Usual intake of meat in Australians: secondary analysis of the 2011-12 National Nutrition and Physical Activity Survey using the NCI method.

INTRODUCTION: Global public health recommendations advise limiting the intake of red and processed meats. There is a need for more comprehensive information on meat consumption in Australia, specifically usual intake of meat from a nationally representative sample. The aim of this study was to use the National Cancer Institute (NCI) method to examine usual meat intakes in the 2011-12 National Nutrition and Physical Activity Survey (NNPAS). METHODS: This was a secondary analysis of the cross-sectional 2011-12 NNPAS, which contains observations for 12 153 respondents (9341 adults and 2812 children/adolescents). Usual consumption of all meat, red and processed meats was calculated using the NCI method. Consumption of meat was explored by age and gender groups, as well as by household type. RESULTS: Amongst adults and children/adolescents, consumption of all meat was significantly higher in males (adults: 187.1 g day-1 ; children/adolescents: 125.0 g day-1 ) than females (adults: 125.5 g day-1 ; children/adolescents: 95.4 g day-1 ). Similar patterns were observed for red (males: adults 85.5 g day-1 , children/adolescents 42.9 g day-1 ; females: adults 57.1 g day-1 , children/adolescents 34.9 g day-1 ) and processed meat, although intakes of processed meats in children and adolescents (males: 26.5 g day-1 ; females: 16.8 g day-1 ) were found to be similar to those of adults aged ≥19 years (males: 28.3 g day-1 ; females: 15.3 g day-1 ). Patterns of meat consumption across household types appeared to differ between genders. CONCLUSIONS: The present study suggests that Australians are likely to be exceeding population recommendations for meat intakes, with differing patterns observed across gender and household types. These findings highlight a need for targeted dietetic and population strategies aimed at promoting a healthy consumption of meats within the Australian population.

Bioavailability of the oral selective phosphodiesterase 4 inhibitor cilomilast.

STUDY OBJECTIVE: To determine the absolute bioavailability of cilomilast, and assess the effects of food, dosing time, and coadministration of antacid agents on its bioavailability and pharmacokinetics in healthy volunteers. SETTING: Clinical pharmacology unit. DESIGN: Five prospective pharmacokinetic studies: one single-blind, dose-escalating, placebo-controlled trial; four open-label, randomized studies. SUBJECTS: Ninety-six healthy adult volunteers who were nonsmokers. INTERVENTION: In the first study, four subjects received intravenous cilomilast 1, 2, and 4 mg. In the second study, 16 subjects received oral cilomilast 15 mg or intravenous cilomilast 4 mg. In the other three studies, a total of 76 subjects were given single oral 15-mg doses; one study compared its effects in fed versus fasted subjects, one looked for differences of morning versus evening dosing, and one examined coadministration with aluminum hydroxide-magnesium hydroxide. MEASUREMENTS AND MAIN RESULTS: After intravenous administration of cilomilast, plasma concentrations increased in an approximately dose-proportional manner; the half-life, approximately 6.5 hours, was dose independent. Cilomilast clearance and volume of distribution were small. After oral dosing, the absolute bioavailability was consistently close to 100%. Absorption was slower in fed subjects than in fasted (median 2-hr delay in time to reach maximum plasma concentration, average 39% reduction in maximum plasma concentration), but the area under the concentration-time curve from time zero to infinity (systemic availability) was unaffected. Pharmacokinetic parameters were not influenced by time of dosing or coadministration of antacid. CONCLUSION: The absolute bioavailability of oral cilomilast was 100%; it was not adversely affected by time of dosing or coadministration with food or antacid.

The putative role of extra-synaptic mesolimbic dopamine in the neurobiology of nicotine dependence.

A majority of habitual tobacco smokers find it very difficult to quit the habit because they become addicted to the nicotine present in tobacco smoke. Nicotine, like other psychostimulant drugs of abuse, increases dopamine release in the principal terminal field of the mesolimbic system, the nucleus accumbens, and there is evidence that this mediates the 'rewarding' properties of the drug, which reinforce its self-administration. This review focuses on the working hypothesis that addiction to nicotine, and other psychostimulant drugs, depends upon their ability to evoke a sustained increase in dopamine release directly into the extracellular space which lies between the cells in the nucleus accumbens where it stimulates extra-synaptic dopamine receptors. It is suggested that increased stimulation of these receptors is associated with increased incentive learning or the attribution of increased incentive salience to the cues associated with acquisition and delivery of the drug. The hypothesis proposes that these cues can become conditioned reinforcers of drug-taking behaviour. The receptors, which mediate the effects of nicotine on mesoaccumbens dopamine neurones, are desensitised by sustained exposure to nicotine at concentrations commonly found in the plasma of habitual smokers. It is proposed that, at times when the plasma nicotine concentration is sufficiently high to cause desensitisation of the receptors, tobacco smoking is maintained by the conditioned reinforcers present in the tobacco smoke. The hypothesis predicts, therefore, that conditioned reinforcement may play a more important role in the addiction to tobacco than for most other addictive behaviours. As a result, studies with nicotine have the potential to contribute to our understanding of the neurobiology of addiction which cannot easily be explored using drugs, such as cocaine and amphetamine, which invariably increase dopamine overflow in the forebrain.

The influence of nicotine pretreatment on mesoaccumbens dopamine overflow and locomotor responses to D-amphetamine.

Pretreatment with psychostimulant drugs causes sensitisation of their effects on locomotor activity and dopamine (DA) overflow in the nucleus accumbens (NAcc) and there is evidence for similarities in the mechanisms involved. This study used in vivo microdialysis in conscious freely moving rats to investigate the extent to which pretreatment with nicotine causes sensitisation to D-amphetamine. Pretreatment with nicotine (0.4 mg/kg s.c. daily for 5 days) caused sensitisation of the locomotor responses to D-amphetamine (0.1-0.5 mg/kg s.c.) but not cocaine (15 mg/kg i.p.). Nicotine pretreatment did not influence the increase in DA overflow into dialysis probes, located in the core of the NAcc, evoked by systemic injections of D-amphetamine or cocaine (15 mg/kg i.p.) but decreased the overflow evoked by the administration of D-amphetamine (1 x 10(-6) M) through the dialysis probe. The results provide further evidence for a dissociation between the expression of sensitised locomotor responses to psychostimulant drugs and sensitisation of their stimulatory effects on DA overflow in the core of the NAcc. The results suggest that the sensitisation of the effects of nicotine on DA overflow in this subdivision of the NAcc may be pharmacologically specific to nicotinic drugs.

Amplification of alpha 1D-adrenoceptor mediated contractions in rat aortic rings partially depolarised with KCl.

Partial depolarisation of smooth muscle in endothelium-denuded rat aortic ring preparations, by increasing physiological buffer KC1 concentrations from 4.7 to 14.7 mM, produced a leftward shift of concentration response curves (CRCs) to the alpha 1-adrenoceptor agonist noradrenaline (NA), phenylephrine and methoxamine, without changing maximal responses, whereas maximal responses to clonidine (CLON), also an alpha 1-agonist in this tissue were considerably increased. Partial depolarisation did not alter responses to 10 nM NA or 100 nM CLON in Ca2+(-free) buffer, but significantly increased the contractions obtained on adding Ca2+ back in the presence of the agonists. The potentiation of NA (2.5 and 5 nm) contractions by partial depolarisation was prevented by the voltage-operated Ca2+ channel (VOCC) antagonist nifedipine (NIF, 1 microM). NIF did not significantly affect NA CRCs in 4.7 mM KCl, whereas responses in 14.7 mM KCl were significantly decreased, indicating VOCC recruitment by NA only in the latter condition. Initial depletion of intracellular Ca2+ stores with 1 microM thapsigargin (THAP) in Ca2+(-free) buffer did not alter NA CRCs subsequently obtained in normal Ca2+. However, after THAP-pretreatment, these NA responses (in both 4.7 and 14.7 mM KC1) were attenuated by NIF, indicating that VOCCs were activated by NA in THAP-treated tissues. SKF 96365 (SKF, 30 microM), which can block VOCC and non-VOCC routes of extracellular Ca2+ influx, inhibited NA responses in 4.7 mM and 14.7 mM KCl, possibly implying a role for both types of Ca2+ entry in contractions. However, the greater inhibitory effects of SKF in THAP-pretreated tissues, probably reflected the mobilisation of VOCCs by NA following THAP exposure, because SKF was shown separately to block VOCC-mediated contractions in tissues depolarised with 100 mM KCl alone. 10 microM niflumic acid, an inhibitor of Ca2+(-activated) Cl- channels, did not affect responses to NA in 4.7 mM or 14.7 mM KC1, suggesting that VOCC opening induced by NA in 14.7 mM KCl was not due to depolarisation produced by alpha 1-adrenoceptor induced Cl- efflux. CRCs for NA were unaffected by pretreatment of rings with 100 ng ml-1 pertussis toxin (PT), suggesting a lack of involvement of PT-sensitive G proteins in the contractions obtained either in 4.7 or 14.7 mM KCl. BMY 7378 (100 microM), a selective antagonist for alpha 1D-adrenoceptors, competitively inhibited NA contractions with apparent pKB values of 8.7 +/- 0.2 and 8.4 +/- 0.1 in 4.7 mM and 14.7 mM KCl, respectively. Pretreatment of rings with chloroethylclonidine (100 microM), an irreversible antagonist of alpha 1B-and alpha 1D-adrenoceptors, produced similar rightward shifts in CRCs to NA by 3.2 +/- 0.2 and 3.7 +/- 0.3 log concentration units in 4.7 mM and 14.7 mM KCl, respectively, without changing maximal responses. Inositol phosphate (IP) turnover produced by NA in aortic rings was not significantly different in 4.7 mM compared with 14.7 mM KCl. As a whole, these results suggest that partial depolarisation of the rat aorta with KCl enhances alpha 1-adrenoceptor mediated contractions predominantly via the alpha 1D-subtype, and by a mechanism to be identified which allows greater recruitment of VOCCs by NA. In addition, the ability of THAP-pretreatment also to enhance VOCC activation by NA suggests that Ca2+ release from, or prevention of its reuptake into, intracellular stores may contribute to those processes leading to VOCC opening.

Sensitization of the mesoaccumbens dopamine response to nicotine.

This article reviews the evidence that pretreatment with nicotine causes a regionally selective sensitization of its stimulatory effects on a pathway, the mesoaccumbens dopamine (DA) system, which has been implicated in the locomotor stimulant response to nicotine and its ability to reinforce self-administration. The sensitization evoked by daily injections of nicotine is associated with a regionally selective downregulation of the control of mesoaccumbens DA neurons by inhibitory autoreceptors and depends upon co-stimulation of NMDA glutamatergic receptors. It is suggested that the sensitization is related to enhanced burst firing of mesoaccumbens neurons, which results in an enhancement of DA release into the extracellular space between the cells where it acts upon putative extrasynaptic dopamine receptors. The studies with NMDA receptor antagonists revealed a dissociation between the expression of sensitized mesoaccumbens DA and locomotor responses to nicotine. It is proposed, therefore, that the sensitized mesoaccumbens DA responses to nicotine may be implicated in psychopharmacological responses to drug concerned more closely with nicotine dependence.

Effects of acute D-CPPene on mesoaccumbens dopamine responses to nicotine in the rat.

Acute administration of the NMDA receptor antagonist, D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid; 2 mg/kg), abolished (P < 0.01) the sensitised mesoaccumbens dopamine response to nicotine (0.4 mg/kg) measured using in vivo microdialysis, but not the increased locomotor activity, observed in rats pretreated with nicotine prior to the test day. D-CPPene enhanced (P < 0.01) the mesoaccumbens dopamine response, but not the locomotor response, to acute nicotine given to drug-naive rats. The data suggest that sensitised mesoaccumbens dopamine responses to nicotine involve co-stimulation of NMDA receptors but that this effect is not closely related to sensitisation of the locomotor response to the drug.

Desensitization of the nicotine-induced mesolimbic dopamine responses during constant infusion with nicotine.

1. The effects of constant nicotine infusions (0.25, 1.0 and 4.0 mg kg-1 day-1) on extracellular dopamine levels in the nucleus accumbens (NAc) and on locomotor activity have been compared with the changes evoked by repeated daily injections (0.4 mg kg-1 day-1 for 5 days) of the drug. 2. The extracellular dopamine concentration in the NAc was significantly increased (P < 0.05) following a challenge dose of nicotine (0.4 mg kg-1, s.c.) in animals which had been pretreated with daily injections of the drug. This effect was accompanied by an enhanced locomotor response to nicotine. 3. The stimulant effects of nicotine on mesolimbic dopamine secretion and on locomotor activity were significantly inhibited (P < 0.01) by the prior administration of mecamylamine (2.0 mg kg-1, s.c.) but not by hexamethonium (2.0 mg kg-1, s.c.). 4. The constant infusion of nicotine at a rate of 1 and 4 but not 0.25 mg kg-1 day-1 abolished the sensitized dopamine response in the NAc to an injection of nicotine in animals pretreated with the drug. The locomotor responses to nicotine in the nicotine-pretreated rats were significantly attenuated by the infusion of nicotine at all 3 doses, although the nicotine induced locomotor activity, in the rats infused with 0.25 mg kg-1 day-1 was also significantly (P < 0.05) higher than that observed in the rats treated acutely with nicotine. 5. Significantly (P<0.01) enhanced mesolimbic dopamine responses, to a challenge injection of nicotine(0.4 mg kg-1, s.c.), were observed 2 and 7 days after termination of the infusion of nicotine (4 mg kg-1 day-1 for 14 days); locomotor responses were enhanced (P<0.01) 1, 2 and 7 days after termination of the infusion.6. The results suggest that sensitized mesolimbic dopamine responses to nicotine occur as a result of stimulation of centrally located nicotinic receptors but that these receptors may be desensitized during periods of chronic exposure to nicotine at doses which may be relevant to smoking.

The influence of the contralateral kidney upon recovery from unilateral warm renal ischemia.

Unilateral warm renal ischemia of 90 min duration was induced in rats and the contralateral normal kidney was removed either immediately or after 1, 2, 4 or 14 d. Contralateral nephrectomy at 2, 4, 14 d increased survival and modified the functional and morphological events of the recovery period. Optimal recovery was obtained by 4 d delay. When contralateral nephrectomy was delayed by 14 d, scarring of the ischemic kidney was more severe suggesting that regeneration of damaged nephrons was impaired when renal homeostasis was sustained by the contralateral kidney. Such biphasic and inverse effects of normal kidney tissue are likely to be important determinants of the natural history of severe unilateral renal damage.

Studies in renal preservation using a rat kidney transplant model: II. The effect of reflushing with citrate.

This study investigated the possible beneficial effects of reflushing renal grafts with isotonic citrate solution. Rat kidneys were initially flushed with isotonic citrate or with Hartmann's solutions at O C. After 2 hr, half the kidneys of each group were reflushed with isotonic citrate; 22 hr later, all kidneys were transplanted into rats of the same inbred strain. All animals receiving kidneys flushed with Hartmann's solution died, whereas reflushing such kidneys with isotonic citrate significantly ameliorated the deleterious effects of Hartmann's solution. All animals receiving citrate-flushed kidneys survived with relatively good renal function and morphology. However, reflushing itself is not a beneficial procedure and is only of value where an ineffective preserving solution has been used to flush the kidneys initially. There is evidence that some of the adverse effects of flushing develop in the renal medulla.

Recovery of renal function after warm ischemia. I. The effect of chlorpromazine and phenoxybenzamine.

The effects of treatment with chlorpromazine (4 mg/kg) and phenoxybenzamine (1 and 5 mg/kg) on renal function and morphology after warm ischemia and contralateral nephrectomy were studied. Chlorpromazine pretreatment by intravenous injection 15 min before warm ischemia of 60 min resulted in the survival of all animals (cf. 75% in untreated group), with better renal function in the first week. Necrosis of the proximal convoluted tubule and ultimate residual cortical damage were less severe than in the untreated groups. Chlorpromazine was also beneficial after 75 min warm ischemia, although mortality was not reduced. Administration of chlorpromazine just prior to revascularization was ineffective, suggesting that sufficient concentration of the drug must be present in the kidney during the ischemic period or immediately after revascularization. Chlorpromazine probably protects the proximal tubular cells from ischemic damage. Phenoxybenzamine (1 mg/kg) was ineffective when administered 15 min before warm ischemia. A higher (5 mg/kg) dosage of the drug proved to be detrimental.

An experimental model for assessment of renal recovery from warm ischemia.

A study was made of the acute and chronic (15 days) functional and morphologic effects on the rat kidney of warm ischemia and contralateral nephrectomy, in order to define a suitable animal model for testing renal transplant preservation techniques when warm ischemia is a contributing factor. Spontaneous recovery from 30-min warm ischemia was complete, and the model was consequently unsuitable; the high mortality from 90 min was unacceptable. Warm ischemia of 60 minutes produced severe renal tubular necrosis, an acceptable mortality, residual morphologic damage, and impairment of isolated kidney perfusion parameters at 15 days. Renal function in vivo was normal in many of these animals, despite appreciable residual morphologic changes, and it is evident that functional data alone are not sufficient for assessment of preservation regimens.