<Emphasis Type="Italic">TCF7L2</Emphasis>variant genotypes and type 2 diabetes risk in Brazil: significant association,but not a significant tool for risk stratification in the general population

Background  

Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population.     

First description of natural <Emphasis Type="Italic">Echinococcus multilocularis</Emphasis> infections in chinchilla (<Emphasis Type="Italic">Chinchilla laniger</Emphasis>) and Prevost’s squirrel (<Emphasis Type="Italic">Callosciurus prevostii borneoensis</Emphasis>)

This report describes for the first time the occurrence of alveolar echinococcosis in two exotic rodent species in Europe. A pet chinchilla (Chinchilla laniger) was euthanized due to a painful enlargement of the abdominal cavity, and a Prevost's squirrel (Callosciurus prevostii borneoensis) was found dead in the enclosure of a zoo. At necropsy, extended liver lesions consisting of small vesicles and cysts were observed in the livers of both animals. Histological examination revealed that these cysts were composed of an outer, homogenous, eosinophilic layer and an inner, cellular germinal layer. The cysts from both animals contained numerous protoscolices. The morphological diagnosis of Echinococcus multilocularis metacestode infections was confirmed by molecular means.     

Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease

Recently, a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 was reported as the cause of chromosome 9p21‐linked frontotemporal dementia‐amyotrophic lateral sclerosis (FTD‐ALS). We here report the prevalence of the expansion in a hospital‐based cohort and associated clinical features indicating a wider clinical spectrum of C9ORF72 disease than previously described. We studied 280 patients previously screened for mutations in genes involved in early onset autosomal dominant inherited dementia disorders. A repeat‐primed polymerase chain reaction amplification assay was used to identify pathogenic GGGGCC expansions. As a potential modifier, confirmed cases were further investigated for abnormal CAG expansions in ATXN2. A pathogenic GGGGCC expansion was identified in a total of 14 probands. Three of these presented with atypical clinical features and were previously diagnosed with clinical olivopontocerebellar degeneration (OPCD), atypical Parkinsonian syndrome (APS) and a corticobasal syndrome (CBS). Further, the pathogenic expansion was identified in six FTD patients, four patients with FTD‐ALS and one ALS patient. All confirmed cases had normal ATXN2 repeat sizes. Our study widens the clinical spectrum of C9ORF72related disease and confirms the hexanucleotide expansion as a prevalent cause of FTD‐ALS disorders. There was no indication of a modifying effect of the ATXN2 gene.     

Management Trends and Early Mortality Rates for Acute Type B Aortic Dissection: A 10-Year Single-Institution Experience

This study was undertaken to assess trends in management over time and to determine predictors of early mortality for acute type B aortic dissection. Fifty-three consecutive patients with acute type B aortic dissection over a 10-year period were reviewed. Baseline demographics as well as in-hospital data regarding symptoms, type of initial management, surgical indications, type of surgical intervention, and early mortality rates were collected. Independent predictors of early mortality were determined by logistic regression. Forty-one of 53 (77.4%) patients were initially managed medically with a total of 26 (49.1%) ultimately undergoing surgical repair during hospitalization. Crude early mortality was 30.8% in the surgical group vs. 14.8% in the medical group (p = 0.20). Improvements in early mortality were observed over time for surgery (58.3%, first half vs. 7.1%, second half; p = 0.019) and medical therapy (21.4%, first half vs. 7.7%, second half; p = 0.64). Early mortality was 50% in 16 patients having open aortic surgery vs. 0% in 10 patients undergoing endovascular stent graft repair (p < 0.005). Independent predictors of early mortality included only renal dysfunction (odds ratio [OR] 7.39), aortic rupture (OR 8.72), and date of admission during the study period (OR 0.712). Despite improvements over time in early mortality that appear associated with the increasing use of endovascular stent grafts, patient-specific factors are still the most important independent predictors of early mortality in acute type B aortic dissection.Presented at the Twenty-eighth Annual Meeting of the Peripheral Vascular Surgery Society, Chicago, IL, June 7, 2003.     

Endograft treatment of ruptured abdominal aortic aneurysms using the Talent aortouniiliac system: an international multicenter study

OBJECTIVE: To understand the potential of endovascular aneurysm repair (EVAR) in patients presenting with a ruptured abdominal aortic aneurysm (rAAA), the proportion in whom this procedure was applicable was assessed. Mortality and morbidity was also determined in patients treated with emergency EVAR (eEVAR) when anatomic and hemodynamic conditions allowed (ie, in the entire cohort with patients receiving endovascular and open repair combined). In addition, a comparison was made between the treatment group with eEVAR and open repair. METHODS: Between February 2003 and September 2004, 10 participating institutions enrolled a representative sample of 100 consecutive patients in whom eEVAR was considered. Patients in the New Endograft treatment in Ruptured abdominal aortic Aneurysm (ERA) trial were offered eEVAR or open repair in accordance with their clinical condition or anatomic configuration. Written informed consent was obtained from all patients or their legal representatives. The study included patients who were treated by stent-graft technique or by open surgery in the case of adverse anatomy for endoluminal stent-grafting or severe hemodynamic instability, or both. Data were collated in a centralized database for analysis. The study was sponsored and supported by Medtronic, and eEVAR was uniquely performed with a Talent aortouniiliac (AUI) system in all patients. Crude and adjusted 30-day or in-hospital and 3-month mortality rates were assessed for the entire group as a whole and the EVAR and open repair category separately. Complication rates were also assessed. RESULTS: Stent-graft repair was performed in 49 patients and open surgery in 51. No significant differences were observed between these treatment groups with regard to comorbidity at presentation, hemodynamic instability, and the proportion of patients who could be assessed by preoperative computed tomography scanning. Patients with eEVAR more frequently demonstrated a suitable infrarenal neck for endovascular repair, a longer infrarenal neck, and suitable iliac arteries for access than patients with open repair. The primary reason to perform open aneurysm repair was an unfavorable configuration of the neck in 80% of the patients. In patients undergoing eEVAR, operative blood loss was less, intensive care admission time was shorter, and the duration of mechanical ventilation was shorter (P < or = .02, all comparisons). The 30-day or in-hospital mortality was 35% in the eEVAR category, 39% in patients with open repair, and 37% overall. There was no statistically significant difference between the treatment groups with regard to crude mortality rates or rates adjusted for age, gender, hemodynamic shock, and pre-existent pulmonary disease. The cumulative 3-month all-cause mortality was 40% in the eEVAR group and 42% in the open repair group (no significant differences at crude and adjusted comparisons). The 3-month primary complication rate in the two treatment groups was similar at 59%. CONCLUSIONS: In approximately half the rAAA patients, eEVAR appeared viable. An unsuitable infrarenal neck was the most frequent cause to select open repair. In dedicated centers using a Talent AUI system, eEVAR appeared to be a feasible method for treatment of a rAAA. The overall first-month mortality did not differ across treatment groups (patients with endovascular and open repair combined), yet was somewhat lower than observed in a recent meta-analysis reporting on open repair.     

CD44 enhances tumor formation and lung metastasis in experimental osteosarcoma and is an additional predictor for poor patient outcome

Formation of metastases in the lungs is the major cause of death in patients suffering from osteosarcoma (OS). Metastases at presentation and poor response to preoperative chemotherapy are strong predictors for poor patient outcome. The elucidation of molecular markers that promote metastasis formation and/or chemoresistance is therefore of importance. CD44 is a plasma membrane glycoprotein that binds to the extracellular matrix component hyaluronan (HA) and has been shown to be involved in metastasis formation in a variety of other tumors. Here we investigated the role of CD44 expression on OS tumor formation and metastasis. High CD44 expression, evaluated with a tissue microarray including samples from 53 OS patients and stained with a pan‐CD44 antibody (Hermes3), showed a tendency (p < 0.08) to shortened overall survival. However, nonresponders and patients with lung metastases and high CD44 expression had significantly poorer prognosis than patients with low CD44 expression. Overexpression of the standard CD44 isoform (CD44s) and its HA‐binding defective mutant R41A in osteoblastic SaOS‐2 cells resulted in HA‐independent higher migration rates and increased chemoresistance, partially dependent on HA. In an orthotopic mouse model of OS, overexpression of CD44s in SaOS‐2 cells resulted in an HA‐dependent increased primary tumor formation and increased numbers of micrometastases and macrometastases in the lungs. In conclusion, although CD44 failed to be an independent predictor for patient outcome in this limited cohort of OS patients, increased CD44 expression was associated with even worse survival in patients with chemoresistance and with lung metastases. CD44‐associated chemoresistance was also observed in vitro, and increased formation of lung metastases was found in vivo in SCID mice. © 2013 American Society for Bone and Mineral Research.     

Compartment-specific expression and function of the chemokine IP-10/CXCL10 in a model of renal endothelial microvascular injury

The recruitment of inflammatory cells into renal tissue, mainly T cells and monocytes, is a typical feature of various renal diseases such as glomerulonephritis, thrombotic angiopathies, allograft rejection, and vasculitis. T cells predominantly infiltrate the tubulointerstitium, whereas monocytes are present in the tubulointerstitial and glomerular compartment. Because chemokines play a pivotal role in leukocyte trafficking under inflammatory conditions, this study investigated whether a differential expression of chemokines contributes to the precise coordination of leukocyte subtype trafficking in a rat model of renal microvascular endothelial injury. Renal microvascular endothelial injury was induced in rats by selective renal artery perfusion with an anti-endothelial antibody. Induction of the disease led to severe glomerular and tubulointerstitial endothelial injury with subsequent upregulation of chemokines followed by inflammatory cell recruitment. Among the analyzed chemokine mRNA, IP-10/CXCL10 (119-fold), acting via CXCR3 on activated T cells, and MCP-1/CCL2 (65-fold), acting via CCR2 on monocytes, were by far the most strongly upregulated chemokines. In situ hybridization revealed that IP-10/CXCL10 mRNA was selectively expressed by endothelial cells in the tubulointerstitial area, co-localizing with infiltrating T cells. Despite extensive damage of glomerular vasculature, no IP-10/CXCL10 expression by glomerular endothelial cells was detected. MCP-1/CCL2 mRNA in contrast was detectable in the glomerulus and the tubulointerstitium. Treatment with a neutralizing anti-IP-10/CXCL10 antibody significantly reduced the number of infiltrating tubulointerstitial T cells without affecting monocyte migration and led to an improved renal function. Our study demonstrates a role of IP-10/CXCL10 on T cell recruitment in a rat model of renal endothelial microvascular injury. Furthermore, a differential chemokine expression profile by endothelial cells in different renal compartments was found. These findings are consistent with the hypothesis that functional heterogeneity of endothelial cells from different vascular sites exists and provide an insight into the molecular mechanisms that may mediate compartment-specific T cell and monocyte recruitment in inflammatory renal disease.     

Assessment of ventriculo-vascular properties in repaired coarctation using cardiac magnetic resonance-derived aortic,left atrial and left ventricular strain

Objectives

In patients with repaired coarctation of aorta (CoA), we assessed ventriculo-vascular characteristics using CMR-derived aortic area strain (AAS), left atrial (LA) and left ventricular (LV) longitudinal and circumferential strain (LS, CS).

Methods

Seventy-five subjects including 50 with repaired CoA divided into hypertensive (n?=?25), normotensive (n?=?25) and 25 controls were studied. AAS was measured at 3 levels: ascending aorta, proximal descending and descending aorta. LA and LV LS were measured using CMR-feature tracking. LA and LV end-diastolic volumes, ejection fraction (EF) and mass were measured.

Results

Mean patient age was 19.7?±?6.7 and controls 23?±?15 (years). All strains (LA, LV, ascending and descending aortic) were lower in CoA subgroups compared to controls except the AAS at diaphragm, which was not different. Comparisons between hypertensive and normotensive CoA showed no differences in LV mass, LV volumetric indices, and LA and LV strain indices; however, ascending AAS was lower in hypertensive subgroup (p?=?0.02). Ascending AAS was correlated with LV mass (r?=??0.4, p?=?0.005), LVEF (r?=??0.4, p?=?0.004), systolic blood pressure (r?=??0.5, p?=?0.0001) and LVLS (r?=?0.5, p?=?0.001).

Conclusions

Ascending AAS correlated with LV mass, EF and LVLS. In hypertensive CoA, ascending AAS was reduced compared to normotensive CoA and controls, indicating vascular remodelling differences influenced by ongoing hypertension.

Key Points

? Impaired arterial strain is a measure of increased stiffness in arteries ? Ascending aorta strain correlates with left ventricular mass and longitudinal strain ? Ascending aorta strain is significantly lower in hypertensive coarctation patients ? Hypertension may be a consequence of vascular pathology persisting despite repair