Sirtuin 1 and sirtuin 3: physiological modulators of metabolism

The sirtuins are a family of highly conserved NAD(+)-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD(+) levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease.     

Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction

Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, worms and flies. Mammals contain seven homologs of yeast Sir2, SIRT1-7. Here, we review recent findings demonstrating the role of these mammalian sirtuins as regulators of physiology, calorie restriction, and aging. The current findings sharpen our understanding of sirtuins as potential pharmacological targets to treat the major diseases of aging.     

Resveratrol,sirtuins, and viruses

Resveratrol is a natural phenolic product found in some plants in response to stress and has been linked to the many health benefits of red wine. Over the past several decades, a great deal of research has identified diverse biological roles associated with resveratrol, including anti‐oxidant, anti‐proliferation, anti‐inflammation, anti‐cancer, anti‐fungal, and antiviral activities. Such biological activities of resveratrol are likely mediated through multiple cellular targets or pathways, such as sirtuins, a family of NAD⁺‐dependent deacetylases. In this treatise, the literatures focusing on the roles of resveratrol and sirtuins in modulating infections by a broad‐spectrum of viruses are reviewed, with an emphasis on its potential antiviral mechanisms. A working model about the effects of resveratrol on virus infection is proposed to stimulate further researches on this exciting topic. Copyright © 2015 John Wiley & Sons, Ltd.     

Cardiorespiratory fitness is associated with atrophy in Alzheimer's and aging over 2 years

We sought to describe change in cardiorespiratory (CR) fitness over 2 years in those with early-stage Alzheimer's disease (AD) and nondemented aging and assess the relationship of CR fitness with cognitive decline, brain atrophy, and dementia progression. Individuals with early-stage AD (n = 37) and without dementia (n = 53) attended clinical evaluations, cognitive and exercise tests, and magnetic resonance imaging (MRI) at baseline and 2 years later. CR fitness was lower in those with AD over the study period. Lower baseline CR fitness was associated with progression of dementia severity in AD. Declining CR fitness over 2 years was associated with brain atrophy in AD, especially in the parahippocampus. In nondemented participants, there was a trend for lower baseline fitness to be related to cognitive decline. Both lower baseline CR fitness and declining CR fitness over 2 years were associated with regional brain atrophy. We conclude that CR fitness is chronically reduced in those with AD. Further, in those with AD, CR fitness is associated with progression of dementia severity and brain atrophy in AD, suggesting a link between progression of dementia severity and cardiorespiratory health.     

Relationship of cognitive reserve and cerebrospinal fluid biomarkers to the emergence of clinical symptoms in preclinical Alzheimer's disease

The levels of β-amyloid (Aβ) and phosphorylated tau (p-tau), as measured in cerebrospinal fluid, have been associated with the risk of progressing from normal cognition to onset of clinical symptoms during preclinical Alzheimer's disease. We examined whether cognitive reserve (CR) modifies this association. Cerebrospinal fluid was obtained at baseline from 239 participants (mean age, 57.2 years) who had been followed for up to 17 years with clinical and cognitive assessments (mean follow-up, 8 years). A composite score based on the National Adult Reading Test, vocabulary, and years of education at baseline was used as an index of CR. Cox regression models showed that the increased risk of progressing from normal cognition to symptom onset was associated with lower CR, lower baseline Aβ, and higher baseline p-tau. There was no interaction between CR and Aβ, suggesting that the protective effects of higher CR are equivalent across the observed range of amyloid levels. In contrast, both tau and p-tau interacted with CR, indicating that CR was more protective at lower levels of tau and p-tau.     

Colonization and infection by colistin-resistant Gram-negative bacteria in a cohort of critically ill patients

In recent years there has been renewed interest in colistin for the treatment of infections by multidrug-resistant Gram-negative bacteria, causing concern that increasing use may be accompanied by the emergence of resistance. This is a retrospective cohort study of colonization and infection by colistin-resistant (CR) gram-negative bacteria in critically ill patients. Colonization data were based on surveillance culture results. Among 150 patients, 78 (52%) were colonized by CR Gram-negative bacteria. Among them, 30 (20%) were colonized by Klebsiella pneumoniae isolates and 51 (34%) were colonized by intrinsically resistant to colistin (CIR) enterobacteriaceae. Seven cases of infection were caused by CR K. pneumoniae and 12 cases by CIR strains. The main risk factor for colonization by CR pathogens was colistin treatment.     

Complement receptors and the shaping of the natural antibody repertoire

Complement and complement receptors have been known for several decades to play important roles in immune effector mechanisms related to pathogen elimination and tissue inflammation. In addition, studies over the last 10 years have clearly demonstrated a key role for the complement C3d activation fragment receptor designated CR2 (complement receptor type 2) in the switched-isotype, high-affinity and memory humoral immune responses to T-dependent foreign antigens. More recent studies have extended those observations to include a key role for CR2 and C3d in the humoral immune response to T-independent foreign antigens. Conversely, as these studies have proceeded, a parallel series of analyses have linked defects in expression or function of complement C4 and other classical pathway activation pathway proteins, as well as CR2 and the closely related CR1, to the loss of self tolerance to nuclear antigens such as double-stranded DNA and chromatin in systemic lupus erythematosus. With regard to the topic of this issue, it is now becoming increasingly clear that CR2 also plays a major role in the development of the natural antibody repertoire. Specifically, in the absence of this receptor natural IgM and IgG develop in the naïve animal that demonstrate clearly altered recognition patterns for specific natural antibody targets. This repertoire change is important physiologically in at least one setting because these CR2-dependent natural antibodies are necessary for the recognition of ischemic self tissues. In addition, it is possible that certain of the phenotypes manifest by CR2-deficient mice may be strongly influenced not only by effects on later stages of B cell activation and maturation, as commonly thought, but also by alterations in the pre-existing pool of natural antibodies that are influenced by this receptor. This review will examine the evidence that has accumulated over the last few years supporting these hypotheses.     

Autologous and Allogeneic Transplantation for Burkitt Lymphoma Outcomes and Changes in Utilization: A Report from the Center for International Blood and Marrow Transplant Research

Trends in utilization and outcomes after autologous or allogeneic hematopoietic cell transplantation (HCT) for Burkitt lymphoma were analyzed in 241 recipients reported to the Center for International Blood and Marrow Transplant Research between 1985 and 2007. The autologous HCT cohort had a higher proportion of chemotherapy-sensitive disease, peripheral blood grafts, and HCT in first complete remission (CR1). The use of autologous HCT has declined over time, with only 19% done after 2001. Overall survival at 5 years for the autologous cohort was 83% for those in CR1 and 31% for those not in CR1. Corresponding progression-free survival (PFS) was 78% and 27%, respectively. After allogeneic HCT, overall survival at 5 years was 53% and 20% for the CR1 and non-CR1 cohorts, whereas PFS was 50% and 19%, respectively. The most common cause of death was progressive lymphoma. Allogeneic HCT performed in a higher-risk subset (per National Comprehensive Cancer Network guidelines) resulted in a 5-year PFS of 27%. Autologous HCT resulted in a 5-year PFS of 44% in those undergoing transplantation in the second CR.     

The role of CR2 in autoimmunity

Complement activation is one of the most powerful mechanisms taking place during inflammation and immune responses. Over the last 30 years increasing evidence has proven the role of C3 and receptors for its activation fragments in the initiation and regulation of immune responses. Since complement also has a basic importance in the maintenance of immune homeostasis, abnormalities affecting complement proteins and their receptors may lead to pathological conditions. Autoimmune conditions develop as a result of a range of genetic and environmental factors. Findings obtained from animal models support the notion that malfunctioning of complement receptors, particularly CR2, might be involved in the breakdown of tolerance and excessive antibody production by auto reactive B-cell clones. In addition to B cells, activated, CR2-bearing T cells may also contribute to the pathogenesis of autoimmunity as they can receive activating/survival signals in the inflamed tissue. Results obtained from mouse experiments however, should be extended to the human system with great care, since there are basic differences between the structure and function of human and murine CR1 and CR2.     

The role of CR2 in autoimmunity

Complement activation is one of the most powerful mechanisms taking place during inflammation and immune responses. Over the last 30 years increasing evidence has proven the role of C3 and receptors for its activation fragments in the initiation and regulation of immune responses. Since complement also has a basic importance in the maintenance of immune homeostasis, abnormalities affecting complement proteins and their receptors may lead to pathological conditions. Autoimmune conditions develop as a result of a range of genetic and environmental factors. Findings obtained from animal models support the notion that malfunctioning of complement receptors, particularly CR2, might be involved in the breakdown of tolerance and excessive antibody production by auto reactive B-cell clones. In addition to B cells, activated, CR2-bearing T cells may also contribute to the pathogenesis of autoimmunity as they can receive activating/survival signals in the inflamed tissue. Results obtained from mouse experiments however, should be extended to the human system with great care, since there are basic differences between the structure and function of human and murine CR1 and CR2.     

Acute nonlymphocytic leukemia with normal karyotype. Is its in vivo drug susceptibility age-dependent?

Nineteen patients with acute nonlymphocytic leukemia (ANLL) de novo who had no detectable chromosomal abnormalities received intensive remission induction chemotherapy. After the first chemotherapy cycle, ten of 14 (71%) patients aged 60 years or less entered complete remission (CR) whereas none of five patients aged more than 65 years attained CR. On the other hand, leukemia showed a drug resistance in three (21%) of the former patients and in four (80%) of the latter patients. One patient in each group died during induction. Generally, older ANLL patients have an inferior CR rate after chemotherapy and a poor prognosis. This has been explained by the facts that the risk of induction death increases and that specific chromosomal abnormalities associated with poor prognosis are considerably more frequent in older patients. Our data may indicate, however, that in ANLL with normal karyotype older patients show a low initial response rate because of drug resistance.     

Benefit of Allogeneic Transplantation in Patients Age ≥ 60 Years with Acute Myeloid Leukemia Is Limited to Those in First Complete Remission at Time of Transplant

We evaluated the impact of age and remission status on 242 consecutive patients who underwent allogeneic hematopoietic cell transplantation for acute myeloid leukemia (AML) in our program between 1999 and 2011. Median age of all patients was 48 years (range, 18 to 71). Based on age and remission status, patients were divided into 4 groups: first complete remission (CR1) age <60 years (n = 116), second complete remission (CR2) age <60 years (n = 78), CR1 age ≥60 years (n = 32), and CR2 age ≥60 years (n = 16). Donors were matched related (n = 155, 64%) or matched unrelated (n = 87, 36%). Median follow-up of survivors was 65 months (range, 12 to 145). In a univariate analysis, 3-year overall survival rates of the 4 groups were 57%, 43%, 39%, and 16% (P = .003), respectively. In a multivariable analysis, hazard ratios of nonrelapse mortality and survival were 2.08 (P = .06) and 1.52 (P = .23), respectively, in patients ≥60 years in CR2 compared with ≥ 60 years in CR1. Although a plateau in survival was observed for patients ≥60 years in CR1 similar to those <60 years in CR1 and CR2, no long-term survivors were seen in patients ≥60 years in CR2. Our data suggest disappointing outcomes in AML patients ≥60 years of age transplanted in CR2. Therefore, if a transplant is indicated, early referral is recommended in patients ≥60 years with AML.     

Outcomes of adults with acute myelogenous leukemia in remission given 550 cGy of single-exposure total body irradiation, cyclophosphamide, and unrelated donor bone marrow transplants.

On the basis of observations from dog models and human studies, we hypothesized that a low-dose (550 cGy), single-exposure total body irradiation (TBI)-based regimen would result in improved survival when given to adult patients with acute myelogenous leukemia (AML) who were undergoing unrelated donor bone marrow transplantation in complete remission (CR). The regimen consisted of single exposure (550 cGy) of TBI given at a high dose rate (30 cGy/min) and cyclophosphamide. Graft-versus-host disease prophylaxis consisted of cyclosporine, methotrexate, and corticosteroids. Thirty-two consecutive adult patients (median age, 47 years) with AML in CR (15 in CR 1 and 17 in CR > or =2) were treated. Sixteen patients (50%) were alive and in remission at last follow-up (median, 2.2 years; range, 0.6-4.0 years). Kaplan-Meier estimates of overall and leukemia-free survival at 3 years were 55% +/- 14% (mean +/- SE) and 57% +/- 14% in CR 1 patients and were both 39% +/- 12% in CR > or =2 patients. Transplant-related mortality was 13% for patients in CR 1 and 41% for those in CR > or =2. Only 1 patient (3%) experienced fatal regimen-related organ toxicity, and only 1 had grade III or IV acute graft-versus-host disease. Graft failure was not observed. Relapse occurred in 22% of patients. This low-dose (550 cGy), single-exposure TBI-based regimen resulted in good survival and a low risk of fatal regimen-related organ toxicity in adult patients with AML who underwent unrelated donor bone marrow transplantation in CR.     

Calorie restriction mimetics: Can you have your cake and eat it,too?

Strong consensus exists regarding the most robust environmental intervention for attenuating aging processes and increasing healthspan and lifespan: calorie restriction (CR). Over several decades, this paradigm has been replicated in numerous nonhuman models, and has been expanded over the last decade to formal, controlled human studies of CR. Given that long-term CR can create heavy challenges to compliance in human diets, the concept of a calorie restriction mimetic (CRM) has emerged as an active research area within gerontology. In past presentations on this subject, we have proposed that a CRM is a compound that mimics metabolic, hormonal, and physiological effects of CR, activates stress response pathways observed in CR and enhances stress protection, produces CR-like effects on longevity, reduces age-related disease, and maintains more youthful function, all without significantly reducing food intake, at least initially. Over 16 years ago, we proposed that glycolytic inhibition could be an effective strategy for developing CRM. The main argument here is that inhibiting energy utilization as far upstream as possible provides the highest chance of generating a broad spectrum of CR-like effects when compared to targeting a singular molecular target downstream. As an initial candidate CRM, 2-deoxyglucose, a known anti-glycolytic, was shown to produce a remarkable phenotype of CR, but further investigation found that this compound produced cardiotoxicity in rats at the doses we had been using. There remains interest in 2DG as a CRM but at lower doses. Beyond the proposal of 2DG as a candidate CRM, the field has grown steadily with many investigators proposing other strategies, including novel anti-glycolytics. Within the realm of upstream targeting at the level of the digestive system, research has included bariatric surgery, inhibitors of fat digestion/absorption, and inhibitors of carbohydrate digestion. Research focused on downstream sites has included insulin receptors, IGF-1 receptors, sirtuin activators, inhibitors of mTOR, and polyamines. In the current review we discuss progress made involving these various strategies and comment on the status and future for each within this exciting research field.     

Long-term outcome of autologous transplantation of peripheral blood progenitor cells as postremission management of patients > or =60 years with acute myelogenous leukemia.

The optimal postremission treatment for elderly patients with acute myelogenous leukemia (AML) is presently unknown, but recent studies report the feasibility of autologous stem cell transplantation in this population. To better understand the long-term outcome of autologous transplantation in AML patients > or =60 years of age, we evaluated high-dose chemoradiotherapy preparative conditioning followed by transplantation of peripheral blood progenitor cells procured after a single cycle of cytarabine-based consolidation chemotherapy as postremission therapy in 27 patients aged 60 to 71 years (median age, 65 years) with newly diagnosed AML in first complete remission (CR). The median follow-up from CR for all patients was 13.6 months (range, 6.0-123.1 months). The median follow-up from remission for surviving patients was 81 months (range, 41.4-123.1 months). Seven patients are alive in continuous CR, 19 died from relapse, and 1 died as a result of treatment-related infection. Leukemia-free survival and overall survival are 10.3 and 13.4 months, respectively. Actuarial leukemia-free and overall survival at 3 years are 25% +/- 9% and 28% +/- 9%, respectively. Our results demonstrate that autologous transplantation of peripheral blood progenitor cells is well tolerated and feasible for patients > or =60 years of age with AML in first CR. Future investigation should focus on a randomized study evaluating a larger group of elderly patients in first CR comparing autologous stem cell transplantation with conventional cytarabine-based consolidation chemotherapy to identify the optimal postremission therapy.     

The complement receptor 1, CR1 (CD35), mediates inhibitory signals in human T-lymphocytes

The modulation the specific, adaptive immune response by complement, particularly of by complement C3, is mainly attributed to its interaction with complement receptors on B-lymphocytes. The function of complement receptors on T-lymphocytes, in contrast, is less well understood, although expression of the complement receptor (CR)1 and CR3 on T-cells has been described years ago. In the present study we investigated the effect of antibodies to CR1 on T-cell lines and peripheral T-cells of healthy donors, respectively. Antibodies to CR1 profoundly inhibited the proliferation of the T-cells; of note is, that exogenously added interleukin 2, though enhancing proliferation, did not overcome the inhibitory effect mediated by anti-CR1. While anti-CR1 had no effect on the activation of the immediate early genes c-jun or c-fos nor on the early increase of gamma interferon- or interleukin 2-specific RNA, the protein synthesis of those cytokines was inhibited. Moreover, synthesis of the proliferating cell nuclear antigen (PCNA) was reduced as was the expression of cyclins, particularly of cyclin A and cyclin D3. Taken together, the data indicate that triggering CR1 inhibits proliferation of T-lymphocytes by a mechanism operating downstream of the initial signalling events.     

Chest imaging within the radiology department by means of photostimulable phosphor computed radiography: A review

Photostimulable phosphor computed radiography has been clinically used outside of Japan for more than 8 years. Results of at least 35 quantitative or semiquantitative studies have been published so far in which the clinical utility of computed radiography (CR) is compared with that of conventional screen/film radiography (FR) for the study of the adult chest within the radiology department. The results can be summarized as follows: CR is superior to FR in the mediastinum, retrocardiac region, and subdiaphragmatic recesses, as well as in the evaluation of coronary artery calcifications. CR is reported to be generally superior or equivalent in the detection and evaluation of pulmonary nodules and larger pulmonary opacities. Equivocal results have been reported for pathologies requiring the inspection of fine details, such as interstitial infiltrates or pneumothorax. The studies indicate that image processing algorithms dedicated to the delineation of specific anatomies or pathologies improve clinical performance.