Diffuse white-matter disease associated with small-vessel disease and dementia is prevalent in the elderly. The biological mechanisms, however, remain elusive. Using pericyte-deficient mice, magnetic ...resonance imaging, viral-based tract-tracing, and behavior and tissue analysis, we found that pericyte degeneration disrupted white-matter microcirculation, resulting in an accumulation of toxic blood-derived fibrin(ogen) deposits and blood-flow reductions, which triggered a loss of myelin, axons and oligodendrocytes. This disrupted brain circuits, leading to white-matter functional deficits before neuronal loss occurs. Fibrinogen and fibrin fibrils initiated autophagy-dependent cell death in oligodendrocyte and pericyte cultures, whereas pharmacological and genetic manipulations of systemic fibrinogen levels in pericyte-deficient, but not control mice, influenced the degree of white-matter fibrin(ogen) deposition, pericyte degeneration, vascular pathology and white-matter changes. Thus, our data indicate that pericytes control white-matter structure and function, which has implications for the pathogenesis and treatment of human white-matter disease associated with small-vessel disease.
Parkinson's disease (PD) is a major neurodegenerative chronic disease, most likely caused by a complex interplay of genetic and environmental factors. Information on various aspects of PD ...pathogenesis is rapidly increasing and needs to be efficiently organized, so that the resulting data is available for exploration and analysis. Here we introduce a computationally tractable, comprehensive molecular interaction map of PD. This map integrates pathways implicated in PD pathogenesis such as synaptic and mitochondrial dysfunction, impaired protein degradation, alpha-synuclein pathobiology and neuroinflammation. We also present bioinformatics tools for the analysis, enrichment and annotation of the map, allowing the research community to open new avenues in PD research. The PD map is accessible at
http://minerva.uni.lu/pd_map
.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Patients with locally advanced gastric cancer benefit from combined pre- and postoperative chemotherapy, although fewer than 50% could receive postoperative chemotherapy. We examined the value of ...purely preoperative chemotherapy in a phase III trial with strict preoperative staging and surgical resection guidelines.
Patients with locally advanced adenocarcinoma of the stomach or esophagogastric junction (AEG II and III) were randomly assigned to preoperative chemotherapy followed by surgery or to surgery alone. To detect with 80% power an improvement in median survival from 17 months with surgery alone to 24 months with neoadjuvant, 282 events were required.
This trial was stopped for poor accrual after 144 patients were randomly assigned (72:72); 52.8% patients had tumors located in the proximal third of the stomach, including AEG type II and III. The International Union Against Cancer R0 resection rate was 81.9% after neoadjuvant chemotherapy as compared with 66.7% with surgery alone (P = .036). The surgery-only group had more lymph node metastases than the neoadjuvant group (76.5% v 61.4%; P = .018). Postoperative complications were more frequent in the neoadjuvant arm (27.1% v 16.2%; P = .09). After a median follow-up of 4.4 years and 67 deaths, a survival benefit could not be shown (hazard ratio, 0.84; 95% CI, 0.52 to 1.35; P = .466).
This trial showed a significantly increased R0 resection rate but failed to demonstrate a survival benefit. Possible explanations are low statistical power, a high rate of proximal gastric cancer including AEG and/or a better outcome than expected after radical surgery alone due to the high quality of surgery with resections of regional lymph nodes outside the perigastic area (celiac trunc, hepatic ligament, lymph node at a. lienalis; D2).
The most effective timing for renal-replacement therapy in critically ill patients is unclear. In this randomized trial, patients with acute kidney injury who were assigned to an accelerated strategy ...did not have a lower risk of death at 90 days than those assigned to a standard strategy.
OBJECTIVE:To define “best possible” outcomes in total minimally invasive transthoracic esophagectomy (ttMIE).
BACKGROUND:TtMIE, performed by experts in patients with low comorbidity, may serve as a ...benchmark procedure for esophagectomy.
PATIENTS AND METHODS:From a cohort of 1057 ttMIE, performed over a 5-year period in 13 high-volume centers for esophageal surgery, we selected a study group of 334 patients (31.6%) that fulfilled criteria of low comorbidity (American Society of Anesthesiologists score ≤2, WHO/ECOG score ≤1, age ≤65 years, body mass index 19–29 kg/m). Endpoints included postoperative morbidity measured by the Clavien-Dindo classification and the comprehensive complication index. Benchmark values were defined as the 75th percentile of the median outcome parameters of the participating centers to represent best achievable results.
RESULTS:Benchmark patients were predominantly male (82.9%) with a median age of 58 years (53–62). High intrathoracic (Ivor Lewis) and cervical esophagogastrostomy (McKeown) were performed in 188 (56.3%) and 146 (43.7%) patients, respectively. Median (IQR) ICU and hospital stay was 0 (0–2) and 12 (9–18) days, respectively. 56.0% of patients developed at least 1 complication, and 26.9% experienced major morbidity (≥grade III), mostly related to pulmonary complications (25.7%), anastomotic leakage (15.9%), and cardiac events (13.5%). Benchmark values at 30 days after hospital discharge were ≤55.7% and ≤30.8% for overall and major complications, ≤18.0% for readmission, ≤3.1% for positive resection margins, and ≥23 for lymph node yield. Benchmarks at 30 and 90 days were ≤1.0% and ≤4.6% for mortality, and ≤40.8 and ≤42.8 for the comprehensive complication index, respectively.
CONCLUSION:This outcome analysis of patients with low comorbidity undergoing ttMIE may serve as a reference to evaluate surgical performance in major esophageal resection.
Habitat heterogeneity is considered a primary causal driver underpinning patterns of diversity, yet the universal role of heterogeneity in structuring biodiversity is unclear due to a lack of ...coordinated experiments testing its effects across geographic scales and habitat types. Furthermore, key species interactions that can enhance heterogeneity, such as facilitation cascades of foundation species, have been largely overlooked in general biodiversity models. Here, we performed 22 geographically distributed experiments in different ecosystems and biogeographical regions to assess the extent to which variation in biodiversity is explained by three axes of habitat heterogeneity: the amount of habitat, its morphological complexity, and capacity to provide ecological resources (e.g. food) within and between co-occurring foundation species. We show that positive and additive effects across the three axes of heterogeneity are common, providing a compelling mechanistic insight into the universal importance of habitat heterogeneity in promoting biodiversity via cascades of facilitative interactions. Because many aspects of habitat heterogeneity can be controlled through restoration and management interventions, our findings are directly relevant to biodiversity conservation.
Purpose of Review
This review brings a major, previously under-recognized dental and general health problem to the attention of the medical and scientific community. The goals are to help clinicians ...make early diagnoses, thereby improving treatment outcomes, and to stimulate increasing research efforts to understand the etiology and ultimately prevention.
Recent Findings
There are two recent systematic reviews of molar incisor hypomineralization (MIH). One reveals the global burden of the condition; mean global prevalence is 13% with 878 million people affected, with 4.8 million cases per year requiring treatment. The review into etiology found a lack of definitive knowledge, but that it is likely to be multifactorial, with childhood illness including fever possibly implicated.
Summary
The review presents details of MIH sufficient to enable clinicians to recognize it and understand its impact on affected children, its management, and the importance of early intervention. Much further research is needed.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Context:
Adrenal tumors have a prevalence of around 2% in the general population. Adrenocortical carcinoma (ACC) is rare but accounts for 2–11% of incidentally discovered adrenal masses. ...Differentiating ACC from adrenocortical adenoma (ACA) represents a diagnostic challenge in patients with adrenal incidentalomas, with tumor size, imaging, and even histology all providing unsatisfactory predictive values.
Objective:
Here we developed a novel steroid metabolomic approach, mass spectrometry-based steroid profiling followed by machine learning analysis, and examined its diagnostic value for the detection of adrenal malignancy.
Design:
Quantification of 32 distinct adrenal derived steroids was carried out by gas chromatography/mass spectrometry in 24-h urine samples from 102 ACA patients (age range 19–84 yr) and 45 ACC patients (20–80 yr). Underlying diagnosis was ascertained by histology and metastasis in ACC and by clinical follow-up median duration 52 (range 26–201) months without evidence of metastasis in ACA. Steroid excretion data were subjected to generalized matrix learning vector quantization (GMLVQ) to identify the most discriminative steroids.
Results:
Steroid profiling revealed a pattern of predominantly immature, early-stage steroidogenesis in ACC. GMLVQ analysis identified a subset of nine steroids that performed best in differentiating ACA from ACC. Receiver-operating characteristics analysis of GMLVQ results demonstrated sensitivity = specificity = 90% (area under the curve = 0.97) employing all 32 steroids and sensitivity = specificity = 88% (area under the curve = 0.96) when using only the nine most differentiating markers.
Conclusions:
Urine steroid metabolomics is a novel, highly sensitive, and specific biomarker tool for discriminating benign from malignant adrenal tumors, with obvious promise for the diagnostic work-up of patients with adrenal incidentalomas.
OBJECTIVE:The aim of this study was to describe anastomotic techniques used for total minimally invasive transthoracic esophagectomy (ttMIE) and to analyze the associated morbidity.
BACKGROUND:ttMIE ...faces increasing application in surgical treatment of esophageal cancer. For esophagogastric reconstruction, different anastomotic techniques are currently used, but their effect on postoperative anastomotic leakage and morbidity has not been investigated.
PATIENTS AND METHODS:Patients were selected from a basic dataset, collected during a 5-year period from 13 international surgical high-volume centers. Endpoints were anastomotic leakage rate and postoperative morbidity in correlation to anastomotic techniques, measured by the Clavien-Dindo classification and the Comprehensive Complication Index (CCI).
RESULTS:Five anastomotic techniques were identified in 966 patients after ttMIEintrathoracic end-to-side circular-stapled technique in 427 patients (double-stapling n = 90, purse-string n = 337), intrathoracic (n = 109) or cervical (n = 255) side-to-side linear-stapled, and cervical end-to-side hand-sewn (n = 175). Leakage rates were similar in intrathoracic and cervical anastomoses (15.9% vs 17.2%, P = 0.601), but overall complications (56.7%% vs 63.7%, P = 0.029) and median 90-day CCI {21 interquartile range (IQR) 0–36 vs 29 IQR 0–40, P = 0.019} favored intrathoracic reconstructions. Leakage rates after intrathoracic end-to-side double-stapling (23.3%) and cervical end-to-side hand-sewn (25.1%) techniques were significantly higher compared with intrathoracic side-to-side linear (15.6%), end-to-side purse-string (13.9%), and cervical side-to-side linear-stapled esophagogastrostomies (11.8%) (P < 0.001). Multivariable analysis confirmed anastomotic technique as independent predictor of leakage after ttMIE.
CONCLUSION:Results of this analysis present the current status of the technical evolution of ttMIE with anastomotic leakage as predominant surgical complication. However, technique-related morbidity requires cautious interpretation considering the long learning curve of this complex surgical procedure.
We describe the design, construction, and performance of the Sloan Digital Sky Survey telescope located at Apache Point Observatory. The telescope is a modified two-corrector Ritchey-Chretien design ...with a 2.5 m, f/2.25 primary, a 1.08 m secondary, a Gascoigne astigmatism corrector, and one of a pair of interchangeable highly aspheric correctors near the focal plane, one for imaging and the other for spectroscopy. The final focal ratio is f/5. The telescope is instrumented by a wide-area, multiband CCD camera and a pair of fiber-fed double spectrographs. Novel features of the telescope include the following: (1) A 3° diameter (0.65 m) focal plane that has excellent image quality and small geometric distortions over a wide wavelength range (3000-10,600 A) in the imaging mode, and good image quality combined with very small lateral and longitudinal color errors in the spectroscopic mode. The unusual requirement of very low distortion is set by the demands of time-delay-and-integrate (TDI) imaging. (2) Very high precision motion to support open-loop TDI observations. (3) A unique wind baffle/enclosure construction to maximize image quality and minimize construction costs. The telescope had first light in 1998 May and began regular survey operations in 2000.
PDF
