143 research outputs found
Property and Empire: The Law of Imperialism in Johnson v. MâIntosh
Chief Justice\u27s Marshall\u27s opinion in Johnson v. M\u27Intosh, 21 U.S. (8 Wheat.)543 (1823) has long been a puzzle, both in its doctrinal structure and in long, strange dicta which are both triumphal and elegiac. In this Essay, I show that the opinion becomes newly intelligible when read in the context of the law and theory of colonialism, concerned, like the case itself, with the expropriation of continents and relations between dominant and subject peoples. I examine several instances where the seeming incoherence of the opinion instead shows its debt to imperial jurisprudence, which rested on a distinction between two bodies of law: one governing relations between civilized nations, the other relations between civilized governments and the imperfect sovereigns of other nations. I then show how Marshall\u27s long dicta reflect the then-prevalent view of the hsitorical progress of societies from hunter-gatherer to commercial orders, with each stage corresponding to a particular set of property institutions.This historical theory lent intelligibility to the legal distinctions between civilized and lesser or imperfect sovereigns by claiming that the latter occupied earlier stages of development and that civilized nations were legally permitted to overrride the property institutions of primitive societies in order to induce progress. The dicta, then, provide the frame for the reasoning of this case, just as the theory of historical progress framed the jurisprudence of colonialisn in general
Histological grade provides significant prognostic information in addition to breast cancer subtypes defined according to St Gallen 2013
Background: The St Gallen surrogate definition of the intrinsic subtypes of breast cancer consist of five subgroups based on estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor type 2 (HER2), and Ki-67. PgR and Ki-67 are used for discriminating between the âLuminal A-likeâ and âLuminal B-like (HER2-negative)â subtypes. Histological grade (G) has prognostic value in breast cancer; however, its relationship to the St Gallen subtypes is not clear. Based on a previous pilot study, we hypothesized that G could be a primary discriminator for ER-positive/HER2-negative breast cancers that were G1 or G3, whereas Ki-67 and PgR could provide additional prognostic information specifically for patients with G2 tumors. To test this hypothesis, a larger patient cohort was examined. Patients and methods: Six hundred seventy-one patients (â„35 years of age, pT1-2, pN0-1) with ER-positive/HER2-negative breast cancer and complete data for PgR, Ki-67, G, lymph node status, tumor size, age, and distant disease-free survival (DDFS; median follow-up 9.2 years) were included. Results: âLuminal A-likeâ tumors were mostly G1 or G2 (90%) whereas âLuminal B-likeâ tumors were mostly G2 or G3 (87%) and corresponded with good and poor DDFS, respectively. In âLuminal B-likeâ tumors that were G1 (n = 23), no metastasis occurred, whereas 14 of 40 âLuminal A-likeâ tumors that were G3 metastasized. In the G2 subgroup, low PgR and high Ki-67 were associated with an increased risk of distant metastases, hazard ratio (HR) and 95% confidence interval (CI) 1.8 (0.95â3.4) and 1.5 (0.80â2.8), respectively. Conclusions: Patients with ER-positive/HER2-negative/G1 breast cancer have a good prognosis, similar to that of âLuminal A-likeâ, while those with ER-positive/HER2-negative/G3 breast cancer have a worse prognosis, similar to that of âLuminal B-likeâ, when assessed independently of PgR and Ki-67. Therapy decisions based on Ki-67 and PgR might thus be restricted to the subgroup G2
Retained NK cell phenotype and functionality in non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD), and the progressive stage non-alcoholic steatohepatitis (NASH), is the predominant cause of chronic liver disease globally. As part of the complex pathogenesis, natural killer (NK) cells have been implicated in the development of liver inflammation in experimental murine models of NASH. However, there is a lack of knowledge on how NK cells are affected in humans with this disease. Here, we explored the presence of disease-specific changes within circulating and tissue-resident NK cell populations, as well as within other major immune cell subsets, in patients with liver biopsy-confirmed NAFLD. Using 18-color-flow cytometry, substantial changes were observed in certain myeloid populations in patients as compared to controls. NK cell numbers, on the other hand, were not altered. Furthermore, only minor differences in expression of activating and inhibitory NK cell receptors were noted, with the exception of an increased expression of NKG2D on NK cells from patients with NASH. NK cell differentiation remained constant, and NK cells from these patients retain their ability to respond adequately upon stimulation. Instead, considerable alterations were observed between liver, adipose tissue, and peripheral blood NK cells, independently of disease status. Taken together, these results increase our understanding of the importance of the local microenvironment in shaping the NK cell compartment and stress the need for further studies exploring how NASH affects intrahepatic NK cells in humans.publishedVersio
Human resident liver myeloid cells protect against metabolic stress in obesity
Although multiple populations of macrophages have been described in the human liver, their function and turnover in patients with obesity at high risk of developing non-alcoholic fatty liver disease (NAFLD) and cirrhosis are currently unknown. Herein, we identify a specific human population of resident liver myeloid cells that protects against the metabolic impairment associated with obesity. By studying the turnover of liver myeloid cells in individuals undergoing liver transplantation, we find that liver myeloid cell turnover differs between humans and mice. Using single-cell techniques and flow cytometry, we determine that the proportion of the protective resident liver myeloid cells, denoted liver myeloid cells 2 (LM2), decreases during obesity. Functional validation approaches using human 2D and 3D cultures reveal that the presence of LM2 ameliorates the oxidative stress associated with obese conditions. Our study indicates that resident myeloid cells could be a therapeutic target to decrease the oxidative stress associated with NAFLD
Gene expression profiling in primary breast cancer distinguishes patients developing local recurrence after breast-conservation surgery, with or without postoperative radiotherapy
Introduction Some patients with breast cancer develop local recurrence after breast-conservation surgery despite postoperative radiotherapy, whereas others remain free of local recurrence even in the absence of radiotherapy. As clinical parameters are insufficient for identifying these two groups of patients, we investigated whether gene expression profiling would add further information. Methods We performed gene expression analysis (oligonucleotide arrays, 26,824 reporters) on 143 patients with lymph node-negative disease and tumor-free margins. A support vector machine was employed to build classifiers using leave-one-out cross-validation. Results Within the estrogen receptor-positive (ER+) subgroup, the gene expression profile clearly distinguished patients with local recurrence after radiotherapy (n = 20) from those without local recurrence (n = 80 with or without radiotherapy). The receiver operating characteristic (ROC) area was 0.91, and 5,237 of 26,824 reporters had a P value of less than 0.001 (false discovery rate = 0.005). This gene expression profile provides substantially added value to conventional clinical markers (for example, age, histological grade, and tumor size) in predicting local recurrence despite radiotherapy. Within the ER- subgroup, a weaker, but still significant, signal was found (ROC area = 0.74). The ROC area for distinguishing patients who develop local recurrence from those who remain local recurrence-free in the absence of radiotherapy was 0.66 (combined ER+/ER-). Conclusion A highly distinct gene expression profile for patients developing local recurrence after breast-conservation surgery despite radiotherapy has been identified. If verified in further studies, this profile might be a most important tool in the decision making for surgery and adjuvant therapy
Metabolic liver cancer: associations of rare and common germline variants in one-carbon metabolism and DNA methylation genes
Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in the overall sample and among non-Hispanic whites. The results show that among non-Hispanic whites, presence of rare functional variants in ABCC2 was associated with 7-fold higher risk of metabolic HCC (ORâ=â6.92, 95% CI: 2.38â20.15, Pâ=â0.0004), and this association remained significant when analyses were restricted to functional rare variants observed in â„2 participants (cases 3.2% versus controls 0.0%, Pâ=â1.02 Ă 10â5). In the overall multiethnic sample, presence of rare functional variants in ABCC2 was nominally associated with metabolic HCC (ORâ=â3.60, 95% CI: 1.52â8.58, Pâ=â0.004), with similar nominal association when analyses were restricted to functional rare variants observed in â„2 participants (cases 2.9% versus controls 0.2%, Pâ=â0.006). A common variant in PNPLA3 (rs738409[G]) was associated with higher HCC risk in the overall sample (Pâ=â6.36 Ă 10â6) and in non-Hispanic whites (Pâ=â0.0002). Our findings indicate that rare functional variants in ABCC2 are associated with susceptibility to metabolic HCC in non-Hispanic whites. PNPLA3-rs738409 is also associated with metabolic HCC risk.U.S. National Institutes of Health | National Cancer Institute (K01 CA237875; P50 CA210964-02A1CEP to S.O.A.), (U01 CA271887, U01 CA230694 to A.G.S.) and (P50 CA210964 to L.R.R.).Peer reviewe
Myopathy of the upper airway in snoring and obstructive sleep apnea
Objective: Previous reports of muscle changes in the upper airways of obstructive sleep apnea (OSA) patients have primarily been attributed to acquired nerve lesions due to snoring vibrations. The aim of this study was to investigate whether alterations reflecting muscle fiber injuries also occur in the upper respiratory tract of snoring and OSA patients and if these changes relate to upper airway dysfunction. Methods: Muscle changes in biopsies from the soft palate of 20 patients suffering from snoring and OSA were investigated with enzyme, immunohistochemical, and morphometric techniques. Biopsies from eight healthy non-snoring subjects were used as controls. Swallowing dysfunction was assessed with videoradiography. Results: Fourteen patients had various degrees of swallowing dysfunction. The muscle samples from all the patients showed changes typical for both motor-nerve lesions and muscle fiber injuries. The most common alterations reflecting myopathy were fibers having aggregates and disorganization of cytoskeletal proteins (15.5 ± 10.7%). Other changes were fibers with vacuole-like structures (5.0 ± 4.4%), centrally positioned myonuclei (7.9 ± 4.8%), subsarcolemmal accumulations of nuclei, and various forms and sizes of ring fibers, that is, fibers where the myofilaments were disorganized peripherally (2.8 ± 2.8%). Conclusion: The results show that muscle changes mirroring both myopathy and neuropathy co-exist in the upper airway of snoring OSA patients. These findings suggest muscle weakness as a contributing factor to the upper airway dysfunction in OSA patients
Characterisation of human soft palate muscles with respect to fibre types, myosins and capillary supply
Four human soft palate muscles, and palatopharyngeus, the uvula, the levator and tensor veli palatini were examined using enzyme-histochemical, immunohistochemical and biochemical methods and compared with human limb and facial muscles. Our results showed that each palate muscle had a distinct morphological identity and that they generally shared more similarities with facial than limb muscles. The palatopharyngeus and uvula muscles contained 2 of the highest proportions of type II fibres ever reported for human muscles. In contrast, the levator and tensor veli palatini muscles contained predominantly type I fibres. A fetal myosin heavy chain isoform (MyHC), not usually found in normal adult limb muscles, was present in a small number of fibres in all palate muscles. The mean muscle fibre diameter was smaller than in limb muscles and the individual and intramuscular variability in diameter and shape was considerable. All palate muscles had a high capillary density and an unusually high mitochondrial enzyme activity in the type II fibres, in comparison with limb muscles. No ordinary muscle spindles were observed. The fibre type and MyHC composition indicate that the palatopharyngeus and uvula muscles are functionally involved in quick movements whereas the levator and tensor veli palatini muscles perform slower and more continuous contractions. The high aerobic capacity and the rich capillarisation suggest that the palate muscles are relatively fatigue resistant. Absence of ordinary muscle spindles indicates a special proprioceptive control system. The special morphology of the palate muscles may be partly related to the unique anatomy with only one skeletal insertion, a feature consistent with muscle work at low load and tension and which may influence the cytoarchitecture of these muscles. Other important factors determining the special morphological characteristics might be specific functional requirements, distinct embryological origin and phylogenetic factors
Collagen content in the vastus lateralis and the soleus muscle following a 90-day bed rest period with or without resistance exercises
INTRODUCTION: spaceflight seems associated with deterioration of the function of the skeletal muscles. Since muscle collagen is critical for muscle function, an improved understanding of the content of the muscle collagen during long-term inactivity seems important. Bed-rest with in-bed resistance training serves as a proxy for the conditions in space. Therefore, ground-based studies may improve the understanding of the consequences of long-term inactivity. PURPOSE: the purpose is to compare the change in collagen protein in the vastus lateralis (VL) and the soleus (SOL) muscle amongst persons exposed to a 90-day bed rest with or without resistance exercise. METHODS: an explorative analysis was completed based on data from a randomized, controlled trial. The intervention group (BRE, SOL n=4, VL n=8) performed supine-based squat exercises, whereas the controls (BE, SOL n=6, VL n=12) remained inactive during follow-up. Muscle biopsies from vastus lateralis and soleus were taken at baseline (pre) and after 90-daysâ follow-up (post). Muscle collagen (ÎŒg collagen/mg protein) was quantified. Two-way repeated measurements ANOVA was used to compare the interaction between the intervention (BRE/BR) and time (pre/post) for each muscle. RESULTS: the collagen content of VL was similar between pre and post in the BRE group (â3.8 ÎŒg collagen/mg protein [95% CI: â22.0; 14.4], p=0.68) while it rose amongst individuals in the BR group (14.9 ÎŒg collagen/mg protein [95% CI: â0.01; 29.7], p=0.05). The difference of 18.66 [95% CI: â6.5; 43.9] between BRE and BR across time was, however, not significant (p=0.14). No significant reduction in SOL muscle collagen content was observed from pre to post in the BR group (â9.3 ÎŒg collagen/mg protein [95% CI: â24.9; 6.4], p=0.25) or in the BRE group (â6.5 ÎŒg collagen/mg protein [95% CI: â25.6; 12.6], p=0.50). There was no difference in the effect of BR versus BRE over time (mean difference â2.78 ÎŒg collagen/mg protein [95% CI: â29.7; 24.1], p=0.82). CONCLUSION: muscle collagen content in the VL or SOL muscle does not seem to differ after a 90-day bed rest period with or without squat exercises
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