Gauge Unification in Highly Anisotropic String Compactifications

It is well-known that heterotic string compactifications have, in spite of their conceptual simplicity and aesthetic appeal, a serious problem with precision gauge coupling unification in the perturbative regime of string theory. Using both a duality-based and a field-theoretic definition of the boundary of the perturbative regime, we reevaluate the situation in a quantitative manner. We conclude that the simplest and most promising situations are those where some of the compactification radii are exceptionally large, corresponding to highly anisotropic orbifold models. Thus, one is led to consider constructions which are known to the effective field-theorist as higher-dimensional or orbifold grand unified theories (orbifold GUTs). In particular, if the discrete symmetry used to break the GUT group acts freely, a non-local breaking in the larger compact dimensions can be realized, leading to a precise gauge coupling unification as expected on the basis of the MSSM particle spectrum. Furthermore, a somewhat more model dependent but nevertheless very promising scenario arises if the GUT breaking is restricted to certain singular points within the manifold spanned by the larger compactification radii.Comment: 34 pages, 4 figures, more references adde

Prognostic Role of Liver Biopsy in Patients With Severe Indeterminate Acute Hepatitis

Background and aims: Severe indeterminate acute hepatitis (sIAH) is a poorly understood rare disease with no specific therapy. This study aims to define the clinicopathological characteristics of sIAH and the role of liver biopsy in determining prognosis. Methods: Patients with sIAH admitted to a single center between 2010 and 2019 were included. Histopathological patterns of liver biopsies were reviewed by 2 histopathologists, and key findings further were specified by multiplex immunofluorescence. Patients that died or underwent liver transplantation were analyzed as nonsurvivors. Results: Of 294 patients with acute hepatitis, 43 with sIAH were included. Seventeen (39.5%) underwent liver transplantation and 7 (16.2%) died within 3 months. Multilobular necrosis was the predominant histopathological feature, being significantly more frequent in nonsurvivors (62.5% vs 21.1%; P = .016). Necrotic areas showed low HNF4α and Ki67 expression but high expression of CK19 and cell death markers identifying areas of severe tissue injury and inadequate regenerative response. Patients with multilobular necrosis had higher international normalized ratio, Model for End-Stage Liver Disease, and Model for End-Stage Liver Disease-Sodium scores compared with those without (P values for all markers <.05). Multivariate Cox analysis revealed that multilobular necrosis (hazard ratio, 3.675; 95% confidence interval, 1.322-10.211) and lower body mass index (hazard ratio, 0.916; 95% confidence interval, 0.848-0.991) independently predicted death or transplantation. Conclusions: The results of this study provide novel insights into the important role of liver biopsy in sIAH patients, suggesting that the presence of multilobular necrosis is an early indicator of poor prognosis.info:eu-repo/semantics/publishedVersio

Presence of multilobular necrosis on liver biopsy identifies corticosteroid responsiveness in acute indeterminate hepatitis

BACKGROUND AND AIMS: Treatment of patients with severe indeterminate hepatitis (IAH) is an unmet need. Corticosteroids are often used in the management of these patients but criteria for selection of patients for this intervention are arbitrary. The aims of this study were to analyze the clinical and pathological features of patients with IAH to define predictors of corticosteroid responsiveness. METHODS: This study included consecutive patients with acute indeterminate hepatitis admitted to a single hospital and underwent a liver biopsy. The clinical manifestation and histopathological features of steroid and non-steroid groups were compared and their relationship with corticosteroids response was evaluated. RESULTS: Forty-eight patients were included, 24 (50%) recovered and the other half underwent liver transplantation or died within 3-months. Of the 48 cases, 24 received corticosteroids (initial dose of 45 ± 12 mg prednisolone). Corticosteroids were initiated 2.7 ± 3.8 days after admission. Liver biopsy was performed 2-days (median, IQR 1-3) after admission. Fifteen (62.5%) patients receiving corticosteroids survived without transplantation compared with 9 (37.5%) that did not receive steroids (p= 0.149). In those with multilobular necrosis, 50% reduction in the death/transplantation rate was observed after steroid treatment (p=0.018). In patients without multilobular necrosis and with or without perivenulitis, corticosteroids did not impact outcome. Response to corticosteroids was independent of the MELD score. CONCLUSIONS: The presence of multilobular necrosis on liver biopsy helps identify a subgroup of IAH cases who may be benefit from administration of corticosteroids

Prognostic Role of Liver Biopsy in Patients With Severe Indeterminate Acute Hepatitis

Background and Aims: Severe indeterminate acute hepatitis (sIAH) is a poorly understood rare disease with no specific therapy. This study aims to define the clinicopathological characteristics of sIAH and the role of liver biopsy in determining prognosis. / Methods: Patients with sIAH admitted to a single center between 2010 and 2019 were included. Histopathological patterns of liver biopsies were reviewed by 2 histopathologists, and key findings further were specified by multiplex immunofluorescence. Patients that died or underwent liver transplantation were analyzed as nonsurvivors. / Results: Of 294 patients with acute hepatitis, 43 with sIAH were included. Seventeen (39.5%) underwent liver transplantation and 7 (16.2%) died within 3 months. Multilobular necrosis was the predominant histopathological feature, being significantly more frequent in nonsurvivors (62.5% vs 21.1%; P = .016). Necrotic areas showed low HNF4α and Ki67 expression but high expression of CK19 and cell death markers identifying areas of severe tissue injury and inadequate regenerative response. Patients with multilobular necrosis had higher international normalized ratio, Model for End-Stage Liver Disease, and Model for End-Stage Liver Disease-Sodium scores compared with those without (P values for all markers <.05). Multivariate Cox analysis revealed that multilobular necrosis (hazard ratio, 3.675; 95% confidence interval, 1.322–10.211) and lower body mass index (hazard ratio, 0.916; 95% confidence interval, 0.848–0.991) independently predicted death or transplantation. / Conclusions: The results of this study provide novel insights into the important role of liver biopsy in sIAH patients, suggesting that the presence of multilobular necrosis is an early indicator of poor prognosis

Heart-Type Fatty Acid-Binding Protein Predicts Long-Term Mortality and Re-Infarction in Consecutive Patients With Suspected Acute Coronary Syndrome Who Are Troponin-Negative

ObjectivesThe purpose of this study was to establish the prognostic value of measuring heart fatty acid-binding protein (H-FABP) in patients with suspected acute coronary syndrome (ACS) (in particular, low- to intermediate-risk patients), in addition to troponin measured with the latest third-generation troponin assay.BackgroundWe have previously shown that H-FABP is a useful prognostic marker in patients with proven ACS.MethodsPatients (n = 1,080) consecutively admitted to the hospital with suspected ACS were recruited over 46 weeks. Siemens Advia Ultra-TnI (Siemens Healthcare Diagnostics, Newbury, United Kingdom) and Randox Evidence H-FABP (Randox Laboratories, Ltd., Co., Antrim, United Kingdom) were analyzed on samples collected 12 to 24 h from symptom onset. After exclusion of patients with ST-segment elevation and new left bundle branch block, 955 patients were included in the analysis.ResultsThe primary outcome measure of death or readmission with myocardial infarction after a minimum follow-up period of 12 months (median 18 months) occurred in 96 of 955 patients (10.1%). The H-FABP concentration was an independent predictor of death or myocardial infarction, after multivariate adjustment. Patients with H-FABP concentrations >6.48 μg/l had significantly increased risk of adverse events (adjusted hazard ratio: 2.62, 95% confidence interval: 1.30 to 5.28, p = 0.007). Among troponin-negative patients (which constituted 79.2% of the cohort), the aforementioned cutoff of 6.48 μg/l identified patients at very high risk for adverse outcomes independent of patient age and serum creatinine.ConclusionsWe have demonstrated that the prognostic value of elevated H-FABP is additive to troponin in low- and intermediate-risk patients with suspected ACS. Other studies suggest that our observations reflect the value of H-FABP as a marker of myocardial ischemia, even in the absence of frank necrosis

Ultrasound Histotripsy on a Viable Perfused Whole Porcine Liver: Histological Aspects, Including 3D Reconstruction of the Histotripsy Site

Non-invasive therapeutic-focused ultrasound (US) can be used for the mechanical dissociation of tissue and is described as histotripsy. We have performed US histotripsy in viable perfused ex vivo porcine livers as a step in the development of a novel approach to hepatocyte cell transplantation. The histotripsy nidus was created with a 2 MHz single-element focused US transducer, producing 50 pulses of 10 ms duration, with peak positive and negative pressure values of P+ = 77.7 MPa and P- = -13.7 MPaat focus, respectively, and a duty cycle of 1%. Here, we present the histological analysis, including 3D reconstruction of histotripsy sites. Five whole porcine livers were retrieved fresh from the abattoir using human transplant retrieval and cold static preservation techniques and were then perfused using an organ preservation circuit. Whilst under perfusion, histotripsy was performed to randomly selected sites on the live. Fifteen lesional sites were formalin-fixed and paraffin-embedded. Sections were stained with Haematoxylin and Eosin and picro-Sirius red, and they were also stained for reticulin. Additionally, two lesion sites were used for 3D reconstruction. The core of the typical lesion consisted of eosinophilic material associated with reticulin loss, collagen damage including loss of birefringence to fibrous septa, and perilesional portal tracts, including large portal vein branches, but intact peri-lesional hepatic plates. The 3D reconstruction of two histotripsy sites was successful and confirmed the feasibility of this approach to investigate the effects of histotripsy on tissue in detail