Rethinking the triggering inflammatory processes of chronic periaortitis.

Chronic periaortitis (CP) is an uncommon inflammatory disease which primarily involves the infrarenal portion of the abdominal aorta. However, CP should be regarded as a generalized disease with three different pathophysiological entities, namely idiopathic retroperitoneal fibrosis (RPF), inflammatory abdominal aortic aneurysm and perianeurysmal RPF. These entities share similar histopathological characteristics and finally will lead to fibrosis of the retroperitoneal space. Beside fibrosis, an infiltrate with variable chronic inflammatory cell is present. The majority of these cells are lymphocytes and macrophages as well as vascular endothelial cells, most of which are HLA-DR-positive. B and T cells are present with a majority of T cells of the T-helper phenotype. Cytokine gene expression analysis shows the presence of interleukin (IL)-1alpha, IL-2, IL-4, interferon-gamma and IL-2 receptors. Adhesion molecules such as E-selectin, intercellular adhesion molecule-1 and the vascular cell adhesion molecule-1 were also found in aortic tissue, and may play a significant role in CP pathophysiology. Although CP pathogenesis remains unknown, an exaggerated inflammatory response to advanced atherosclerosis (ATS) has been postulated to be the main process. Autoimmunity has also been proposed as a contributing factor based on immunohistochemical studies. The suspected allergen may be a component of ceroid, which is elaborated within the atheroma. We review the pathogenesis and the pathophysiology of CP, and its potential links with ATS. Clinically relevant issues are summarized in each section with regard to the current working hypothesis of this complex inflammatory disease.

Antibiotic lock technique combined with systemic antimicrobial therapy for management of port-related bloodstream infections in onco-haematological patients without catheter removal

Background : Port-related bloodstream infection (PRBSI) is a common complication associated with long-term use of ports systems. Systemic antimicrobial therapy (ST) and removal of the device is the standard management of PRBSI. However, a conservative management combining ST with antibiotic lock therapy (ALT) without port removal has been suggested as an alternative management option for infections due to gram-positive skin colonizers with low virulence.¦Objectives : i) to assess the frequency of management of PRBSI in onco-hematological patients by combining the ALT with ST, without catheter removal and ii) to analyze the efficacy of such an approach.¦Methods : Retrospective observational study over a 6-year period between 2005 and 2010, including patients who where diagnosed with PRBSI and who were treated with ST and ALT. PRBSI diagnosis consisted in clinical signs of bacteremia with blood cultures positive for gram-positive skin colonizers. The primary endpoint was failure to cure the PRBSI.¦Results : 61 port infections were analysed, of which 23 PRBSI met the inclusion criteria. All the patients were suffering from haematological conditions and 75% were neutropenic at the time of PRBSI diagnosis. S. epidermidis was responsible for 91% of PRBSI (21/23). The median duration of ST was 14 days (range 7-35) and the median duration of ALT was 15 days (range 8-41). Failure to cure the PRBSI requiring port removal was observed in 4 patients, but was not associated with severe infectious complications. Kaplan-Meier analysis showed a success rate in port salvage at day 180 (6 months) of 78% (95%CI 59-97%).¦Conclusion : The success rate observed in the present study suggests that combining ST and ALT is an effective option to conservatively treat PRBSI caused by pathogens of low virulence such as S. epidermidis.

Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome associated with mutations in the cardiac ryanodine receptor gene (Ryr2) in the majority of patients. Previous studies of CPVT patients mainly involved probands, so current insight into disease penetrance, expression, genotype-phenotype correlations, and arrhythmic event rates in relatives carrying the Ryr2 mutation is limited. METHODS AND RESULTS: One-hundred sixteen relatives carrying the Ryr2 mutation from 15 families who were identified by cascade screening of the Ryr2 mutation causing CPVT in the proband were clinically characterized, including 61 relatives from 1 family. Fifty-four of 108 antiarrhythmic drug-free relatives (50%) had a CPVT phenotype at the first cardiological examination, including 27 (25%) with nonsustained ventricular tachycardia. Relatives carrying a Ryr2 mutation in the C-terminal channel-forming domain showed an increased odds of nonsustained ventricular tachycardia (odds ratio, 4.1; 95% CI, 1.5-11.5; P=0.007, compared with N-terminal domain) compared with N-terminal domain. Sinus bradycardia was observed in 19% of relatives, whereas other supraventricular dysrhythmias were present in 16%. Ninety-eight (most actively treated) relatives (84%) were followed up for a median of 4.7 years (range, 0.3-19.0 years). During follow-up, 2 asymptomatic relatives experienced exercise-induced syncope. One relative was not being treated, whereas the other was noncompliant. None of the 116 relatives died of CPVT during a 6.7-year follow-up (range, 1.4-20.9 years). CONCLUSIONS: Relatives carrying an Ryr2 mutation show a marked phenotypic diversity. The vast majority do not have signs of supraventricular disease manifestations. Mutation location may be associated with severity of the phenotype. The arrhythmic event rate during follow-up was low.

Penetrating or Stricturing Diseases are the Major Determinants of Time to First and Repeat Resection Surgery in Crohn's Disease.

Background: About 80% of patients with Crohn's disease (CD) require bowel resection and up to 65% will undergo a second resection within 10 years. This study reports clinical risk factors for resection surgery (RS) and repeat RS. Methods: Retrospective cohort study, using data from patients included in the Swiss Inflammatory Bowel Disease Cohort. Cox regression analyses were performed to estimate rates of initial and repeated RS. Results: Out of 1,138 CD cohort patients, 417 (36.6%) had already undergone RS at the time of inclusion. Kaplan-Meier curves showed that the probability of being free of RS was 65% after 10 years, 42% after 20 years, and 23% after 40 years. Perianal involvement (PA) did not modify this probability to a significant extent. The main adjusted risk factors for RS were smoking at diagnosis (hazard ratio (HR) = 1.33; p = 0.006), stricturing with vs. without PA (HR = 4.91 vs. 4.11; p < 0.001) or penetrating disease with vs. without PA (HR = 3.53 vs. 4.58; p < 0.001). The risk factor for repeat RS was penetrating disease with vs. without PA (HR = 3.17 vs. 2.24; p < 0.05). Conclusion: The risk of RS was confirmed to be very high for CD in our cohort. Smoking status at diagnosis, but mostly penetrating and stricturing diseases increase the risk of RS.

Immunosuppressive effects of streptozotocin-induced diabetes result in absolute lymphopenia and a relative increase of T regulatory cells.

OBJECTIVE Streptozotocin (STZ) is the most widely used diabetogenic agent in animal models of islet transplantation. However, the immunomodifying effects of STZ and the ensuing hyperglycemia on lymphocyte subsets, particularly on T regulatory cells (Tregs), remain poorly understood. RESEARCH DESIGN AND METHODS This study evaluated how STZ-induced diabetes affects adaptive immunity and the consequences thereof on allograft rejection in murine models of islet and skin transplantation. The respective toxicity of STZ and hyperglycemia on lymphocyte subsets was tested in vitro. The effect of hyperglycemia was assessed independently of STZ in vivo by the removal of transplanted syngeneic islets, using an insulin pump, and with rat insulin promoter diphtheria toxin receptor transgenic mice. RESULTS Early lymphopenia in both blood and spleen was demonstrated after STZ administration. Direct toxicity of STZ on lymphocytes, particularly on CD8(+) cells and B cells, was shown in vitro. Hyperglycemia also correlated with blood and spleen lymphopenia in vivo but was not lymphotoxic in vitro. Independently of hyperglycemia, STZ led to a relative increase of Tregs in vivo, with the latter retaining their suppressive capacity in vitro. The higher frequency of Tregs was associated with Treg proliferation in the blood, but not in the spleen, and higher blood levels of transforming growth factor-β. Finally, STZ administration delayed islet and skin allograft rejection compared with naive mice. CONCLUSIONS These data highlight the direct and indirect immunosuppressive effects of STZ and acute hyperglycemia, respectively. Thus, these results have important implications for the future development of tolerance-based protocols and their translation from the laboratory to the clinic.

Haben selektive COX-2-Hemmer unerwünschte renale und kardiovaskuläre Wirkungen [Do selective COX-2 inhibitors have adverse renal and cardiovascular effects?].

Selective cyclooxygenase-2-inhibitors (COX-2) were developed as an alternative to the non-steroidal anti-inflammatory drugs (NSAID) in order to reduce their known gastrointestinal and renal toxicity. Several recent studies have shown the complex mechanism of the cyclooxygenase-2. The inhibition of the COX-2 has effects on renal hemodynamics, renal salt and water retention and may increase the thromboembolic and therefore the cardiovascular risk. The renal toxicity of the COX-2 inhibitors is similar to that of traditional NSAID. Regarding these data, COX-2 inhibitors should be prescribed with much caution to high risk patients, that is, patients with renal failure and/or cardiovascular diseases.

Vitae sanctorum.

Abdo et Sennes (262-263v) ; Acisclus et Victoria (163-165) ; Adrianus (72v-77) ; Affra (45v) ; Amancius (122-125v) ; Andochius (90v-92v) ; Andreas (186-194v) ; Antoninus (68v-70v, 221v) ; Apollinaris (1bis-1bis v); Audardus (254-259) ; Augustinus (231-232v) ; Bartholomeus (55v-59v) ; Bricius Turonensis (162v-163) ; Caprasius (107-108) ; Caprasius et Fides (218-219v) ; Cassianus (48v) ; Cecilia (168v-174v) ; Christina (12-16v) ; Christoforus (22-24) ; Ciricus et Julita (2v-6, 260v-262) ; Cirillus (2-2v) ; Ciprianus (47v-48v) ; Claudius, Asterius, Neo (54v-55v) ; Clemens (174v-176) ; Cosmas et Damianus (97v-98v) ; Crisantus et Daria (179-182v) ; Crucis exaltatio (83-84) ; Cucufas (24-25) ; Dalmacius Rutenae urbis (131-132v) ; Desiderius Caturcensis (207v-217v) ; Dionisius (105-106v) ; Donatus (263v-265v) ; Eleazarus (38-38v) ; Eptadius (59v-61v) ; Eufemia (84-86) ; Eugenia (78-83) ; Eulalia (195v-199) ; Eustachius (125v-129v) ; Fabius (34v-36v) ; Fausta (52-53v) ; Faustus, Januarius et Marcialis (106v-107) ; Felix (36v-38) ; Felix Nolensis ep. (25-27) ; Filibertus (227v-231) ; Genesius Arelatensis (61v-62v) ; Germanus Autissiodorensis (33-34) ; Gervasius et Protasius (259v-260v) ; Gregorius papa (222-224v) ; Grisogonus (176v-178) ; Jacobus major (20v-21v) ; Jeronimus (100-102) ; Johannis Baptistae decollatio (66v-68v) ; Johannes et Paulus (227-227v) ; Julia (11-12) ; Julianus (64-64v) ; Julianus, auct. Gregorio Turonense (265v-272) ; Julius (178-178v) ; Justa et Rufina (6v-7) ; Justina et Ciprianus (92v-97v) ; Justus et Pastor (44v-45) ; Laurianus (167v-168v) ; Leochadia (195-195v) ; Leodegarius (102-104v) ; Licerius (62v-64) ; Longinus (195) ; Lucia (199-200v) ; Machabei (34-34v) ; Mammes (45v-47v) ; Marcellinus et Petrus (259-259v) ; Marcellus (114) ; Marcellus Cavalonis (219v-220) ; Marcellus Kavilonensis (1v-1bis) ; Marcus (224v-225) ; Marciana (129v-131) ; Marcianus (206-206v) ; Margarita (7-11) ; Mariae assumptio (48v-51) ; Martinus, auct. Sulpicio Severo (133-160v) ; Matheus (86-89) ; Mauricius (89-90v) ; Mauricius, Exuperius, Candidus, Innocentius, Victor cum sociis eorum (272-272v) ; Maurinus (245-247v) ; Maximus (241-244v) ; Medardus (225-227) ; Mennas (160v-162v) ; Michael (98v-100) ; Mimius (39v-40) ; Nazarius et Celsus (27-31v) ; Omnes Sancti (118v-122) ; Pantaleo (31v-32v) ; Petri cathedra (220-221v, 249-250) ; Petrus, ep. Alexandriae (248-249) ; Procopius (39-39v) ; Quintinus (114-118v) ; Regina (70v-72v) ; Reparata (104v-105) ; Romanus (165-167) ; Sabina (64v-66v) ; Salvius (77-78) ; Saturninus et Sisinnius (178v) ; Saturninus Tolosanensis (182v-185v, 232v-239) ; Segolena (16v-20v) ; Servandus et Germanus (108-109) ; Sixtus, Laurentius et Ypolitus (40-44v); Symo et Judas (109-112v) ; Symphorianus (53v-54v) ; Teodota (38v-39) ; Terencianus (239-241) ; Theodardus Narbonensis (250-254) ; Thomas (200v-206) ; Valerianus (206v-207) ; Vamnes (51-52) ; Vincentius et Savina (112v-114). Le f. 220v contient un catalogue ancien de la bibliothèque de Moissac.

Indicadores clínicos e pré-hospitalares de sobrevivência no trauma fechado: uma análise multivariada

O objetivo do estudo foi identificar os indicadores clínicos e pré-hospitalares associados à sobrevivência de vítimas de trauma fechado. Foram utilizadas a análise de sobrevivência de Kaplan Meier, e de Riscos Proporcionais de Cox, para analisar a associação de 33 variáveis ao óbito precoce e tardio, propondo modelos multivariados. Os modelos finais até 48h pós-trauma evidenciaram altos coeficientes de risco promovidos pelas lesões abdominais, Injury Severity Score >25, procedimentos respiratórios avançados e compressões torácicas pré-hospitalares. No modelo até 7 dias, a pressão arterial sistólica na cena do acidente, se menor de 75mmHg, foi associada a maior risco de óbito e se ausente, foi associada ao mais elevado risco de óbito após 7 dias. A reposição de volume pré-hospitalar apresentou efeito protetor em todos os períodos. Os resultados sugerem que a magnitude da hipoxemia e da instabilidade hemodinâmica diante da hemorragia, influenciaram de forma significante o óbito precoce e tardio desse grupo de vítimas.

Impact of recommendation updates in well-controlled patients on nonrecommended antiretroviral therapies: the Swiss HIV cohort study.

BACKGROUND: HIV treatment recommendations are updated as clinical trials are published. Whether recommendations drive clinicians to change antiretroviral therapy in well-controlled patients is unexplored. METHODS: We selected patients with undetectable viral loads (VLs) on nonrecommended regimens containing double-boosted protease inhibitors (DBPIs), triple-nucleoside reverse transcriptase inhibitors (NRTIs), or didanosine (ddI) plus stavudine (d4T) at publication of the 2006 International AIDS Society recommendations. We compared demographic and clinical characteristics with those of control patients with undetectable VL not on these regimens and examined clinical outcome and reasons for treatment modification. RESULTS: At inclusion, 104 patients were in the DBPI group, 436 in the triple-NRTI group, and 19 in the ddI/d4T group. By 2010, 28 (29%), 204 (52%), and 1 (5%) patient were still on DBPIs, triple-NRTIs, and ddI plus d4T, respectively. 'Physician decision,' excluding toxicity/virological failure, drove 30% of treatment changes. Predictors of recommendation nonobservance included female sex [adjusted odds ratio (aOR) 2.69, 95% confidence interval (CI) 1 to 7.26; P = 0.01] for DPBIs, and undetectable VL (aOR 3.53, 95% CI 1.6 to 7.8; P = 0.002) and lack of cardiovascular events (aOR 2.93, 95% CI 1.23 to 6.97; P = 0.02) for triple-NRTIs. All patients on DBPIs with documented diabetes or a cardiovascular event changed treatment. Recommendation observance resulted in lower cholesterol values in the DBPI group (P = 0.06), and more patients having undetectable VL (P = 0.02) in the triple-NRTI group. CONCLUSION: The physician's decision is the main factor driving change from nonrecommended to recommended regimens, whereas virological suppression is associated with not switching. Positive clinical outcomes observed postswitch underline the importance of observing recommendations, even in well-controlled patients.

Climatic extremes improve predictions of spatial patterns of tree species.

Understanding niche evolution, dynamics, and the response of species to climate change requires knowledge of the determinants of the environmental niche and species range limits. Mean values of climatic variables are often used in such analyses. In contrast, the increasing frequency of climate extremes suggests the importance of understanding their additional influence on range limits. Here, we assess how measures representing climate extremes (i.e., interannual variability in climate parameters) explain and predict spatial patterns of 11 tree species in Switzerland. We find clear, although comparably small, improvement (+20% in adjusted D(2), +8% and +3% in cross-validated True Skill Statistic and area under the receiver operating characteristics curve values) in models that use measures of extremes in addition to means. The primary effect of including information on climate extremes is a correction of local overprediction and underprediction. Our results demonstrate that measures of climate extremes are important for understanding the climatic limits of tree species and assessing species niche characteristics. The inclusion of climate variability likely will improve models of species range limits under future conditions, where changes in mean climate and increased variability are expected.

ASTRAL Score Predicts 5-Year Dependence and Mortality in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: The ASTRAL score was externally validated showing remarkable consistency on 3-month outcome prognosis in patients with acute ischemic stroke. The present study aimed to evaluate ASTRAL score's prognostic accuracy to predict 5-year outcome. METHODS: All consecutive patients with acute ischemic stroke registered in the Athens Stroke Registry between January 1, 1998, and December 31, 2010, were included. Patients were excluded if admitted >24 hours after symptom onset or if any ASTRAL score component was missing. End points were 5-year unfavorable functional outcome, defined as modified Rankin Scale 3 to 6, and 5-year mortality. For each outcome, the area under the receiver operating characteristics curve was calculated; also, a multivariate Cox proportional hazards analysis was performed to investigate whether the ASTRAL score was an independent predictor of outcome. The Kaplan-Meier product limit method was used to estimate the probability of 5-year survival for each ASTRAL score quartile. RESULTS: The area under the receiver operating characteristics curve of the score to predict 5-year unfavorable functional outcome was 0.89, 95% confidence interval 0.88 to 0.91. In multivariate Cox proportional hazards analysis, the ASTRAL score was independently associated with 5-year unfavorable functional outcome (hazard ratio, 1.09; 95% confidence interval, 1.08-1.10). The area under the receiver operating characteristics curve for the ASTRAL score's discriminatory power to predict 5-year mortality was 0.81 (95% confidence interval, 0.78-0.83). In multivariate analysis, the ASTRAL score was independently associated with 5-year mortality (hazard ratio, 1.09, 95% confidence interval, 1.08-1.10). During the 5-year follow-up, the probability of survival was significantly lower with increasing ASTRAL score quartiles (log-rank test <0.001). CONCLUSIONS: The ASTRAL score reliably predicts 5-year functional outcome and mortality in patients with acute ischemic stroke.

Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia.

ZFP36L1 and ZFP36L2 are RNA-binding proteins (RBPs) that interact with AU-rich elements in the 3' untranslated region of mRNA, which leads to mRNA degradation and translational repression. Here we show that mice that lacked ZFP36L1 and ZFP36L2 during thymopoiesis developed a T cell acute lymphoblastic leukemia (T-ALL) dependent on the oncogenic transcription factor Notch1. Before the onset of T-ALL, thymic development was perturbed, with accumulation of cells that had passed through the beta-selection checkpoint without first expressing the T cell antigen receptor beta-chain (TCRbeta). Notch1 expression was higher in untransformed thymocytes in the absence of ZFP36L1 and ZFP36L2. Both RBPs interacted with evolutionarily conserved AU-rich elements in the 3' untranslated region of Notch1 and suppressed its expression. Our data establish a role for ZFP36L1 and ZFP36L2 during thymocyte development and in the prevention of malignant transformation.