Dietary antioxidant intake and the risk of developing Barrett's oesophagus and oesophageal adenocarcinoma.

BACKGROUND: We investigated in a cohort study, for the first time using 7-day food diaries (7-DFDs), for age-dependent inverse associations with antioxidants, which have anti-carcinogenic properties, and development of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). METHODS: A total of 24,068 well individuals completed 7-DFDs and donated blood. Vitamins C and E, carotenes, zinc and selenium intakes, and plasma vitamin C were measured. Participants were monitored for 15 years for BO and OAC. Hazard ratios (HRs) were estimated for: quintiles of intake and in participants younger and >=65 years at recruitment, the midpoint of BO peak prevalence. RESULTS: A total of 197 participants developed BO and 74 OAC. There were no significant associations between antioxidants and BO or OAC in the whole cohort or if >65 years at recruitment. In participants <65 years, for BO, there was an inverse trend across plasma vitamin C quintiles (trend HR = 0.82; 95% CI = 0.71-0.96, P = 0.01), OAC for plasma vitamin C (trend HR = 0.58; 95% CI = 0.37-0.92, P = 0.02) and for dietary vitamins C and E (trend HR = 0.71 95% CI = 0.51-0.99, P = 0.04 and trend HR = 0.70; 95% CI = 0.51-0.96; P = 0.03). CONCLUSIONS: Data supports a role for dietary antioxidants prevent BO and OAC, perhaps at the earlier stages of carcinogenesis.

Dietary Polyphenols in the Aetiology of Crohn's Disease and Ulcerative Colitis-A Multicenter European Prospective Cohort Study (EPIC).

BACKGROUND: Oxidative stress may be involved in the aetiology of inflammatory bowel disease and whether dietary polyphenols, which possess antioxidants properties, prevent its development is unknown. METHODS: A total of 401,326 men and women aged 20 to 80 years from 8 countries were recruited between 1991 and 1998 and at baseline completed validated food frequency questionnaires. Dietary polyphenol intake was measured using Phenol-Explorer, a database with information on the content of 502 polyphenols. Incident cases of Crohn's diseases (CD) and ulcerative colitis (UC) were identified during the follow-up period of up to December 2010. A nested case-control study using conditional logistic regression estimated the odds ratios (ORs), and 95% confidence intervals, for polyphenol intake (categories based on quartiles) and developing CD or UC. RESULTS: In total, 110 CD (73% women) and 244 UC (57% women) cases were identified and matched to 440 and 976 controls, respectively. Total polyphenol intake was not associated with CD (P trend = 0.17) or UC (P trend = 0.16). For flavones and CD, there were reduced odds for all quartiles, which were statistically significant for the third (OR3rd versus 1st quartile = 0.33; 95% confidence interval, 0.15-0.69) and there was an inverse trend across quartiles (P = 0.03). Similarly, for resveratrol, there was an inverse association with CD (OR4th versus 1st quartile = 0.40; 95% confidence interval, 0.20-0.82) with an inverse trend across quartiles (P = 0.02). No significant associations between subtypes of polyphenols and UC were found. Effect modification by smoking in CD was documented with borderline statistical significance. CONCLUSIONS: The data supports a potential role of flavones and resveratrol in the risk of developing CD; future aetiological studies should investigate these dietary components and further examine the potential for residual confounding.

Is there a role for vitamin C in preventing osteoporosis and fractures? A review of the potential underlying mechanisms and current epidemiological evidence.

Osteoporosis and related fractures are a major global health issue, but there are few preventative strategies. Previously reported associations between higher intakes of fruits and vegetables and skeletal health have been suggested to be partly attributable to vitamin C. To date, there is some evidence for a potential role of vitamin C in osteoporosis and fracture prevention but an overall consensus of published studies has not yet been drawn. The present review aims to provide a summary of the proposed underlying mechanisms of vitamin C on bone and reviews the current evidence in the literature, examining a potential link between vitamin C intake and status with osteoporosis and fractures. The Bradford Hill criteria were used to assess reported associations. Recent animal studies have provided insights into the involvement of vitamin C in osteoclastogenesis and osteoblastogenesis, and its role as a mediator of bone matrix deposition, affecting both the quantity and quality of bone collagen. Observational studies have provided some evidence for this in the general population, showing positive associations between dietary vitamin C intake and supplements and higher bone mineral density or reduced fracture risk. However, previous intervention studies were not sufficiently well designed to evaluate these associations. Epidemiological data are particularly limited for vitamin C status and for fracture risk and good-quality randomised controlled trials are needed to confirm previous epidemiological findings. The present review also highlights that associations between vitamin C and bone health may be non-linear and further research is needed to ascertain optimal intakes for osteoporosis and fracture prevention.

Phasic dopamine release in the nucleus accumbens in response to pro-social 50 kHz ultrasonic vocalizations in rats.

Rats emit ultrasonic vocalizations (USVs) that are thought to serve as situation-dependent affective signals and accomplish important communicative functions. In appetitive situations, rats produce 50 kHz USVs, whereas 22 kHz USVs occur in aversive situations. Reception of 50 kHz USVs induces social approach behavior, while 22 kHz USVs lead to freezing behavior. These opposite behavioral responses are paralleled by distinct brain activation patterns, with 50 kHz USVs, but not 22 kHz USVs, activating neurons in the nucleus accumbens (NAcc). The NAcc mediates appetitive behavior and is critically modulated by dopaminergic afferents that are known to encode the value of reward. Therefore, we hypothesized that 50 kHz USVs, but not 22 kHz USVs, elicit NAcc dopamine release. While recording dopamine signaling with fast-scan cyclic voltammetry, freely moving rats were exposed to playback of four acoustic stimuli via an ultrasonic speaker in random order: (1) 50 kHz USVs, (2) 22 kHz USVs, (3) time- and amplitude-matched white noise, and (4) background noise. Only presentation of 50 kHz USVs induced phasic dopamine release and elicited approach behavior toward the speaker. Both of these effects, neurochemical and behavioral, were most pronounced during initial playback, but then declined rapidly with subsequent presentations, indicating a close temporal relationship between the two measures. Moreover, the magnitudes of these effects during initial playback were significantly correlated. Collectively, our findings show that NAcc dopamine release encodes pro-social 50 kHz USVs, but not alarming 22 kHz USVs. Thus, our results support the hypothesis that these call types are processed in distinct neuroanatomical regions and establish a functional link between pro-social communicative signals and reward-related neurotransmission.

Dietary antioxidants and the aetiology of pancreatic cancer: a cohort study using data from food diaries and biomarkers.

OBJECTIVE: To investigate whether the dietary antioxidants vitamins C and E, selenium and zinc decrease the risk of developing pancreatic cancer, for the first time using 7-day food diaries, the most accurate dietary methodology in prospective work. DESIGN: 23,658 participants, aged 40-74 years, recruited into the EPIC-Norfolk Study completed 7-day food diaries which recorded foods, brands and portion sizes. Nutrient intakes were calculated in those later diagnosed with pancreatic cancer and in 3970 controls, using a computer program with information on 11,000 foods. Vitamin C was measured in serum samples. The HRs of developing pancreatic cancer were estimated across quartiles of intake and thresholds of the lowest quartile (Q1) against a summation of the three highest (Q2-4). RESULTS: Within 10 years, 49 participants (55% men), developed pancreatic cancer. Those eating a combination of the highest three quartiles of all of vitamins C and E and selenium had a decreased risk (HR=0.33, 95% CI 0.13 to 0.84, p<0.05). There were threshold effects (Q2-4 vs Q1) for selenium (HR=0.49, 95% CI 0.26 to 0.93, p<0.05) and vitamin E (HR=0.57, 95% CI 0.29 to 1.09, p<0.10). The HRs of quartiles for antioxidants, apart from zinc, were <1, but not statistically significant. For vitamin C, there was an inverse association with serum measurements (HR trend=0.67, 95% CI 0.49 to 0.91, p=0.01), but the threshold effect from diaries was not significant (HR=0.68, 95% CI 0.37 to 1.26). CONCLUSION: The results support measuring antioxidants in studies investigating the aetiology of pancreatic cancer. If the association is causal, 1 in 12 cancers might be prevented by avoiding the lowest intakes.

Effects of a surface topography composite with puerariae radix on human STRO-1-positive stem cells.

Human skeletal stem cells (STRO-1 positive/STRO-1+) respond to different topographical features in various ways. On a flat surface these cells spread and tend to develop a fibroblast-like morphology. On a microgrooved surface enriched skeletal stem cell populations prefer to stretch along the grooves, which affects their cellular structure and differentiation, a phenomenon known as contact guidance. Growth factors, hormones and chemicals can also stimulate cell differentiation. A traditional Chinese medicine, puerariae radix, has previously been observed to stimulate bone formation. The active ingredients have been identified as isoflavones with estrogen-like bioactivity. This study combined the effects of microgrooved topology and hormone-like isoflavones in the biodegradable polymer polycaprolactone (PCL). Human osteogenic cells (STRO-1+) were cultured on flat PCL, grooved PCL and puerariae powder-impregnated grooved PCL for 5 weeks. Coomassie staining indicated that cell growth and survival was similar on flat PCL, grooved PCL and grooved PCL impregnated with 1 wt.% or 2 wt.% puerariae powder. Grooved PCL impregnated with 2 wt.% puerariae powder was observed to have an influence on protein expression, as observed by positive osteocalcin staining. Protein expression profiles were analyzed by difference gel electrophoresis to identify proteins that showed modulation of expression in response to these different environments. Overall, our results suggest that puerariae powder has an additive effect, along with microgrooved topographical stimulation, to promote changes in the STRO-1+ proteome that affect cell phenotype.

Dietary n-3 polyunsaturated fatty acids and the aetiology of ulcerative colitis: a UK prospective cohort study.

OBJECTIVES: The aetiology of ulcerative colitis (UC) is largely unknown, although it is plausible that dietary n-3 polyunsaturated fatty acids (PUFAs) may be protective. Metabolites derived from n-3 PUFAs are less proinflammatory than those from n-6 PUFAs. Earlier, no prospective cohort studies have investigated this hypothesis, using dietary information collected from food diaries. The aim of this study was to investigate the total dietary intake of n-3 PUFAs and the specific n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the risk of developing incident UC. METHODOLOGY: Twenty-five thousand six hundred and thirty-nine participants, living in Norfolk UK, aged 45-74 years (median age at recruitment of 59.2 years), completed 7-day food diaries. These were interpreted using a computer programme, which converted food items into nutrients, including n-3 PUFAs. The cohort was monitored for participants who developed UC. Each case was matched with four controls and an analysis performed using conditional logistic regression. RESULTS: In the cohort, 22 incident cases of UC were identified after a median follow-up time of 4.2 years (range 1.8-8.3 years). A statistically significant protective odds ratio (OR) for the trend across tertiles was found for DHA [OR = 0.43, 95% confidence interval (CI)=0.22-0.86, P = 0.02] and borderline statistically significant differences for trends for total total n-3 PUFAs (OR = 0.56, 95% CI=0.28-1.13, P = 0.10) and EPA (OR = 0.53, 95% CI=0.27-1.03, P = 0.06) after adjusting for age, sex, total energy intake, smoking, and other fatty acids. CONCLUSION: Total dietary n-3 PUFAs, EPA, and DHA, particularly DHA were associated with protection from UC in a cohort aged over 45 years. If the association is causal, then increasing the population's intake of n-3 PUFAs from oily fish may help prevent UC.

Increased consumption of fatty and lean fish reduces serum C-reactive protein concentrations but not inflammation markers in feces and in colonic biopsies.

Fish consumption is associated with a reduced colorectal cancer risk. A possible mechanism by which fish consumption could decrease colorectal cancer risk is by reducing inflammation. However, thus far, intervention studies investigating both systemic and local gut inflammation markers are lacking. Our objective in this study was to investigate the effects of fatty and lean fish consumption on inflammation markers in serum, feces, and gut. In an intervention study, participants were randomly allocated to receive dietary advice (DA) plus either 300 g of fatty fish (salmon) or 300 g of lean fish (cod) per week for 6 mo, or only DA. Serum C-reactive protein (CRP) concentrations were measured pre- and postintervention (n = 161). In a subgroup (n = 52), we explored the effects of the fish intervention on fecal calprotectin and a wide range of cytokines and chemokines in fecal water and in colonic biopsies. Serum CRP concentrations were lower in the salmon (-0.5 mg/L; 95% CI -0.9, -0.2) and cod (-0.4 mg/L; 95% CI -0.7, 0.0) groups compared with the DA group. None of the inflammation markers in fecal water and colonic biopsies differed between the DA group and the groups that consumed extra fish. In conclusion, increasing salmon or cod consumption for 6 mo resulted in lower concentrations of the systemic inflammation marker CRP. However, exploratory analysis of local markers of inflammation in the colon or feces did not reveal an effect of fish consumption.

Acetyl-l-carnitine increases nerve regeneration and target organ reinnervation - a morphological study.

Peripheral nerve injury frequently results in functional morbidity since standard management fails to adequately address many of the neurobiological hurdles to optimal regeneration. Neuronal survival and regeneration are neurotrophin dependent and require increased aerobic capacity. Acetyl-l-carnitine (ALCAR) facilitates this need and prevents neuronal loss. ALCAR is clinically safe and is shown here to significantly improve nerve regeneration and target organ reinnervation. Two groups of five rats underwent sciatic nerve division followed by immediate repair. One group received parenteral ALCAR (50mg/kg/day) from time of operation until termination at 12 weeks. A 'sham treatment' group received normal saline. A third group was left unoperated and did not receive any treatment. A segment of nerve was harvested between 5mm proximal and 10mm distal to the repair in operated groups, and at the corresponding level in the unoperated group. Mean axonal count in normal, non-axotomised nerve was 14,720 (SD 2378). That of the saline group (17,217 SD 1808) was not significantly different from normal nerve (P=0.0985). Mean number of myelinated axons in the ALCAR group (24,460 SD 3750) was significantly greater than both sham group (P<0.01) and normal nerve (P=0.0012). Mean myelin thickness in the saline treated group (0.408 microm SD 0.067 microm) was less than normal nerve (0.770 microm SD 0.143 microm) (P<0.001). Mean myelin thickness in the ALCAR group (0.627 microm SD 0.052 microm) was greater than the sham (saline) group (P<0.01) and not statistically different from normal nerve (P=0.07). ALCAR increased dermal PGP9.5 staining by 210% compared to sham treatment (P<0.0001) and significantly reduced the mean percentage weight loss in gastrocnemius muscle (ALCAR group 0.203% vs. 0.312% in sham group P=0.015). ALCAR not only increases the number of regenerating nerve fibres but also morphologically improves the quality of regeneration and target organ reinnervation. Adjuvant ALCAR treatment may improve both sensory and motor outcomes and merits further investigation.

Fabrication of pillar-like titania nanostructures on titanium and their interactions with human skeletal stem cells.

Surface nanotopography is known to influence the interaction of human skeletal (mesenchymal) stem cells (hMSC) with a material surface. While most surface nanopatterning has been performed on polymer-based surfaces there is a need for techniques to produce well-defined topography features with tuneable sizes on relevant load-bearing implant materials such as titanium (Ti). In this study titania nanopillar structures with heights of either 15, 55 or 100 nm were produced on Ti surfaces using anodization through a porous alumina mask. The influence of the surface structure heights on hMSC adhesion, spreading, cytoskeletal formation and differentiation was examined. The 15 nm high topography features resulted in the greatest cell response with bone matrix nodule forming on the Ti surface after 21 days.

Cardiovascular effects of Nemopilema nomurai (Scyphozoa: Rhizostomeae) jellyfish venom in rats.

Over the past few years, populations of the giant jellyfish Nemopilema nomurai (Scyphozoa: Rhizostomeae) have increased dramatically in the waters of China, Korea, and Japan without any definitive reason. This has resulted in severe damage to fisheries in the areas. During a pilot study, we observed that the venom of N. nomurai produced a functional cardiac depression in mice. However, the mechanism of action was not examined. In the present study, we investigated the cardiovascular effects of nematocyst-derived venom from N. nomurai in anesthetized rats. Venom (0.1-2.4 mg protein/kg, i.v.) produced dose-dependent hypotension (65+/-12% of initial at a cumulative dose of 3 mg/kg) and bradycardia (80+/-5% of initial at a cumulative dose of 3 mg/kg). At the highest dose, this was characterized by a transient decrease in blood pressure (phase 1) followed by a return to basal level and then a slower decrease in blood pressure (phase 2). Venom also produced a decrease in rate and force of contraction in the rat isolated atria. Interestingly, venom induced a contraction of isolated aortic rings which was blocked by felodipine but not by prazosin, suggesting the contraction is mediated by calcium channel activation. These results suggest that the negative inotropic and chronotropic effects of the venom of N. nomurai may be due to a direct effect on the heart.

Systemic acetyl-L-carnitine eliminates sensory neuronal loss after peripheral axotomy: a new clinical approach in the management of peripheral nerve trauma.

Several hundred thousand peripheral nerve injuries occur each year in Europe alone. Largely due to the death of around 40% of primary sensory neurons, sensory outcome remains disappointingly poor despite considerable advances in surgical technique; yet no clinical therapies currently exist to prevent this neuronal death. Acetyl- L-carnitine (ALCAR) is a physiological peptide with roles in mitochondrial bioenergetic function, which may also increase binding of nerve growth factor by sensory neurons. Following unilateral sciatic nerve transection, adult rats received either one of two doses of ALCAR or sham, or no treatment. Either 2 weeks or 2 months later, L4 and L5 dorsal root ganglia were harvested bilaterally, in accordance with the Animal (Scientific Procedures) Act 1986. Neuronal death was quantified with a combination of TUNEL [TdT (terminal deoxyribonucleotidyl transferase) uptake nick end labelling] and neuron counts obtained using the optical disector technique. Sham treatment had no effect upon neuronal death. ALCAR treatment caused a large reduction in the number of TUNEL-positive neurons 2 weeks after axotomy (sham treatment 33/group; low-dose ALCAR 6/group, P=0.132; high-dose ALCAR 3/group, P<0.05), and almost eliminated neuron loss (sham treatment 21%; low-dose ALCAR 0%, P=0.007; high-dose ALCAR 2%, P<0.013). Two months after axotomy the neuroprotective effect of high-dose ALCAR treatment was preserved for both TUNEL counts (no treatment five/group; high-dose ALCAR one/group) and neuron loss (no treatment 35%; high-dose ALCAR -4%, P<0.001). These results provide further evidence for the role of mitochondrial bioenergetic dysfunction in post-traumatic sensory neuronal death, and also suggest that acetyl- L-carnitine may be the first agent suitable for clinical use in the prevention of neuronal death after peripheral nerve trauma.