Published Science

Mitochondrial-nucleus cross talks and mitochondrial retrograde regulation can play a significant role in cellular properties. Transmitochondrial cybrid systems (cybrids) are an excellent tool to study specific effects of altered mitochondria under a defined nuclear background. The majority of the studies using the cybrid model focused on the significance of specific mitochondrial DNA variations in mitochondrial function or tumor properties. However, most of these variants are benign polymorphisms without known functional significance. From an objective of rectifying mitochondrial defects in cancer cells and to establish mitochondria as a potential anticancer drug target, understanding the role of functional mitochondria in reversing oncogenic properties under a cancer nuclear background is very important. Here we analyzed the potential reversal of oncogenic properties of a highly metastatic cell line with the introduction of non-cancerous mitochondria. Cybrids were established by fusing the mitochondria DNA depleted 143B TK- r0 cells from an aggressive osteosarcoma cell line with mitochondria from benign breast epithelial cell line MCF10A, moderately metastatic breast cancer cell line MDAMB-468 and 143B cells. In spite of the uniform cancerous nuclear background, as observed with the mitochondria donor cells, cybrids with benign mitochondria showed high mitochondrial functional properties including increased ATP synthesis, oxygen consumption and respiratory chain activities compared to cybrids with cancerous mitochondria. Interestingly, benign mitochondria could reverse different oncogenic characteristics of 143B TK- cell including cell proliferation, viability under hypoxic condition, anti-apoptotic properties, resistance to anti-cancer drug, invasion, and colony formation in soft agar, and in vivo tumor growth in nude mice. Microarray analysis suggested that several oncogenic pathways observed in cybrids with cancer mitochondria are inhibited in cybrids with non-cancerous mitochondria. These results suggest the critical oncogenic regulation by mitochondrial-nuclear cross talk and highlights rectifying mitochondrial functional properties as a promising target in cancer therapy.

Background Lifestyle behavior modification is an essential component of self-management of type 2 diabetes. We evaluated the prevalence of engagement in lifestyle behaviors for management of the disease, as well as the impact of healthcare professional support on these behaviors. Methods Self-reported data were available from 2682 adult respondents, age 20 years or older, to the 2011 Survey on Living with Chronic Diseases in Canada’s diabetes component. Associations with never engaging in and not sustaining self-management behaviors (of dietary change, weight control, exercise, and smoking cessation) were evaluated using binomial regression models. Results The prevalence of reported dietary change, weight control/loss, increased exercise and smoking cessation (among those who smoked since being diagnosed) were 89.7%, 72.1%, 69.5%, and 30.6%, respectively. Those who reported not receiving health professional advice in the previous 12 months were more likely to report never engaging in dietary change (RR = 2.7, 95% CI 1.8 – 4.2), exercise (RR = 1.7, 95% CI 1.3 – 2.1), or weight control/loss (RR = 2.2, 95% CI 1.3 – 3.6), but not smoking cessation (RR = 1.0; 95% CI: 0.7 – 1.5). Also, living with diabetes for more than six years was associated with not sustaining dietary change, weight loss and smoking cessation. Conclusion Health professional advice for lifestyle behaviors for type 2 diabetes self-management may support individual actions. Patients living with the disease for more than 6 years may require additional support in sustaining recommended behaviors.

Although early studies showed that saturated fat diets with very low levels of PUFAs increase serum cholesterol, whereas other studies showed high serum cholesterol increased the risk of coronary artery disease (CAD), the evidence of dietary saturated fats increasing CAD or causing premature death was weak. Over the years, data revealed that dietary saturated fatty acids (SFAs) are not associated with CAD and other adverse health effects or at worst are weakly associated in some analyses when other contributing factors may be overlooked. Several recent analyses indicate that SFAs, particularly in dairy products and coconut oil, can improve health. The evidence of ω6 polyunsaturated fatty acids (PUFAs) promoting inflammation and augmenting many diseases continues to grow, whereas ω3 PUFAs seem to counter these adverse effects. The replacement of saturated fats in the diet with carbohydrates, especially sugars, has resulted in increased obesity and its associated health complications. Well-established mechanisms have been proposed for the adverse health effects of some alternative or replacement nutrients, such as simple carbohydrates and PUFAs. The focus on dietary manipulation of serum cholesterol may be moot in view of numerous other factors that increase the risk of heart disease. The adverse health effects that have been associated with saturated fats in the past are most likely due to factors other than SFAs, which are discussed here. This review calls for a rational reevaluation of existing dietary recommendations that focus on minimizing dietary SFAs, for which mechanisms for adverse health effects are lacking.

Purpose: To explore the barriers to diabetes management among West African immigrants living in Rhode Island. Study Design and Methods: Semi-structured interviews with adults (N=5); men (n=2), women (n=3), Nigerian (n=3), Liberian (n=1), and Ghanaian (n=1) ages ≥18 with Type 1 or Type 2 diabetes, living in Rhode Island. Demographic information of the participants was obtained using a questionnaire. Interviews were conducted by the researcher and lasted approximately 50 minutes, and were scheduled to accommodate participants’ needs. Interviews were audio-taped and statements of the study participants were recorded. Subjects were redirected to clarify responses when necessary. Content analysis and coding, as proposed by Miles and Huberman (1994), were completed. Eight pertinent themes were identified. Results: All participants had Type 2 diabetes and reported various barriers to diabetes management: (1) financial difficulties, (2) poor dietary habits, (3) non adherence to daily maintenance, (4) cultural attachment to traditional management of diabetes, (5) cultural beliefs, (6) negative relationship with primary care doctor, (7) non-adherence to medication regimen, and (8) their practitioner’s inadequate knowledge of cultural care. Clinical Implications: These findings revealed that barriers exist for suitable diabetes management by some West African immigrants living in RI. Reducing the risk for complications, morbidity, and mortality can only occur with reduction of identified barriers.

The objective of this review is to discuss the effect of white vegetable consumption on glycemia, satiety, and food intake. White vegetables is a term used to refer to vegetables that are white or near white in color and include potatoes, cauliflowers, turnips, onions, parsnips, white corn, kohlrabi, and mushrooms (technically fungi but generally considered a vegetable). They vary greatly in their contribution to the energy and nutrient content of the diet and glycemia and satiety. As with other foods, the glycemic effect of many white vegetables has been measured. The results illustrate that interpretation of the semiquantitative comparative ratings of white vegetables as derived by the glycemic index must be context dependent. As illustrated by using the potato as an example, the glycemic index of white vegetables can be misleading if not interpreted in the context of the overall contribution that the white vegetable makes to the carbohydrate and nutrient composition of the diet and their functionality in satiety and metabolic control within usual meals. It is concluded that application of the glycemic index in isolation to judge the role of white vegetables in the diet and, specifically in the case of potato as consumed in ad libitum meals, has led to premature and possibly counterproductive dietary guidance.

“Makes an important contribution to our understanding of the challenges our ancestors faced during the transition from hunting and gathering to agriculture. . . . A well-organized and highly readable volume that synthesizes an enormous amount of data on what is perhaps the most significant economic transformation in the history of our species.”—American AnthropologistIn 1982, the Conference on Paleopathology and Socioeconomic Change at the Origins of Agriculture was held in Plattsburgh, New York, to examine previously untested theories about how the adoption of agriculture had impacted human health. The collection of those conference proceedings transformed into this landmark book that set the standard for how to collect, analyze, and interpret osteological data in the study of health transitions. Using skeletal pathologies, the contributors examine how the transition from foraging to farming affected human health and nutrition.            Now back in print and for the first time in paperback, Paleopathology at the Origins of Agriculture is a foundational piece in bioarchaeological literature and a central source of information regarding the impact of early farming on socioeconomic evolution. It remains a highly cited reference for archaeologists and physical anthropologists.          Contributors present data from nineteen different regions before, during, and after agricultural transitions, analyzing populations in Africa, Asia, the Middle East, Europe, and South America while primarily focusing on North America. A wide range of health indicators are discussed, including mortality, episodic stress, physical trauma, degenerative bone conditions, isotopes, and dental pathology. Mark Nathan Cohen is Distinguished Professor of anthropology at SUNY at Plattsburgh. He was awarded a Guggenheim Fellowship on the basis of this book’s impact. George J. Armelagos is the Goodrich C. White professor of anthropology at Emory University and a recipient of the Viking Fund Medal.

In recent years, the roles of chronic stress and depression as independent risk factors for decreased insulin sensitivity and the development of diabetes have been increasingly recognized. However, an understanding of the mechanisms linking insulin resistance and acute psychological stress are very limited. We hypothesized that acute psychological stress may cause the development of insulin resistance, which may be a risk factor in developing type 2 diabetes. We tested the hypothesis in a well-established mouse model using 180 episodes of inescapable foot shock (IES) followed by a behavioral escape test. In this study, mice that received IES treatment were tested for acute insulin resistance by measuring glucose metabolism and insulin signaling. When compared with normal and sham mice, mice that were exposed to IES resulting in escape failure (defined as IES with behavioral escape failure) displayed elevated blood glucose levels in both glucose tolerance and insulin tolerance tests. Furthermore, mice with IES exposure and behavioral escape failure exhibited impaired hepatic insulin signaling via the insulin-induced insulin receptor/insulin receptor substrate 1/Akt pathway, without affecting similar pathways in skeletal muscle, adipose tissue, and brain. Additionally, a rise in the murine growth-related oncogene KC/GRO was associated with impaired glucose metabolism in IES mice, suggesting a mechanism by which psychological stress by IES may influence glucose metabolism. The present results indicate that psychological stress induced by IES can acutely alter hepatic responsiveness to insulin and affect whole-body glucose metabolism.

Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is noninvasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states.

BACKGROUND: Atherosclerosis is thought to be a disease of modern human beings and related to contemporary lifestyles. However, its prevalence before the modern era is unknown. We aimed to evaluate preindustrial populations for atherosclerosis. METHODS: We obtained whole body CT scans of 137 mummies from four different geographical regions or populations spanning more than 4000 years. Individuals from ancient Egypt, ancient Peru, the Ancestral Puebloans of southwest America, and the Unangan of the Aleutian Islands were imaged. Atherosclerosis was regarded as definite if a calcified plaque was seen in the wall of an artery and probable if calcifications were seen along the expected course of an artery. FINDINGS: Probable or definite atherosclerosis was noted in 47 (34%) of 137 mummies and in all four geographical populations: 29 (38%) of 76 ancient Egyptians, 13 (25%) of 51 ancient Peruvians, two (40%) of five Ancestral Puebloans, and three (60%) of five Unangan hunter gatherers (p=NS). Atherosclerosis was present in the aorta in 28 (20%) mummies, iliac or femoral arteries in 25 (18%), popliteal or tibial arteries in 25 (18%), carotid arteries in 17 (12%), and coronary arteries in six (4%). Of the five vascular beds examined, atherosclerosis was present in one to two beds in 34 (25%) mummies, in three to four beds in 11 (8%), and in all five vascular beds in two (1%). Age at time of death was positively correlated with atherosclerosis (mean age at death was 43 [SD 10] years for mummies with atherosclerosis vs 32 [15] years for those without; p<0·0001) and with the number of arterial beds involved (mean age was 32 [SD 15] years for mummies with no atherosclerosis, 42 [10] years for those with atherosclerosis in one or two beds, and 44 [8] years for those with atherosclerosis in three to five beds; p

Central nervous system oxygen toxicity (CNS-OT) seizures occur with little or no warning, and no effective mitigation strategy has been identified. Ketogenic diets (KD) elevate blood ketones and have successfully treated drug-resistant epilepsy. We hypothesized that a ketone ester given orally as R,S-1,3-butanediol acetoacetate diester (BD-AcAc2) would delay CNS-OT seizures in rats breathing hyperbaric oxygen (HBO2). Adult male rats (n = 60) were implanted with radiotelemetry units to measure electroencephalogram (EEG). One week postsurgery, rats were administered a single oral dose of BD-AcAc2, 1,3-butanediol (BD), or water 30 min before being placed into a hyperbaric chamber and pressurized to 5 atmospheres absolute (ATA) O2. Latency to seizure (LS) was measured from the time maximum pressure was reached until the onset of increased EEG activity and tonic-clonic contractions. Blood was drawn at room pressure from an arterial catheter in an additional 18 animals that were administered the same compounds, and levels of glucose, pH, Po2, Pco2, β-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone were analyzed. BD-AcAc2 caused a rapid (30 min) and sustained (>4 h) elevation of BHB (>3 mM) and AcAc (>3 mM), which exceeded values reported with a KD or starvation. BD-AcAc2 increased LS by 574 ± 116% compared with control (water) and was due to the effect of AcAc and acetone but not BHB. BD produced ketosis in rats by elevating BHB (>5 mM), but AcAc and acetone remained low or undetectable. BD did not increase LS. In conclusion, acute oral administration of BD-AcAc2 produced sustained ketosis and significantly delayed CNS-OT seizures by elevating AcAc and acetone.

Abstract. Streptococcus mutans is widely recognized as one of the key etiological agents of human dental caries. Despite its role in this important disease, ou

The objectives of this work were to compare the conventional and organic crops of BRS258 soybeans obtained concurrently by the Agricultural Center of Palma (RS, Brazil) in relation to protein, total phenolics, isoflavone contents, in vitro antioxidant capacity, and trypsin inhibitory activity. The results showed that organic soybeans had a higher protein content and lower trypsin inhibitory activity than soybean cultivated by the conventional system. Levels of isoflavones and phenolic compounds from organic soybeans were also significantly lower. Isoflavone distribution was also different: the highest percentage of glycitein (glycitein plus glycitein derivatives) was found in organic soybeans and the highest percentage of daidzein (daidzein plus daidzein derivatives) in conventionally grown soybeans. Conventional soybeans presented a higher DPPH scavenging capacity but there was no difference in the ferric reducing antioxidant power (FRAP), compared to organic cultivation, despite the higher phenolics and isoflavone contents, compounds known for their antioxidant capacity.

Prostate cancer is a major health concern as it has the second highest incidence rate among cancers in men. Despite progress in tumor diagnostics and therapeutic approaches, prognosis for men with advanced disease remains poor. In this review we provide insight into the changes of the intermediary metabolism in normal prostate and prostate cancer. In contrast to normal cells, prostate cancer cells are reprogrammed for optimal energy-efficiency with a functional Krebs cycle and minimal apoptosis rates. A key element in this relationship is the uniquely high zinc level of normal prostate epithelial cells. Zinc is transported by the SLC30 and SLC39 families of zinc transporters. However, in prostate cancer the intracellular zinc content is remarkably reduced and expression levels of certain zinc transporters are altered. Here, we summarize the role of different zinc transporters in the development of prostate cancer.

PurposeTo examine challenges in diabetes self-management among Korean Americans to guide clinicians in providing culturally appropriate and population-targeted diabetes care.MethodsFive focus groups with 23 Korean Americans with type 2 diabetes, 30 to 75 years of age, were conducted. Open-ended questions were presented focusing on previous experiences in living with diabetes; digital recordings were transcribed verbatim; transcripts were coded and themes were identified.ResultsMost participants were reluctant to disclose diabetes because of social stigma and said that they did not know much about diabetes and its complications. Diabetes self-management is not always a top priority for Korean Americans over other family obligations or financial stability in their busy immigration lives. Many Korean Americans experience conflicts with family members in managing diabetes or would not request support from family members for their diabetes care. Traditional women?s roles and demanding immigration life seem to leave women particularly vulnerable to a lack of self-care. Lack of English proficiency limits access to mainstream health care.ConclusionsProviding diabetes education at the community level is important to raise public awareness of diabetes and to eliminate social stigma. To facilitate family support for individuals with type 2 diabetes, it is appropriate to include the entire family in diabetes educational programs and to promote individual family members? health in the context of maintaining their role within the family. Future efforts should be made with full implementation of language services in various clinical encounters and diabetes education.

The dental health of two Cambodian Iron Age (500 BC to 500 AD) communities is interpreted through an analysis of advanced wear, caries, periapical lesions, and antemortem tooth loss (AMTL). The two communities, Phum Snay and Phum Sophy, just 40km apart, are temporally situated at a time of significant socio-political change prior to the establishment of Angkorian state rule. Dental pathology frequencies are compared between the two communities and with other prehistoric sites throughout Southeast Asia to determine whether dental health was affected by socio-political changes and the intensification of rice agriculture that also occurred at this time. The people of Snay and Sophy, despite their proximity, were found to exhibit significant differences in dental health. When subdivided by age and sex, Sophy older age class teeth had significantly more advanced wear, and older females had more periapical lesions, while the Phum Snay older age dentitions had significantly more AMTL. Caries rates were similar between the samples. When compared in the broader context of the Iron Age in prehistoric Southeast Asia, both Phum Snay and Phum Sophy suggest a trend of declining dental health during the period prior to the rise of the Angkorian state.

Objectives Cystic fibrosis (CF) is an inherited disease that requires more intensive treatments as the disease progresses. Recent medical advancements have improved survival but have also increased costs. Our lack of understanding on the relationship between disease severity and lifetime health care costs is a major impediment to the timely economic assessment of new treatments. Methods Using data from three waves of the Australian Cystic Fibrosis Australia Data Registry, we estimate the annual costs of CF care by age and health state. We define health states on the basis of annual lung-function scores and patient’s organ transplant status. We exploit the longitudinal nature of the data to model disease progression, and we use this to estimate lifetime health care costs. Results The mean annual health care cost for treating CF is US $15,571. Costs for patients with mild, moderate, and severe disease are US $10,151, US $25,647, and US $33,691, respectively. Lifetime health care costs are approximately US $306,332 (3.5% discount rate). The majority of costs are accounted for by hospital inpatients (58%), followed by pharmaceuticals (29%), medical services (10%), complications (2%), and diagnostic tests (1%). Conclusions Our study is the first of its kind using the Australian Cystic Fibrosis Data Registry, and demonstrates the utility of longitudinal registry data for the purpose of economic analysis. Our results can be used as an input to future economic evaluations by providing analysts with a better understanding of the long-term cost impact when new treatments are developed.

BACKGROUND: Diet regulates gene expression profiles by several mechanisms. The objective of this study was to examine gene expression in relation with dietary patterns. METHODS: Two hundred and fifty four participants from the greater Quebec City metropolitan area were recruited. Two hundred and ten participants completed the study protocol. Dietary patterns were derived from a food frequency questionnaire (FFQ) by factor analysis. For 30 participants (in fasting state), RNA was extracted from peripheral blood mononuclear cells (PBMCs) and expression levels of 47,231 mRNA transcripts were assessed using the Illumina Human-6 v3 Expression BeadChips®. Microarray data was pre-processed with Flexarray software and analysed with Ingenuity Pathway Analysis (IPA). RESULTS: Two dietary patterns were identified. The Prudent dietary pattern was characterised by high intakes of vegetables, fruits, whole grain products and low intakes of refined grain products and the Western dietary pattern, by high intakes of refined grain products, desserts, sweets and processed meats. When individuals with high scores for the Prudent dietary pattern where compared to individuals with low scores, 2,083 transcripts were differentially expressed in men, 1,136 transcripts in women and 59 transcripts were overlapping in men and women. For the Western dietary pattern, 1,021 transcripts were differentially expressed in men with high versus low scores, 1,163 transcripts in women and 23 transcripts were overlapping in men and women. IPA reveals that genes differentially expressed for both patterns were present in networks related to the immune and/or inflammatory response, cancer and cardiovascular diseases. CONCLUSION: Gene expression profiles were different according to dietary patterns, which probably modulate the risk of chronic diseases. TRIAL REGISTRATION: NCT: NCT01343342.

Objective To evaluate the effectiveness of replacing dietary saturated fat with omega 6 linoleic acid, for the secondary prevention of coronary heart disease and death., Design Evaluation of recovered data from the Sydney Diet Heart Study, a single blinded, parallel group, randomized controlled trial conducted in 1966-73; and an updated meta-analysis including these previously missing data., Setting Ambulatory, coronary care clinic in Sydney, Australia., Participants 458 men aged 30-59 years with a recent coronary event., Interventions Replacement of dietary saturated fats (from animal fats, common margarines, and shortenings) with omega 6 linoleic acid (from safflower oil and safflower oil polyunsaturated margarine). Controls received no specific dietary instruction or study foods. All non-dietary aspects were designed to be equivalent in both groups., Outcome measures All cause mortality (primary outcome), cardiovascular mortality, and mortality from coronary heart disease (secondary outcomes). We used an intention to treat, survival analysis approach to compare mortality outcomes by group., Results The intervention group (n=221) had higher rates of death than controls (n=237) (all cause 17.6% v 11.8%, hazard ratio 1.62 (95% confidence interval 1.00 to 2.64), P=0.05; cardiovascular disease 17.2% v 11.0%, 1.70 (1.03 to 2.80), P=0.04; coronary heart disease 16.3% v 10.1%, 1.74 (1.04 to 2.92), P=0.04). Inclusion of these recovered data in an updated meta-analysis of linoleic acid intervention trials showed non-significant trends toward increased risks of death from coronary heart disease (hazard ratio 1.33 (0.99 to 1.79); P=0.06) and cardiovascular disease (1.27 (0.98 to 1.65); P=0.07)., Conclusions Advice to substitute polyunsaturated fats for saturated fats is a key component of worldwide dietary guidelines for coronary heart disease risk reduction. However, clinical benefits of the most abundant polyunsaturated fatty acid, omega 6 linoleic acid, have not been established. In this cohort, substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, coronary heart disease, and cardiovascular disease. An updated meta-analysis of linoleic acid intervention trials showed no evidence of cardiovascular benefit. These findings could have important implications for worldwide dietary advice to substitute omega 6 linoleic acid, or polyunsaturated fats in general, for saturated fats., Trial registration Clinical trials NCT01621087.

The long-lasting discussion, why plants produce secondary metabolites, which are pharmacologically and toxicologically active towards mammals traces back to the eminent role of medicinal plants in the millennia-old history of manhood. In recent years, the concept of an animal plant warfare emerged, which focused on the co-evolution between plants and herbivores. As a reaction to herbivory, plants developed mechanical defenses such as thorns and hard shells, which paved the way for adapted animal physiques. Plants evolved further defense systems by producing chemicals that exert toxic effects on the animals that ingest them. As a result of this selective pressure, animals developed special enzymes, e.g. cytochrome P450 monooxigenases (CYP450) that metabolize xenobiotic phytochemicals. As a next step in the evolutionary competition between plants and animals, plants evolved to produce non-toxic pro-drugs, which become toxic only after ingestion by animals through metabolization by enzymes such as CYP450. Because these sequestered evolutionary developments call to mind an arms race, the term animal plant warfare has been coined. The evolutionary competition between plants and animals may help to better understand the modes of action of medicinal plants and to foster the efficient and safe use of phytotherapy nowadays.

This is the third in a series of articles, invited by the editors of Diabetes, that describes the research programs and aims of organizations committed to funding and fostering diabetes-related research. The first piece, contributed by the Juvenile Diabetes Research Foundation, appeared in the January 2012 issue of Diabetes. The second piece that describes the American Diabetes Association’s research program appeared in the June 2012 issues of Diabetes and Diabetes Care.

Biodiversity loss and climate change secondary to human activities are now being associated with various adverse health effects. However, less attention is being paid to the effects of biodiversity loss on environmental and commensal (indigenous) microbiotas. Metagenomic and other studies of healthy and diseased individuals reveal that reduced biodiversity and alterations in the composition of the gut and skin microbiota are associated with various inflammatory conditions, including asthma, allergic and inflammatory bowel diseases (IBD), type1 diabetes, and obesity. Altered indigenous microbiota and the general microbial deprivation characterizing the lifestyle of urban people in affluent countries appear to be risk factors for immune dysregulation and impaired tolerance. The risk is further enhanced by physical inactivity and a western diet poor in fresh fruit and vegetables, which may act in synergy with dysbiosis of the gut flora. Studies of immigrants moving from non-affluent to affluent regions indicate that tolerance mechanisms can rapidly become impaired in microbe-poor environments. The data on microbial deprivation and immune dysfunction as they relate to biodiversity loss are evaluated in this Statement of World Allergy Organization (WAO). We propose that biodiversity, the variability among living organisms from all sources are closely related, at both the macro- and micro-levels. Loss of the macrodiversity is associated with shrinking of the microdiversity, which is associated with alterations of the indigenous microbiota. Data on behavioural means to induce tolerance are outlined and a proposal made for a Global Allergy Plan to prevent and reduce the global allergy burden for affected individuals and the societies in which they live.

BACKGROUND: Post-translational modifications (PTMs) of histones and other proteins are perturbed in tumours. For example, reduced levels of acetylated H4K16 and trimethylated H4K20 are associated with high tumour grade and poor survival in breast cancer. Drug-like molecules that can reprogram selected histone PTMs in tumour cells are therefore of interest as potential cancer chemopreventive agents. In this study we assessed the effects of the phytocompounds garcinol and curcumin on histone and p53 modification in cancer cells, focussing on the breast tumour cell line MCF7. METHODS: Cell viability/proliferation assays, cell cycle analysis by flow cytometry, immunodetection of specific histone and p53 acetylation marks, western blotting, siRNA and RT-qPCR. RESULTS: Although treatment with curcumin, garcinol or the garcinol derivative LTK-14 hampered MCF7 cell proliferation, differential effects of these compounds on histone modifications were observed. Garcinol treatment resulted in a strong reduction in H3K18 acetylation, which is required for S phase progression. Similar effects of garcinol on H3K18 acetylation were observed in the osteosarcoma cells lines U2OS and SaOS2. In contrast, global levels of acetylated H4K16 and trimethylated H4K20 in MCF7 cells were elevated after garcinol treatment. This was accompanied by upregulation of DNA damage signalling markers such as γH2A.X, H3K56Ac, p53 and TIP60. In contrast, exposure of MCF7 cells to curcumin resulted in increased global levels of acetylated H3K18 and H4K16, and was less effective in inducing DNA damage markers. In addition to its effects on histone modifications, garcinol was found to block CBP/p300-mediated acetylation of the C-terminal activation domain of p53, but resulted in enhanced acetylation of p53K120, and accumulation of p53 in the cytoplasmic compartment. Finally, we show that the elevation of H4K20Me3 levels by garcinol correlated with increased expression of SUV420H2, and was prevented by siRNA targeting of SUV420H2. CONCLUSION: In summary, although garcinol and curcumin can both inhibit histone acetyltransferase activities, our results show that these compounds have differential effects on cancer cells in culture. Garcinol treatment alters expression of chromatin modifying enzymes in MCF7 cells, resulting in reprogramming of key histone and p53 PTMs and growth arrest, underscoring its potential as a cancer chemopreventive agent.

Molecular Pathology of Neoplastic Gastrointestinal Diseases reviews the molecular aspects that characterize the spectrum of neoplastic conditions that affect the gastrointestinal tract, providing the reader with current up-to-date knowledge. For each disease entity chapters provide reviews on:the molecular basis of the individual diseasemolecular testing approaches currently available or in development for diagnosis or for gene target characterization for selective targeted therapiesrecommended guidelines for clinical application of molecular tests are included whenever availablemolecular testing for hereditary predisposition or disease riskanimal models and cell culture models of disease

An artificial selection experiment demonstrates that large-brained guppies learn better, but produce less offspring and have smaller guts. A close link between brain size and fertility suggests that energetic trade-offs play an important role in brain size evolution.

Besides technical improvements and a reduction of food losses in the food chain, diet shifts offer practicable opportunities to reduce environmental impacts in the agri-food sector on a low-cost basis. In this paper we analyze the environmental impacts of nutrition in Germany in the year 2006. Based on an equalized daily energy uptake of 2000 kcal person(-1) day(-1), we compared these impacts with those of four dietary scenarios (D-A-CH, UGB, ovo-lacto vegetarian, vegan) and with average nutrition from 20 years ago, differentiating between effects caused by altering food losses, food wastage, and changed diets. In the year 2006 gender-related impacts were considered separately. With regard to the scenarios analyzed, the highest impact changes would be expected from the vegan and the ovo-lacto vegetarian diet. The impact potentials of the recommendations of UGB and D-A-CH rank third and fourth, but are still significant. Concerning gender, the average female diet is already closer to the recommendations than men's. In comparison to the years 1985-1989, all indicators (with the exception of blue water) show lower impacts, due mainly to changes in diet. In comparison to this, impact changes resulting from food wastage were lower and mainly contrarian, which could be explained by higher food wastage in 2006 compared to 1985-1989.

Concentrations of acetyl–coenzyme A and nicotinamide adenine dinucleotide (NAD+) affect histone acetylation and thereby couple cellular metabolic status and transcriptional regulation. We report that the ketone body d-β-hydroxybutyrate (βOHB) is an endogenous and specific inhibitor of class I histone deacetylases (HDACs). Administration of exogenous βOHB, or fasting or calorie restriction, two conditions associated with increased βOHB abundance, all increased global histone acetylation in mouse tissues. Inhibition of HDAC by βOHB was correlated with global changes in transcription, including that of the genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment of cells with βOHB increased histone acetylation at the Foxo3a and Mt2 promoters, and both genes were activated by selective depletion of HDAC1 and HDAC2. Consistent with increased FOXO3A and MT2 activity, treatment of mice with βOHB conferred substantial protection against oxidative stress.

Concentrations of acetyl-coenzyme A and nicotinamide adenine dinucleotide (NAD(+)) affect histone acetylation and thereby couple cellular metabolic status and transcriptional regulation. We report that the ketone body d-β-hydroxybutyrate (βOHB) is an endogenous and specific inhibitor of class I histone deacetylases (HDACs). Administration of exogenous βOHB, or fasting or calorie restriction, two conditions associated with increased βOHB abundance, all increased global histone acetylation in mouse tissues. Inhibition of HDAC by βOHB was correlated with global changes in transcription, including that of the genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment of cells with βOHB increased histone acetylation at the Foxo3a and Mt2 promoters, and both genes were activated by selective depletion of HDAC1 and HDAC2. Consistent with increased FOXO3A and MT2 activity, treatment of mice with βOHB conferred substantial protection against oxidative stress.

Context—Increased inflammatory biomarkers predict antidepressant non-response, and inflammatory cytokines can sabotage and circumvent mechanisms of action of conventional antidepressant therapy.

AIM: Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time. METHODS: Documentary study. We searched the web-sites of the Europ

Monocytes/macrophages (MΦ), considered as plastic cells, can differentiate into either a pro-inflammatory (M1) subtype, also known as a classically activated subtype, or an anti-inflammatory alternatively activated subtype (M2) according to their microenvironment. Phenotypic markers of mouse polarized MΦ have been extensively studied, whereas their human counterparts remain less characterized. The main goal of this study was therefore to carefully characterize phenotypic and genomic markers of primary human MΦ generated from M-CSF-treated blood monocytes and polarized towards M1 or M2 subtype upon the action of lipopolysaccharide and interferon-γ (for M1) or interleukin (IL)-4 (for M2). Membrane expression of the markers CD80 and CD200R was found to be specific of human M1 and M2 polarized MΦ, respectively, whereas, by contrast, mannose receptor (CD206) expression did not discriminate between M1 and M2. mRNA expression analysis further identified six markers of M1 polarization (IL-12p35, CXCL10, CXCL11, CCL5, CCR7 and IDO1), five markers of M2 polarization (TGF-β, CCL14, CCL22, SR-B1 and PPARγ) and transcription factors involved in MΦ polarization. Ability of human M-CSF-generated MΦ to polarize toward M1 or M2 subtype was also associated with enhanced secretion of TNFα, IL-1β, IL-12p40, CXCL10 and IL-10 (for M1) or CCL22 (for M2). Moreover, the comparison of the expression of M1 markers in M-CSF- and GM-CSF-MΦ polarized towards M1 subtype has revealed similarities. In conclusion, we demonstrated that human M-CSF MΦ can polarize toward a M1 type after IFNγ/LPS stimulation. Moreover, the M1 and M2 markers of human polarized MΦ identified in the present study may be useful to better identify human MΦ subtypes, particularly at the tissue level, in order to better understand their respective roles in the development of pathologies.

BACKGROUND: Sexual offending is a legal construct that overlaps, but is not entirely congruent with, clinical constructs of disorders of sexual preference. Sexual offending is both a social and a public health issue. Victim surveys illustrate high incidence and prevalence levels, and it is commonly accepted that there is considerable hidden sexual victimisation. There are significant levels of psychiatric morbidity in survivors of sexual offences.Psychological interventions are generally based on behavioural or psychodynamic theories.Behavioural interventions fall into two main groups: those based on traditional classical conditioning and/or operant learning theory and those based on cognitive behavioural approaches. Approaches may overlap. Interventions associated with traditional classical and operant learning theory are referred to as behaviour modification or behaviour therapy, and focus explicitly on changing behaviour by administering a stimulus and measuring its effect on overt behaviour. Within sex offender treatment, examples include aversion therapy, covert sensitisation or olfactory conditioning. Cognitive behavioural therapies are intended to change internal processes - thoughts, beliefs, emotions, physiological arousal - alongside changing overt behaviour, such as social skills or coping behaviours. They may involve establishing links between offenders' thoughts, feelings and actions about offending behaviour; correction of offenders' misperceptions, irrational beliefs and reasoning biases associated with their offending; teaching offenders to monitor their own thoughts, feelings and behaviours associated with offending; and promoting alternative ways of coping with deviant sexual thoughts and desires.Psychodynamic interventions share a common root in psychoanalytic theory. This posits that sexual offending arises through an imbalance of the three components of mind: the id, the ego and the superego, with sexual offenders having temperamental imbalance of a powerful id (increased sexual impulses and libido) and a weak superego (a low level of moral probation), which are also impacted by early environment.This updates a previous Cochrane review but is based on a new protocol. OBJECTIVES: To assess the effects of psychological interventions on those who have sexually offended or are at risk of offending. SEARCH METHODS: In September 2010 we searched: CENTRAL, MEDLINE, Allied and Complementary Medicine (AMED), Applied Social Sciences Index and Abstracts (ASSIA), Biosis Previews, CINAHL, COPAC, Dissertation Abstracts, EMBASE, International Bibliography of the Social Sciences (IBSS), ISI Proceedings, Science Citation Index Expanded (SCI), Social Sciences Citation Index (SSCI), National Criminal Justice Reference Service Abstracts Database, PsycINFO, OpenSIGLE, Social Care Online, Sociological Abstracts, UK Clinical Research Network Portfolio Database and ZETOC. We contacted numerous experts in the field. SELECTION CRITERIA: Randomised trials comparing psychological intervention with standard care or another psychological therapy given to adults treated in institutional or community settings for sexual behaviours that have resulted in conviction or caution for sexual offences, or who are seeking treatment voluntarily for behaviours classified as illegal. DATA COLLECTION AND ANALYSIS: At least two authors, working independently, selected studies, extracted data and assessed the studies' risk of bias. We contacted study authors for additional information including details of methods and outcome data. MAIN RESULTS: We included ten studies involving data from 944 adults, all male.Five trials involved primarily cognitive behavioural interventions (CBT) (n = 664). Of these, four compared CBT with no treatment or wait list control, and one compared CBT with standard care. Only one study collected data on the primary outcome. The largest study (n = 484) involved the most complex intervention versus no treatment. Long-term outcome data are reported for groups in which the mean years 'at risk' in the community are similar (8.3 years for treatment (n = 259) compared to 8.4 in the control group (n = 225)). There was no difference between these groups in terms of the risk of reoffending as measured by reconviction for sexual offences (risk ratio (RR) 1.10; 95% CI 0.78 to 1.56).Four trials (n = 70) compared one behavioural programme with an alternative behavioural programme or with wait list control. No meta-analysis was possible for this comparison. For two studies (both cross-over, n = 29) no disaggregated data were available. The remaining two behavioural studies compared imaginal desensitisation with either covert sensitisation or as part of adjunctive drug therapy (n = 20 and 21, respectively). In these two studies, results for the primary outcome (being 'charged with anomalous behaviour') were encouraging, with only one new charge for the treated groups over one year in the former study, and in the latter study, only one new charge (in the drug-only group) over two years.One study compared psychodynamic intervention with probation. Results for this study (n = 231) indicate a slight trend in favour of the control group (probation) over the intervention (group therapy) in terms of sexual offending as measured by rearrest (RR 1.87; 95% CI 0.78 to 4.47) at 10-year follow-up.Data for adverse events, 'sexually anomalous urges' and for secondary outcomes thought to be 'dynamic' risk factors for reoffending, including anger and cognitive distortions, were limited. AUTHORS' CONCLUSIONS: The inescapable conclusion of this review is the need for further randomised controlled trials. While we recognise that randomisation is considered by some to be unethical or politically unacceptable (both of which are based on the faulty premise that the experimental treatment is superior to the control - this being the point of the trial to begin with), without such evidence, the area will fail to progress. Not only could this result in the continued use of ineffective (and potentially harmful) interventions, but it also means that society is lured into a false sense of security in the belief that once the individual has been treated, their risk of reoffending is reduced. Current available evidence does not support this belief. Future trials should concentrate on minimising risk of bias, maximising quality of reporting and including follow-up for a minimum of five years 'at risk' in the community.

The evolution of C4 photosynthesis was a signal shift in the history of life on Earth, including at least 50 independent origins in 19 families of higher plants (1). Today, C4 plants account for a quarter of the primary productivity on the planet despite representing a small fraction (∼3%) of the estimated 250,000 land plant species (2). Most C4 plants are grasses (family Poaceae, 4,500 species), followed by sedges (family Cyperaceae, 1,500 species) and dicots (1,200 species). A few C4 plant species contribute significantly to the human diet, either directly as domesticated cereals (e.g., maize, sorghum, millet) and additives (e.g., cane sugar, corn syrup) or indirectly via animals raised on C4 crops and pastures. As a result, human tissues can have high δ13C values because C4 plants and their consumers are enriched in 13C (3). In recent years, this telltale signature of a C4-based diet has also been found in a wide range of hominin species (4), a finding that has both informed and fueled debate. Now, paleoanthropologists must contend with a unique and surprising finding. In PNAS, Lee-Thorp et al. (5) report carbon isotope data from the tooth enamel of Australopithecus bahrelghazali , a hominin species that lived in the Chad Basin ca. 3.5 million years ago. Their findings, which indicate an early dependence … [↵][1]1E-mail: nathaniel.j.dominy{at}dartmouth.edu. [1]: #xref-corresp-1-1

#### Ancient microbes in a salty, ice-sealed Antarctic lake Antarctica’s Lake Vida. Antarctica’s Lake Vida, which is five times saltier than seawater and permanently covered by more than 20 m of ice, represents one of the least hospitable ecosystems on Earth. Using sanitary procedures and equipment, Alison Murray et al. (pp. 20626–20631) removed cores of ice from the frozen lake, collected samples of the brine in the lake ice, and assessed the brine’s potential for sustaining life. Previous studies of Lake Vida indicate that the brine has been isolated from the surface environment for at least 2,800 years. Despite the cold, dark, and isolated nature of the ecosystem, the authors found that the brine harbors a diverse assemblage of metabolically active bacteria. The authors report that the brine is oxygen-free, slightly acidic, and contains very high levels of organic carbon, molecular hydrogen, as well as oxidized and reduced compounds—an unusual finding considering the brine has been isolated from external sources of energy for millennia. Geochemical analyses suggest that chemical reactions between the brine and the underlying sediment generate nitrous oxide and molecular hydrogen, the latter of which may in part provide the energy needed to support the brine’s microbes. The findings shed light on the limits to life in extreme environments on Earth and other icy planets, according …

Despite decades of study, it is still unclear whether regional brain glucose uptake is lower in the cognitively healthy elderly. Whether regional brain uptake of ketones (β-hydroxybutyrate and acetoacetate [AcAc]), the main alternative brain fuel to glucose, changes with age is unknown. We used a sequential, dual tracer positron emission tomography (PET) protocol to quantify brain (18)F-fluorodeoxyglucose ((18)F-FDG) and (11)C-AcAc uptake in two studies with healthy, male Sprague-Dawley rats: (i) Aged (21 months; 21M) versus young (4 months; 4M) rats, and (ii) The effect of a 14 day high-fat ketogenic diet (KD) on brain (18)F-FDG and (11)C-AcAc uptake in 24 month old rats (24M). Similar whole brain volumes assessed by magnetic resonance imaging, were observed in aged 21M versus 4M rats, but the lateral ventricles were 30% larger in the 21M rats (p=0.001). Whole brain cerebral metabolic rates of AcAc (CMR(AcAc)) and glucose (CMR(glc)) did not differ between 21M and 4M rats, but were 28% and 44% higher, respectively, in 24M-KD compared to 24M rats. The region-to-whole brain ratio of CMR(glc) was 37-41% lower in the cortex and 40-45% lower in the cerebellum compared to CMR(AcAc) in 4M and 21M rats. We conclude that a quantitative measure of uptake of the brain's two principal exogenous fuels was generally similar in healthy aged and young rats, that the % of distribution across brain regions differed between ketones and glucose, and that brain uptake of both fuels was stimulated by mild, experimental ketonemia.

Background Given that acne is a rare condition in societies with higher consumption of omega-3 (n-3) relative to omega-6 (n-6) fatty acids, supplementation with n-3 may suppress inflammatory cytokine production and thereby reduce acne severity. Methods 13 individuals with inflammatory acne were given three grams of fish oil containing 930 mg of EPA to their unchanged diet and existing acne remedies for 12 weeks. Acne was assessed using an overall severity grading scale, total inflammatory lesion counts, and colorimetry. Findings There was no significant change in acne grading and inflammatory counts at week 12 compared to baseline. However, there was a broad range of response to the intervention on an individual basis. The results showed that acne severity improved in 8 individuals, worsened in 4, and remained unchanged in 1. Interestingly, among the individuals who showed improvement, 7 were classified as having moderate to severe acne at baseline, while 3 of the 4 whose acne deteriorated were classified as having mild acne. Conclusion There is some evidence that fish oil supplementation is associated with an improvement in overall acne severity, especially for individuals with moderate to severe acne. Divergent responses to fish oil in our pilot study indicates that dietary and supplemental lipids are worthy of further investigation in acne.

The Latino community continues to grow in the rural Midwest, and diabetes is a pertinent disease for research in this demographic. Patient self-management is an important aspect of comprehensive care for diabetes and may mitigate complications. A cross-sectional survey assessed various activities including self-monitoring of blood glucose, personal foot inspection, diet adherence, and diabetes self-management education. Less than half of the sample performed self-monitoring of blood glucose daily (40 %), adhered strictly to special diabetes diet recommendations (44 %), or attended a diabetes self-management education class (48 %). Participants advised on personal foot inspection were three times more likely to perform the self-care activity. Improvements are indicated in these self-management activities. Further research is needed to discern disparities and barriers in self-monitoring of blood glucose among this target population. An increased emphasis on enrollment in diabetes self-management classes should target foreign-born Latinos with lower levels of education.

The growing incidence of diabetes among Hispanics is a serious public health concern. To identify factors that influence diabetes self-management in Hispanics, qualitative data gathered through five focus group interviews was examined using grounded theory methods. Four major themes emerged which were perceived by participants as enhancing or limiting factors: (1) access to resources, (2) struggle with diet, (3) self-efficacy, and (4) social support. The family’s role as a determinant of diabetes self-management emerged as the underlying sub-theme to all four themes and underscores its importance among Hispanics living with diabetes. Results suggest that for the family to be an enhancing factor, health care providers need to educate, empower, and include the family in diabetes management and prevention. Programs which aim to improve the practice of self-management should incorporate the sociocultural and socioeconomic context in which Hispanics with diabetes live.

Abstract. Linoleic acid (LA) and α-linolenic acid (ALA) are essential fatty acids that play an important role in modulation of T cell proliferation. The effect

BACKGROUND: Children with attention-deficit/hyperactivity disorder (ADHD) are two to three times more likely to experience sleep problems. The purpose of this study is to determine the relative contributions of circadian preferences and behavioral problems to sleep onset problems experienced by children with ADHD and to test for a moderation effect of ADHD diagnosis on the impact of circadian preferences and externalizing problems on sleep onset problems. METHODS: After initial screening, parents of children meeting inclusion criteria documented child bedtime over 4 nights, using a sleep log, and completed questionnaires regarding sleep, ADHD and demographics to assess bedtime routine prior to PSG. On the fifth night of the study, sleep was recorded via ambulatory assessment of sleep architecture in the child's natural sleep environment employing portable polysomnography equipment. Seventy-five children (26 with ADHD and 49 controls) aged 7-11 years (mean age 8.61 years, SD 1.27 years) participated in the present study. RESULTS: In both groups of children, externalizing problems yielded significant independent contributions to the explained variance in parental reports of bedtime resistance, whereas an evening circadian tendency contributed both to parental reports of sleep onset delay and to PSG-measured sleep-onset latency. No significant interaction effect of behavioral/circadian tendency with ADHD status was evident. CONCLUSIONS: Sleep onset problems in ADHD are related to different etiologies that might require different interventional strategies and can be distinguished using the parental reports on the CSHQ.