Summary
Background
Non‐alcoholic fatty liver disease (NAFLD) is an umbrella term, which encompasses simple steatosis and non‐alcoholic steatohepatitis (NASH). The entire spectrum of NAFLD has been ...associated with metabolic syndrome. NASH is associated with increased mortality compared with that of the general population. Many therapeutic options for NASH have been studied. However, there is very little evidence supporting the efficacy of most regimens for the treatment of NASH.
Aim
To provide a review focusing on the current therapeutic options available for patients with NASH as well as to briefly introduce possible future interventions.
Methods
A MEDLINE, Pubmed and Cochrane Review database search using a combination of keywords, which included non‐alcoholic fatty liver disease, non‐alcoholic hepatic steatosis, NAFLD, NASH, treatment, therapeutics, vitamin E, orlistat and bariatric surgery. An overall summary of the articles was developed for each section of discussion in this review.
Results
NASH associated with metabolic syndrome can progress advanced fibrosis and cirrhosis. Weight loss and lifestyle modification have been shown to improve NASH. Other medications used for weight loss and metabolic syndrome have been evaluated, such as orlistat, metformin and thiazolidinediones. Alternative regimens using ursodeoxycholic acid, statins and probiotics as well as bariatric surgery have been evaluated, but have not been recommended as first‐line treatment for NASH. Vitamin E for NASH patients without diabetes seems to be promising. The lack of effective treatment for NASH suggests the heterogeneity of patients presenting with the NASH phenotype. The best treatment strategy for these patients may be to identify their pathogenic target and develop personalised treatment protocols.
Conclusions
Currently, there are few options available for the management of NASH. Future targeted treatment strategies based on the pathogenic pathways may be needed to develop effective treatment for patients with NASH.
Abstract
Adult bone regeneration is orchestrated by the precise actions of osteoprogenitor cells (OPCs). However, the mechanisms by which OPC proliferation and differentiation are linked and thereby ...regulated are yet to be defined. Here, we present evidence that during intramembranous bone formation OPC proliferation is controlled by Notch signaling, while differentiation is initiated by activation of canonical Wnt signaling. The temporospatial separation of Notch and Wnt signal activation during the early stages of bone regeneration suggests crosstalk between the two pathways. In vitro and in vivo manipulation of the two essential pathways demonstrate that Wnt activation leads to initiation of osteogenic differentiation and at the same time inhibits Notch signaling, which results in termination of the proliferative phase. Here, we establish canonical Wnt signaling as a key regulator that facilitates the crosstalk between OPC proliferation and differentiation during intramembranous, primary bone healing.
Aim: The study aimed to evaluate the effect on condylar guidance values with casts mounted by facebow transfer (Guichet's point as the third point of reference), Bonwill's, and radiographic method. ...Materials and Methods: The dentulous subject's casts were mounted to a semi-adjustable articulator (Artex Type AR) after facebow transfer with Guichet's point as the third point of reference and also by Bonwill's method. Protrusive records made earlier were utilized to program the right and left side condylar guidance value. Two digital lateral cephalograms were made, one in centric relation, and one in protrusion and the condyles were traced and overlapped. The condylar guidance readings obtained by Bonwill's method, facebow transfer, and lateral cephalometric tracings were compared in this study using the SPSS (Version 17.0 Illinois, Chicago, USA) software. Results: The condylar guidance values obtained from Bonwill's and the facebow transfer method (p < 0.001) was lesser than the radiographic method. The values obtained by casts mounted to the Bonwill's method differed significantly (p < 0.001) from the other two methods. Conclusion: The values obtained by facebow transfer were closer to the radiographic values whereas the values obtained by Bonwill's method mounting differed markedly.
After every other failure mode has been considered, in the end, the high-performance limit of all lasers is set by optical damage. The demands of inertial confinement fusion (ICF) pushed lasers ...designed as ICF drivers into this limit from their very earliest days. The first ICF lasers were small, and their pulses were short. Their goal was to provide as much power to the target as possible. Typically, they faced damage due to high intensity on their optics. As requests for higher laser energy, longer pulse lengths, and better symmetry appeared, new kinds of damage also emerged, some of them anticipated and others unexpected. This paper will discuss the various types of damage to large optics that had to be considered, avoided to the extent possible, or otherwise managed as the National Ignition Facility (NIF) laser was designed, fabricated, and brought into operation. It has been possible for NIF to meet its requirements because of the experience gained in previous ICF systems and because NIF designers have continued to be able to avoid or manage new damage situations as they have appeared.
Electrocardiographic bundle branch block (BBB) has higher cardiac and all-cause death. However, reports on the association between BBBs and mortality in the general populations are conflicting. The ...aim of this study was to evaluate the risk for coronary heart disease (CHD) and all-cause death associated with left BBB (LBBB) and right BBB (RBBB) during 14 years of follow-up in 66,450 participants from the Women's Health Initiative (WHI) study. Cox proportional-hazards regression was performed for mortality risk in Women with LBBB (n = 714) and those with RBBB (n = 832). In risk models adjusted for demographic and clinical risk factors in women with cardiovascular disease (CVD), hazard ratios for CHD death were 2.92 (95% confidence interval 2.08 to 4.08, p <0.001) for LBBB and 1.62 (95% confidence interval 1.08 to 2.43, p <0.05) for RBBB, and only LBBB was a significant predictor of all-cause death (hazard ratio 1.43, 95% confidence interval 1.11 to 1.83, p <0.01). In CVD-free women, only LBBB was a significant predictor of CHD death (fully adjusted hazard ratio 2.17, 95% confidence interval 1.37 to 3.43, p <0.01), and neither blocks was predictive of all-cause death. From several repolarization variables that were significant mortality predictors in univariate risk models, after adjustment for other electrocardiographic covariates and risk factors, ST J-point depression in lead aVL ≤−30 μV in women with LBBB was an independent predictor of CHD death, with a more than fivefold increase in risk. None of the repolarization variables were independent predictors in women with RBBB. In conclusion, prevalent LBBB in CVD-free women and LBBB and RBBB in women with CVD were significant predictors of CHD death. In women with LBBB, ST J-point depression in lead aVL was a strong independent predictor of CHD death.
Event-related potentials (ERPs) provide a critical link between the hemodynamic response, as measured by functional magnetic resonance imaging, and the dynamics of the underlying neuronal activity. ...Single-trial ERP recordings capture the oscillatory activity that are hypothesized to underlie both communication between brain regions and amplified processing of behaviorally relevant stimuli. However, precise interpretations of ERPs are precluded by uncertainty about their neural mechanisms. One influential theory holds that averaged sensory ERPs are generated by partial phase resetting of ongoing electroencephalographic oscillations, while another states that ERPs result from stimulus-evoked neural responses. We formulated critical predictions of each theory and tested these using direct, intracortical analyses of neural activity in monkeys. Our findings support a predominant role for stimulus-evoked activity in sensory ERP generation, and they outline both logic and methodology necessary for differentiating evoked and phase resetting contributions to cognitive and motor ERPs in future studies.
Randomized data show a survival benefit of stereotactic ablative body radiation therapy in selected patients with oligometastases (OM). Stereotactic magnetic resonance guided adaptive radiation ...therapy (SMART) may facilitate the delivery of ablative dose for OM lesions, especially those adjacent to historically dose-limiting organs at risk, where conventional approaches preclude ablative dosing.
The RSSearch Registry was queried for OM patients (1-5 metastatic lesions) treated with SMART. Freedom from local progression (FFLP), freedom from distant progression (FFDP), progression-free survival (PFS), and overall survival (LS) were estimated using the Kaplan-Meier method. FFLP was evaluated using RECIST 1.1 criteria. Toxicity was evaluated using Common Terminology Criteria for Adverse Events version 4 criteria.
Ninety-six patients with 108 OM lesions were treated on a 0.35 T MR Linac at 2 institutions between 2018 and 2020. SMART was delivered to mostly abdominal or pelvic lymph nodes (48.1%), lung (18.5%), liver and intrahepatic bile ducts (16.7%), and adrenal gland (11.1%). The median prescribed radiation therapy dose was 48.5 Gy (range, 30-60 Gy) in 5 fractions (range, 3-15). The median biologically effective dose corrected using an alpha/beta value of 10 was 100 Gy10 (range, 48-180). No acute or late grade 3+ toxicities were observed with median 10 months (range, 3-25) follow-up. Estimated 1-year FFLP, FFDP, PFS, and OS were 92.3%, 41.1%, 39.3%, and 89.6%, respectively. Median FFDP and PFS were 8.9 months (95% confidence interval, 5.2-12.6 months) and 7.6 months (95% confidence interval, 4.5-10.6 months), respectively.
To our knowledge, this represents the largest analysis of SMART using ablative dosing for non-bone OM. A median prescribed biologically effective dose of 100 Gy10 resulted in excellent early FFLP and no significant toxicity, likely facilitated by continuous intrafraction MR visualization, breath hold delivery, and online adaptive replanning. Additional prospective evaluation of dose-escalated SMART for OM is warranted.
The majority of cases of the autosomal recessive disorder Nijmegen breakage syndrome (NBS) are associated with null mutations in the NBS1 gene, which encodes a 95 kDa protein, nibrin. Cell lines ...established from NBS patients fail to express nibrin and display hypersensitivity to ionizing radiation and dysregulation of the nuclear localization of two key proteins involved in DNA repair, Mre11 and Rad50. Conclusive proof that mutations in the NBS1 gene are responsible for NBS requires that re-expression of normal nibrin in NBS cells complements these phenotypes. In the current study, retroviral expression vectors containing a normal copy of the NBS1 gene or a mutated form derived from a NBS patient were introduced into a well- characterized NBS cell line. Introduction of a normal copy of the NBS1 gene, but not the mutant form, resulted in robust expression of nibrin that displayed correct nuclear localization. Expression of nibrin also restored the ability of nibrin, Mre11 and Rad50 to complex and to redistribute within the nucleus in response to ionizing radiation. Radiation sensitivity of NBS cells expressing wild-type nibrin was restored to normal levels. Hence, introduction of the NBS1 gene can correct the phenotypes observed in NBS cells.
Objective Cardiopulmonary bypass has been shown to be associated with platelet dysfunction, which has a potential for increasing the risk of perioperative bleeding. Off-pump coronary artery bypass ...surgery is thought to avoid this deleterious effect of pump use on platelets. However, the influence of off-pump coronary artery bypass surgery on platelets has not been thoroughly studied. Methods Accordingly, we evaluated 60 patients undergoing coronary artery bypass grafting prospectively using cardiopulmonary bypass and warm cardioplegic arrest (n = 30) or an off-pump technique (n = 30). Platelet function was evaluated before and 2 hours after coronary artery bypass grafting. Results Among patients undergoing on-pump coronary artery bypass surgery, all studies of platelet function were significantly abnormal after surgical intervention compared with results before surgical intervention. Similarly, among patients undergoing off-pump coronary artery bypass surgery, evidence of platelet dysfunction after surgical intervention was noted, with a lower platelet count and a higher proportion of P-selectin– and Annexin V–positive platelets. However, compared with the preprocedural value, the postprocedural decrease in platelet count (78,200 × 103 /μL vs 103,000 × 103 /μL) and platelet aggregation (0.8% vs 10.9%) and increase in bleeding time (0 minutes vs +1.3 minutes), P-selectin–positive platelets (6.0% vs 9.1%), and Annexin V–positive platelets (1.7% vs 3.7%) were significantly lower in the off-pump coronary artery bypass surgery group compared with those in the on-pump coronary artery bypass surgery group, respectively. Conclusions Early postoperative decrease in platelet count and increase in platelet activation occurs to a much lesser extent and does not alter bleeding time or adenosine diphosphate–induced platelet aggregation in patients undergoing off-pump coronary artery bypass surgery. This lack of significant effects on platelets might in part account for the potential decreased risk in bleeding and for the preserved hemostasis seen in patients undergoing off-pump coronary artery bypass surgery compared with those undergoing on-pump coronary artery bypass grafting surgery.
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