Immune cells are highly dynamic in terms of their growth, proliferation, and effector functions as they respond to immunological challenges. Different immune cells can adopt distinct metabolic ...configurations that allow the cell to balance its requirements for energy, molecular biosynthesis, and longevity. However, in addition to facilitating immune cell responses, it is now becoming clear that cellular metabolism has direct roles in regulating immune cell function. This review article describes the distinct metabolic signatures of key immune cells, explains how these metabolic setups facilitate immune function, and discusses the emerging evidence that intracellular metabolism has an integral role in controlling immune responses.
Activated natural killer (NK) cells engage in a robust metabolic response that is required for normal effector function. Using genetic, pharmacological and metabolic analyses, we demonstrated an ...essential role for Srebp transcription factors in cytokine-induced metabolic reprogramming of NK cells that was independent of their conventional role in the control of lipid synthesis. Srebp was required for elevated glycolysis and oxidative phosphorylation and promoted a distinct metabolic pathway configuration in which glucose was metabolized to cytosolic citrate via the citrate-malate shuttle. Preventing the activation of Srebp or direct inhibition of the citrate-malate shuttle inhibited production of interferon-γ and NK cell cytotoxicity. Thus, Srebp controls glucose metabolism in NK cells, and this Srebp-dependent regulation is critical for NK cell effector function.
Natural killer (NK) cells are lymphocytes with important anti-tumour functions. Cytokine activation of NK cell glycolysis and oxidative phosphorylation (OXPHOS) are essential for robust NK cell ...responses. However, the mechanisms leading to this metabolic phenotype are unclear. Here we show that the transcription factor cMyc is essential for IL-2/IL-12-induced metabolic and functional responses in mice. cMyc protein levels are acutely regulated by amino acids; cMyc protein is lost rapidly when glutamine is withdrawn or when system L-amino acid transport is blocked. We identify SLC7A5 as the predominant system L-amino acid transporter in activated NK cells. Unlike other lymphocyte subsets, glutaminolysis and the tricarboxylic acid cycle do not sustain OXPHOS in activated NK cells. Glutamine withdrawal, but not the inhibition of glutaminolysis, results in the loss of cMyc protein, reduced cell growth and impaired NK cell responses. These data identify an essential role for amino acid-controlled cMyc for NK cell metabolism and function.
Diabet. Med. 28, 1144–1153 (2011)
Aim To quantify global variation in the incidence of lower extremity amputations in light of the rising prevalence of diabetes mellitus.
Methods An electronic ...search was performed using the EMBASE and MEDLINE databases from 1989 until 2010 for incidence of lower extremity amputation. The literature review conformed to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement standards.
Results Incidence of all forms of lower extremity amputation ranges from 46.1 to 9600 per 105 in the population with diabetes compared with 5.8–31 per 105 in the total population. Major amputation ranges from 5.6 to 600 per 105 in the population with diabetes and from 3.6 to 68.4 per 105 in the total population. Significant reductions in incidence of lower extremity amputation have been shown in specific at‐risk populations after the introduction of specialist diabetic foot clinics.
Conclusion Significant global variation exists in the incidence of lower extremity amputation. Ethnicity and social deprivation play a significant role but it is the role of diabetes and its complications that is most profound. Lower extremity amputation reporting methods demonstrate significant variation with no single standard upon which to benchmark care. Effective standardized reporting methods of major, minor and at‐risk populations are needed in order to quantify and monitor the growing multidisciplinary team effect on lower extremity amputation rates globally.
Despite decades of research on spatial memory, we know surprisingly little about how the brain guides navigation to goals. While some models argue that vectors are represented for navigational ...guidance, other models postulate that the future path is computed. Although the hippocampal formation has been implicated in processing spatial goal information, it remains unclear whether this region processes path- or vector-related information.
We report neuroimaging data collected from subjects navigating London's Soho district; these data reveal that both the path distance and the Euclidean distance to the goal are encoded by the medial temporal lobe during navigation. While activity in the posterior hippocampus was sensitive to the distance along the path, activity in the entorhinal cortex was correlated with the Euclidean distance component of a vector to the goal. During travel periods, posterior hippocampal activity increased as the path to the goal became longer, but at decision points, activity in this region increased as the path to the goal became closer and more direct. Importantly, sensitivity to the distance was abolished in these brain areas when travel was guided by external cues.
The results indicate that the hippocampal formation contains representations of both the Euclidean distance and the path distance to goals during navigation. These findings argue that the hippocampal formation houses a flexible guidance system that changes how it represents distance to the goal depending on the fluctuating demands of navigation.
Abdominal aortic aneurysms (AAAs) are found in up to 8% of men aged >65 years, yet usually remain asymptomatic until they rupture. Rupture of an AAA and its associated catastrophic physiological ...insult carries overall mortality in excess of 80%, and 2% of all deaths are AAA-related. Pathologically, AAAs are associated with inflammation, smooth muscle cell apoptosis, and matrix degradation. Once thought to be a consequence of advanced atherosclerosis, accruing evidence indicates that AAAs are a focal representation of a systemic disease of the vasculature. Risk factors for AAAs include increasing age, male sex, smoking, and low HDL-cholesterol levels. Familial associations exist and although susceptibility genes have been described on the basis of candidate-gene studies, robust genetic studies have failed to discover causative gene mutations. The surgical management of AAAs has been revolutionized by minimally invasive endovascular repair. Ongoing randomized trials will establish whether endovascular repair confers a survival advantage over open surgery for patients with a ruptured AAA. In many countries, centralization of vascular surgical services has largely been driven by the improved outcomes of elective aneurysm surgery in specialized centers, the widespread adoption of endovascular techniques, and the introduction of screening programs.
Thresholds for repair of abdominal aortic aneurysms vary considerably among countries.
We examined differences between England and the United States in the frequency of aneurysm repair, the mean ...aneurysm diameter at the time of the procedure, and rates of aneurysm rupture and aneurysm-related death. Data on the frequency of repair of intact (nonruptured) abdominal aortic aneurysms, in-hospital mortality among patients who had undergone aneurysm repair, and rates of aneurysm rupture during the period from 2005 through 2012 were extracted from the Hospital Episode Statistics database in England and the U.S. Nationwide Inpatient Sample. Data on the aneurysm diameter at the time of repair were extracted from the U.K. National Vascular Registry (2014 data) and from the U.S. National Surgical Quality Improvement Program (2013 data). Aneurysm-related mortality during the period from 2005 through 2012 was determined from data obtained from the Centers for Disease Control and Prevention and the U.K. Office of National Statistics. Data were adjusted with the use of direct standardization or conditional logistic regression for differences between England and the United States with respect to population age and sex.
During the period from 2005 through 2012, a total of 29,300 patients in England and 278,921 patients in the United States underwent repair of intact abdominal aortic aneurysms. Aneurysm repair was less common in England than in the United States (odds ratio, 0.49; 95% confidence interval CI, 0.48 to 0.49; P<0.001), and aneurysm-related death was more common in England than in the United States (odds ratio, 3.60; 95% CI, 3.55 to 3.64; P<0.001). Hospitalization due to an aneurysm rupture occurred more frequently in England than in the United States (odds ratio, 2.23; 95% CI, 2.19 to 2.27; P<0.001), and the mean aneurysm diameter at the time of repair was larger in England (63.7 mm vs. 58.3 mm, P<0.001).
We found a lower rate of repair of abdominal aortic aneurysms and a larger mean aneurysm diameter at the time of repair in England than in the United States and lower rates of aneurysm rupture and aneurysm-related death in the United States than in England. (Funded by the Circulation Foundation and others.).
To provide data regarding the etiology and timing of retrograde type A aortic dissection (RTAD) after thoracic endovascular aortic repair (TEVAR).
Details of patients who had RTAD after TEVAR were ...obtained from the MOTHER Registry supplemented by data from a systematic review of the literature. Univariate analysis and binary logistic regression analysis of patient or technical factors was performed.
In MOTHER, RTAD developed in 16 of the 1010 patients (1.6%). Binary logistic regression demonstrated that an indication of TEVAR for aortic dissection (acute P = 0.000212; chronic P = 0.006) and device oversizing (OR 1.14 per 1% increase in oversizing above 9%, P < 0.0001) were significantly more frequent in patients with RTAD. Data from the systematic review was pooled with MOTHER data and demonstrated that RTAD occurred in 1.7% (168/9894). Most of RTAD occurred in the immediate postoperative (58%) period and was associated with a high mortality rate (33.6%). The odds ratio of RTAD for an acute aortic dissection was 10.0 (CI: 4.7-21.9) and 3.4 (CI: 1.3-8.8) for chronic aortic dissection. The incidence of RTAD was not significantly different for endografts with proximal bare stent (2.8%) or nonbare stent (1.9%) (P = 0.1298).
Although RTAD after TEVAR is an uncommon complication, it has a high mortality rate. RTAD is significantly more frequent in patients treated for acute and chronic type B dissection, and when the endograft is significantly oversized. The proximal endograft configuration was not associated with any difference in the incidence of RTAD.
B-type natriuretic peptide (BNP) is used widely to exclude heart failure (HF) in patients with dyspnea. However, most studies of BNP have focused on diagnosing HF with reduced ejection fraction (EF). ...The aim of this study was to test the hypothesis that a normal BNP level (≤100 pg/ml) is relatively common in HF with preserved EF (HFpEF), a heterogenous disorder commonly associated with obesity. A total of 159 consecutive patients enrolled in the Northwestern University HFpEF Program were prospectively studied. All subjects had symptomatic HF with EF >50% and elevated pulmonary capillary wedge pressure. BNP was tested at baseline in all subjects. Clinical characteristics, echocardiographic parameters, invasive hemodynamics, and outcomes were compared among patients with HFpEF with normal (≤100 pg/ml) versus elevated (>100 pg/ml) BNP. Of the 159 patients with HFpEF, 46 (29%) had BNP ≤100 pg/ml. Subjects with normal BNP were younger, were more often women, had higher rates of obesity and higher body mass index, and less commonly had chronic kidney disease and atrial fibrillation. EFs and pulmonary capillary wedge pressures were similar in the normal and elevated BNP groups (62 ± 7% vs 61 ± 7%, p = 0.67, and 25 ± 8 vs 27 ± 9 mm Hg, p = 0.42, respectively). Elevated BNP was associated with enlarged left atrial volume, worse diastolic function, abnormal right ventricular structure and function, and worse outcomes (e.g., adjusted hazard ratio for HF hospitalization 4.0, 95% confidence interval 1.6 to 9.7, p = 0.003). In conclusion, normal BNP levels were present in 29% of symptomatic outpatients with HFpEF who had elevated pulmonary capillary wedge pressures, and although BNP is useful as a prognostic marker in HFpEF, normal BNP does not exclude the outpatient diagnosis of HFpEF.
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