Proton magnetic resonance spectroscopy of lymphocytes: An historical perspective

Proton magnetic resonance spectroscopy can be used to elucidate alterations to cellular chemistry associated with specific biological functions. It became apparent that this type of information was present in the magnetic resonance spectra from intact viable lymphocytes in the late 1970s. It was not until the 1980s, however, that one-dimensional multipulse sequences were used to filter the large signal contributions from water and fat, which had until then masked weaker signals from other molecules. When this technology was combined with two-dimensional spectroscopy, unambiguous assignment of the biologically relevant chemical species became possible. In vitro activated, stimulated, transformed, and malignant lymphocytes, as well as embryonic fibroblasts and malignant cells of epithelial origin, all gave rise to a strong triglyceride spectrum and resonances from a multitude of cellular metabolites. Two-dimensional spectroscopy and the analyses of highly purified membranes determined that the triglyceride signals originated, at least in part, from the plasma membrane. Based on physicochemical data, a new model for the structural arrangement of plasma membrane lipid in these cells was proposed. While differences exist between the proton magnetic resonance spectra of stimulated lymphocytes and malignant cells in vitro, they share a high-resolution lipid spectrum. In tissue, however, the presence of activated lymphocytes does not always produce the lipid spectrum, particularly in the vicinity of tumors

The use of proton MR in cancer pathology

This chapter describes the use of proton MR in cancer pathology. Water-based MRI is, at present, independently unable to identify the pathology of human tumors. The literature and work in this domain indicate that by studying carefully controlled model systems and excised human tissues, 1H MRS can extract chemical information relating directly to the pathology. In addition, by tailoring data acquisition and processing parameters to report specifically on those molecules of known diagnostic relevance, 1H MRS can diagnose invasive cancer in many organs ex vivo and some in vivo. 1H MRS has the potential to provide an independent modality that can: (1) report on the presence of invasive or preinvasive neoplastic cells in biopsy specimens; (2) detect the microfoci of metastatic cells missed by routine histopathology, and; (3) provide a precise diagnosis to aid in the decision on treatment and subsequent patient management. Cancer can be diagnosed by 1H MRS if the pathological criteria are linked to specific chemical changes ascertained from intact cells and tissues. This concept was demonstrated by the cervix program where CSI (ex vivo) not only defined the pathology of the tissue but also provided a spatial map of the diseased areas

Further evidence that the narrow 1H magnetic resonance signals from malignant cells do not arise from intracellular lipid droplets

1H magnetic resonance (MR) spectroscopy of intact viable malignant cells yields high resolution spectra from lipid. In previous studies we have provided evidence that these signals are generated by neutral lipid located in the plasma membrane in unique domains. We show that intracellular lipid droplets do not contribute to the MR signal. Two malignant Chinese hamster ovary cell lines, EOT and its parental line WT were studied. The EOT cells have a more highly resolved lipid spectrum than the WT, a result which correlates with slightly increased levels of triglyceride in highly purified plasma membranes. The intracellular lipid droplets of both lines were quantified using both fluorescence and electron microscopy but no significant differences were observed. Together these results provide evidence that narrow 1H MR signals from malignant cells arise from neutral lipid in the plasma membrane, rather than from intracellular lipid droplets

Hyperlipidemia as a biochemical basis of magnetic resonance plasma test for cancer

An increase in the plasma levels of apoprotein B-containing lipoproteins is the basis of the magnetic resonance (MR) test for cancer. The narrow MR line width reported by Fossel and co-workers to be associated with the presence of malignant disease is due to a relative increase of very low density lipoprotein. In contrast, the plasma from healthy controls, which has a much broader spectrum, has a higher proportion of high density lipoprotein. However, plasma from patients with hyperlipidemia unrelated to cancer also show narrow MR line widths and are therefore a confounding variable. We used magnetic resonance spectroscopy (MRS) to assess the plasma from 253 patients with a range of lipid related diseases and cancer, and 28 controls. A significant difference (p ≤ 0.0005) of 10 Hz exists between the mean line width of the controls and hyperlipidemics without malignant disease. However, in patients with solid tumours a difference of 7 Hz (p ≤ 0.0005) in the mean values is recorded although there is an overlap of 6 Hz compared with the controls. Moreover the MRS method was not found to distinguish patients with lymphomas from the control population. The index was not found to be related to patient age or tumour burden

Global variations in heart failure etiology, management, and outcomes

Importance: Most epidemiological studies of heart failure (HF) have been conducted in high-income countries with limited comparable data from middle- or low-income countries. Objective: To examine differences in HF etiology, treatment, and outcomes between groups of countries at different levels of economic development. Design, Setting, and Participants: Multinational HF registry of 23 341 participants in 40 high-income, upper–middle-income, lower–middle-income, and low-income countries, followed up for a median period of 2.0 years. Main Outcomes and Measures: HF cause, HF medication use, hospitalization, and death. Results: Mean (SD) age of participants was 63.1 (14.9) years, and 9119 (39.1%) were female. The most common cause of HF was ischemic heart disease (38.1%) followed by hypertension (20.2%). The proportion of participants with HF with reduced ejection fraction taking the combination of a β-blocker, renin-angiotensin system inhibitor, and mineralocorticoid receptor antagonist was highest in upper–middle-income (61.9%) and high-income countries (51.1%), and it was lowest in low-income (45.7%) and lower–middle-income countries (39.5%) (P < .001). The age- and sex- standardized mortality rate per 100 person-years was lowest in high-income countries (7.8 [95% CI, 7.5-8.2]), 9.3 (95% CI, 8.8-9.9) in upper–middle-income countries, 15.7 (95% CI, 15.0-16.4) in lower–middle-income countries, and it was highest in low-income countries (19.1 [95% CI, 17.6-20.7]). Hospitalization rates were more frequent than death rates in high-income countries (ratio = 3.8) and in upper–middle-income countries (ratio = 2.4), similar in lower–middle-income countries (ratio = 1.1), and less frequent in low-income countries (ratio = 0.6). The 30-day case-fatality rate after first hospital admission was lowest in high-income countries (6.7%), followed by upper–middle-income countries (9.7%), then lower–middle-income countries (21.1%), and highest in low-income countries (31.6%). The proportional risk of death within 30 days of a first hospital admission was 3- to 5-fold higher in lower–middle-income countries and low-income countries compared with high-income countries after adjusting for patient characteristics and use of long-term HF therapies. Conclusions and Relevance: This study of HF patients from 40 different countries and derived from 4 different economic levels demonstrated differences in HF etiologies, management, and outcomes. These data may be useful in planning approaches to improve HF prevention and treatment globally

Alirocumab and cardiovascular outcomes after acute coronary syndrome

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