Evolutionary basis for the human diet: consequences for human health.

The relationship of evolution with diet and environment can provide insights into modern disease. Fossil evidence shows apes, and early human ancestors were fruit eaters living in environments with strongly seasonal climates. Rapid cooling at the end of the Middle Miocene (15-12 Ma: millions of years ago) increased seasonality in Africa and Europe, and ape survival may be linked with a mutation in uric acid metabolism. Climate stabilized in the later Miocene and Pliocene (12-5 Ma), and fossil apes and early hominins were both adapted for life on ground and in trees. Around 2.5 Ma, early species of Homo introduced more animal products into their diet, and this coincided with developing bipedalism, stone tool technology and increase in brain size. Early species of Homo such as Homo habilis still lived in woodland habitats, and the major habitat shift in human evolution occurred at 1.8 Ma with the origin of Homo erectus. Homo erectus had increased body size, greater hunting skills, a diet rich in meat, control of fire and understanding about cooking food, and moved from woodland to savannah. Group size may also have increased at the same time, facilitating the transmission of knowledge from one generation to the next. The earliest fossils of Homo sapiens appeared about 300 kyr, but they had separated from Neanderthals by 480 kyr or earlier. Their diet shifted towards grain-based foods about 100 kyr ago, and settled agriculture developed about 10 kyr ago. This pattern remains for many populations to this day and provides important insights into current burden of lifestyle diseases.

Biomimetics - Nature's roadmap to insights and solutions for burden of lifestyle diseases.

There are over 8 million species in this world that live in widely varying environments, from hot thermal fissures to cold arctic settings. These species have evolved over millions of years and vary markedly in how they have adapted to their environments. In the last decades, studies of how species have succeeded in surviving in different environments and with different resources have been recognized to provide not only insights into disease but also novel means for developing treatments. Here, we provide an overview of two related and overlapping approaches (biomimetics and zoobiquity), which are turning to the natural world for insights to better understand, treat and prevent human 'burden of lifestyle' pathologies from heart disease and cancer to degeneration and premature ageing. We suggest that expanding biomedical investigation beyond its decades old conventional practices to new approaches based on a broad awareness of the diversity of animal life and comparative physiology can accelerate innovations in health care under the motto 'Nature knows best'.

Fructose metabolism as a common evolutionary pathway of survival associated with climate change, food shortage and droughts.

Mass extinctions occur frequently in natural history. While studies of animals that became extinct can be informative, it is the survivors that provide clues for mechanisms of adaptation when conditions are adverse. Here, we describe a survival pathway used by many species as a means for providing adequate fuel and water, while also providing protection from a decrease in oxygen availability. Fructose, whether supplied in the diet (primarily fruits and honey), or endogenously (via activation of the polyol pathway), preferentially shifts the organism towards the storing of fuel (fat, glycogen) that can be used to provide energy and water at a later date. Fructose causes sodium retention and raises blood pressure and likely helped survival in the setting of dehydration or salt deprivation. By shifting energy production from the mitochondria to glycolysis, fructose reduced oxygen demands to aid survival in situations where oxygen availability is low. The actions of fructose are driven in part by vasopressin and the generation of uric acid. Twice in history, mutations occurred during periods of mass extinction that enhanced the activity of fructose to generate fat, with the first being a mutation in vitamin C metabolism during the Cretaceous-Paleogene extinction (65 million years ago) and the second being a mutation in uricase that occurred during the Middle Miocene disruption (12-14 million years ago). Today, the excessive intake of fructose due to the availability of refined sugar and high-fructose corn syrup is driving 'burden of life style' diseases, including obesity, diabetes and high blood pressure.

Nutrition and its role in human evolution.

Our understanding of human evolution has improved rapidly over recent decades, facilitated by large-scale cataloguing of genomic variability amongst both modern and archaic humans. It seems clear that the evolution of the ancestors of chimpanzees and hominins separated 7-9 million years ago with some migration out of Africa by the earlier hominins; Homo sapiens slowly emerged as climate change resulted in drier, less forested African conditions. The African populations expanded and evolved in many different conditions with slow mutation and selection rates in the human genome, but with much more rapid mutation occurring in mitochondrial DNA. We now have evidence stretching back 300 000 years of humans in their current form, but there are clearly four very different large African language groups that correlate with population DNA differences. Then, about 50 000-100 000 years ago a small subset of modern humans also migrated out of Africa resulting in a persistent signature of more limited genetic diversity amongst non-African populations. Hybridization with archaic hominins occurred around this time such that all non-African modern humans possess some Neanderthal ancestry and Melanesian populations additionally possess some Denisovan ancestry. Human populations both within and outside Africa also adapted to diverse aspects of their local environment including altitude, climate, UV exposure, diet and pathogens, in some cases leaving clear signatures of patterns of genetic variation. Notable examples include haemoglobin changes conferring resistance to malaria, other immune changes and the skin adaptations favouring the synthesis of vitamin D. As humans migrated across Eurasia, further major mitochondrial changes occurred with some interbreeding with ancient hominins and the development of alcohol intolerance. More recently, an ability to retain lactase persistence into adulthood has evolved rapidly under the environmental stimulus of pastoralism with the ability to husband lactating ruminants. Increased amylase copy numbers seem to relate to the availability of starchy foods, whereas the capacity to desaturase and elongate monounsaturated fatty acids in different societies seems to be influenced by whether there is a lack of supply of readily available dietary sources of long-chain polyunsaturated fatty acids. The process of human evolution includes genetic drift and adaptation to local environments, in part through changes in mitochondrial and nuclear DNA. These genetic changes may underlie susceptibilities to some modern human pathologies including folate-responsive neural tube defects, diabetes, other age-related pathologies and mental health disorders.

Pharmacokinetics of liposomal encapsulated buprenorphine suspension following subcutaneous administration to cats.

We investigated the effects of liposome encapsulation at prolonging the systemic exposure of buprenorphine following subcutaneous administration in cats. Seven healthy male cats were dosed intravenously with 0.02 mg/kg buprenorphine solution (STD-BUP), followed 14 days later by a subcutaneous injection of 0.2 mg/kg buprenorphine as a liposomal suspension (SUS-BUP) containing drug molecules both in liposomes and the suspending vehicle. Buprenorphine time plasma concentration data for both dosing routes were analyzed simultaneously with four compartmental models. Goodness of fit was assessed both graphically and with the Akaike information criterion. The time-course of intravenous STD-BUP was biphasic, with a 4.39 h average terminal half-life. The subcutaneous SUS-BUP produced plasma buprenorphine concentrations above 0.5 µg/L for more than 96 h, with three distinct peaks in the first 15 h. The model with best fit comprised a central and a peripheral compartment, plus three subcutaneous absorption compartments: one of dissolved drug molecules that were absorbed through a first-order process, and two of liposome-encapsulated drug molecules that were transferred to the solution compartment through separate zero-order processes. Liposomes effectively prolonged the systemic exposure of buprenorphine in cats.

The influence of geographical location, host maturity and sex on intestinal helminth communities of the double-crested cormorant Phalacrocorax auritus from the eastern United States.

Here the intestinal helminth infracommunities of 218 double-crested cormorants (Phalacrocorax auritus) from 11 locations in Alabama, Minnesota, Mississippi and Vermont are documented. Trematode infections were present in 98% of hosts; 65% of cormorants carried cestode infections, 4% were infected with acanthocephalans and 66% had nematode intestinal parasites. Parasite infracommunities of hosts collected on wintering grounds had higher richness and diversity than did birds collected on breeding grounds. Differences in parasite richness and diversity between male and female P. auritus were also detected, but not between immature and mature bird hosts. Parasite intensity did not differ by sex, maturity, or between breeding and wintering season. The most common parasite was Drepanocephalus auritus (spathans), which is recognized as a disease agent that negatively impacts the catfish aquaculture industry in the US. Echinochasmus sp. in double-crested cormorants is documented for the first time in the United States. We suggest that the differences observed among parasite infracommunities could be associated with the foraging distances travelled by P. auritus during breeding and wintering seasons, which is limited by allocation of parental care during the breeding season.

Estimated insulin sensitivity predicts regression of albuminuria in Type 1 diabetes.

AIM: To test the hypothesis that greater baseline insulin sensitivity would predict regression of albuminuria over 6 years in adults with Type 1 diabetes. METHOD: We enrolled 81 people aged 30-48 years with albuminuria at baseline in the present study and re-examined them 6 years later. Urinary albumin excretion rate was measured and albuminuria was defined as urinary albumin excretion rate ≥ 20 µg/min. Regression of albuminuria was defined as normoalbuminuria (urinary albumin excretion rate < 20 µg/min) at follow-up. Predictors of regression of albuminuria were examined in stepwise logistic regression. The variables age, diabetes duration, sex, serum uric acid, HbA1c , systolic blood pressure, LDL cholesterol, HDL cholesterol, BMI, baseline albumin excretion rate, estimated insulin sensitivity at baseline, change in estimated insulin sensitivity from baseline to follow-up and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were considered for inclusion in the model. RESULTS: Estimated insulin sensitivity was significantly higher at both baseline (4.6 ± 1.2 vs 3.4 ± 1.7; P = 0.002) and follow-up (5.2 ± 1.9 vs. 3.5 ± 1.7; P < 0.0001) in people who had regression of albuminuria vs those who did not. HbA1c (odds ratio 0.4, 95% CI 0.2-0.8; P = 0.006), estimated insulin sensitivity (odds ratio 2.5, 95% CI 1.3-4.9; P = 0.006) at baseline and change in estimated insulin sensitivity from baseline to follow-up (odds ratio 2.7, 95% CI 1.4-5.3; P = 0.003) were independently associated with regression of albuminuria in a multivariable stepwise model. CONCLUSIONS: In conclusion, over 6 years, higher baseline estimated insulin sensitivity and change in estimated insulin sensitivity independently predicted regression of albuminuria. Improving insulin sensitivity in people with Type 1 diabetes is a potential therapeutic target to increase rates of regression of albuminuria.

Accuracy of preoperative CT T staging of renal cell carcinoma: which features predict advanced stage?

AIMS: To characterise CT findings in renal cell carcinoma (RCC), and establish which features are associated with higher clinical T stage disease, and to evaluate patterns of discrepancy between radiological and pathological staging of RCC. MATERIALS AND METHODS: Preoperative CT studies of 92 patients with 94 pathologically proven RCCs were retrospectively reviewed. CT stage was compared with pathological stage using the American Joint Committee on Cancer (AJCC), 7(th) edition (2010). The presence or absence of tumour necrosis, perinephric fat standing, thickening of Gerota's fascia, collateral vessels were noted, and correlated with pT stage. The sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) for predicting pT stage ≥pT3a were derived separately for different predictors using cross-tabulations. RESULTS: Twenty-four lesions were pathological stage T1a, 21 were T1b, seven were T2a, 25 were T3a, 11 were T3b, four were T3c, and two were T4. There were no stage T2b. Sixty-three (67%) patients had necrosis, 27 (29%) thickening of Gerota's fascia (1 T1a), 25 had collateral vessels (0 T1a), 28 (30%) had fat stranding of <2 mm, 20 (21%) of 2-5mm and one (1%) of >5 mm. For pT stage ≥pT3a, the presence of perinephric fat stranding had a sensitivity, specificity, PPV and NPV of 74%, 65%, 63%, and 76%, respectively. Presence of tumour necrosis had a sensitivity, specificity, PPV, and NPV of 81%, 44%, 54%, and 72%, respectively. Thickening of Gerota's fascia had a sensitivity, specificity, PPV, and NPV of 52%, 90%, 81% and 70%, respectively; and enlarged collateral vessels had a sensitivity, specificity, PPV, and NPV value of 52%, 94%, 88%, and 71% respectively. CONCLUSION: The presence of perinephric stranding and tumour necrosis were not reliable signs for pT stage >T3a. Thickening of Gerota's fascia and the presence of collateral vessels in the peri- or paranephric fat had 90% and 94% specificity, with 82% and 88% PPV, respectively, for the presence of tumour stage for pT stage >T3a. These are considered reliable signs of locally advanced renal cancer.

Mechanisms by Which Dehydration May Lead to Chronic Kidney Disease.

Dehydration, a condition that characterizes excessive loss of body water, is well known to be associated with acute renal dysfunction; however, it has largely been considered reversible and to be associated with no long-term effects on the kidney. Recently, an epidemic of chronic kidney disease has emerged in Central America in which the major risk factor seems to be recurrent heat-associated dehydration. This has led to studies investigating whether recurrent dehydration may lead to permanent kidney damage. Three major potential mechanisms have been identified, including the effects of vasopressin on the kidney, the activation of the aldose reductase-fructokinase pathway, and the effects of chronic hyperuricemia. The discovery of these pathways has also led to the recognition that mild dehydration may be a risk factor in progression of all types of chronic kidney diseases. Furthermore, there is some evidence that increasing hydration, particularly with water, may actually prevent CKD. Thus, a whole new area of investigation is developing that focuses on the role of water and osmolarity and their influence on kidney function and health.

Hydrochlorothiazide-induced hyperuricaemia in the pharmacogenomic evaluation of antihypertensive responses study.

OBJECTIVE: Elevations in uric acid (UA) and the associated hyperuricaemia are commonly observed secondary to treatment with thiazide diuretics. We sought to identify novel single nucleotide polymorphisms (SNPs) associated with hydrochlorothiazide (HCTZ)-induced elevations in UA and hyperuricaemia. METHODS: A genome-wide association study of HCTZ-induced changes in UA was performed in Caucasian and African American participants from the pharmacogenomic evaluation of antihypertensive responses (PEAR) study who were treated with HCTZ monotherapy. Suggestive SNPs were replicated in Caucasians and African Americans from the PEAR study who were treated with HCTZ add-on therapy. Replicated regions were followed up through expression and pathway analysis. RESULTS: Five unique gene regions were identified in African Americans (LUC7L2, ANKRD17/COX18, FTO, PADI4 and PARD3B), and one region was identified in Caucasians (GRIN3A). Increases in UA of up to 1.8 mg dL(-1) were observed following HCTZ therapy in individuals homozygous for risk alleles, with heterozygotes displaying an intermediate phenotype. Several risk alleles were also associated with an increased risk of HCTZ-induced clinical hyperuricaemia. A composite risk score, constructed in African Americans using the 'top' SNP from each gene region, was strongly associated with HCTZ-induced UA elevations (P = 1.79 × 10(-7) ) and explained 11% of the variability in UA response. Expression studies in RNA from whole blood revealed significant differences in expression of FTO by rs4784333 genotype. Pathway analysis showed putative connections between many of the genes identified through common microRNAs. CONCLUSION: Several novel gene regions were associated with HCTZ-induced UA elevations in African Americans (LUC7L2, COX18/ANKRD17, FTO, PADI4 and PARD3B), and one region was associated with these elevations in Caucasians (GRIN3A).

Changes to the articular cartilage thickness profile of the tibia following anterior cruciate ligament injury.

OBJECTIVES: We sought to determine if anterior cruciate ligament (ACL)-injured subjects demonstrated side-to-side differences in tibial cartilage thickness soon after injury, and if uninjured-control subjects displayed side-to-side symmetry in cartilage thickness. Second, we aimed to investigate associations between body mass index (BMI), cross-sectional area (CSA) of the proximal tibia, and articular cartilage thickness differences. METHODS: Bilateral Magnetic Resonance Images (MRIs) were obtained on 88 ACL-injured subjects (27 male; 61 female) a mean 27 days post-injury, and 88 matched uninjured control subjects. Within ACL-injured and uninjured control subjects, side-to-side differences in medial and lateral tibial articular cartilage thickness were analyzed with adjustment for tibial position relative to the femur during MRI acquisition. Associations between tibial CSA and cartilage thickness differences were tested within high and low BMI groups. RESULTS: Within the medial tibial compartment, ACL-injured females displayed significant increases: mean (confidence interval (CI)) = +0.18 mm (0.17, 0.19) and decreases: mean (CI) = -0.14 mm (-0.13, -0.15) in tibial cartilage thickness within the central and posterior cartilage regions respectively. Adjustment for tibial position revealed a decreased area of significant cartilage thickness differences, though 46% of points maintained significance. In the lateral compartment anterior region, there was a significantly different relationship between cartilage thickness differences and CSA, within high and low BMI groups (BMI group*CSA interaction, P = 0.007). Within the low BMI group, a significant negative correlation between cartilage thickness and CSA was identified (P = 0.03). CONCLUSIONS: ACL-injured females displayed cartilage thickness differences in the central, and posterior medial tibial cartilage regions. Tibial position effected thickness differences, but did not account for all significant differences.

Plasma CD147 reflects histological features in patients with lupus nephritis.

OBJECTIVE: A glycosylated transmembrane protein, CD147, has been implicated in regulating lymphocyte responsiveness and leukocyte recruitment. As lupus nephritis (LN) often follows a relapsing-remitting disease course, accurate understanding of the disease activity would be extremely helpful in improving prognosis. Unfortunately, neither clinical nor serological data can accurately reflect the histological features of LN. The present study investigated whether CD147 can accurately predict pathological features of LN. METHODS: Plasma and spot urine samples were collected from 64 patients who underwent renal biopsy between 2008 and 2011. Disease activity for LN tissues was evaluated using the biopsy activity index, and compared to levels of biomarkers including CD147. RESULTS: In LN tissues, CD147 induction was striking in injured glomeruli and infiltrating inflammatory cells, but not in damaged tubules representing atrophy. Plasma CD147 levels accurately reflected the histological disease activity. However, prediction using a single molecule would be quite difficult because of the complex pathogenesis of LN. The diagnostic accuracy of multiplex parameters indicated that the combination including plasma CD147 might yield excellent diagnostic abilities for guiding ideal LN therapy. CONCLUSION: Plasma CD147 levels might offer useful insights into disease activity as a crucial biomarker in patients with LN.

Standardized deceased donor kidney donation rates in the UK reveal marked regional variation and highlight the potential for increasing kidney donation: a prospective cohort study†.

BACKGROUND: The UK has implemented a national strategy for organ donation that includes a centrally coordinated network of specialist nurses in organ donation embedded in all intensive care units and a national organ retrieval service for deceased organ donors. We aimed to determine whether despite the national approach to donation there is significant regional variation in deceased donor kidney donation rates. METHODS: The UK prospective audit of deaths in critical care was analysed for a cohort of patients who died in critical care between April 2010 and December 2011. Multivariate logistic regression was used to identify the factors associated with kidney donation. The logistic regression model was then used to produce risk-adjusted funnel plots describing the regional variation in donation rates. RESULTS: Of the 27 482 patients who died in a critical care setting, 1528 (5.5%) became kidney donors. Factors found to influence donation rates significantly were: type of critical care [e.g. neurointensive vs general intensive care: OR 1.53, 95% confidence interval (CI) 1.34-1.75, P<0.0001], patient ethnicity (e.g. 'Asian' vs 'white': OR 0.17, 95% CI 0.11-0.26, P<0.0001), age (e.g. age >69 vs age 18-39 yr: OR 0.2, 0.15-0.25, P<0.0001), and cause of death [e.g. 'other' (excluding 'stroke' and 'trauma') vs 'trauma': OR 0.04, 95% CI 0.03-0.05, P<0.0001]. Despite correction for these variables, kidney donation rates for the 20 UK kidney donor regions showed marked variation. The overall standardized donation rate ranged from 3.2 to 7.5%. Four regions had donation rates of >2 standard deviations (sd) from the mean (two below and two above). Regional variation was most marked for donation after circulatory death (DCD) kidney donors with 9 of the 20 regions demonstrating donation rates of >2 sd from the mean (5 below and 4 above). CONCLUSIONS: The marked regional variation in kidney donation rates observed in this cohort after adjustment for factors strongly associated with donation rates suggests that there is considerable scope for further increasing kidney donation rates in the UK, particularly DCD.

Prodrug activation in malaria parasites mediated by an imported erythrocyte esterase, acylpeptide hydrolase (APEH).

The continued emergence of antimalarial drug resistance highlights the need to develop new antimalarial therapies. Unfortunately, new drug development is often hampered by poor drug-like properties of lead compounds. Prodrugging temporarily masks undesirable compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs of phosphonic acid antibiotics, such as fosmidomycin, exhibit significantly higher antimalarial potency than their parent compounds (1). However, the activating enzymes for these prodrugs were unknown. Here, we show that an erythrocyte enzyme, acylpeptide hydrolase (APEH) is the major activating enzyme of multiple lipophilic ester prodrugs. Surprisingly, this enzyme is taken up by the malaria parasite, Plasmodium falciparum, where it localizes to the parasite cytoplasm and retains enzymatic activity. Using a novel fluorogenic ester library, we characterize the structure activity relationship of APEH, and compare it to that of P. falciparum esterases. We show that parasite-internalized APEH plays an important role in the activation of substrates with branching at the alpha carbon, in keeping with its exopeptidase activity. Our findings highlight a novel mechanism for antimicrobial prodrug activation, relying on a host-derived enzyme to yield activation at a microbial target. Mutations in prodrug activating enzymes are a common mechanism for antimicrobial drug resistance (2-4). Leveraging an internalized host enzyme would circumvent this, enabling the design of prodrugs with higher barriers to drug resistance.

Resistance of neoplasms to immunological destruction: role of a macrophage chemotaxis inhibitor.

Several tissue culture lines of 6C3HED, a murine lymphoma, were more susceptible to immunologic destruction in vivo than the highly virulent 6C3HED line maintained by serial intramuscular transplantation. The attenuated tissue culture cells were rejected by normal syngeneic recipients, but thymectomized mice were unable to reject attenuated cells. In such mice, the growth rate of attenuated cells was equivalent to the growth rate of virulent cells in normal syngeneic mice. The increased susceptibility of attenuated cells to destruction by syngeneic hosts was shown to correlate with decreased production by the tumor cells of a macrophage chemotaxis inhibitor, and not with altered antigen density. In addition, when inhibitor isolated from virulent cells was administered to mice challenged with attenuated cells, the latter cells became virulent in vivo. When attenuated and virulent cells were administered simultaneously in the same host, the attenuated cells were able to develop into progressively growing tumors. The data suggest that the successful growth of neoplastic cells in normal may require tumor cells to produce factors which subvert the ability of the host to mobilize macrophages rapidly at the tumor site.

Antibody-mediated suppression of grafted lymphoma. IV. Influence of time of tumor residency in vivo and tumor size upon the effectiveness of suppression by syngeneic antibody.

In the suppression of the growth of a mouse lymphoma 6C3HED by antibody, the effectiveness of antibody in suppressing growing or established tumor cells and comparable number of freshly injected tumor cells is quantitatively similar. The effectiveness of antibody diminishes markedly when the number of tumor cells per mouse reaches the level of 10(6) due to the development of a macrophage shortage. At the 10(5) tumor cells level, antibody-mediated suppression takes place in an optimal manner and between 10(5) and 10(4) tumor cell numbers, the amount of antibody required to suppress 50% of the tumor cells is directly proportional to the number of tumor cells suppressed.

The human neutrophil serine proteinases, elastase and cathepsin G, can mediate glomerular injury in vivo.

We infused microgram quantities of active or inactive PMN elastase and cathepsin G into the renal arteries of rats. Both active and inactive elastase localized to the glomerular capillary wall equally, and in amounts that could be achieved physiologically in GN. However, elastase-perfused rats developed marked proteinuria (196 +/- 32 mg/24 h) compared with control rats receiving inactive elastase (19 +/- 2 mg/24 h, p less than 0.005). Similar results were seen with active and inactive cathepsin G. Neither elastase nor cathepsin G infusion was associated with histologic evidence of glomerular injury. We conclude that the PMN neutral serine proteinases elastase and cathepsin G can mediate marked changes in glomerular permeability in vivo due to their proteolytic activity, and thus, may contribute to the proteinuria observed in PMN-dependent models of GN.

Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor.

Platelet-derived growth factor (PDGF), a potent mitogen for mesenchymal cells in culture, is expressed in vivo in a variety of inflammatory conditions associated with cell proliferation, including atherosclerosis, wound repair, pulmonary fibrosis, and glomerulonephritis. However, it is not known if PDGF mediates the fibroproliferative responses that characterize these inflammatory disorders. We administered neutralizing anti-PDGF IgG or control IgG to rats with mesangial proliferative nephritis. Inhibition of PDGF resulted in a significant reduction in mesangial cell proliferation, and largely prevented the increased deposition of extracellular matrix associated with the disease. This suggests that PDGF may have a central role in proliferative glomerular disease.

Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response.

BACKGROUND: Excessive fructose intake causes metabolic syndrome in animals and can be partially prevented by lowering the uric acid level. We tested the hypothesis that fructose might induce features of metabolic syndrome in adult men and whether this is protected by allopurinol. METHODS: A randomized, controlled trial of 74 adult men who were administered 200 g fructose daily for 2 weeks with or without allopurinol. Primary measures included changes in ambulatory blood pressure (BP), fasting lipids, glucose and insulin, homeostatic model assessment (HOMA) index, body mass index and criteria for metabolic syndrome. RESULTS: The ingestion of fructose resulted in an increase in ambulatory BP (7+/-2 and 5+/-2 mm Hg for systolic (SBP) and diastolic BP (DBP), P<0.004 and P<0.007, respectively). Mean fasting triglycerides increased by 0.62+/-0.23 mmol l(-1) (55+/-20 mg per 100 ml), whereas high-density lipoprotein cholesterol decreased by 0.06+/-0.02 mmol l(-1) (2.5+/-0.7 mg per 100 ml), P<0.002 and P<0.001, respectively. Fasting insulin and HOMA indices increased significantly, whereas plasma glucose level did not change. All liver function tests showed an increase in values. The metabolic syndrome increased by 25-33% depending on the criteria. Allopurinol lowered the serum uric acid level (P<0.0001) and prevented the increase in 24-h ambulatory DBP and daytime SBP and DBP. Allopurinol treatment did not reduce HOMA or fasting plasma triglyceride levels, but lowered low-density lipoprotein cholesterol relative to control (P<0.02) and also prevented the increase in newly diagnosed metabolic syndrome (0-2%, P=0.009). CONCLUSIONS: High doses of fructose raise the BP and cause the features of metabolic syndrome. Lowering the uric acid level prevents the increase in mean arterial blood pressure. Excessive intake of fructose may have a role in the current epidemics of obesity and diabetes.