'The Drug Survey App': a protocol for developing and validating an interactive population survey tool for drug use among Aboriginal and Torres Strait Islander Australians.

BACKGROUND: Disadvantage and transgenerational trauma contribute to Aboriginal and Torres Strait Islander (Indigenous) Australians being more likely to experience adverse health consequences from alcohol and other drug use than non-Indigenous peoples. Addressing these health inequities requires local monitoring of alcohol and other drug use. While culturally appropriate methods for measuring drinking patterns among Indigenous Australians have been established, no similar methods are available for measuring other drug use patterns (amount and frequency of consumption). This paper describes a protocol for creating and validating a tablet-based survey for alcohol and other drugs ("The Drug Survey App"). METHODS: The Drug Survey App will be co-designed with stakeholders including Indigenous Australian health professionals, addiction specialists, community leaders, and researchers. The App will allow participants to describe their drug use flexibly with an interactive, visual interface. The validity of estimated consumption patterns, and risk assessments will be tested against those made in clinical interviews conducted by Indigenous Australian health professionals. We will then trial the App as a population survey tool by using the App to determine the prevalence of substance use in two Indigenous communities. DISCUSSION: The App could empower Indigenous Australian communities to conduct independent research that informs local prevention and treatment efforts

The correlates of urinary albumin to creatinine ratio (ACR) in a high risk Australian Aboriginal community

Background: Albuminuria marks renal disease and cardiovascular risk. It was estimated to contribute 75% of the risk of all-cause natural death in one Aboriginal group. The urine albumin/creatinine ratio (ACR) is commonly used as an index of albuminuria. This study aims to examine the associations between demographic factors, anthropometric index, blood pressure, lipid-protein measurements and other biomarkers and albuminuria in a cross-sectional study in a high-risk Australian Aboriginal population. The models will be evaluated for albuminuria at or above the microalbuminuria threshold, and at or above the "overt albuminuria" threshold with the potential to distinguish associations they have in common and those that differ

Presynaptic External Calcium Signaling Involves the Calcium-Sensing Receptor in Neocortical Nerve Terminals

Nerve terminal invasion by an axonal spike activates voltage-gated channels, triggering calcium entry, vesicle fusion, and release of neurotransmitter. Ion channels activated at the terminal shape the presynaptic spike and so regulate the magnitude and duration of calcium entry. Consequently characterization of the functional properties of ion channels at nerve terminals is crucial to understand the regulation of transmitter release. Direct recordings from small neocortical nerve terminals have revealed that external [Ca(2+)] ([Ca(2+)](o)) indirectly regulates a non-selective cation channel (NSCC) in neocortical nerve terminals via an unknown [Ca(2+)](o) sensor. Here, we identify the first component in a presynaptic calcium signaling pathway.By combining genetic and pharmacological approaches with direct patch-clamp recordings from small acutely isolated neocortical nerve terminals we identify the extracellular calcium sensor. Our results show that the calcium-sensing receptor (CaSR), a previously identified G-protein coupled receptor that is the mainstay in serum calcium homeostasis, is the extracellular calcium sensor in these acutely dissociated nerve terminals. The NSCC currents from reduced function mutant CaSR mice were less sensitive to changes in [Ca(2+)](o) than wild-type. Calindol, an allosteric CaSR agonist, reduced NSCC currents in direct terminal recordings in a dose-dependent and reversible manner. In contrast, glutamate and GABA did not affect the NSCC currents.Our experiments identify CaSR as the first component in the [Ca(2+)](o) sensor-NSCC signaling pathway in neocortical terminals. Decreases in [Ca(2+)](o) will depress synaptic transmission because of the exquisite sensitivity of transmitter release to [Ca(2+)](o) following its entry via voltage-activated Ca(2+) channels. CaSR may detects such falls in [Ca(2+)](o) and increase action potential duration by increasing NSCC activity, thereby attenuating the impact of decreases in [Ca(2+)](o) on release probability. CaSR is positioned to detect the dynamic changes of [Ca(2+)](o) and provide presynaptic feedback that will alter brain excitability

ATP release via anion channels

ATP serves not only as an energy source for all cell types but as an ‘extracellular messenger-for autocrine and paracrine signalling. It is released from the cell via several different purinergic signal efflux pathways. ATP and its Mg2+ and/or H+ salts exist in anionic forms at physiological pH and may exit cells via some anion channel if the pore physically permits this. In this review we survey experimental data providing evidence for and against the release of ATP through anion channels. CFTR has long been considered a probable pathway for ATP release in airway epithelium and other types of cells expressing this protein, although non-CFTR ATP currents have also been observed. Volume-sensitive outwardly rectifying (VSOR) chloride channels are found in virtually all cell types and can physically accommodate or even permeate ATP4- in certain experimental conditions. However, pharmacological studies are controversial and argue against the actual involvement of the VSOR channel in significant release of ATP. A large-conductance anion channel whose open probability exhibits a bell-shaped voltage dependence is also ubiquitously expressed and represents a putative pathway for ATP release. This channel, called a maxi-anion channel, has a wide nanoscopic pore suitable for nucleotide transport and possesses an ATP-binding site in the middle of the pore lumen to facilitate the passage of the nucleotide. The maxi-anion channel conducts ATP and displays a pharmacological profile similar to that of ATP release in response to osmotic, ischemic, hypoxic and salt stresses. The relation of some other channels and transporters to the regulated release of ATP is also discussed

Short screening tools for risky drinking in Aboriginal and Torres Strait Islander Australians: modified AUDIT-C and a new approach.

BACKGROUND: Alcohol consumption among Indigenous Australians can involve a stop-start pattern of drinking, with consumption well above recommended guidelines on each occasion. Such intermittent drinking patterns can make screening for risky drinking difficult. This study evaluates the ability of several short alcohol screening tools, contained in the Grog Survey Application, to detect short- or long-term risky drinking as defined by Australian guidelines. Tested tools include a modification of Alcohol Use Disorders Identification Test-Consumption (AUDIT-Cm). METHODS: Alcohol consumption was assessed in current drinkers in the past year (n = 184) using AUDIT-Cm and using the last four drinking occasions (Finnish method). Sensitivity and specificity were assessed relative to the Finnish method, for how AUDIT-Cm score (3 + for women, 4 + for men), and how subsets of AUDIT-Cm questions (AUDIT-1m and AUDIT-2m; and AUDIT-3mV alone) were able to determine short- or long-term risk from drinking. Responses to AUDIT-Cm were used to calculate the average standard drinks consumed per day, and the frequency at which more than four standard drinks were consumed on single occasions. Finally, shorter versions of the Finnish method (1, 2, or 3 occasions of drinking) were compared to the full Finnish method, by examining the percentage of variance retained by shorter versions. RESULTS: AUDIT-Cm has a high sensitivity in detecting at-risk drinking compared with the Finnish method (sensitivity = 99%, specificity = 67%). The combination of AUDIT-1m and AUDIT-2m was able to classify the drinking risk status for all but four individuals in the same way as the Finnish method did. For the Finnish method, two drinking sessions to calculate drinks per drinking occasion, and four to calculate frequency resulted in nearly identical estimates to data on all four of the most recent drinking occasions (r2 = 0.997). CONCLUSIONS: The combination of AUDIT-1m and AUDIT-2m may offer advantages as a short screening tool, over AUDIT-3mV, in groups where intermittent and high per occasion drinking is common. As an alternative to the full Finnish method, the quantity consumed on the last two occasions and timing of the last four occasions may provide a practical short screening tool

L-phenylalanine modulates gut hormone release and glucose tolerance, and suppresses food intake through the calcium sensing receptor in rodents

Objectives: High protein diets are associated with greater satiety and weight loss than diets rich in other macronutrients. The exact mechanisms by which high protein diets exert their effects are unclear. However, evidence suggests that the sensing of amino acids produced as a result of protein digestion may play a role in appetite regulation and satiety. We investigated the effects of L-phenylalanine (L-Phe) on food intake and glucose homeostasis in rodents. Methods: We investigated the effects of the aromatic amino acid and calcium sensing receptor (CaSR) agonist L-phenylalanine (L-Phe) on food intake and the release of the gastrointestinal hormones peptide YY (PYY), glucagon-like peptide-1 (GLP-1) and ghrelin in rodents, and the role of the CaSR in mediating these effects in vitro and in vivo. We also examined the effect of oral L-Phe administration on glucose tolerance in rats. Results: Oral administration of L-Phe acutely reduced food intake in rats and mice, and chronically reduced food intake and body weight in diet-induced obese mice. Ileal L-Phe also reduced food intake in rats. L-Phe stimulated GLP-1 and PYY release, and reduced plasma ghrelin, and also stimulated insulin release and improved glucose tolerance in rats. Pharmacological blockade of the CaSR attenuated the anorectic effect of intra-ileal L-Phe in rats, and L-Phe-induced GLP-1 release from STC-1 and primary L cells was attenuated by CaSR blockade. Conclusions: L-Phe reduced food intake, stimulated GLP-1 and PYY release and reduced plasma ghrelin in rodents. Our data provides evidence that the anorectic effects of L-Phe are mediated via the CaSR, and suggest that L-Phe and the CaSR system in the gastrointestinal tract may have therapeutic utility in the treatment of obesity and diabetes. Further work is required to determine the physiological role of the CaSR in protein sensing in the gut, and the role of this system in humans