Efficacy and safety of antihyperglycaemic drug regimens added to metformin and sulphonylurea therapy in Type 2 diabetes: a network meta-analysis.

AIM: To assess the efficacy and safety of third-line adjuvant antihyperglycaemic agents in people with Type 2 diabetes mellitus failing metformin and sulphonylurea combination therapy. METHODS: We searched MEDLINE, CENTRAL, clinicaltrials.gov and regulatory websites, and conducted a manual search of references in the identified studies. Randomized trials evaluating antihyperglycaemic agents in adults with Type 2 diabetes experiencing poor glycaemic control despite optimized metformin and sulphonylurea therapy (≥ 1500 mg metformin or maximum tolerated dose; ≥ 50% of maximum sulphonylurea dose for ≥ 3 weeks) were included. Data extraction included: study characteristics; change in HbA1c concentration; weight; systolic blood pressure; and relative risk of hypoglycaemia, urinary tract infections; and genital tract infections. A network meta-analysis was performed. RESULTS: A total of 20 trials evaluating 13 antihyperglycaemic agents were included. Compared with placebo/control, all antihyperglycaemic agents reduced HbA1c levels, albeit by differing magnitudes [range 7 mmol/mol (0.6%) for acarbose to 13 mmol/mol (1.20%) for liraglutide]. Sodium glucose cotransporter-2 inhibitors reduced weight (1.43-2.07 kg) whereas thiazolidinediones, glargine and sitagliptin caused weight gain (1.48-3.62 kg) compared with placebo/control. Sodium glucose cotransporter-2 inhibitors, rosiglitazone and liraglutide decreased systolic blood pressure compared with placebo/control, pioglitazone, glargine and sitagliptin (2.41-8.88 mm Hg). Glargine, thiazolidinediones, liraglutide, sitagliptin and canagliflozin increased hypoglycaemia risk compared with placebo/control (relative risk 1.92-7.47), while glargine and rosiglitazone increased hypoglycaemia compared with most antihyperglycaemic agents (relative risk 2.81-7.47). No antihyperglycaemic agent increased the risk of urinary tract infection, but canagliflozin increased the risk of genital tract infection by 3.9-fold compared with placebo/control. CONCLUSIONS: When added to metformin and a sulphonylurea, antihyperglycaemic agents had varying effects on efficacy and safety endpoints. These conclusions should be considered when clinicians choose between possible adjunctive agents.

Improper disclosure: tobacco packaging and emission labelling regulations.

OBJECTIVES: Cigarette packets in many countries display emission numbers such as tar. These numbers may be misleading as they do not represent the amount of toxins delivered to human smokers. This study examined how consumers interpret and understand numerical and descriptive emission information. STUDY DESIGN: A discrete choice study was conducted among adult smokers (n = 312) and non-smokers (n = 291) in Ontario, Canada. METHODS: Participants viewed groups of cigarette packets with emission labels from the European Union (EU), Canada and Australia. Participants completed ratings on perceived tar delivery, health risks, and usefulness and understandability of the information. RESULTS: Participants were significantly more likely to believe that Canadian and EU packets with lower emission numbers would have lower tar delivery (92.2% and 89.9%, respectively) and lower health risks (89.5% and 82.9%, respectively) than packets with higher numbers. Approximately 74% of participants rated the numerical Canadian label as providing the most useful information; however, 62% also rated this label as most difficult to understand. Most participants rated the descriptive Australian label as easiest to understand. CONCLUSIONS: Labels featuring quantitative emission values are associated with false beliefs regarding lower tar delivery and health risks. Descriptive statements about emissions are easier to understand and associated with more accurate beliefs.

Analytical performance and potential clinical utility of the GenMark Dx ePlex® blood culture identification gram-positive panel.

The test performance and potential clinical utility of the ePlex® BCID Gram-Positive (GP) Panel was evaluated relative to MALDI-TOF mass spectrometry on bacterial isolates and traditional antimicrobial susceptibility testing. All GP bacteria (n = 100) in the study were represented on the panel including 50 common skin contaminants, and 7/7 coinfections. The positive percent agreement (PPA) was 97/97 with 2 false positives. Detection of vanA yielded a PPA of 4/4 and NPA of 9/9. mecA gene detection exhibited a PPA of 14/14 and NPA of 14/14 for S. aureus and a PPA of 31/32(97%) and NPA of 16/16 for CNS with 1 false negative. Chart reviews (n = 80) identified a mean 24.4h faster time to organism identification, 53.4h earlier optimization in 15(18.8%) patients based on AMR gene detection, 29.2h earlier optimization for 8(10%) patients infected with organisms, such as streptococci, with very low resistance rates, and 42.9h earlier discontinuation of antimicrobials for 14(17.5%) patients with contaminant cultures.

Antiplatelet agents for the prevention of arteriovenous fistula and graft thrombosis: a meta analysis.

AIMS: The aim of this study was to evaluate the impact of antiplatelet agents on the thrombosis rates of arteriovenous fistulae and grafts used for haemodialysis access. METHODS: In this meta analysis, a systematic search of the literature was used to identify randomised controlled trials evaluating the effect of antiplatelet agents in graft or fistula thrombosis or bleeding. Two authors identified eligible trials and abstracted data on outcomes and study characteristics. The incidence of thrombosis was the primary outcome of interest and was calculated separately for studies evaluating grafts and those evaluating fistulae. A random-effects model was used for statistical pooling. RESULTS: Ten trials were included in the analysis, nine of which reported outcomes on graft or fistula thrombosis. Antiplatelet agents reduced the rate of arteriovenous fistulae thrombosis (OR 0.54, 95% CI 0.31-0.94) but not grafts (OR 0.50, 95% CI 0.16-1.53). Both analyses had a moderate degree of statistical heterogeneity, likely because of differences in study design, antiplatelet agent and dose, as well as other possible factors. Review of bleeding events did not reveal a concerning risk of bleeding, but could not be statistically evaluated. CONCLUSIONS: Antiplatelet agents reduce the rate of arteriovenous fistula thrombosis; however, at this time, research does not support the use of these agents for preventing arteriovenous graft thrombosis.

DDE residues and eggshell changes in Alaskan falcons and hawks.

Eggshell thickness after exposure to DDT was reduced by 21.7 percent in Alaskan tundra peregrines, by 16.8 percent in taiga peregrines, by 7.5 percent in Aleutian peregrines, by 3.3 percent in rough-legged hawks, and not at all in gyrfalcons. Tundra peregrine eggs contain an average of 889 parts of DDE per million (lipid basis); taiga peregrine eggs contain 673 parts per million; Aleutian peregrine eggs contain 167 parts per million; rough-legged hawk eggs contain 22.5 parts per million; and gyrfalcon eggs contain 3.88 parts per million. These changes in eggshell thickness and the pesticide residues reflect different degrees of exposure to contamination. There is a highly significant negative correlation between shell thickness and DDE content in peregrine eggs. Tundra and taiga peregrines have fledged progressively fewer young each year since 1966.

Salvaging the dehisced glans penis.

OBJECTIVE: The glans penis may show a deep groove (surgically favorable), or may appear flat with an absent sulcus (unfavorable). Glans dehiscence following hypospadias repair, especially after multiple surgeries, frequently results in a scarred, obliterated, or absent urethral plate. The glans penis appears to be flat and grooveless. This study reported on the outcome of a two-stage salvage repair for glans dehiscence in 49 consecutive patients. MATERIALS AND METHODS: Retrospective chart review was performed for all patients who underwent repair for glans dehiscence following hypospadias repair. RESULTS: Between January 2009 and April 2015, 49 children aged 16 months to 18 years presented with glans dehiscence following hypospadias repair. The prior number of operations ranged from one to six. Eleven children had urethral fistulas, and seven had chordee. In the first stage, the flat glans was incised deeply to visualize, but spare, the corpora. Thereafter, a free graft of oral mucosa harvested either from the lower lip or cheek, or the residual preputial skin, was sutured to the glans cleft. The grafts were fenestrated, quilted in the midline, and a tie-over dressing was applied. Any fistula or chordee was repaired during the first stage. The neo-plate was tubularized 6-12 months later, and urine drainage with a catheter was maintained for 10-14 days. In 11 patients, skin flaps appeared dusky, and nitroglycerine ointment 2% was applied for 24 h to enhance the blood supply of the tissues. Subsequently, six of these children received nine or ten 90-min hyperbaric oxygen therapy sessions. Following the first stage, two patients developed hypertrophy of the mucosal grafts, and one skin graft contracted. These three patients underwent revision using a second buccal mucosal graft harvested from the cheek. One recurrent fistula was closed during the second stage. Following the second stage two patients developed a urethral fistula, and the distal sutures broke down in one patient, resulting in an over-sized meatus. None developed meatal stenosis or glans dehiscence. CONCLUSION: Graft initial take and subsequent behavior were unpredictable, but the two stage approach optimized the process of take and healing. Glans dehiscence was repaired safely and successfully by developing a deep groove, with creation of a new urethral plate followed by tubularization in two stages.

The influence of resting blood pressure on muscle strength in healthy adults.

Adverse alterations in the skeletal muscle response to exercise have been noted among adults with hypertension. The influence of resting blood pressure (BP) on muscle strength is unknown. We hypothesized that adults with high BP would exhibit lower muscular strength than adults with normal BP. An isokinetic dynamometer tested 21 measures of isometric and isokinetic muscle strength. BP was measured by auscultation. Patients were categorized into having normal (<120 and <80 mmHg) or high (≥120 and/or ≥80 mmHg) BP. Height (cm) and weight (kg) were measured to calculate BMI (kg/m). Analysis of covariance tested differences in muscle strength between BP groups with sex, age, and height as covariates. Patients [420 (49%) men] were middle-aged (44.1±16.1 years) and overweight (26.4±4.8 kg/m) with 187 having normal (107.7±7.3/68.3±6.3 mmHg) and 233 having high (127.8±9.8/80.8±8.1 mmHg) BP. For upper body, three of five extension measures and five of five flexion measures, as well as handgrip, were greater in the high than the normal BP group (P≤0.05). For lower body, five of five extension measures were greater in the high than the normal BP group, whereas there were no differences between BP groups for the five flexion measures (P>0.05). Contrary to our hypothesis, adults with high BP displayed greater muscle strength than adults with normal BP. Reasons for our findings are unclear, but may be because of shifts in muscle fiber type from type I to type IIb/x and oxidative to glycolytic metabolism; alterations may result in a more strength-adapted phenotype among adults with high BP such as we observed.

A prospective study of physiotherapist prescribed community based exercise in inflammatory peripheral neuropathy.

There is insufficient evidence to support the use of exercise in the management of chronic disablement in people with inflammatory peripheral neuropathy. Therefore, our study aimed to determine the feasibility and effectiveness of a physiotherapist prescribed community based exercise programme for reducing chronic disablement in patients with stable motor neuropathy. We assessed the effects of a 12 week unsupervised, community based strengthening, aerobic and functional exercise programme on activity limitation and other measures of functioning in 16 people with stable motor neuropathy and 10 healthy control subjects. Fourteen of 16 patients and 8 out of 10 healthy control subjects completed the study and exercised safely in the community with no adverse events. Significant improvements were seen in all measures of activity limitation and in wider measures of health including anxiety, depression and fatigue in the patient group. Improvements were sustained at six months after completion of the exercise programme, except for depression. Ten patients continued to exercise regularly at six months. These findings demonstrate that individually prescribed community based exercise is feasible and acceptable for people with stable motor neuropathy and participation in exercise may be successful in reducing chronic disablement. Future randomised controlled trials are needed to examine the efficacy of this complex community based intervention.

A self-sustaining process model of inertial layer dynamics in high Reynolds number turbulent wall flows.

Field observations and laboratory experiments suggest that at high Reynolds numbers Re the outer region of turbulent boundary layers self-organizes into quasi-uniform momentum zones (UMZs) separated by internal shear layers termed 'vortical fissures' (VFs). Motivated by this emergent structure, a conceptual model is proposed with dynamical components that collectively have the potential to generate a self-sustaining interaction between a single VF and adjacent UMZs. A large-Re asymptotic analysis of the governing incompressible Navier-Stokes equation is performed to derive reduced equation sets for the streamwise-averaged and streamwise-fluctuating flow within the VF and UMZs. The simplified equations reveal the dominant physics within-and isolate possible coupling mechanisms among-these different regions of the flow.This article is part of the themed issue 'Toward the development of high-fidelity models of wall turbulence at large Reynolds number'.

Molecular fingerprinting of principal neurons in the rodent hippocampus: A neuroinformatics approach.

Neurons are often classified by their morphological and molecular properties. The online knowledge base Hippocampome.org primarily defines neuron types from the rodent hippocampal formation based on their main neurotransmitter (glutamate or GABA) and the spatial distributions of their axons and dendrites. For each neuron type, this open-access resource reports any and all published information regarding the presence or absence of known molecular markers, including calcium-binding proteins, neuropeptides, receptors, channels, transcription factors, and other molecules of biomedical relevance. The resulting chemical profile is relatively sparse: even for the best studied neuron types, the expression or lack thereof of fewer than 70 molecules has been firmly established to date. The mouse genome-wide in situ hybridization mapping of the Allen Brain Atlas provides a wealth of data that, when appropriately analyzed, can substantially augment the molecular marker knowledge in Hippocampome.org. Here we focus on the principal cell layers of dentate gyrus (DG), CA3, CA2, and CA1, which together contain approximately 90% of hippocampal neurons. These four anatomical parcels are densely packed with somata of mostly excitatory projection neurons. Thus, gene expression data for those layers can be justifiably linked to the respective principal neuron types: granule cells in DG and pyramidal cells in CA3, CA2, and CA1. In order to enable consistent interpretation across genes and regions, we screened the whole-genome dataset against known molecular markers of those neuron types. The resulting threshold values allow over 6000 very-high confidence (>99.5%) expressed/not-expressed assignments, expanding the biochemical information content of Hippocampome.org more than five-fold. Many of these newly identified molecular markers are potential pharmacological targets for major neurological and psychiatric conditions. Furthermore, our approach yields reasonable expression/non-expression estimates for every single gene in each of these four neuron types with >90% average confidence, providing a considerably complete genetic characterization of hippocampal principal neurons.

Name-calling in the hippocampus (and beyond): coming to terms with neuron types and properties.

Widely spread naming inconsistencies in neuroscience pose a vexing obstacle to effective communication within and across areas of expertise. This problem is particularly acute when identifying neuron types and their properties. Hippocampome.org is a web-accessible neuroinformatics resource that organizes existing data about essential properties of all known neuron types in the rodent hippocampal formation. Hippocampome.org links evidence supporting the assignment of a property to a type with direct pointers to quotes and figures. Mining this knowledge from peer-reviewed reports reveals the troubling extent of terminological ambiguity and undefined terms. Examples span simple cases of using multiple synonyms and acronyms for the same molecular biomarkers (or other property) to more complex cases of neuronal naming. New publications often use different terms without mapping them to previous terms. As a result, neurons of the same type are assigned disparate names, while neurons of different types are bestowed the same name. Furthermore, non-unique properties are frequently used as names, and several neuron types are not named at all. In order to alleviate this nomenclature confusion regarding hippocampal neuron types and properties, we introduce a new functionality of Hippocampome.org: a fully searchable, curated catalog of human and machine-readable definitions, each linked to the corresponding neuron and property terms. Furthermore, we extend our robust approach to providing each neuron type with an informative name and unique identifier by mapping all encountered synonyms and homonyms.

Dose-response relationships for the binding of benzo(a)pyrene metabolites to DNA and protein in lung, liver, and forestomach of control and butylated hydroxyanisole-treated mice.

In this study, the formation of benzo(a)pyrene (BP) metabolite:DNA adducts in lung, liver, and forestomach of control and butylated hydroxyanisole (BHA)-treated (5 mg/g diet) female A/HeJ mice was examined as a function of BP dose (p.o.), ranging from 2 to 1351 mumol/kg. The major identified adduct in each tissue at each dose was the (+)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDEI):deoxyguanosine adduct. A 7 beta,8 alpha-dihydroxy-9 beta,10 beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene:deoxyguanosine adduct, a(-)-BPDEI:deoxyguanosine adduct, and an unidentified adduct were also observed. In lung and liver of untreated animals, the dose-response curves for BPDEI:DNA adduct levels were sigmoidal. In forestomach, there was no indication of saturation of DNA binding over the BP dose range examined. The dose-response curves became linear as BP dose approached zero and thus, no threshold dose existed below which binding of BPDEI to DNA did not occur, at least in lung, liver, and forestomach of these mice. In forestomach, the dose-response curve for BPDEI:DNA adducts in BHA-treated mice, 0.5% of diet for 2 weeks, was parallel to the curve for control animals and thus, the inhibition (45%) of adduct formation is independent of BP dose. In contrast, BHA treatment diminished the curvilinear nature of the dose-response curves for BPDE adducts in lung and liver. The inhibition of BPDEI:DNA adduct formation by BHA in lung and liver was dose dependent. The inhibition of lung (68%) and liver (82%) adduct formation was highest at a BP dose of 270 mumol/kg. As the BP dose approached zero, the inhibition of BPDEI:DNA adduct formation by BHA decreased with BP dose and approached values of approximately 40% (lung) and 55% (liver). The dose dependency of the binding of BP metabolites to protein was also examined. BPDEI:DNA adduct concentrations ranged from 2 to 10% of protein binding concentrations in liver of untreated animals, from 3 to 7% in forestomach, and from 5 to 7% in lung. The dose-response curves for protein binding of BP metabolites in lung and liver from BHA-treated animals were essentially parallel to those in control animals and thus, the inhibition of protein binding by BHA treatment had no dose dependency in these organs. No consistent BHA effect was observed on the amount of binding of BP metabolites to forestomach protein.

Cell selective alkylation of DNA in rat lung following low dose exposure to the tobacco specific carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone.

The molecular dosimetry of O6-methylguanine (O6MG) in DNA from lung and specific cell populations isolated from lung was determined during multiple administrations of the tobacco specific carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to Fischer 344 rats. O6MG accumulated with doses of NNK ranging from 0.1 to 100 mg/kg/day. The dose response for NNK was nonlinear; the O6MG to dose ratio, an index of alkylation efficiency, increased dramatically as the dose of carcinogen decreased. These data suggest that low and high Km pathways may exist for activation of NNK to a methylating agent. Marked differences in O6MG concentration were observed in specific lung cell populations. The Clara cell, one of the suggested progenitor cells for nitrosamine-induced neoplasia, was found to possess the greatest concentration of O6MG. Moreover, as the dose of NNK was decreased from 100 to 0.3 mg/kg, the alkylation efficiency in this cell population increased 38-fold. The high level of DNA adduct formation in Clara cells following low dose exposure to NNK was supported by autoradiographic studies. Four h after treatment with 1 mg/kg [3H]NNK, silver grains were more heavily concentrated over Clara cells than over other cell types in the lung. Comparative studies on dimethylnitrosamine, a weak carcinogen in the rat lung, did not demonstrate this cell specificity for DNA alkylation. Thus, the presence of a high affinity pathway in the Clara cell for activation of NNK may contribute to the carcinogenicity of this tobacco specific carcinogen.

Dose-response relationship between O6-methylguanine formation in Clara cells and induction of pulmonary neoplasia in the rat by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

The relationship between the formation of O6-methylguanine (O6MG) and the induction of lung, liver, and nasal tumors in the Fisher 344 rat by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was examined in a dose-response study. Animals were treated for 20 wk (3 times/wk) with concentrations of NNK ranging from 0.03 to 50 mg/kg to induce tumors. Steady-state concentrations of O6MG were quantitated, and cytotoxicity was assessed in target cells and tissues after 4 wk of treatment with NNK. No cytotoxicity was detected in the lung during treatment with NNK. The formation of O6MG was greatest in Clara cells compared with macrophages, type II cells, small cells, and whole lung at all doses examined. The difference in adduct concentration between the Clara cell and other pulmonary cell types was most pronounced with low doses of carcinogen. The O6MG:dose ratio, an index of alkylation efficiency, increased 29-fold as the dose of NNK was decreased from 50 to 1 mg/kg of carcinogen. In contrast, only a small increase in alkylation efficiency was observed in type II cells and whole lung. A significant number of tumors were induced in the lung at doses of 0.1 to 50 mg/kg with incidences ranging from 10% at the lowest dose up to 87% in the group of animals which received 50 mg/kg of NNK. A linear relationship was observed when the concentration of O6MG in Clara cells as a function of dose was plotted against the corresponding tumor incidence. This relationship was not observed using DNA adduct concentrations in type II cells or whole lung. The development of pulmonary tumors appeared to involve the formation of alveolar hyperplasias which progressed to adenomas and finally to carcinomas. The majority of adenomas were solid, whereas carcinomas were mainly papillary. Examination of the ultrastructure of the hyperplasias, adenomas, and carcinomas revealed morphological structures (e.g., lamellar bodies, tubular myelin) which are associated with type II cells. Thus, these data suggest that the majority of neoplasms in the lung begin as type II cell proliferations with progression to adenomas and carcinomas within the areas of hyperplasia. The lack of agreement between biochemical and morphological findings makes it difficult to hypothesize a cell of origin for the pulmonary neoplasms. In contrast to the lung, tumors were induced in the liver and nasal passages only after exposure to high doses of NNK. Moreover, both the formation of DNA adducts and cytotoxicity appear obligatory for the generation of tumors in these tissues.(ABSTRACT TRUNCATED AT 400 WORDS)

Accumulation and persistence of DNA adducts in respiratory tissue of rats following multiple administrations of the tobacco specific carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone.

4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a major nitrosamine formed in tobacco smoke, induces a high incidence of lung, liver, and nasal cavity tumors in rats. Since alpha-hydroxylation of NNK by target tissues can lead to the generation of a methylating agent, the formation and removal of 7-methylguanine and the promutagenic lesions O6-methylguanine (O6mGua) and O4-methyldeoxythymidine were determined over 12 days of NNK administration to rats (100 mg/kg/day). DNA alkylation was greatest in the nasal mucosa, followed by liver and lung after 1 dose of NNK. No DNA adducts were detected in kidney and brain under these conditions. The concentration of O6mGua increased steadily in lung throughout the treatment regimen, while O6-methylguanine-DNA methyltransferase decreased to less than 5% of control. The concentration of O4-methyldeoxythymidine in lung DNA reached a steady state after 4 days of carcinogen treatment. After NNK treatment was discontinued, O6mGua persisted, while O4-methyldeoxythymidine was removed rapidly in the lung, suggesting that different repair pathways exist for the removal of these adducts in vivo. In hepatocytes, nonparenchymal cells, and nasal mucosa, O6mGua concentrations were maximal after 1-2 days and declined by 50-80% during the remaining 10 days of treatment. The decrease in O6mGua levels in nasal mucosa paralleled a decline in O6-methylguanine-DNA methyltransferase activity and was associated with marked cytotoxicity to Bowman's glands, portions of the lateral nasal gland, and the olfactory and respiratory mucosa during carcinogen treatment. In contrast, the decline in O6mGua in hepatocytes was attributed to the induction of O6-methylguanine-DNA methyltransferase activity, since an 18-fold reduction in the ratio of O6mGua:7-methylguanine was observed over the 12 days of treatment. These studies have demonstrated a marked accumulation of promutagenic DNA adducts in target tissues during repeated exposure to NNK.

Taxol-dependent transcriptional activation of IL-8 expression in a subset of human ovarian cancer.

Taxol is important in the treatment of both primary and drug-resistant ovarian cancer. Although Taxol is known to stabilize microtubules and block cell mitosis, the effectiveness of this drug exceeds that of other antimitotic agents, suggesting it may have an additional mode of action. Stimulated by murine macrophage studies indicating cytokine induction by Taxol, we have investigated proinflammatory cytokine expression in a series of cell lines and recent explants of human ovarian cancer. Taxol induced secretion of interleukin (IL) 8 but not IL-6, IL-1alpha, or IL-1beta in 4 of 10 samples. Induction was dependent on transcriptional activation, and, in contrast to murine macrophage studies, was apparently independent of an active lipopolysaccharide signaling pathway. Confluent cultures secreted as much IL-8 as proliferating cells. Taxol did not induce IL-8 in breast carcinoma, endometrial stromal, or T-lymphocyte or monocyte cultures. We propose that the local expression of this chemokine in vivo may elicit a host response similar in effectiveness to that of cytokine gene therapy. These data are the first to suggest that a chemotherapeutic agent may have a direct effect on transcription of cytokine and/or growth factor genes in ovarian cancer, and that this effect may not be restricted to proliferating tumor cells.

Screening for non-adherence to antihypertensive treatment as a part of the diagnostic pathway to renal denervation.

Renal denervation is a potential therapeutic option for resistant hypertension. A thorough clinical assessment to exclude reversible/spurious causes of resistance to antihypertensive therapy is required prior to this procedure. The extent to which non-adherence to antihypertensive treatment contributes to apparent resistance to antihypertensive therapy in patients considered for renal denervation is not known. Patients (n=34) referred for renal denervation entered the evaluation pathway that included screening for adherence to antihypertensive treatment by high-performance liquid chromatography-tandem mass spectrometry-based urine analysis. Biochemical non-adherence to antihypertensive treatment was the most common cause of non-eligibility for renal denervation-23.5% of patients were either partially or completely non-adherent to prescribed antihypertensive treatment. About 5.9% of those referred for renal denervation had admitted non-adherence prior to performing the screening test. Suboptimal pharmacological treatment of hypertension and 'white-coat effect' accounted for apparently resistant hypertension in a further 17.7 and 5.9% of patients, respectively. Taken together, these three causes of pseudo-resistant hypertension accounted for 52.9% of patients referred for renal denervation. Only 14.7% of referred patients were ultimately deemed eligible for renal denervation. Without biochemical screening for therapeutic non-adherence, the eligibility rate for renal denervation would have been 38.2%. Non-adherence to antihypertensive treatment and other forms of therapeutic pseudo-resistance are by far the most common reason of 'resistant hypertension' in patients referred for renal denervation. We suggest that inclusion of biochemical screening for non-adherence to antihypertensive treatment may be helpful in evaluation of patients with 'resistant hypertension' prior to consideration of renal denervation.

Mutation of beta-catenin is an early event in chemically induced mouse hepatocellular carcinogenesis.

beta-catenin activation, and subsequent upregulation of Wnt-signaling, is an important event in the development of certain human and rodent cancers. Recently, mutations in the beta-catenin gene in the region of the serine-threonine glycogen kinase (GSK)-3beta phosphorylation target sites have been identified in hepatocellular neoplasms from humans and transgenic mice. In this study we examined 152 hepatocellular neoplasms from B6C3F1 mice included in five chemical treatment groups and controls for mutations in the beta-catenin gene. Twenty of 29 hepatocellular neoplasms from mice treated with methyleugenol had point mutations at codons 32, 33, 34 or 41, sites which are mutated in colon and other cancers. Likewise, nine of 24 methylene chloride-induced hepatocellular neoplasms and 18 of 42 oxazepam-induced neoplasms exhibited similar mutations. In contrast, only three of 18 vinyl carbamate-induced liver tumors, one of 18 TCDD-induced liver tumors, and two of 22 spontaneous liver neoplasms had mutations in beta-catenin. Thus, there appears to be a chemical specific involvement of beta-catenin activation in mouse hepatocellular carcinogenesis. Expression analyses using Western blot and immunohistochemistry indicate that beta-catenin protein accumulates along cell membranes following mutation. The finding of mutations in both adenomas and carcinomas from diverse chemical treatment groups and the immunostaining of beta-catenin protein in an altered hepatocellular focus suggest that these alterations are early events in mouse hepatocellular carcinogenesis.

Homozygous deletions at chromosome 9p21 and mutation analysis of p16 and p15 in microdissected primary non-small cell lung cancers.

Loss of heterozygosity on chromosome 9p has been detected in many primary human tumors and cell lines, suggesting that this chromosomal arm harbors one or more tumor suppressor genes. The recently cloned p16 and p15 genes, mapped to 9p21, are likely candidates for such tumor suppressors. To map the deletion at chromosome 9p21 in non-small cell lung tumors, we analyzed DNA from 25 tumors and matching normal DNAs at six microsatellite markers that flank the region occupied by the p16 and p15 genes. Loss of heterozygosity of at least one microsatellite marker on chromosome 9p21 was detected in 13 (52%) of 25 tumors, including one tumor that exhibited homozygous deletion of both human IFNalpha and D9S171. Six tumors analyzed by a comparative multiplex PCR technique showed homozygous deletions of the sequence tag site marker c5.1 (within p16). Screening for mutations in p16 and p15 revealed one tumor with a non-sense mutation in exon 2 of p16, but no mutations were detected in p15 in any of the tumors. Thus, in these analyses approximately one-half of the non-small cell lung tumors had loss of heterozygosity at chromosome 9p21, and of these tumors, one-half had homozygous deletions of the region that includes p16. This appears to confirm the importance of a locus in this region critical to growth control in lung. The apparent lack of other mutations in p16 and p15 in the tumors with loss of heterozygosity leaves open the possibility of an unidentified gene in this region that may function as a tumor suppressor.

A randomized trial testing the efficacy of modifications to the nutrition facts table on comprehension and use of nutrition information by adolescents and young adults in Canada.

INTRODUCTION: Given the proposed changes to nutrition labelling in Canada and the dearth of research examining comprehension and use of nutrition facts tables (NFts) by adolescents and young adults, our objective was to experimentally test the efficacy of modifications to NFts on young Canadians' ability to interpret, compare and mathematically manipulate nutrition information in NFts on prepackaged food. METHODS: An online survey was conducted among 2010 Canadians aged 16 to 24 years drawn from a consumer sample. Participants were randomized to view two NFts according to one of six experimental conditions, using a between-groups 2 x 3 factorial design: serving size (current NFt vs. standardized serving-sizes across similar products) x percent daily value (% DV) (current NFt vs. "low/med/high" descriptors vs. colour coding). The survey included seven performance tasks requiring participants to interpret, compare and mathematically manipulate nutrition information on NFts. Separate modified Poisson regression models were conducted for each of the three outcomes. RESULTS: The ability to compare two similar products was significantly enhanced in NFt conditions that included standardized serving-sizes (p ≤ .001 for all). Adding descriptors or colour coding of % DV next to calories and nutrients on NFts significantly improved participants' ability to correctly interpret % DV information (p ≤ .001 for all). Providing both standardized serving-sizes and descriptors of % DV had a modest effect on participants' ability to mathematically manipulate nutrition information to calculate the nutrient content of multiple servings of a product (relative ratio = 1.19; 95% confidence limit: 1.04-1.37). CONCLUSION: Standardizing serving-sizes and adding interpretive % DV information on NFts improved young Canadians' comprehension and use of nutrition information. Some caution should be exercised in generalizing these findings to all Canadian youth due to the sampling issues associated with the study population. Further research is needed to replicate this study in a more heterogeneous sample in Canada and across a range of food products and categories.

TITRE: Essai randomisé mesurant l'efficacité des modifications apportées au tableau de la valeur nutritive sur la compréhension et l'utilisation de l'information nutritionnelle par les adolescents et les jeunes adultes au Canada. INTRODUCTION: Compte tenu des changements proposés à l'étiquetage nutritionnel au Canada et de la rareté des travaux de recherche portant sur la compréhension et l'utilisation des tableaux de la valeur nutritive (tVN) chez les adolescents et les jeunes adultes, notre objectif consistait à réaliser un essai expérimental pour déterminer si les modifications apportées au tVN permettaient d'améliorer efficacement la façon dont les jeunes Canadiens interprètent, comparent et manipulent, sur le plan mathématique, l'information nutritionnelle figurant dans le tVN de denrées préemballées. MÉTHODOLOGIE: Une enquête en ligne a été menée auprès d'un échantillon de consommateurs composé de 2 010 Canadiens âgés de 16 à 24 ans. Nous avons réparti les participants de façon aléatoire en six groupes d'étude, et nous avons présenté à chacun des groupes deux des six tVN définis comme conditions expérimentales, selon un plan factoriel 2 x 3 : portion de référence (tVN actuel et portions de référence normalisées pour tous les produits similaires) x pourcentage de la valeur quotidienne (% VQ) (tVN actuel, ajout des descripteurs « faible/moyen/élevé ¼ et ajout d'un code de couleurs). L'enquête comprenait sept tâches consistant à interpréter, comparer et manipuler, sur le plan mathématique, l'information nutritionnelle figurant dans les tVN. Des modèles de régression de Poisson modifiés ont été élaborés pour chacun des trois résultats. RÉSULTATS: La capacité à comparer deux produits similaires s'est révélée significativement meilleure quand le tVN incluait une portion de référence normalisée (p ≤ 0,001 dans tous les cas). L'ajout de descripteurs ou d'un code de couleurs indiquant, sur le tVN, le % VQ pour les calories et les nutriments a amélioré de façon significative la capacité des participants à interpréter correctement l'information à propos de ce % VQ (p ≤ 0,001 dans tous les cas). Le fait de présenter aux participants des portions de référence normalisées et des descripteurs du % VQ a eu un effet modeste sur leur capacité à manipuler, sur le plan mathématique, l'information nutritionnelle pour calculer la valeur nutritive de plusieurs portions d'un produit (ratio relatif = 1,19; intervalle de confiance à 95 % : 1,04 à 1,37). CONCLUSION: La normalisation des portions de référence et l'ajout d'information sur l'interprétation du % VQ dans le tVN ont permis aux jeunes Canadiens de mieux comprendre et utiliser l'information nutritionnelle. Il faut néanmoins faire preuve de prudence avant de généraliser les résultats de l'enquête à l'ensemble des jeunes Canadiens en raison de l'échantillonnage de la population à l'étude. D'autres travaux de recherche sont nécessaires afin de reproduire cette étude au Canada avec un échantillon plus hétérogène, et en utilisant un éventail de produits alimentaires et de catégories d'aliments.