Erythropoietin-Induced Activation of the JAK2/STAT5, PI3K/Akt, and Ras/ERK Pathways Promotes Malignant Cell Behavior in a Modified Breast Cancer Cell Line

Abstract Erythropoietin (Epo), the major regulator of erythropoiesis, and its cognate receptor (EpoR) are also expressed in nonerythroid tissues, including tumors. Clinical studies have highlighted the potential adverse effects of erythropoiesis-stimulating agents when used to treat cancer-related anemia. We assessed the ability of EpoR to enhance tumor growth and invasiveness following Epo stimulation. A benign noninvasive rat mammary cell line, Rama 37, was used as a model system. Cell signaling and malignant cell behavior were compared between parental Rama 37 cells, which express few or no endogenous EpoRs, and a modified cell line stably transfected with human EpoR (Rama 37-28). The incubation of Rama 37-28 cells with pharmacologic levels of Epo led to the rapid and sustained increases in phosphorylation of signal transducers and activators of transcription 5, Akt, and extracellular signal-regulated kinase. The activation of these signaling pathways significantly increased invasion, migration, adhesion, and colony formation. The Epo-induced invasion capacity of Rama 37-28 cells was reduced by the small interfering RNA-mediated knockdown of EpoR mRNA levels and by inhibitors of the phosphoinositide 3-kinase/Akt and Ras/extracellular signal-regulated kinase signaling pathways with adhesion also reduced by Janus-activated kinase 2/signal transducers and activators of transcription 5 inhibition. These data show that Epo induces phenotypic changes in the behavior of breast cancer cell lines and establishes links between individual cell signaling pathways and the potential for cancer spread.

RS-0406 arrests amyloid-B oligomer-induced behavioural deterioration in vivo

Clinically accessible compounds that arrest or reverse the effects of amyloid-ß (Aß) on progressively developing behavioural symptomatology and neuropathology in Alzheimer's disease (AD) have yet to become available. However, a viable strategy may be to target and neutralise soluble Aß oligomers, which have been shown to mediate synaptic dysfunction and to produce cognitive deficits in the intact organism. Inhibiting the aggregation of Aß is therapeutically attractive, as Aß aggregation is a pathological event and pharmacological interventions targeting this are likely to have a non-toxic profile. A behavioural assay, the alternating-lever cyclic-ratio schedule, was used to assess the effect of Aß oligomers and the non-peptide small molecule RS-0406 in male Sprague-Dawley rats. RS-0406 has been shown to inhibit Aß1-42 fibrillogenesis and protect against Aß1-42–induced cytotoxicity in primary hippocampal neurons. In the current study, RS-0406 ameliorated the adverse effects of secreted oligomers of human Aß on behaviour and dose dependently reduced the behavioural effects of Aß oligomers, with the highest dose, 10 µM, maintaining behaviour approximately at control levels. This effect appeared to be central; peripheral confounds having been extensively investigated. This is the first published report on the effects of RS-0406 in vivo and indicates that RS-0406 has potential as a pharmacotherapeutic intervention for behavioural deficits seen in the early stages of AD, and possibly as an intervention in the development of AD neuropathology. Indeed, an analogue of RS-0406 that could be administered peripherally might be a realistic candidate for the clinical treatment of AD.

Comparison of three adjuvants used to produce polyclonal antibodies to veterinary drugs

Two commercially available adjuvants, Gerbu LQ 3000 and Montanide ISA 50V, were assessed as potential replacements for Freund's adjuvant by evaluating their efficacy in the production of polyclonal antibodies to veterinary drugs in rabbits. The aim was to find an adjuvant that could produce a similar (or enhanced) immune response in the host animal without the undesirable side effects associated with Freund's complete and incomplete adjuvant. The assessment involved the examination of each injection site and the characterisation of the resultant antibodies with regards to antibody titre and sensitivity. It was found that the rabbits immunised with Gerbu adjuvant produced some of the most sensitive antibodies. However, titres were relatively low and adverse effects at injection sites were relatively common. Montanide adjuvant produced no adverse effects and the related antibodies were found to be of adequate sensitivity when compared to those from rabbits immunised with Freund's. It was concluded that Montanide ISA 50V could be considered as a suitable replacement to Freund's for the production of polyclonal antibodies, to low molecular weight compounds in rabbits. (C) 2007 Elsevier B.V. All rights reserved.

Indicators of the impact of climate change on migratory species

The Bonn Convention on the Conservation of Migratory Species of Wild Animals adopted a Resolution in 2005 recognising the impacts of climate change on migratory species. It called on Contracting Parties to undertake more research to improve our understanding of these impacts and to implement adaptation measures to reduce foreseeable adverse effects. Given the large diversity of taxa and species affected by climate change, it is impossible to monitor all species and effects thereof. However, it is likely that many of the key ecological and physical processes through which climate change may impact wildlife could be monitored using a suite of indicators, each comprising parameters of species/populations or groups of species as proxies for wider assemblages, habitats and ecosystems. Herein, we identify a suite of 17 indicators whose attributes could reveal negative impacts of climate change on the global status of migratory species: 4 for birds, 4 for marine mammals, 2 for sea turtles, 1 for fish, 3 for land mammals and 3 for bats. A few of these indicators would be relatively straightforward to develop, but most would require additional data collation, and in many cases methodological development. Choosing and developing indicators of the impacts of climate change on migratory species is a challenge, particularly with endangered species, which are subject to many other pressures. To identify and implement conservation measures for these species, indicators must account for the full ensemble of pressures, and link to a system of alerts and triggers for action.

Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia

Background: This is an update of a previous review (McGuinness 2006). Hypertension and cognitive impairment are prevalent in older people. Hypertension is a direct risk factor for vascular dementia (VaD) and recent studies have suggested hypertension impacts upon prevalence of Alzheimer's disease (AD). Therefore does treatment of hypertension prevent cognitive decline?
Objectives: To assess the effects of blood pressure lowering treatments for the prevention of dementia and cognitive decline in patients with hypertension but no history of cerebrovascular disease.
Search strategy: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS as well as many trials databases and grey literature sources were searched on 13 February 2008 using the terms: hypertens$ OR anti-hypertens$. Selection criteria: Randomized, double-blind, placebo controlled trials in which pharmacological or non-pharmacological interventions to lower blood pressure were given for at least six months.
Data collection and analysis: Two independent reviewers assessed trial quality and extracted data. The following outcomes were assessed: incidence of dementia, cognitive change from baseline, blood pressure level, incidence and severity of side effects and quality of life.
Main results: Four trials including 15,936 hypertensive subjects were identified. Average age was 75.4 years. Mean blood pressure at entry across the studies was 171/86 mmHg. The combined result of the four trials reporting incidence of dementia indicated no significant difference between treatment and placebo (236/7767 versus 259/7660, Odds Ratio (OR) = 0.89, 95% CI 0.74, 1.07) and there was considerable heterogeneity between the trials. The combined results from the three trials reporting change in Mini Mental State Examination (MMSE) did not indicate a benefit from treatment (Weighted Mean Difference (WMD) = 0.42, 95%CI 0.30, 0.53). Both systolic and diastolic blood pressure levels were reduced significantly in the three trials assessing this outcome (WMD = -10.22, 95% CI -10.78, -9.66 for systolic blood pressure, WMD = -4.28, 95% CI -4.58, -3.98 for diastolic blood pressure). Three trials reported adverse effects requiring discontinuation of treatment and the combined results indicated no significant difference (OR = 1.01, 95% CI 0.92, 1.11). When analysed separately, however, more patients on placebo in Syst Eur 1997 were likely to discontinue treatment due to side effects; the converse was true in SHEP 1991. Quality of life data could not be analysed in the four studies. Analysis of the included studies in this review was problematic as many of the control subjects received antihypertensive treatment because their blood pressures exceeded pre-set values. In most cases the study became a comparison between the study drug against a usual antihypertensive regimen.
Authors' conclusions: There is no convincing evidence fromthe trials identified that blood pressure lowering in late-life prevents the development of dementia or cognitive impairment in hypertensive patients with no apparent prior cerebrovascular disease. There were significant problems identified with analysing the data, however, due to the number of patients lost to follow-up and the number of placebo patients who received active treatment. This introduced bias. More robust results may be obtained by conducting a meta-analysis using individual patient data.

Statins for the prevention of dementia

Background: This is an update of a Cochrane review first published in 2001. At that stage there was insufficient evidence to recommend statins for the prevention of Alzheimer's disease (AD). The scope of this review has been expanded to include all forms of dementia.
Objectives: To assess the effects of statins in the prevention of dementia.
Search strategy: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 10 October 2007 using the terms statin*, lovastatin*, pravastatin*, simvastatin*, fluvastatin*, atorvastatin* and rosuvastatin*. The CDCIG Register contains records from many healthcare databases, SIGLE, LILACS as well as many trials databases and is updated regularly.
Selection criteria: Double-blind randomized placebo-controlled trials of statins in people at risk of AD and dementia.
Data collection and analysis: Two independent reviewers extracted and assessed data independently and agreement was reached after discussion. Adverse effects were noted.
Main results: Two trials were identified with 26,340 participants; HPS 2002 and PROSPER 2002. Age range was 40-82 years across the two studies, PROSPER 2002 included 5804 patients aged 70-82 years and HPS included 20,536 patients with 5806 at least 70 years old at study entry. Mean total cholesterol 5.9 mmol/l, LDL cholesterol 3.4 mmol/l at study entry with mean reduction in LDL cholesterol of 1.0mmol/l in simvastatin treated patients compared to placebo in HPS 2002. Mean total cholesterol 5.7 mmol/l, LDL cholesterol 3.8 mmol/l at study entry with mean reduction in LDL cholesterol of 1.02 mmol/l in pravastatin treated patients compared to placebo in PROSPER 2002. Mean follow-up 3.2 years in PROSPER, 5 years in HPS 2002. Cognition was measured at different times and with different scales so could not be combined in a meta-analysis. There was no difference in incidence of dementia in HPS 2002 (31 cases in simvastatin group, 31 cases in placebo group) nor in performance on the modified Telephone Interview for Cognitive Status at final follow-up (23.7% simvastatin group cognitively impaired vs 24.2% in placebo group). There was no difference in cognition between groups either in relation to age at study entry or previous history of cerebrovascular disease. Cognitive function declined at the same rate in both treatment groups in PROSPER 2002, there was no significant difference between pravastatin treated and placebo groups in performance on letter digit codes, picture word learning test, Stroop and Mini Mental State Examination. There was no evidence that statins were detrimental to cognition.
Authors' conclusions : There is good evidence from RCTs that statins given in late life to individuals at risk of vascular disease have no effect in preventing AD or dementia. Biologically it seems feasible that statins could prevent dementia due to their role in cholesterol reduction and initial evidence from observational studies was very promising. Indication bias may have been a factor in these studies however and the evidence from subsequent RCTs has been negative.

Exercise and Auricular Acupuncture for Chronic Low Back Pain: A Feasibility Randomised Controlled Trial

Objectives: To evaluate the feasibility of a randomized-controlled trial (RCT) investigating the effects of adding auricular acupuncture (AA) to exercise for participants with chronic low-back pain (CLBP). Methods: Participants with CLBP were recruited from primary care and a university population and were randomly allocated (n=51) to 1 of 2 groups: (1) "Exercise Alone (E)"-12-week program consisting of 6 weeks of supervised exercise followed by 6 weeks unsupervised exercise (n=27); or (2) "Exercise and AA (EAA)"-12-week exercise program and AA (n=24). Outcome measures were recorded at baseline, week 8, week 13, and 6 months. The primary outcome measure was the Oswestry Disability Questionnaire. Results: Participants in the EAA group demonstrated a greater mean improvement of 10.7% points (95% confidence interval, -15.3,-5.7) (effect size=1.20) in the Oswestry Disability Questionnaire at 6 months compared with 6.7% points (95% confidence interval, -11.4,-1.9) in the E group (effect size=0.58). There was also a trend towards a greater mean improvement in quality of life, LBP intensity and bothersomeness, and fear-avoidance beliefs in the EAA group. The dropout rate for this trial was lower than anticipated (15% at 6 mo), adherence with exercise was similar (72% E; 65% EAA). Adverse effects for AA ranged from 1% to 14% of participants. Discussion: Findings of this study showed that a main RCT is feasible and that 56 participants per group would need to be recruited, using multiple recruitment approaches. AA was safe and demonstrated additional benefits when combined with exercise for people with CLBP, which requires confirmation in a fully powered RCT.

Effect of Inhibitor Compounds on N-epsilon-(Carboxymethyl)lysine (CML) and N-epsilon-(Carboxyethyl)lysine (CEL) Formation in Model Foods

The possible adverse effects on health of diet-derived advanced glycation endproducts (AGES) and advanced lipoxidation endproducts (ALES) is of current interest. This study had the objective of determining the effects of the addition of AGE/ALE inhibitors and different types of sugar and cooking oil on N-epsilon-(carboxymethyl)lysine (CML) and N-epsilon-(carboxyethyl)lysine (CEL) formation in model foods (sponge cakes). The cake baked using glucose produced the highest level of CML (2.07 +/- 0.24 mmol/mol lysine), whereas the cake baked using fructose produced the highest concentration of CEL (25.1 +/- 0.15 mmol/mol lysine). There were no significant differences between CML concentrations formed in the cakes prepared using different types of cooking oil, but significant differences (P

Long Term Use of HU210 Adversely Affects Spermatogenesis in Rats by modulating the Endocannabinoid System

Recent societal acceptance of cannabinoids as recreational and therapeutic drugs has posed a potential hazard to male reproductive health. Mammals have a highly sophisticated endogenous cannabinoid (ECS) system that regulates male (and female) reproduction and exo-cannabinoids may influence it adversely. Therefore it is imperative to determine their effects on male reproduction so that men can make informed choices as to their use. Here, an animal model was used to administer HU210, a synthetic analogue of ?9-tetrahydrocannabinol (THC) and potent cannabinoid receptor (CB) agonist to determine its effects on reproductive organ weights, spermatogenesis, testicular histology and sperm motility. Its effects on the physiological endocannabinoid system were also investigated. Spermatogenesis was markedly impaired with reductions in total sperm count after 2 weeks of exposure. Spermatogenic efficiency was depleted, and Sertoli cell number decreased as exposure time increased with seminiferous tubules showing germ cell depletion developing into atrophy in some cases. Sperm motility was also adversely affected with marked reductions from 2 weeks on. HU210 also acted on the sperm’s endocannabinoid system. Long term use of exo-cannabinoids has adverse effects on both spermatogenesis and sperm function. These findings highlight the urgent need for studies evaluating the fertility potential of male recreational drug users.

N-epsilon-(carboxymethyl)lysine content of foods commonly consumed in a Western style diet

The potential adverse effects on health of diet-derived advanced glycation end-products (AGEs) is of current interest, due to their proposed involvement in the disease progression of diabetic and uraemic conditions. However, accurate information about levels of AGEs in foods is lacking. The objective of this investigation was to determine the level of one particular AGE, N-epsilon-(carboxymethyl)lysine (CML), a marker of AGE formation, in a wide range of foods commonly consumed in a Western style diet. Individual foods (n = 257) were mixed, lyophilised, ground, reduced, fat-extracted, hydrolysed, and underwent solid-phase extraction. Extracts were analysed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Cereal (2.6 mg/100 g food) and fruit and vegetable (0.13 mg/100 g food) categories had the highest and lowest mean level of CML, respectively, when expressed in mg/100 g food. These data can be used for estimating potential consumer intakes, and provide information that can be used to educated consumers on how to reduce their CML intake. (C) 2011 Elsevier Ltd. All rights reserved.

Cognitive-behavioural interventions for children who have been sexually abused

Background: Despite differences in how it is defined, there is a general consensus amongst clinicians and researchers that the sexual abuse of children and adolescents (’child sexual abuse’) is a substantial social problem worldwide. The effects of sexual abuse manifest in a wide range of symptoms, including fear, anxiety, post-traumatic stress disorder and various externalising and internalising behaviour problems, such as inappropriate sexual behaviours. Child sexual abuse is associated with increased risk of psychological problems in adulthood. Cognitive-behavioural approaches are used to help children and their non-offending or ’safe’ parent tomanage the sequelae of childhood sexual abuse. This review updates the first Cochrane review of cognitive-behavioural approaches interventions for children who have been sexually abused, which was first published in 2006.

Objectives: To assess the efficacy of cognitive-behavioural approaches (CBT) in addressing the immediate and longer-term sequelae of sexual abuse on children and young people up to 18 years of age.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2011 Issue 4); MEDLINE (1950 to November Week
3 2011); EMBASE (1980 to Week 47 2011); CINAHL (1937 to 2 December 2011); PsycINFO (1887 to November Week 5 2011); LILACS (1982 to 2 December 2011) and OpenGrey, previously OpenSIGLE (1980 to 2 December 2011). For this update we also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP).

Selection criteria: We included randomised or quasi-randomised controlled trials of CBT used with children and adolescents up to age 18 years who had experienced being sexually abused, compared with treatment as usual, with or without placebo control.

Data collection and analysis: At least two review authors independently assessed the eligibility of titles and abstracts identified in the search. Two review authors independently extracted data from included studies and entered these into Review Manager 5 software. We synthesised and presented data in both written and graphical form (forest plots).

Main results: We included 10 trials, involving 847 participants. All studies examined CBT programmes provided to children or children and a nonoffending parent. Control groups included wait list controls (n = 1) or treatment as usual (n = 9). Treatment as usual was, for the most part, supportive, unstructured psychotherapy. Generally the reporting of studies was poor. Only four studies were judged ’low risk of bias’ with regards to sequence generation and only one study was judged ’low risk of bias’ in relation to allocation concealment. All studies were judged ’high risk of bias’ in relation to the blinding of outcome assessors or personnel; most studies did not report on these, or other issues of bias. Most studies reported results for study completers rather than for those recruited.

Depression, post-traumatic stress disorder (PTSD), anxiety and child behaviour problems were the primary outcomes. Data suggest that CBT may have a positive impact on the sequelae of child sexual abuse, but most results were not statistically significant. Strongest evidence for positive effects of CBT appears to be in reducing PTSD and anxiety symptoms, but even in these areas effects tend to be 'moderate’ at best. Meta-analysis of data from five studies suggested an average decrease of 1.9 points on the Child Depression Inventory immediately after intervention (95% confidence interval (CI) decrease of 4.0 to increase of 0.4; I2 = 53%; P value for heterogeneity = 0.08), representing a small to moderate effect size. Data from six studies yielded an average decrease of 0.44 standard deviations on a variety of child post-traumatic stress disorder scales (95% CI 0.16 to 0.73; I2 = 46%; P value for heterogeneity = 0.10). Combined data from five studies yielded an average decrease of 0.23 standard deviations on various child anxiety scales (95% CI 0.3 to 0.4; I2=0%; P value for heterogeneity = 0.84). No study reported adverse effects.

Authors’ conclusions: The conclusions of this updated review remain the same as those when it was first published. The review confirms the potential of CBT to address the adverse consequences of child sexual abuse, but highlights the limitations of the evidence base and the need for more carefully conducted and better reported trials.

Thalidomide for managing cancer cachexia [review paper]

Cancer cachexia is a multidimensional syndrome characterised by wasting, loss of weight, loss of appetite, metabolic alterations, fatigue and reduced performance status. A significant number of patients with advanced cancer develop cachexia before death. There is no identified optimum treatment for cancer cachexia. While the exact mechanism of the action of thalidomide is unclear, it is known to have immunomodulatory and anti-inflammatory properties, which are thought to help reduce the weight loss associated with cachexia. Preliminary studies of thalidomide have demonstrated encouraging results. This review aimed to (1) evaluate the effectiveness of thalidomide, and (2) identify and assess adverse effects from thalidomide for cancer cachexia. Electronic searches were undertaken in CENTRAL, MEDLINE, EMBASE, Web of Science and CINAHL (from inception to April 2011). Reference lists from reviewed articles, trial registers, relevant conference documents and thalidomide manufacturers identified additional literature. This review included randomised controlled trials (RCTs) and non-RCTs. Participants were adults diagnosed with advanced or incurable cancer and weight loss or a clinical diagnosis of cachexia who were administered thalidomide. All titles and abstracts retrieved by electronic searching were downloaded to a reference management database. Duplicates were removed and the remaining citations were read by two review authors and checked for eligibility. Studies that were deemed ineligible for inclusion had clear reasons for exclusion documented. Data were extracted independently by two review authors for all eligible studies. While a meta-analysis was planned for this review, this was not possible due to the small number of studies included and high heterogeneity among them. Thus a narrative synthesis of the findings is presented. The literature search revealed a dearth of large, well conducted trials in this area. This has hindered the review authors' ability to make an informed decision about thalidomide for the management of cancer cachexia. At present, there is insufficient evidence to refute or support the use of thalidomide for the management of cachexia in advanced cancer patients. The review authors cannot confirm or refute previous literature on the use of thalidomide for patients with advanced cancer who have cachexia and there is inadequate evidence to recommend it for clinical practice. Additional, well conducted, large RCTs are needed to test thalidomide both singularly and in combination with other treatment modalities to ascertain its true benefit, if any, for this population. Furthermore, one study (out of the three reviewed) highlighted that thalidomide was poorly tolerated and its use needs to be explored further in light of the frailty of this population

Pharmacological Activity of Ibuprofen Release from Measoporous Silica

Novel drug delivery systems (DDS) to improve the pharmacokinetic profile of hydrophobic drugs following oral administration are an area of keen interest in drug research. An ideal DDS should not adversely affect drug activity, be capable of delivering a therapeutic dose of drug, and allow homogenous drug loading and drug release. Mesoporous silica has been proposed for this application, with ibuprofen employed as the model drug. It was hypothesised that mesoporous silica MCM-41 is capable of delivering a pharmacologically therapeutic dose of ibuprofen. Ibuprofen-loaded MCM-41 can be prepared reproducibly at a drug to carrier ratio of 30% (wt/wt). The release profile was seen to be 90% within 2 h. Initial assessment of COX-1 inhibitory activity suggests the absence of adverse effects attributable to drug-carrier interaction. The results of this study provide further evidence in support of the proposed use of mesoporous silica in drug delivery.

Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial

BACKGROUND:
Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE--an international, open-label, randomised controlled trial--uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A).
METHODS:
Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544.
FINDINGS:
2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·94 (95% CI 0·74-1·20). [corrected]. 2-year FFS was 51% (95% CI 46-56) in arm A and 51% (95% CI 43-58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20-27] patients in arm A and 64 [25%, 19-30] in arm D). The most common grade 3-5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee.
INTERPRETATION:
Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival.

Vegetarian diets, low-meat diets and health:a review

OBJECTIVE: To review the epidemiological evidence for vegetarian diets, low-meat dietary patterns and their association with health status in adults. DESIGN: Published literature review focusing primarily on prospective studies and meta-analyses examining the association between vegetarian diets and health outcomes. RESULTS: Both vegetarian diets and prudent diets allowing small amounts of red meat are associated with reduced risk of diseases, particularly CHD and type 2 diabetes. There is limited evidence of an association between vegetarian diets and cancer prevention. Evidence linking red meat intake, particularly processed meat, and increased risk of CHD, cancer and type 2 diabetes is convincing and provides indirect support for consumption of a plant-based diet. CONCLUSIONS: The health benefits of vegetarian diets are not unique. Prudent plant-based dietary patterns which also allow small intakes of red meat, fish and dairy products have demonstrated significant improvements in health status as well. At this time an optimal dietary intake for health status is unknown. Plant-based diets contain a host of food and nutrients known to have independent health benefits. While vegetarian diets have not shown any adverse effects on health, restrictive and monotonous vegetarian diets may result in nutrient deficiencies with deleterious effects on health. For this reason, appropriate advice is important to ensure a vegetarian diet is nutritionally adequate especially for vulnerable groups.