Hospital Universitario de Canarias

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) are afflicted by comorbidities. Few studies have prospectively evaluated COPD comorbidities and mortality risk. OBJECTIVES: To prospectively evaluate COPD comorbidities and mortality risk. METHODS: We followed 1,664 patients with COPD in five centers for a median of 51 months. Systematically, 79 comorbidities were recorded. We calculated mortality risk using Cox proportional hazard, and developed a graphic representation of the prevalence and strength of association to mortality in the form of a "comorbidome". A COPD comorbidity index (COPD specific comorbidity test [COTE]) was constructed based on the comorbidities that increase mortality risk using a multivariate analysis. We tested the COTE index as predictor of mortality and explored whether the COTE index added predictive information when used with the validated BODE index. MEASUREMENTS AND MAIN RESULTS: Fifteen of 79 comorbidities differed in prevalence between survivors and nonsurvivors. Of those, 12 predicted mortality and were integrated into the COTE index. Increases in the COTE index were associated with an increased risk of death from COPD-related (hazard ratio [HR], 1.13; 95% confidence interval, 1.08-1.18; P < 0.001) and non-COPD-related causes (HR, 1.18; 95% confidence interval, 1.15-1.21; P < 0.001). Further, increases in the BODE and COTE were independently associated with increased risk of death. A COTE score of greater than or equal to 4 points increased by 2.2-fold the risk of death (HR, 2.26-2.68; P < 0.001) in all BODE quartile. CONCLUSIONS: Comorbidities are frequent in COPD and 12 of them negatively influence survival. A simple disease-specific comorbidities index (COTE) helps assess mortality risk in patients with COPD.

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BACKGROUND: Colonoscopy and fecal immunochemical testing (FIT) are accepted strategies for colorectal-cancer screening in the average-risk population. METHODS: In this randomized, controlled trial involving asymptomatic adults 50 to 69 years of age, we compared one-time colonoscopy in 26,703 subjects with FIT every 2 years in 26,599 subjects. The primary outcome was the rate of death from colorectal cancer at 10 years. This interim report describes rates of participation, diagnostic findings, and occurrence of major complications at completion of the baseline screening. Study outcomes were analyzed in both intention-to-screen and as-screened populations. RESULTS: The rate of participation was higher in the FIT group than in the colonoscopy group (34.2% vs. 24.6%, P<0.001). Colorectal cancer was found in 30 subjects (0.1%) in the colonoscopy group and 33 subjects (0.1%) in the FIT group (odds ratio, 0.99; 95% confidence interval [CI], 0.61 to 1.64; P=0.99). Advanced adenomas were detected in 514 subjects (1.9%) in the colonoscopy group and 231 subjects (0.9%) in the FIT group (odds ratio, 2.30; 95% CI, 1.97 to 2.69; P<0.001), and nonadvanced adenomas were detected in 1109 subjects (4.2%) in the colonoscopy group and 119 subjects (0.4%) in the FIT group (odds ratio, 9.80; 95% CI, 8.10 to 11.85; P<0.001). CONCLUSIONS: Subjects in the FIT group were more likely to participate in screening than were those in the colonoscopy group. On the baseline screening examination, the numbers of subjects in whom colorectal cancer was detected were similar in the two study groups, but more adenomas were identified in the colonoscopy group. (Funded by Instituto de Salud Carlos III and others; ClinicalTrials.gov number, NCT00906997.).

BACKGROUND: A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined. METHODS: We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives. RESULTS: Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency. CONCLUSIONS: The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.

INTRODUCTION Diabetes Mellitus Diabetes mellitus is one of the most common chronic diseases in the world, with an estimated worldwide prevalence of over 176 million in 2000. Furthermore, the prevalence of the disease is expected to increase in the coming years as industrialized societies become older, more obese, and more sedentary, and it is predicted to rise to 370 million by 2030 (1). Acute metabolic complications of diabetes are associated with high mortality rates; in particular, hyperosmolar hyperglycemia (approximately 15%) and ketoacidosis (up to 5%). The prognosis in these conditions is substantially worse in older patients and those with coma or hypotension (2). Following a review of epidemiologic and pathologic evidence, the American Heart Association has also classified diabetes a major independent risk factor for cardiovascular disease (CVD) (3–8). Manifestations of CVD include atherosclerotic coronary heart disease (CHD), heart failure (diabetic cardiomyopathy), myocardial infarction, stroke, and peripheral vascular disease (7). The risk for stroke has been reported to be two to four times higher in patients with diabetes (7,9). Furthermore, patients with diabetes who develop CVD have a worse prognosis for survival than patients with CVD but without diabetes (8–11). In fact, CVD is listed as the cause of death in approximately 65% of patients with diabetes (12). In addition to the risk for macrovascular complications, diabetes is associated with long-term microvascular complications including neuropathy, retinopathy, nephropathy, and erectile dysfunction. Diabetic nephropathy is the most common single cause of end-stage renal disease in the United States and Europe (13). With respect to retinopathy, after 20 years with the condition, almost all individuals with type 1 diabetes and over 60% with type 2 diabetes have a degree of retinopathy that may progress to loss of vision (14). In fact, diabetes is now considered the leading cause of blindness in developed countries, causing 12,000 to 24,000 new cases each year (15,16). New-Onset Diabetes after Transplantation Diabetes and impaired glucose tolerance occurring as a complication of organ transplantation have been recognized for many years. However, incidence figures for new-onset diabetes after transplantation across different studies have ranged between 2% and 53% (17). Precise figures have been difficult to determine because there has been no consensus regarding the definition of the condition and hence different clinical studies have used a variety of diagnostic criteria. 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transplantation the for the of patients with type 2 diabetes is that glucose in patients with type 1 or type 2 diabetes in of complications In addition to the of patients the and also be who develop diabetes after transplantation also for the of complications, including retinopathy and may also be to for the of the of has been for the transplant with new-onset the who diabetes after transplantation of The of patients with diabetes to in glucose has the to glucose be an of the of all patients or may also be for patients diabetes is by of the for patients with diabetes the of risk all and in each these and of to the and be year in patients because of in in patients with diabetes and the of of in with patients with diabetes after transplantation have to determine or glucose is with the to the Diabetes and to be used in all cases The of the used and the of the transplant patients diabetes it is that is a is to be to long-term complications but may be difficult to in most may be in most patients but may be to are to an risk for long-term complications, and and of The or may be to different for the of diabetes to the of each it is that an of or higher the for for be that is for of new-onset diabetes after transplantation because it is for Furthermore, in patients with or be with because conditions with the and the may be Diabetic The of new-onset diabetes after transplantation many with type 2 diabetes and it is that transplant who develop new-onset diabetes also be risk of the long-term complications of as retinopathy and it is that all patients with new-onset diabetes are for complications, including an and a The of in the is an of nephropathy in patients with type 1 and type 2 and is a for cardiovascular and is an for for vascular disease and in these to cardiovascular risk (13). for is for all patients with diabetes for type 2 diabetes and after years for type 1 to of nephropathy (13). the of has been in transplant may also be considered in transplant who have developed new-onset diabetes to the of However, it be that many transplant have renal and may have without In may be difficult to in with chronic studies are to the of in transplant with new-onset to diabetes after transplantation of patients with diabetes after transplantation a to that for patients with type 2 diabetes and to of patients with of diabetes after of the most for the of patients with and diabetes after transplantation loss and of loss a as has also been to peripheral and in patients with type 2 diabetes the and are as the in the of type 2 with a of diabetes including of glucose glucose is with and is the to has been the be the of of and of also be The of an may be an is the most used a a or a of each of these is associated with and also the and and of common In the of transplant with impaired it is to the of as with and with is associated with an increase in the risk for CVD and are common with with or are more common with is in the of for transplant patients and be may be the of in the for in transplant patients with renal may be because are in patients with renal or and with be that no of have been in patients to is with a single a of with different of be with the of the are used in the of patients with type 2 or or the of of the also be that of these has been in in transplant may be to or to may be a with or without of and is used in patients with type 2 has been in patients with new-onset diabetes after of may be of is or glucose to than and to than after with an than may be in the of a single of glucose be by the addition of or the by be may also be to are with and of be to glucose be to an or for of and of is that of the risk of chronic heart disease in patients with diabetes all patients with new-onset diabetes after transplantation are high risk of it is that patients also in with the for of to of and In patients with In patients with to be also may be the of in patients with including renal transplant have been the of and as of chronic heart disease are of is reported to the of patients with diabetes in the and is associated with an risk of cardiovascular death a of for the of patients with diabetes have that be in patients to for patients with diabetes in the no studies to have the of in patients with new-onset diabetes after transplantation, an may be expected to be of there is studies of with diabetes and in the that or is associated with a in cardiovascular and a of is for patients with new-onset diabetes after transplantation may be with an with addition of to to the In may to a of in renal no are in transplant studies are to the of these in be to the of to the risk of cardiovascular of new-onset diabetes after transplantation The in the of these the of diabetes as a major complication of transplantation and the that may in However, that a of may the of diabetes in Furthermore, and the long-term complications of the have been developed to a definition and of new-onset diabetes after transplantation and to for of the condition that be used to transplant of these in patients risk of diabetes after transplantation that be in the of these be expected to the risk of new-onset diabetes after transplantation and the long-term associated with the condition of diabetes after

Islands provide classic model biological systems. We review how growing appreciation of geoenvironmental dynamics of marine islands has led to advances in island biogeographic theory accommodating both evolutionary and ecological phenomena. Recognition of distinct island geodynamics permits general models to be developed and modified to account for patterns of diversity, diversification, lineage development, and trait evolution within and across island archipelagos. Emergent patterns of diversity include predictable variation in island species-area relationships, progression rule colonization from older to younger land masses, and syndromes including loss of dispersability and secondary woodiness in herbaceous plant lineages. Further developments in Earth system science, molecular biology, and trait data for islands hold continued promise for unlocking many of the unresolved questions in evolutionary biology and biogeography.

The 6-min walk distance (6MWD) predicted values have been derived from small cohorts mostly from single countries. The aim of the present study was to investigate differences between countries and identify new reference values to improve 6MWD interpretation. We studied 444 subjects (238 males) from seven countries (10 centres) ranging 40-80 yrs of age. We measured 6MWD, height, weight, spirometry, heart rate (HR), maximum HR (HR(max)) during the 6-min walk test/the predicted maximum HR (HR(max) % pred), Borg dyspnoea score and oxygen saturation. The mean ± sd 6MWD was 571 ± 90 m (range 380-782 m). Males walked 30 m more than females (p < 0.001). A multiple regression model for the 6MWD included age, sex, height, weight and HR(max) % pred (adjusted r² = 0.38; p < 0.001), but there was variability across centres (adjusted r² = 0.09-0.73) and its routine use is not recommended. Age had a great impact in 6MWD independent of the centres, declining significantly in the older population (p < 0.001). Age-specific reference standards of 6MWD were constructed for male and female adults. In healthy subjects, there were geographic variations in 6MWD and caution must be taken when using existing predictive equations. The present study provides new 6MWD standard curves that could be useful in the care of adult patients with chronic diseases.

Bladder cancer has been associated with exposure to chlorination by-products in drinking water, and experimental evidence suggests that exposure also occurs through inhalation and dermal absorption. The authors examined whether bladder cancer risk was associated with exposure to trihalomethanes (THMs) through ingestion of water and through inhalation and dermal absorption during showering, bathing, and swimming in pools. Lifetime personal information on water consumption and water-related habits was collected for 1,219 cases and 1,271 controls in a 1998-2001 case-control study in Spain and was linked with THM levels in geographic study areas. Long-term THM exposure was associated with a twofold bladder cancer risk, with an odds ratio of 2.10 (95% confidence interval: 1.09, 4.02) for average household THM levels of >49 versus < or =8 micro g/liter. Compared with subjects not drinking chlorinated water, subjects with THM exposure of >35 micro g/day through ingestion had an odds ratio of 1.35 (95% confidence interval: 0.92, 1.99). The odds ratio for duration of shower or bath weighted by residential THM level was 1.83 (95% confidence interval: 1.17, 2.87) for the highest compared with the lowest quartile. Swimming in pools was associated with an odds ratio of 1.57 (95% confidence interval: 1.18, 2.09). Bladder cancer risk was associated with long-term exposure to THMs in chlorinated water at levels regularly occurring in industrialized countries.

OBJECTIVES: Changing patterns in medical practice may contribute to temporal changes in the incidence of upper and lower gastrointestinal (GI) complications. There are limited data on the incidence of lower GI complications in clinical practice and most studies that have been done have serious methodological limitations to inferring the actual burden of this problem. The aims of this study were to analyze time trends of hospitalizations resulting from GI complications originating both from the upper and lower GI tract in the general population, and to determine the risk factors, severity, and clinical impact of these GI events. METHODS: This was a population-based study of patients hospitalized because of GI complications in 10 general hospitals between 1996 and 2005 in Spain. We report the age- and gender-specific rates, estimate the regression coefficients of the upper and lower GI event trends, and evaluate the severity and associated risk factors. GI hospitalization charts were validated by an independent review of large random samples of unspecific and specific codes distributed among all hospitals and study years. RESULTS: Upper GI complications fell from 87/100,000 persons in 1996 to 47/100,000 persons in 2005, whereas lower GI complications increased from 20/100,000 to 33/100,000. Overall, mortality rates decreased, but the case fatality remained constant over time. Lower GI events had a higher mortality rate (8.8 vs. 5.5%), a longer hospitalization (11.6+/-13.9 vs. 7.9+/-8.8 days), and higher resource utilization than did upper GI events. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) without concomitant proton pump inhibitor was more frequently recorded among upper GI complications than among lower GI complications. When comparing upper GI events with lower GI events, we found that male gender (adjusted odds ratio (OR): 1.94; 95% confidence interval (CI): 1.70-2.21), and recorded NSAID use (OR: 1.92; 95% CI: 1.60-2.30) were associated to a greater extent with upper GI events, whereas older age (OR: 0.83; 95% CI: 0.77-0.89), number of comorbidities (OR: 0.91; 95% CI: 0.86-0.96), and having a diagnosis in recent years (OR: 0.92; 95% CI: 0.90-0.94) were all associated to a greater extent with lower GI events than with upper GI events after adjusting for age, sex, hospitalization, and discharge year. CONCLUSIONS: Over the past decade, there has been a progressive change in the overall picture of GI events leading to hospitalization, with a clear decreasing trend in upper GI events and a significant increase in lower GI events, causing the rates of these two GI complications to converge. Overall, mortality has also decreased, but the in-hospital case fatality of upper or lower GI complication events has remained constant. It will be a challenge to improve future care in this area unless we develop new strategies to reduce the number of events originating in the lower GI tract, as well as reducing their associated mortality.

The study of islands as model systems has played an important role in the development of evolutionary and ecological theory. The 50th anniversary of MacArthur and Wilson's (December 1963) article, 'An equilibrium theory of insular zoogeography', was a recent milestone for this theme. Since 1963, island systems have provided new insights into the formation of ecological communities. Here, building on such developments, we highlight prospects for research on islands to improve our understanding of the ecology and evolution of communities in general. Throughout, we emphasise how attributes of islands combine to provide unusual research opportunities, the implications of which stretch far beyond islands. Molecular tools and increasing data acquisition now permit re-assessment of some fundamental issues that interested MacArthur and Wilson. These include the formation of ecological networks, species abundance distributions, and the contribution of evolution to community assembly. We also extend our prospects to other fields of ecology and evolution - understanding ecosystem functioning, speciation and diversification - frequently employing assets of oceanic islands in inferring the geographic area within which evolution has occurred, and potential barriers to gene flow. Although island-based theory is continually being enriched, incorporating non-equilibrium dynamics is identified as a major challenge for the future.

MAIN RECOMMENDATIONS: The following recommendations for post-polypectomy endoscopic surveillance should be applied only after a high quality baseline colonoscopy with complete removal of all detected neoplastic lesions.1 In the low risk group (patients with 1 - 2 tubular adenomas < 10 mm with low grade dysplasia), the ESGE recommends participation in existing national screening programmes 10 years after the index colonoscopy. If no screening programme is available, repetition of colonoscopy 10 years after the index colonoscopy is recommended (strong recommendation, moderate quality evidence). 2 In the high risk group (patients with adenomas with villous histology or high grade dysplasia or ≥10 mm in size, or ≥ 3 adenomas), the ESGE recommends surveillance colonoscopy 3 years after the index colonoscopy (strong recommendation, moderate quality evidence). Patients with 10 or more adenomas should be referred for genetic counselling (strong recommendation, moderate quality evidence). 3 In the high risk group, if no high risk adenomas are detected at the first surveillance examination, the ESGE suggests a 5-year interval before a second surveillance colonoscopy (weak recommendation, low quality evidence). If high risk adenomas are detected at first or subsequent surveillance examinations, a 3-year repetition of surveillance colonoscopy is recommended (strong recommendation, low quality evidence).4 The ESGE recommends that patients with serrated polyps < 10 mm in size with no dysplasia should be classified as low risk (weak recommendation, low quality evidence). The ESGE suggests that patients with large serrated polyps (≥ 10 mm) or those with dysplasia should be classified as high risk (weak recommendation, low quality evidence).5 The ESGE recommends that the endoscopist is responsible for providing a written recommendation for the post-polypectomy surveillance schedule (strong recommendation, low quality evidence).

Automated diagnosis of glaucoma disease has been studied for years. A great amount of research work in this field has been focused on the analysis of retinal fundus images to localize, detect and evaluate the optic disc. An open fundus image database with accurate gold standards of the optic nerve head has been implemented. A variability measurement by zones of the optic disc is also proposed. The relevance of this work is to provide accurate ONH segmentations and a segmentation assessment procedure to allow the design of computerized methods for glaucoma detection.

IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

BACKGROUND: The risks and benefits of coxibs, non-steroidal anti-inflammatory drugs (NSAIDs), and aspirin treatment are under intense debate. OBJECTIVE: To determine the risk of peptic ulcer upper gastrointestinal bleeding (UGIB) associated with the use of coxibs, traditional NSAIDs, aspirin or combinations of these drugs in clinical practice. METHODS: A hospital-based, case-control study in the general community of patients from the National Health System in Spain. The study included 2777 consecutive patients with endoscopy-proved major UGIB because of the peptic lesions and 5532 controls matched by age, hospital and month of admission. Adjusted relative risk (adj RR) of UGIB determined by conditional logistic regression analysis is provided. RESULTS: Use of non-aspirin-NSAIDs increased the risk of UGIB (adj RR 5.3; 95% confidence interval (CI) 4.5 to 6.2). Among non-aspirin-NSAIDs, aceclofenac (adj RR 3.1; 95% CI 2.3 to 4.2) had the lowest RR, whereas ketorolac (adj RR 14.4; 95% CI 5.2 to 39.9) had the highest. Rofecoxib treatment increased the risk of UGIB (adj RR 2.1; 95% CI 1.1 to 4.0), whereas celecoxib, paracetamol or concomitant use of a proton pump inhibitor with an NSAID presented no increased risk. Non-aspirin antiplatelet treatment (clopidogrel/ticlopidine) had a similar risk of UGIB (adj RR 2.8; 95% CI 1.9 to 4.2) to cardioprotective aspirin at a dose of 100 mg/day (adj RR 2.7; 95% CI 2.0 to 3.6) or anticoagulants (adj RR 2.8; 95% CI 2.1 to 3.7). An apparent interaction was found between low-dose aspirin and use of non-aspirin-NSAIDs, coxibs or thienopyridines, which increased further the risk of UGIB in a similar way. CONCLUSIONS: Coxib use presents a lower RR of UGIB than non-selective NSAIDs. However, when combined with low-dose aspirin, the differences between non-selective NSAIDs and coxibs tend to disappear. Treatment with either non-aspirin antiplatelet or cardioprotective aspirin has a similar risk of UGIB.

The Spanish Myeloma Group conducted a trial to compare bortezomib/thalidomide/dexamethasone (VTD) versus thalidomide/dexamethasone (TD) versus vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone/bortezomib (VBMCP/VBAD/B) in patients aged 65 years or younger with multiple myeloma. The primary endpoint was complete response (CR) rate postinduction and post-autologous stem cell transplantation (ASCT). Three hundred eighty-six patients were allocated to VTD (130), TD (127), or VBMCP/VBAD/B (129). The CR rate was significantly higher with VTD than with TD (35% vs 14%, P = .001) or with VBMCP/VBAD/B (35% vs 21%, P = .01). The median progression-free survival (PFS) was significantly longer with VTD (56.2 vs 28.2 vs 35.5 months, P = .01). In an intention-to-treat analysis, the post-ASCT CR rate was higher with VTD than with TD (46% vs 24%, P = .004) or with VBMCP/VBAD/B (46% vs 38%, P = .1). Patients with high-risk cytogenetics had a shorter PFS and overall survival in the overall series and in all treatment groups. In conclusion, VTD resulted in a higher pre- and posttransplantation CR rate and in a significantly longer PFS although it was not able to overcome the poor prognosis of high-risk cytogenetics. Our results support the use of VTD as a highly effective induction regimen prior to ASCT. The study was registered with http://www.clinicaltrials.gov (NCT00461747) and Eudra CT (no. 2005-001110-41).

The following recommendations for post-polypectomy colonoscopic surveillance apply to all patients who had one or more polyps that were completely removed during a high quality baseline colonoscopy. 1: ESGE recommends that patients with complete removal of 1 - 4 < 10 mm adenomas with low grade dysplasia, irrespective of villous components, or any serrated polyp < 10 mm without dysplasia, do not require endoscopic surveillance and should be returned to screening.Strong recommendation, moderate quality evidence.If organized screening is not available, repetition of colonoscopy 10 years after the index procedure is recommended.Strong recommendation, moderate quality evidence. 2: ESGE recommends surveillance colonoscopy after 3 years for patients with complete removal of at least 1 adenoma ≥ 10 mm or with high grade dysplasia, or ≥ 5 adenomas, or any serrated polyp ≥ 10 mm or with dysplasia. Strong recommendation, moderate quality evidence. 3: ESGE recommends a 3 - 6-month early repeat colonoscopy following piecemeal endoscopic resection of polyps ≥ 20 mm.Strong recommendation, moderate quality evidence. A first surveillance colonoscopy 12 months after the repeat colonoscopy is recommended to detect late recurrence.Strong recommendation, high quality evidence. 4: If no polyps requiring surveillance are detected at the first surveillance colonoscopy, ESGE suggests to perform a second surveillance colonoscopy after 5 years. Weak recommendation, low quality evidence.After that, if no polyps requiring surveillance are detected, patients can be returned to screening. 5: ESGE suggests that, if polyps requiring surveillance are detected at first or subsequent surveillance examinations, surveillance colonoscopy may be performed at 3 years. Weak recommendation, low quality evidence.A flowchart showing the recommended surveillance intervals is provided (Fig. 1).

We describe a second primase in human cells, PrimPol, which has the ability to start DNA chains with deoxynucleotides unlike regular primases, which use exclusively ribonucleotides. Moreover, PrimPol is also a DNA polymerase tailored to bypass the most common oxidative lesions in DNA, such as abasic sites and 8-oxoguanine. Subcellular fractionation and immunodetection studies indicated that PrimPol is present in both nuclear and mitochondrial DNA compartments. PrimPol activity is detectable in mitochondrial lysates from human and mouse cells but is absent from mitochondria derived from PRIMPOL knockout mice. PRIMPOL gene silencing or ablation in human and mouse cells impaired mitochondrial DNA replication. On the basis of the synergy observed with replicative DNA polymerases Polγ and Polε, PrimPol is proposed to facilitate replication fork progression by acting as a translesion DNA polymerase or as a specific DNA primase reinitiating downstream of lesions that block synthesis during both mitochondrial and nuclear DNA replication.

Diabetic macular edema (DME) can cause blindness in diabetic patients suffering from diabetic retinopathy (DR). DM parameters controls (glycemia, arterial tension, and lipids) are the gold standard for preventing DR and DME. Although the vascular endothelial growth factor (VEGF) is known to play a role in the development of DME, the pathological processes leading to the onset of this disease are highly complex and the exact sequence in which they occur is still not completely understood. Angiogenesis and inflammation have been shown to be involved in the pathogenesis of this disease. However, it still remains to be clarified whether angiogenesis following VEGF overexpression is a cause or a consequence of inflammation. This paper provides a review of the data currently available, focusing on VEGF, angiogenesis, and inflammation. Our analysis suggests that angiogenesis and inflammation act interdependently during the development of DME. Knowledge of DME etiology seems to be important in treatments with anti-VEGF or anti-inflammatory drugs. Current diagnostic techniques do not permit us to differentiate between both etiologies. In the future, diagnosing the physiopathology of each patient with DME will help us to select the most effective drug.

Abstract Aim Higher‐elevation areas on islands and continental mountains tend to be separated by longer distances, predicting higher endemism at higher elevations; our study is the first to test the generality of the predicted pattern. We also compare it empirically with contrasting expectations from hypotheses invoking higher speciation with area, temperature and species richness. Location Thirty‐two insular and 18 continental elevational gradients from around the world. Methods We compiled entire floras with elevation‐specific occurrence information, and calculated the proportion of native species that are endemic (‘percent endemism’) in 100‐m bands, for each of the 50 elevational gradients. Using generalized linear models, we tested the relationships between percent endemism and elevation, isolation, temperature, area and species richness. Results Percent endemism consistently increased monotonically with elevation, globally. This was independent of richness–elevation relationships, which had varying shapes but decreased with elevation at high elevations. The endemism–elevation relationships were consistent with isolation‐related predictions, but inconsistent with hypotheses related to area, richness and temperature. Main conclusions Higher per‐species speciation rates caused by increasing isolation with elevation are the most plausible and parsimonious explanation for the globally consistent pattern of higher endemism at higher elevations that we identify. We suggest that topography‐driven isolation increases speciation rates in mountainous areas, across all elevations and increasingly towards the equator. If so, it represents a mechanism that may contribute to generating latitudinal diversity gradients in a way that is consistent with both present‐day and palaeontological evidence.