated with postoperative morbidity in patients undergoing hepatectomy within an ERAS program., Objectives and Methods: Data were prospectively collected on patients undergoing elective hepatectomy between October 2009 and April 2011. The relationships between CPET derived variables; postoperative complications and length of stay were investigated., Results: Of 267 patients undergoing surgery, 197 had undergone standard cycle ergometer CPET. The relative oxygen uptake [VO2 (ml kg(-1) min(-1))] and ventilatory equivalent of CO2 (VE/VCO2) at the anaerobic threshold (AT) were not associated with complications or length of stay. Greater absolute oxygen uptake at AT [VO2 at AT (L min(-1) )] was associated with early hospital discharge [OR 2.16 (95% CI 1.18-3.96), P = 0.013] on multivariable analysis., Conclusions: When CPET is used to delineate perioperative management a low relative oxygen uptake [VO2 (ml kg(-1) min(-1) )] at the AT does not place patients at significantly higher risk of postoperative complications. This suggests CPET assessed "poor" fitness should not be used as a barrier to surgical intervention., (© 2014 Wiley Periodicals, Inc.)

Background: There is limited evidence for the use of enhanced recovery after surgery (ERAS) in patients undergoing hepatectomy, and the impact of the evolution of ERAS over time has not been examined. This study sought to evaluate the effect of an evolving ERAS program in patients undergoing hepatectomy for colorectal liver metastases (CRLM)., Methods: A multimodal ERAS program was introduced in 2/2008. Consecutive patients undergoing hepatectomy for CRLM between 2/2008 and 9/2012 were included in the study. Data were collected prospectively. Retrospective analysis compared an early ERAS cohort (2/2008-4/2010) with a later cohort with a matured ERAS program (5/2010-8/2012)., Results: Length of stay reduced as experience of ERAS increased (Log-rank χ(2)  = 10.43, P = 0.001). Although median length of stay remained unchanged (6 days), the probability of hospitalization beyond 10 days was 25% in the early cohort compared with 7% in the later cohort. Critical care utilization reduced over time (75.5% vs. 54.7%, P < 0.0001). Complications occurred in 38.2%, with no difference in between cohorts. One postoperative death occurred in the early cohort (<0.3%)., Conclusions: This study suggests that as experience of ERAS evolves, there is a progressive reduction in hospitalization and critical care admission. This is without any increase in morbidity and mortality., (© 2014 Wiley Periodicals, Inc.)

In early 2012 deaths (all-cause mortality) in England and Wales showed an unexpected and unexplained increase which continued for 18 months before abating. The highest percentage increase in deaths was noted to be for neurological degenerations (mainly dementia, Alzheimer's, Parkinson's). This study seeks to understand why increased deaths should focus on these conditions and if an unrecognized infectious outbreak could be implicated. Cause of death statistics for England and Wales were compared for 2012 versus 2011 as was the diagnosis for first outpatient appointment and inpatient admissions for these conditions. Deaths for dementia, Alzheimer's and Parkinson's showed a 15% increase with associated age specificity. The increase could not be explained by changes in the coding relating to cause of death. The increase coincided with increased GP referral (as first outpatient attendance) and inpatient admission for a range of neurological conditions. These increases were also observed on previous occasions of a similar event where deaths peaked in 2003 and 2008. A cascade of debility leading to immobility and institutionalization along with specific immune impairments appears to render those suffering from neurological degenerations sensitive to infectious outbreaks and more specifically to the particular agent behind these events. These and other studies point to outbreaks of a previously uncharacterized agent with the outbreak peaking in 2003, 2008 and 2012 (and in other years prior to these dates). Cytomegalovirus is a potential candidate and the necessary research to test this hypothesis is outlined., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: Liver resection offers the chance of a cure for liver cancer. However, when extended hepatectomies were performed in combination with resection of the inferior vena cava (IVC), the procedures were reported to have a surgical mortality rate in excess of 5 %. While most of these operations were performed with the use of veno-venous bypass, this study presents our experience performing the procedure without the bypass., Methods: Data were collected from a prospectively maintained database. A retrospective evaluation of a consecutive series of concomitant IVC and liver resections was performed., Results: Five hundred and seventy-five liver resections were performed between June 2008 and November 2011. Eleven patients (1.9 %) underwent concomitant IVC and liver resections. One patient required segmental IVC replacement, and four IVC defects were closed using a bovine pericardial patch without bypass. Only one patient had histologically confirmed IVC invasion. There was no postoperative mortality. Nine postoperative complications occurred in five patients. No complications in terms of IVC patency were seen. Five patients had disease recurrence, one of whom died within 12 months of surgery., Conclusion: Concomitant liver and IVC resection is safe without using a bypass procedure, with acceptable short-term results. Meticulous technique, careful patient selection and a specialized anesthetic team are key to obtaining low postoperative morbidity and mortality rates and an acceptable oncological outcome.

Colorectal cancer is the fourth most common cancer diagnosis in the world (around 1.2 million diagnoses each year), and accounts for the second highest number of deaths. Over half of patients with colorectal cancer will develop liver metastases, with one quarter presenting in stage IV. There is growing evidence that patients with liver-limited disease represent a distinct biological cohort who will benefit from aggressive management. Only a minority of patients are technically resectable, but around 40% of patients with resected liver limited disease are alive 5 years after diagnosis compared with less than 1% for those with disseminated disease. Novel surgical techniques have been developed to allow more patients to undergo resection and there is also growing recognition that the chemotherapeutic manipulation of irresectable disease may bring some patients to resection with good long-term outcome. Perioperative chemotherapy can also improve long-term outcome through improved biological selection and destruction of occult micrometastases. This review outlines current oncosurgical treatment strategies for liver-limited stage IV colorectal cancer, and discusses some of the controversies surround the management of these complex patients., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aims: Long-term survival has been demonstrated for patients with irresectable colorectal liver metastases who are brought to resection by chemotherapy. However, it remains unclear whether improved long-term outcome seen with modern therapies translates to increased rates of secondary resection and whether response rates correlate with rates of secondary liver resection., Methods: A systematic review of literature published between January 1998 and September 2013 was performed. Phase II/III trials were included if they reported the rate of objective response and the rate of secondary resection of initially irresectable metastases. For the phase III trials, the ratio between response and resection rates within the trials was investigated as well as the correlation for both parameters in all trials., Results: Twenty-five studies were identified. Response rate demonstrated a strong correlation with rates of secondary resection (R(2)=0.44, p=0.008). Ratios of response/resection between both arms of 10 randomised control trials (RCTs) were calculated to control for selection bias, and showed that in a randomised setting response rates correlate with increased rates of secondary resection in an intra-trial comparison (R(2)=0.87, p=0.002). Linear regression analysis demonstrated a significant difference between studies where criteria for resectability were defined (median 39.5%), and those where it was not (median 11%) (p=0.006)., Conclusion: There is a clear correlation between radiological response and rates of secondary resection, with studies that define resectability achieving much higher rates. All trials investigating first line treatment in patients with metastatic colorectal cancer should have criteria for resection, with conversion to secondary resection as a defined study end-point., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The adjacent fibrinogen (Fg)- and fibronectin (Fn)-binding sites on Fn-binding protein A (FnBPA), a cell surface protein from Staphylococcus aureus, are implicated in the initiation and persistence of infection. FnBPA contains a single Fg-binding site (that also binds elastin) and multiple Fn-binding sites. Here, we solved the structure of the N2N3 domains containing the Fg-binding site of FnBPA in the apo form and in complex with a Fg peptide. The Fg binding mechanism is similar to that of homologous bacterial proteins but without the requirement for "latch" strand residues. We show that the Fg-binding sites and the most N-terminal Fn-binding sites are nonoverlapping but in close proximity. Although Fg and a subdomain of Fn can form a ternary complex on an FnBPA protein construct containing a Fg-binding site and single Fn-binding site, binding of intact Fn appears to inhibit Fg binding, suggesting steric regulation. Given the concentrations of Fn and Fg in the plasma, this mechanism might result in targeting of S. aureus to fibrin-rich thrombi or elastin-rich tissues.

The treatment of colorectal cancer metastatic to the liver is increasingly complex as a result of changes in the patient population, advances in preoperative staging, changing definitions of resectability, advances in surgical technique and the expanding chemotherapeutic armamentarium. Management of these patients within a multidisciplinary team is increasingly important and associated with better outcomes. In patients with irresectable hepatic metastases, high secondary resection rates can be achieved with multiagent chemotherapy when managed in conjunction with a liver specialist. Perioperative mortality rates are reducing but morbidity remains high, and enhanced recovery could help reduce morbidity. Despite the advancing age and comorbidity of the patient population, multimodal management is likely to lead to further improvements in perioperative and long-term outcomes., Competing Interests: Financial & competing interests disclosure G Poston is on advisory boards for Merck Serono, Sanofi Aventis, BTG Biocompatibles and Bayer; and on speaker panels for Merck Serono, Sanofi Aventis and BTG Biocompatibles. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Colorectal cancer remains one of the most common cancers worldwide. The treatment of metastatic disease has advanced considerably in the past 10 years both in terms of surgical technique and development of novel chemotherapeutic agents. The widespread use of multiple chemotherapeutic agents has lead to recognition of distinct patterns of hepatotoxicity associated with specific drugs. These side-effects have potential implications for both the patient and medical professional, but the underlying mechanisms involved in these conditions remains poorly understood. This review explores the mechanisms of action of the commonly used chemotherapeutic agents and the potential mechanisms for their hepatotoxicity. It is important that all medical professionals involved in the management of metastatic colorectal cancer understand the problems of hepatotoxicity and the impact they have on the patient., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Transcatheter hepatic therapy with irinotecan-eluting beads (DEBIRI(®)) allows targeted delivery of irinotecan direct to liver tissue and colorectal liver metastases (CRLM). Accurate assessment of tumour response to therapy is vital to guide optimal treatment. Preliminary work has suggested existing criteria for radiological response may not reflect pathological response after neoadjuvant DEBIRI. This study assessed the relationship between existing and novel radiological response criteria and pathological tumour response as well as long-term outcome., Methods: Patients with easily resectable CRLM were treated with DEBIRI 4 weeks prior to resection and pathological tumour response graded using a validated system. Radiological response was assessed using RECIST and novel morphological response criteria., Results: Twenty-two patients with 37 lesions were treated with DEBIRI. Median residual tumour was 20% (range 0-80), median necrosis 45% (10-100) and median fibrosis 10% (10-70). Twenty patients (91%) demonstrated stable disease by RECIST, with 11 (50%) demonstrating partial morphological response. Neither radiological response criteria correlated with pathological response. Overall median disease free survival (DFS) was 13.6 months (95% CI 4.7-22.5). Radiological response was not associated with DFS., Conclusion: Existing criteria reporting short-term radiological response to DEBIRI do not accurately predict pathological tumour response or long-term outcome. Further work is necessary to define the optimum timing and method of assessing response to DEBIRI., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Re-introduction is an important tool for recovering endangered species; however, the magnitude of genetic consequences for re-introduced populations remains largely unknown, in particular the relative impacts of historical population bottlenecks compared to those induced by conservation management. We characterize 14 microsatellite loci developed for the Seychelles paradise flycatcher and use them to quantify temporal and spatial measures of genetic variation across a 134-year time frame encompassing a historical bottleneck that reduced the species to ~28 individuals in the 1960s, through the initial stages of recovery and across a second contemporary conservation-introduction-induced bottleneck. We then evaluate the relative impacts of the two bottlenecks, and finally apply our findings to inform broader re-introduction strategy. We find a temporal trend of significant decrease in standard measures of genetic diversity across the historical bottleneck, but only a nonsignificant downward trend in number of alleles across the contemporary bottleneck. However, accounting for the different timescales of the two bottlenecks (~40 historical generations versus <1 contemporary generation), the loss of genetic diversity per generation is greater across the contemporary bottleneck. Historically, the flycatcher population was genetically structured; however, extinction on four of five islands has resulted in a homogeneous contemporary population. We conclude that severe historical bottlenecks can leave a large footprint in terms of sheer quantity of genetic diversity lost. However, severely depleted genetic diversity does not render a species immune to further genetic erosion upon re-introduction. In some cases, the loss of genetic diversity per generation can, initially at least, be greater across re-introduction-induced bottlenecks., (© 2013 John Wiley & Sons Ltd.)

Background: Ablation with or without resection for colorectal liver metastases has been suggested as a potential method of improving survival if complete surgical resection is not possible. This study assessed the safety and efficacy of surgical microwave ablation (MWA) with or without resection for colorectal liver metastases., Methods: A retrospective case series was reviewed. Data was extracted for all patients treated with open MWA with or without resection for colorectal liver metastases. Endpoints included postoperative 30-day morbidity and mortality, local treatment failure, disease free survival and overall survival., Results: A total of 43 patients with technically irresectable disease were treated with MWA; 28 underwent combined MWA and resection, whilst 15 underwent MWA as the sole treatment modality. Overall post-operative morbidity was 35%, 30-day postoperative mortality 2%. At a median follow-up of 15 months, local treatment failure was observed in 4% of ablated lesions. 3-year OS was 36% for MWA group, compared to 45% for the combined ablate/resect group with 3-year DFS of 32% and 8% respectively., Conclusion: Microwave ablation with or without resection is a safe and effective method of achieving local disease control. Ablation with or without resection is associated with good long-term outcomes, and may be a suitable treatment option for small non-resectable colorectal liver metastases., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: The response of colorectal liver metastases to the cytotoxic agent irinotecan varies widely. Attempts to correlate tumour metabolism with response have been mixed. This study investigated the hepatic metabolism of irinotecan as a potential predictor of tumour response to irinotecan-eluting beads (DEBIRI)., Methods: Ten patients with colorectal liver metastases were treated with 200 mg irinotecan (as DEBIRI) as part of the PARAGON II study. Hepatic expression of key metabolising enzymes was measured using mass spectrometry-based proteomics. Serum drug concentrations and hepatic irinotecan metabolism were characterised and correlated with tumour response., Results: Serum concentrations of irinotecan metabolites did not correlate with hepatic metabolism or pathological response. There was a strong correlation between hepatic CES-2 expression and activation of irinotecan (r (2) = 0.96, p < 0.001). Patients with a UGT1A1*28 6/7 SNP showed no difference in drug metabolism or pathological response. Hepatic CES-2 mediated activation of irinotecan clearly correlated with tumour replacement by fibrosis (r (2) = 0.54, p = 0.01)., Conclusion: This study provides the first evidence that hepatic activation of irinotecan predicts tumour response. Delivery of liver-targeted irinotecan to normal liver tissue rather than tumour may be a more rational approach to maximise response.

Following the publication of the EORTC trial (40983), perioperative chemotherapy has become the standard of care for all patients with resectable colorectal cancer liver metastases (CRLM). However recently presented data suggest that the earlier advantage seen in progression free survival (PFS) may not translate over into a meaningful overall survival (OS) advantage. At the other end of the spectrum, patients with irresectable but liver limited CRLM continue to be offered treatment based on improving PFS, at the expense of regimens with greater response rates (but maybe poorer PFS rates) that could bring them to potentially curative liver resection. We therefore argue that patients with liver limited CRLM should be managed in three separate groups: Group One: those with easily resectable disease who should be offered immediate surgery, followed by adjuvant therapy if considered appropriate. Group Two: those with borderline resectable or high recurrence risk CRLM who could be offered appropriate systemic neoadjuvant therapy prior to planned liver surgery. Group Three: those with inoperable but liver limited CRLM who should be offered the most effective and appropriate systemic therapy with the primary purpose of achieving maximal disease response (and not PFS) with the intention of conversion to surgical resectability with curative intent., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Aims: Staging laparoscopy has been recommended in the management of patients with colorectal liver metastases prior to hepatectomy in order to reduce the incidence and associated morbidity of futile laparotomies. The utility of staging laparoscopy has not been assessed in patients undergoing CT, PET-CT and MRI as standard preoperative staging., Methods: All patients undergoing attempted open hepatectomy for colorectal liver metastases between 1/4/2008 and 31/3/2012 were identified from a prospectively maintained research database. All patients who underwent futile laparotomy were identified, with demographics and operative notes subsequently analysed., Results: A total of 274 patients underwent attempted open hepatectomy during the study period. At laparotomy 12 (4.4%) patients were found to have irresectable disease. There were no unifying demographic factors within the patients undergoing futile laparotomy., Conclusions: With modern imaging, the potential yield of staging laparoscopy is low. Staging laparoscopy should not be used routinely, but may have a role in the case of specific clinical concerns., (Copyright © 2013. Published by Elsevier Ltd.)

Background: Liver resection for metastatic colorectal cancer became established without randomized trials. Proponents of surgical resection point out 5-year survival approaching 50% whilst critics question how much of the apparent effect is due to patient selection., Method: A 2006 systematic review of reported outcomes provided the starting point for citation analysis followed by thematic analysis of the texts of the most cited papers., Results: 54 reports from 1988 to 2002 cited 709 unique publications a total of 1714 times. The 15 most cited papers were explored in detail, and showed clear examples of duplicate reporting and overlapping data sets. Textual analysis revealed proposals for a randomized controlled trial, but this was argued to be unethical by others, and no trial was undertaken., Conclusions: This critical review reveals how the case for this surgery was made, and examines the arguments that influenced acceptance and adoption of this surgery., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Irinotecan-loaded drug-eluting beads represent a novel drug delivery method that allows for the locoregional delivery of irinotecan to colorectal liver metastases (CRLM). The method has shown impressive response rates. However, the pathological response to this treatment has not previously been demonstrated., Methods: Patients with easily resectable CRLM were treated with drug-eluting beads delivering irinotecan (DEBIRI) 4 weeks prior to resection. Pathological tumour response was graded using a validated system. The intraoperative detection of previously unidentified disease allowed for the assessment of pathological responses directly attributable to bead treatment., Results: In Patient 1, segmental embolization of the target lesion in segment VIII resulted in 100% necrosis (0% viability). An untreated lesion in segment IV was found to be 30% viable. In Patient 2, subsegmental embolization of the target lesion in segment VI resulted in 60% necrosis and 40% fibrosis (0% viability). An untreated lesion in segment VI remained 60% viable. In Patient 3, lobar embolization of the target lesion in segment II resulted in 0% viability. Two further lesions within the treated hemiliver, both with 0% viability, and one lesion in the untreated hemiliver with 45% viability were discovered at laparotomy., Conclusions: This series demonstrates the effectiveness of DEBIRI in the treatment of CRLM. High rates of tumour destruction are possible, even with the proximal lobar administration of DEBIRI. Lobar administration appears to be an appropriate method of delivery for integration into future therapeutic regimens., (© 2012 International Hepato-Pancreato-Biliary Association.)

This review focuses on the embryology and normal imaging anatomy of the pulmonary circulation, with emphasis on the major arterial and venous vasculature. The pulmonary circulation and parenchyma have a complex intertwined embryologic origin. Understanding the embryologic basis of normal pulmonary vasculature aids recognition of anomalies and visceral situs in the chest. Adaptive changes to congenital anomalies of the pulmonary arterial vasculature are used to contrast from normal and review associated temporal adaptive vascular and parenchymal changes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: One hundred and ten patients were treated with palliative chemotherapy, of whom 53 had liver-only disease and had not been reviewed by a specialist liver surgeon. One scan was excluded as all reviewers felt it to be of insufficient quality to assess. Improved surgical technique and better chemotherapeutic manipulation of metastatic disease has increased the number of patients eligible for potentially curative resection of colorectal liver metastases. The rapid evolution in this field suggests that non-specialist decision-making may lead to inappropriate management. This study aimed to assess the management of colorectal liver metastases by non-liver surgeons., Methods: All patients who underwent chemotherapy with palliative intent for metastatic colorectal cancer at a regional oncology centre between 1 January and 31 December 2009 were identified from a prospectively maintained local database. Six resectional liver surgeons blinded to patient management and outcome reviewed pretreatment imaging and assigned each scan a score based on their own management choice. A consensus decision was reached on the appropriateness of palliative chemotherapy., Results: One hundred and ten patients were treated with palliative chemotherapy, of whom 53 had liver-only disease and had not been reviewed by a specialist liver surgeon. One scan was excluded as all reviewers felt it to be of insufficient quality to assess [corrected]. Tumours in 33 patients (63 per cent) were considered potentially resectable, with a high level of interobserver agreement (κ = 0 · 577). When individual approach to management was considered, interobserver agreement was less marked (κ = 0 · 378)., Conclusion: Management of patients with colorectal liver metastases without the involvement of a specialist liver multidisciplinary team can lead to patients being denied potentially curative treatments. Management of these patients must involve a specialist liver surgeon to ensure appropriate management., (Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

While reinforcement may play a role in all major modes of speciation, relatively little is known about the timescale over which species hybridize without evolving complete reproductive isolation. Birds have high potential for hybridization, and islands provide simple settings for uncovering speciation and hybridization patterns. Here we develop a phylogenetic hypothesis for a phenotypically diverse radiation of finch-like weaver-birds (Foudia) endemic to the western Indian Ocean islands. We find that unlike Darwin's finches, each island-endemic Foudia population is a monophyletic entity for which speciation can be considered complete. In explaining the only exceptions-mismatches between taxonomy, mitochondrial, and nuclear data-phylogenetic and coalescent methods support introgressive hybridization rather than incomplete lineage sorting. Human introductions of known timing of one island-endemic species, to all surrounding archipelagos provide two fortuitous experiments; (1) population sampling at known times in recent evolutionary history, (2) bringing allopatric lineages of an island radiation into secondary contact. Our results put a minimum time bound on introgression (235 years), and support hybridization between species in natural close contact (parapatry), but not between those in natural allopatry brought into contact by human introduction. Time in allopatry, rather than in sympatry, appears key in the reproductive isolation of Foudia species., (© 2012 The Author(s). Evolution© 2012 The Society for the Study of Evolution.)

Background: The evidence surrounding optimal follow-up after liver resection for colorectal metastases remains unclear. A significant proportion of recurrences occur in the early postoperative period, and some groups advocate more intensive review at this time., Methods: A systematic review of literature published between January 2003 and May 2010 was performed. Studies that described potentially curative primary resection of colorectal liver metastases that involved a defined follow-up protocol and long-term survival data were included. For meta-analysis, studies were grouped into intensive (more frequent review in the first 5 years after resection) and uniform (same throughout) follow-up., Results: Thirty-five studies were identified that met the inclusion criteria, involving 7330 patients. Only five specifically addressed follow-up. Patients undergoing intensive early follow-up had a median survival of 39·8 (95 per cent confidence interval 34·3 to 45·3) months with a 5-year overall survival rate of 41·9 (34·4 to 49·4) per cent. Patients undergoing routine follow-up had a median survival of 40·2 (33·4 to 47·0) months, with a 5-year overall survival rate of 38·4 (32·6 to 44·3) months., Conclusion: Evidence regarding follow-up after liver resection is poor. Meta-analysis failed to identify a survival advantage for intensive early follow-up., (Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Parrots are among the most recognisable and widely distributed of all bird groups occupying major parts of the tropics. The evolution of the genera that are found in and around the Indian Ocean region is particularly interesting as they show a high degree of heterogeneity in distribution and levels of speciation. Here we present a molecular phylogenetic analysis of Indian Ocean parrots, identifying the possible geological and geographical factors that influenced their evolution. We hypothesise that the Indian Ocean islands acted as stepping stones in the radiation of the Old-World parrots, and that sea-level changes may have been an important determinant of current distributions and differences in speciation. A multi-locus phylogeny showing the evolutionary relationships among genera highlights the interesting position of the monotypic Psittrichas, which shares a common ancestor with the geographically distant Coracopsis. An extensive species-level molecular phylogeny indicates a complex pattern of radiation including evidence for colonisation of Africa, Asia and the Indian Ocean islands from Australasia via multiple routes, and of island populations 'seeding' continents. Moreover, comparison of estimated divergence dates and sea-level changes points to the latter as a factor in parrot speciation. This is the first study to include the extinct parrot taxa, Mascarinus mascarinus and Psittacula wardi which, respectively, appear closely related to Coracopsis nigra and Psittacula eupatria., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: This study assessed the relationship between time, power and ablation size using a novel high-frequency 14.5 GHz microwave applicator in ex vivo human hepatic parenchyma and colorectal liver metastases. Previous examination has demonstrated structurally normal but non-viable cells within the ablation zone. This study aimed to further investigate how ablation affects these cells, and to confirm non-viability., Materials and Methods: Ablations were performed in ex vivo human hepatic parenchyma and tumour for a variety of time (10-180 s) and power (10-50 W) settings. Histological examination was performed to assess cellular anatomy, whilst enzyme histochemistry was used to confirm cellular non-viability. Transmission electron microscopy was used to investigate the subcellular structural effects of ablation within these fixed cells. Preliminary proteomic analysis was also performed to explore the mechanism of microwave cell death., Results: Increasing time and power settings led to a predictable and reproducible increase in size of ablation. At 50 W and 180 s application, a maximum ablation diameter of 38.8 mm (±1.3) was produced. Ablations were produced rapidly, and at all time and power settings ablations remained spherical (longest:shortest diameter <1.2). Routine histological analysis using haematoxylin-eosin (H&E) confirmed well preserved cellular anatomy despite ablation. Transmission electron microscopy demonstrated marked subcellular damage. Enzyme histochemistry showed complete absence of viability in ablated tissue., Conclusions: Large spherical ablation zones can be rapidly and reproducibly achieved in ex vivo human hepatic parenchyma and colorectal liver metastases using a 14.5 GHz microwave generator. Despite well preserved cellular appearance, ablated tissue is non-viable.

Blood donors' motivations and reasons for lapsing and never donating were determined from a questionnaire completed by 489 adults (89 regular donors, 105 lapsed donors, 295 never donors) in Leeds, UK. The free text responses were classified according to themes that arose. Altruistic motivations including reciprocation and kinship towards family, friends, and unknowns were most numerous. Other motivations related to the NHS or National Blood Service, obligation, occupation, self-interest, convenience, peer-influence, health benefits, a rare blood group, donations being useful, a TV programme, or ethnicity. Reasons for non-donation were personal, medical, donation centre- or procedure-related, exclusions, and age-related. Suggestions are offered to increase the blood supply., (© 2011 The Author(s). Vox Sanguinis © 2011 International Society of Blood Transfusion.)

The higher than expected increase in medical emergency hospital admissions has been a matter of debate for many years. While regular growth of around 1.0-1.5% per annum may be expected due to demography recent evidence has emerged from England and Scotland that the increase over time appears to occur in concentrated spurts of growth at an interval of 3 to 6 years resulting in an approximate 10% step-like increase in certain medical and mental health related diagnoses. A characteristic time-related pattern in admissions then follows each step-increase. Outbreaks of a previously uncharacterised infectious disease have been proposed to account for this behaviour. Evidence is presented to show that simultaneous outbreak(s) across the remainder of the UK (Wales and Northern Ireland) are occurring with step-like increases in a similar range of diagnoses. The infectious agent is proposed to be a member of the group of persistent viruses and appears to show some form of collective switch to a dormant state around 3½ years after the initial outbreak. This behaviour accounts for the unique pattern of hospital admissions seen over time and is so strong that any underlying demographic trends are overwhelmed. This particular pattern of admissions will have uniquely profound financial effects upon the cost pressures experienced within the health services., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A corollary of island biogeographical theory is that islands are largely colonized from their nearest mainland source. Despite Madagascar's extreme isolation from India and proximity to Africa, a high proportion of the biota of the Madagascar region has Asian affinities. This pattern has rarely been viewed as surprising, as it is consistent with Gondwanan vicariance. Molecular phylogenetic data provide strong support for such Asian affinities, but often not for their vicariant origin; most divergences between lineages in Asia and the Madagascar region post-date the separation of India and Madagascar considerably (up to 87 Myr), implying a high frequency of dispersal that mirrors colonization of the Hawaiian archipelago in distance. Indian Ocean bathymetry and the magnitude of recent sea-level lowstands support the repeated existence of sizeable islands across the western Indian Ocean, greatly reducing the isolation of Madagascar from Asia. We put forward predictions to test the role of this historical factor in the assembly of the regional biota. © The Willi Hennig Society 2009., (© The Willi Hennig Society 2009.)

Current methods used to calculate the required size of hospitals are underestimating the true capacity needed for operational efficiency. Trends in occupied bed-days (rather than admissions and length of stay) give better estimates of future bed requirements. Hospital occupancy rates depend on volatility in demand, not efficiency. Larger bed pools and hospitals can operate at higher average occupancy. Cost efficiency should be focusing on staffing based on the patients in the beds and not on the available beds. Hospitals require supporting climatalogical forecasts to allow for seasonal and other climate-related changes in admissions, if flexible staff deployment is to become a reality.

For many years medical admissions to acute hospitals have been increasing at a rate far higher than expected from demographic change. Analysis shows that the admissions tend to increase in a step-like manner at an interval of 3-6 years. This study characterises the specific diagnoses associated with the step-changes and uses the resulting pattern in admissions over time to identify further diagnoses with a far lower incidence which may also conform to this pattern. All of the diagnoses located using this method have a common immune function linkage in the expression of the chronic form of the condition. It is proposed that the wider use of data mining techniques may enable association between diagnoses associated with the need for inpatient care arising from unexpected common causes., (Copyright 2010 Elsevier Ltd. All rights reserved.)

To operate as a rotary motor, the ATP-hydrolyzing domain of the vacuolar H(+)-ATPase must be connected to a fixed structure in its membrane-bound proton pump domain by a mechanical stator. Although low-resolution structural data and spectroscopic analysis indicate that a filament-like subunit E/subunit G heterodimer performs this role, more detailed information about the relative arrangement of these subunits is limited. We have used a site-directed cross-linking approach to show that, in both bacterial and yeast V-type ATPases, the N-terminal alpha-helical segments of the G and E subunits are closely aligned over a distance of up to 40 A. Furthermore, cross-linking coupled to mass spectrometry shows that the C-terminal end of G is anchored at the C-terminal globular domain of subunit E. These data are consistent with a stator model comprising two approximately 150 A long parallel alpha-helices linked to each other at both ends, stabilized by a coiled-coil arrangement and capped by the globular C-terminal domain of E that connects the cytoplasmic end of the helical structure to the V-ATPase catalytic domain.

Background: To identify molecular mechanisms underlying SCN5A-related sick sinus syndrome (SSS), a rare type of SSS, in parallel experiments we elucidated the electrophysiological properties and the cell surface localization of thirteen human Na(v)1.5 (hNa(v)1.5) mutant channels previously linked to this disease., Methodology/principal Findings: Mutant hNa(v)1.5 channels expressed by HEK293 cells and Xenopus oocytes were investigated by whole-cell patch clamp and two-microelectrode voltage clamp, respectively. HEK293 cell surface biotinylation experiments quantified the fraction of correctly targeted channel proteins. Our data suggested three distinct mutant channel subtypes: Group 1 mutants (L212P, P1298L, DelF1617, R1632H) gave peak current densities and cell surface targeting indistinguishable from wild-type hNa(v)1.5. Loss-of-function of these mutants resulted from altered channel kinetics, including a negative shift of steady-state inactivation and a reduced voltage dependency of open-state inactivation. Group 2 mutants (E161K, T220I, D1275N) gave significantly reduced whole-cell currents due to impaired cell surface localization (D1275N), altered channel properties at unchanged cell surface localization (T220I), or a combination of both (E161K). Group 3 mutant channels were non-functional, due to an almost complete lack of protein at the plasma membrane (T187I, W1421X, K1578fs/52, R1623X) or a probable gating/permeation defect with normal surface localisation (R878C, G1408R)., Conclusions/significance: This study indicates that multiple molecular mechanisms, including gating abnormalities, trafficking defects, or a combination of both, are responsible for SCN5A-related familial SSS.

For many years medical admissions to acute hospitals have been increasing at a rate far higher than expected from demographic change. Factors such as emergency re-admission, GP thresholds, breakdown of the family unit and deficiencies in community and social care have been suggested to explain this widening gap. Solutions to the problem have revolved around demand management strategies. While such strategies do result in a relative reduction in demand they are unable to prevent the underlying long-term behaviour. Analysis of daily admissions in Scotland, England and at individual hospitals over the past 25 years shows that the admissions tend to increase in a step-like manner at an interval of three to six years. This causes a typical 10% step-increase in physician work-load and inpatient medical costs and across England adds over 1,200,000 occupied bed days of additional bed demand into the health service within the space of around three months. There are knock-on effects to demand for ambulance services, accident and emergency attendance and GP referral. The step-increase is characterised by a cluster of diagnoses, increases with age and effects women more than men. Such behaviour has similarities to an infectious outbreak and the evidence for this and alternative hypotheses are discussed.

Purpose: AMD has a complex etiology with environmental and genetic risk factors. Ten fibulin 5 sequence variants have been associated with AMD and two other fibulin 5 mutations cause autosomal-recessive cutis laxa. Fibulin 5 is a 52-kDa calcium-binding epidermal growth factor (cbEGF)-rich extracellular matrix protein that is essential for the formation of elastic tissues. Biophysical techniques were used to detect structural changes in the fibulin 5 mutants and to determine whether changes are predictive of pathogenicity., Methods: Native PAGE, nonreduced SDS-PAGE, size-exclusion column multiangle laser light scattering, sedimentation velocity, and circular dichroism (CD) were used to investigate the mobility, hydrodynamic radii, folding, and oligomeric states of the fibulin 5 mutants in the absence and presence of Ca(2+)., Results: CD showed that all mutants are folded, although perturbations to secondary structure contents were detected. Both cutis laxa mutants increased dimerization. Most other mutants slightly increased self-association in the absence of Ca(2+) but this was also demonstrated by G202R, a polymorphism detected in a control individual. The AMD-associated mutant G412E showed lower-than-expected mobility during native-PAGE, the largest hydrodynamic radius for the monomer form and the highest levels of aggregation in both the absence and presence of Ca(2+)., Conclusions: The results identified structural differences for the disease-causing cutis laxa mutants and for one AMD variant (G412E), suggesting that this may also be pathogenic. Although the other AMD-associated mutants showed no gross structural differences, they cannot be excluded as pathogenic by differences outside the scope of this study-for example, disruption of heterointeractions.

Fibulin 5 is a 52-kDa calcium-binding epidermal growth factor (cbEGF)-rich extracellular matrix protein that is essential for the formation of elastic tissues. Missense mutations in fibulin 5 cause the elastin disorder cutis laxa and have been associated with age-related macular degeneration, a leading cause of blindness. We investigated the structure, hydrodynamics, and oligomerization of fibulin 5 using small angle x-ray scattering, EM, light scattering, circular dichroism, and sedimentation. Compact structures for the monomer were determined by small angle x-ray scattering and EM, and are supported by close agreement between the theoretical sedimentation of the structures and the experimental sedimentation of the monomer in solution. EM showed that monomers associate around a central cavity to form a dimer. Light scattering and equilibrium sedimentation demonstrated that the equilibrium between the monomer and the dimer is dependent upon NaCl and Ca2+ concentrations and that the dimer is dominant under physiological conditions. The dimerization of fragments containing just the cbEGF domains suggests that intermolecular interactions between cbEGFs cause dimerization of fibulin 5. It is possible that fibulin 5 functions as a dimer during elastinogenesis or that dimerization may provide a method for limiting interactions with binding partners such as tropoelastin.

Rationale and Objectives: The purpose of this study was to evaluate the effect of reduced tube current (dose) on lung nodule detection in pediatric multidetector array computed tomography (MDCT)., Materials and Methods: The study included normal clinical chest MDCT images of 13 patients (aged 1-7 years) scanned at tube currents of 70 to 180 mA. Calibrated noise addition software was used to simulate cases as they would have been acquired at 70 mA (the lowest original tube current), 35 mA (50% reduction), and 17.5 mA (75% reduction). Using a validated nodule simulation technique, small lung nodules of 3 to 5 mm in diameter were inserted into the cases, which were then randomized and rated independently by three experienced pediatric radiologists for nodule presence on a continuous scale ranging from zero (definitely absent) to 100 (definitely present). The observer data were analyzed to assess the influence of dose on detection accuracy using the Dorfman-Berbaum-Mets method for multiobserver, multitreatment receiver-operating characteristic (ROC) analysis and the Williams trend test., Results: The areas under the ROC curves were 0.95, 0.91, and 0.92 at 70, 35, and 17.5 mA, respectively, with standard errors of 0.02 and interobserver variability of 0.02. The Dorfman-Berbaum-Mets method and the Williams trend test yielded P values for the effect of dose of .09 and .05, respectively., Conclusion: Tube current (dose) has a weak effect on the detection accuracy of small lung nodules in pediatric MDCT. The effect on detection accuracy of a 75% dose reduction was comparable to interobserver variability, suggesting a potential for dose reduction.

Metals are detoxified and sequestered into subcellular compartments when accumulated by earthworms. Differential centrifugation was used to quantify subcellular Pb in three separate studies to measure 14-day acute toxicity (lethality), 28/56-day reproductive effects, and 90-day bioaccumulation in spiked-soil exposed earthworms, Eisenia fetida. Observed toxicity and total body Pb was consistent with published work of others. Pb showed concentration-dependent toxicity relationships (lethality and reproduction) for total and subcellular Pb. Toxic fraction and total Pb showed similar concentration-response patterns in the 14-day and 28/56-day studies and tended to increase towards a plateau at higher concentrations. Linear correlations of subcellular to total Pb was observed in all studies except the 90-day bioaccumulation study in which toxic fraction Pb appeared to approach a maximum over the period between Day 56 and Day 90. In a follow-on study using two different contaminated soil types, toxic fraction and total Pb concentrations as related to reproductive effects were consistent with data from our spiked soil studies, and this suggests it may be possible to use such values to "factor out" matrix-specific influences that otherwise skew toxicity values when expressed relative to soil concentrations. Our findings, however, suggest the subcellular fractionation approach may not offer advantages over total Pb determination in short-term exposure studies but may become important when longer exposure periods (greater than 90 days) are considered. In this respect, the technique we describe has the potential to provide valuable information for assessing and interpreting Pb toxicity as a function of earthworm body burden.

The purpose of this study was to develop and validate a technique for three-dimensional (3D) modelling of small lung nodules on paediatric multidetector array computed tomography (MDCT) images. Clinical images were selected from 21 patients (<18 years old) who underwent MDCT examinations. Sixteen of the patients had one or more real lung nodules with diameters between 2.5 and 6 mm. A mathematical simulation technique was developed to emulate the 3D characteristics of the real nodules. To validate this technique, MDCT images of 34 real nodules and 55 simulated nodules were randomised and rated independently by four experienced paediatric radiologists on a continuous scale of appearance between 0 (definitely not real) and 100 (definitely real). Receiver operating characteristic (ROC) analysis, t-test, and equivalence test were performed to assess the radiologists' ability to distinguish between simulated and real nodules. The two types of nodules were also compared in terms of measured shape and contrast profile irregularities. The areas under the ROC curves were 0.59, 0.60, 0.40, and 0.63 for the four observers. Mean score differences between simulated and real nodules were -8, -11, 13, and -4 for the four observers with p-values of 0.17, 0.06, 0.17, and 0.26, respectively. The simulated and real nodules were perceptually equivalent and had comparable shape and contrast profile irregularities. In conclusion, mathematical simulation is a feasible technique for creating realistic small lung nodules on paediatric MDCT images.

Objective: The purpose of this study was to compare the diagnostic capabilities of standard- and reduced-dose CT in the detection of nephroureterolithiasis in children., Materials and Methods: Forty-five patients 20 years old or younger divided into two groups weighing 50 kg or less and more than 50 kg underwent unenhanced 16-MDCT in the evaluation of acute flank pain. An investigational computer-simulated tube current reduction tool was used to produce additional 80- and 40-mA examination sets (total number of image sets=135). Three independent blinded readers ranked random images for stones (confidence scale, 1-5, least to most), hydronephrosis, noise-based image quality, and presence of nonrenal lesions., Results: Compared with the standard tube current used for the original CT scans, there was no significant reduction (p=0.37) in detection of renal stones at the 80-mA setting (mean dose reduction, 67%; range, 43-81%); and at the 40-mA setting (mean dose reduction, 82%; range, 72-90%), the detection rate was significantly lower (p=0.05). At the 40-mA setting, there was no significant difference among the children weighing 50 kg or less (p=0.4). Detection of ureteral stones and hydronephrosis was not significantly different at 80 and 40 mA; however, disease frequency was low, and no definite conclusion can be made., Conclusion: Simulated dose reduction is a useful tool for determining diagnostic thresholds for MDCT detection of renal stones in children. Use of the 80-mA setting for all children and 40 mA for children weighing 50 kg or less does not significantly affect the diagnosis of pediatric renal stones.

We describe the case of a 27-year-old Caucasian woman with corrected transposition of the great vessels, who presented with cardiac failure. She had severe regurgitation of the systemic tricuspid valve with a huge annulus that was not suitable for annuloplasty. She underwent a successful repair using the Alfieri edge-to-edge technique and was asymptomatic 15 months after surgery. Such a repair has not been reported in the past.

Frequent utilization of copper formulations as aquatic herbicides and algaecides can lead to potentially elevated sediment-copper concentrations. This research investigated relationships between copper fractionation (through sequential extractions) and bioavailability in three reservoir sediments over a 60d contact duration. Copper was initially associated with exchangeable, carbonate, and oxidizable fractions for copper-amended sediments; and redistributed to the reducible and oxidizable fractions after 60d. Hyalella azteca mortality declined over time for organisms exposed to copper-amended reservoir sediments, indicating concomitant declines in sediment copper bioavailability. Comparisons between sequential extractions and organism responses indicated that bioavailability was primarily associated with the exchangeable fraction. Results of this research indicated fractionation and bioavailability of amended copper in sediments were influenced by contact duration along with sediment and overlying water characteristics. The influence of contact duration on copper bioavailability in sediments is important for assessing potential risks incurred by repeated applications of copper-containing algaecides in reservoirs.

We present two new avian molecular sexing techniques for nonpasserine and passerine birds (Neognathae), which are more suitable for use with museum specimens than earlier methods. The technique for nonpasserines is based on a new primer (M5) which, in combination with the existing P8 primer, targets a smaller amplicon in the CHD1 sex-linked gene than previously. Primers targeting ATP5A1, an avian sex-linked gene not previously used for sex identification, were developed for passerines. Comprehensive testing across species demonstrated that both primer pairs sex a range of different species within their respective taxonomic groups. Rigorous evaluation of each method within species showed that these permitted sexing of specimens dating from the 1850s. For corn bunting museum specimens, the ATP5A1 method sexed 98% of 63 samples (1857-1966). The M5/P8 CHD1 method was similarly successful, sexing 90% of 384 moorhen specimens from six different museum collections (1855-2001). In contrast, the original P2/P8 CHD1 sexing method only identified the sex of less than half of 111 museum moorhen samples. In addition to dried skin samples, these methods may be useful for other types of material that yield degraded or damaged DNA, and are hence potential new sexing tools for avian conservation genetics, population management and wildlife forensics., (© 2007 The Authors.)

We present a comprehensive protocol for extracting DNA from egg membranes and other internal debris recovered from the interior of blown museum bird eggs. A variety of commercially available DNA extraction methods were found to be applicable. DNA sequencing of polymerase chain reaction (PCR) products for a 176-bp fragment of mitochondrial DNA was successful for most egg samples (> 78%) even though the amount of DNA extracted (mean = 14.71 ± 4.55 ng/µL) was significantly less than that obtained for bird skin samples (mean = 67.88 ± 4.77 ng/µL). For PCR and sequencing of snipe (Gallinago) DNA, we provide eight new primers for the 'DNA barcode' region of COI mtDNA. In various combinations, the primers target a range of PCR products sized from 72 bp to the full 'barcode' of 751 bp. Not all possible combinations were tested with archive snipe DNA, but we found a significantly better success rate of PCR amplification for a shorter 176-bp target compared with a larger 288-bp fragment (67% vs. 39%). Finally, we explored the feasibility of whole genome amplification (WGA) for extending the use of archive DNA in PCR and sequencing applications. Of two WGA approaches, a PCR-based method was found to be able to amplify whole genomic DNA from archive skins and eggs from museum bird collections. After WGA, significantly more archive egg samples produced visible PCR products on agarose (56.9% before WGA vs. 79.0% after WGA). However, overall sequencing success did not improve significantly (78.8% compared with 83.0%)., (© 2007 The Authors.)

As part of an investigation determining the trophically available fraction of metals in a model terrestrial food web, i.e., invertebrate prey to Western fence lizards (Sceloporus occidentalis), we evaluated the ability of several invertebrate prey to bioaccumulate lead and to form metals-rich granules, which are hypothesized to be non-available to predators. Crickets (Acheta domestica), tenebroid beetle larvae (Tenebrio molitor), and isopods (Porcellio scaber) were selected as model prey organisms. Lack of standard exposure methodologies for these species has presented a barrier to trophic transfer evaluations, as each species has particular requirements that create challenges for designing exposure conditions. We were able to devise exposure conditions for all three species that allow long-term exposure studies. All prey organisms accumulated lead from contaminated food, and for all species the majority of the accumulated Pb was associated with the exoskeleton (>50%), with metals-rich granules accounting for most of the remaining accumulated lead.

Background: In the UK, all ethnic minority groups have higher rates of diabetes than the general population. Although there have been a number of projects to assess diabetic care amongst minority ethnic groups in the United Kingdom, little is known about the extent to which the needs of ethnic minority groups are actually met by the National Health Service (NHS) Scotland. Therefore we conducted this study to understand of the current situation for diabetes care available to minority ethnic groups in Scotland., Methods: We conducted this cross-sectional study in all health boards in Scotland. A questionnaire was designed based on expert comments. It was completed by Local Health Care Cooperatives (LHCC) managers, chairs, diabetes specialist nurses and public health practitioners., Results: 57 of questionnaires were returned (response rate = 69.5%). Of these LHCCs, 71% responded that diabetes was part of their LHCC plan. However 69% answered that ethnic group was not recorded by community services and GPs, and 80% of LHCCs did not monitor trends of complications of diabetes by ethnic group., Conclusion: Improvement is needed in quality, completeness, and availability of minority ethnic group data for diabetes at a national level, particularly if NHS Primary Care Organisations are to be responsible for providing diabetes care as laid out in the Scottish Diabetes Framework.

Molecular phylogenetic hypotheses of species-rich lineages in regions where geological history can be reliably inferred may provide insights into the scale of processes driving diversification. Here we sample all extant or recently extinct white-eye (Zosterops) taxa of the southwest Indian Ocean, combined with samples from all principal continental lineages. Results support a high dispersal capability, with at least two independent continental sources for white-eyes of the region. An early (within 1.8 million years ago) expansion into the Indian Ocean may have originated either from Asia or Africa; the three resulting lineages show a disparate distribution consistent with considerable extinction following their arrival. Africa is supported as the origin of a later expansion into the region (within 1.2 million years ago). On two islands, a pair of Zosterops species derived from independent immigrations into the Indian Ocean co-occur or may have formerly co-occurred, providing strong support for their origin by double-island colonization rather than within-island (sympatric or microallopatric) speciation. On Mauritius and La Réunion, phylogenetic placement of sympatric white-eyes allow us to rule out a scenario in which independent within-island speciation occurred on both islands; one of the species pairs must have arisen by double colonization, while the other pair is likely to have arisen by the same mechanism. Long-distance immigration therefore appears to be responsible for much of the region's white-eye diversity. Independent immigrations into the region have resulted in lineages with mutually exclusive distributions and it seems likely that competition with congeneric species, rather than arrival frequency, may limit present-day diversity.

Background: The current risk stratification systems in upper gastrointestinal bleeding do not correct for the intake of low-dose aspirin and other antithrombotic drugs., Aim: To test the Blatchford scores in evaluating the clinical outcome in bleeders using these drugs., Methods: We calculated the Blatchford scores in 510 bleeders, including 123 on low-dose aspirin, 44 on other antithrombotic drugs, and 68 on non-steroidal anti-inflammatory drugs., Results: The median clinical scores distributed according to aetiological risk factors were as follows: no risk factors, 5; non-steroidal anti-inflammatory drugs, 8; aspirin, 7; other antithrombotics, 6; excess alcohol, 4; multiple risk factors, 7; (P = 0.003, Kruskal-Wallis test). Scores correlated positively with the duration of admission in the entire group (r(s) = 0.285; P < 0.001) and in those taking aspirin and antithrombotics (r(s) = 0.211; P = 0.029). The median scores in patients requiring the blood transfusion were 10 in the entire group and 11 in users of aspirin or antithrombotics, compared with 3 and 4, respectively, in those not transfused (P < 0.001)., Conclusions: The Blatchford scores are significantly elevated in users of non-steroidal anti-inflammatory drugs, low-dose aspirin, and other antithrombotic drugs. They correlate positively with the duration of admission and the need for blood transfusion.

Age-related macular degeneration (ARMD) is the leading cause of irreversible visual loss in the Western world, affecting approximately 25 million people worldwide. The pathogenesis is complex and missense mutations in FBLN5 have been reported in association with ARMD. We have investigated the role of fibulin 5 in ARMD by completing the first European study of the gene FBLN5 in ARMD (using 2 European cohorts of 805 ARMD patients and 279 controls) and by determining the functional effects of the missense mutations on fibulin 5 expression. We also correlated the FBLN5 genotype with the ARMD phenotype. We found two novel sequence changes in ARMD patients that were absent in controls and expressed these and the other nine reported FBLN5 mutations associated with ARMD and two associated with the autosomal recessive disease cutis laxa. Fibulin 5 secretion was significantly reduced (P<0.001) for four ARMD (p.G412E, p.G267S, p.I169 T, and p.Q124P) and two cutis laxa (p.S227P, p.C217R) mutations. These results suggest that some missense mutations associated with ARMD lead to decreased fibulin 5 secretion with a possible corresponding reduction in elastinogenesis. This study confirms the previous work identifying an association between FBLN5 mutations and ARMD and for the first time suggests a functional mechanism by which these mutations can lead to ARMD. It further demonstrates that FBLN5 mutations can be associated with different phenotypes of ARMD (not limited to the previously described cuticular drusen type). Such knowledge may ultimately lead to the development of novel therapies for this common disease., (Copyright 2006 Wiley-Liss, Inc.)

Background: Epidemiologic data have shown that the prevalence of Type 2 diabetes varies with ethnic origin. Type 2 diabetes is up to four times more common in British South Asians than in the indigenous white population. The aim of this study was to develop a culturally appropriate educational intervention programme for South Asians with Type 2 diabetes. We then investigated whether this intervention could produce an improvement, and finally whether any improvement was greater than background changes in knowledge in comparison groups., Methods: A multi-site prospective, randomised controlled study was conducted in all day care centres and three general practice registers with high proportion patients from different ethnic minority groups in Glasgow, Scotland. The intervention consisted of 18 educational sessions in 6 separate programmes. A modified questionnaire was used to measure the knowledge, attitudes, and practice of diabetes before and after intervention., Results: Baseline assessment showed that Indian and Pakistani subjects had less knowledge about diabetes, regarded the disease less seriously, and had a lesser understanding of the relationship between control and complications than the white population. No differences in initial responses were found between those who completed the second assessment and those who did not. The intervention group showed significant improvements in scores for Knowledge (+12.5%); Attitudes toward seriousness (+13.5%), complications (+8.1%), Practice (+20.0%). However there were also changes in the ethnic control group scores; respectively +5.0%, +16.3% (significant P < 0.001), +1.5%, +1.7%. The single white control group also showed some improvements; respectively +12.2%, +12.4% (P = 0.04), +6.0%, +25.0% (P = 0.007), but the differences in improvement between these two control groups were not significant. Overall, the improvement seen was similar in both intervention and ethnic control groups and there was no significant difference in the amount of change (P = 0.36 CI -0.9 to +2.6)., Conclusion: This study has shown that conducting a culturally-competent educational intervention in patients with Type 2 diabetes from ethnic minority groups is feasible and can improve their knowledge and attitudes and practice. However there was no net benefit compared with the control group.