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Background Research on the effects of restricting bar opening hours and alcohol sales in middle-income countries is very limited. We assessed compliance with and possible effects of a law enacted in Zacatecas, Mexico on December 30, 2017 and implemented in 2018 and 2019 that established a 2 AM bar closing time and 10 PM cut-off for alcohol sales by off-premises stores. Methods Monthly observations of bars and off-premises stores and alcohol mystery shopping visits from 2018 to early 2020 were conducted to assess compliance with the law. Breath tests were conducted in 2018 and 2019 with samples of pedestrians in the nighttime entertainment districts of Zacatecas and a comparison city (Aguascalientes). Surveys of bar owners/managers and staff, emergency medical personnel (EMP), and police officers were conducted in Zacatecas in 2018 and 2019 to assess awareness and support of the law and possible effects of the law on alcohol-related problems such as violence and injuries. Results Monthly observations indicated that a substantial percentage of bars and off-premises package stores did not comply with the law. Pedestrian breath tests in 2018 and 2019 indicated significant reductions in blood alcohol concentration and heavy drinking among pedestrians in Zacatecas from 11 PM to 2 AM compared to Aguascalientes, but not after 2 AM. Surveys of bar owners/managers indicated that most were aware and supportive of the law. EMP surveys indicated reductions in incidents of physical fighting and drunk or injured customers during the annual September fair in Zacatecas. Conclusions This study suggests that restricting bar opening hours and alcohol sales may not result in full compliance by bars and off-premises stores, but may help to reduce excessive alcohol use and related harms in a middle-income country. A more rigorous evaluation with pre-intervention data is needed, however, to fully address this latter question.

Baroreceptors are a promising new drug target for treating high blood pressure (hypertension). Hypertension is the world’s commonest killer disease because it is the biggest underlying risk factor for cardiovascular disease, stroke and kidney failure (WHO). These account for over 7 m deaths per year. The WHO regards current treatments as inadequate. Even in the developed world most patients need multiple drugs, both for the initial condition and combatting the side-effects the primary medication produces. Even with multi-drug therapies,>10% of patients are unresponsive. No more effective drugs have been introduced for over 20 years. We hypothesise this is because of the focus on old targets. Therefore, the WHO has asked urgently for new therapeutic targets. Baroreceptors are emerging as such a novel, and highly effective target. Electrical stimulation of baroreceptor nerves reduces long-term blood pressure by >20 mmHg even in the most drug-resistant patients. In some cases, it can even replace medication. However, only a small number of patients get this treatment, as it is highly invasive, expensive and requires rare surgical expertise. Thus, only resistant hypertensives are treated. Even then, this is a high-risk patient group, and only 50% are deemed suitable due to the anatomical condition of the stimulation site, and the difficulties of post-operative stimulation optimisation, gagging reflex activation, equipment maintenance, etc. We propose a pharmaceutical targeting of baroreceptors could be just as effective, and would be suitable for all patients, plus avoid the side-effects associated with current medications. We have discovered a modulatory system controlling mechanosensory terminal sensitivity that involves an unusual glutamate receptor with highly atypical pharmacology. We are therefore pharmacologically characterising the receptor in the aorta-aortic depressor nerve (ADN) system, as a translational step towards the clinic. Isolated aorta-ADN or working-heart brainstem (WHBS) preparations were humanely prepared (ASPA, 1986) from adult Sprague-Dawley rats. Baroreceptor immunolabelling for the atypical glutamate receptor (PLD-GluR) showed it to be present. In physiological experiments, pressure pulses were delivered periodically to the isolated or WHBS aorta. The effects of glutamate receptor or transducer channel ligands on ADN firing was recorded, as well as effects on sympathetic output and heart rate. PLD-GluR agonists robustly increased baroreceptor firing. Concanavalin A increased kainate-mediated enhancement by blocking receptor desensitisation. Blocking TRP or DEG/ENaC channels with 2-APB or amiloride inhibited pressure-evoked firing. Glutamatergic stimulation of baroreceptors also inhibited sympathetic output, indicating decreased sympathetic tone. Selective PLD-GluR antagonist PCCG-13 inhibited pressure-evoked firing and changes in sympathetic tone. These data show baroreceptor firing can be pharmacologically controlled. And, this influences baroreflex, inhibiting sympathetic output. Thus, glutamate receptor activation on baroreceptors offer a novel target, increasing baroreceptor stretch-sensitivity and the baroreflex response which may have important clinical implications. Further experiments are planned to fully characterise this response and the GluR involved.

Mechanotransduction by proprioceptive sensory organs is poorly understood. Evidence was recently shown that muscle spindle and hair follicle primary afferents (lanceolates) constantly release glutamate from synaptic-like vesicles (SLVs) within the terminals. The secreted glutamate activates a highly unusual metabotropic glutamate receptor (mGluR) to modulate the firing rate (spindles) and SLV recycling (lanceolates). This receptor has yet to be isolated and sequenced. To further investigate this receptor's pharmacology, ligands selective for classical mGluRs have been recently characterised for their ability to alter stretch-evoked spindle firing and SLV endocytosis in these different endings. Here, it is described how the results of these screens facilitated the development of novel compounds to be used in the process of isolating and sequencing of this non-canonical mGluR. This study shows how the compounds were tested for their ability to alter stretch-evoked afferent firing in muscle spindles and SLV endocytosis in the lanceolate endings of hair follicles to ensure they maintained their ability to bind to the receptor. For the development of novel compounds, kainate was chosen as the parent ligand due to its potency and ease of chemical modification. Novel kainate derivatives were then synthesised and tested to find potent analogues suitable for ‘click-chemistry’, an established technique for relatively quick, cheap, stereospecific and high-yield chemical modifications (Angewandte Chemie (International ed. in English), 40, 2001, pp2004). Of the novel kainate analogues developed, unfortunately ZCZ49 and ZCZ50 lost the ability to produce a significant change in spindle stretch-evoked firing. However, ZCZ90 was as potent as kainate, increasing firing by a similar margin at 1 μm (n = 8; P

(-)-Kainic acid potently increases stretch-induced afferent firing in muscle spindles, probably acting through a hitherto uncloned phospholipase D (PLD)-coupled mGlu receptor. Structural modification of (-)-kainic acid was undertaken to explore the C-4 substituent effect on the pharmacology related to muscle spindle firing. Three analogues 1a-c were synthesised by highly stereoselective additions of a CF3, a hydride and an alkynyl group to the Re face of the key pyrrolidin-4-one intermediate 5a followed by further structural modifications. Only the 4-(1,2,3-triazolyl)-kainate derivative 1c retained the kainate-like agonism, increasing firing in a dose-dependent manner. Further modification of 1c by introduction of a PEG-biotin chain on the 1,2,3-triazole fragment afforded compound 14 which retained robust agonism at 1 mu M and appears to be suitable for future use in pull-down assays and far western blotting for PLD-mGluR isolation.

Item does not contain fulltext Abstract Our aim in the present study was to determine whether a glutamatergic modulatory system involving synaptic-like vesicles (SLVs) is present in the lanceolate ending of the mouse and rat hair follicle and, if so, to assess its similarity to that of the rat muscle spindle annulospiral ending we have described previously. Both types of endings are formed by the peripheral sensory terminals of primary mechanosensory dorsal root ganglion cells, so the presence of such a system in the lanceolate ending would provide support for our hypothesis that it is a general property of fundamental importance to the regulation of the responsiveness of the broad class of primary mechanosensory endings. We show not only that an SLV-based system is present in lanceolate endings, but also that there are clear parallels between its operation in the two types of mechanosensory endings. In particular, we demonstrate that, as in the muscle spindle: (i) FM1-43 labels the sensory terminals of the lanceolate ending, rather than the closely associated accessory (glial) cells; (ii) the dye enters and leaves the terminals primarily by SLV recycling; (iii) the dye does not block the electrical response to mechanical stimulation, in contrast to its effect on the hair cell and dorsal root ganglion cells in culture; (iv) SLV recycling is Ca(2+) sensitive; and (v) the sensory terminals are enriched in glutamate. Thus, in the lanceolate sensory ending SLV recycling is itself regulated, at least in part, by glutamate acting through a phospholipase D-coupled metabotropic glutamate receptor.

The assessment of the postoperative patient is critical in identifying the patient's current condition and to monitor any complications that might occur. However, many nurses fail to realize the implications that philosophical paradigms, knowledge and theoretical concepts bring to the assessment practice and the manner in which assessment is conducted; in particular, within 24 h after surgery. This article seeks to explore the usefulness of philosophy, knowledge and theory as they relate to nursing assessment of the postoperative patient within the initial 24 h after surgery. It is the duty of nurses to select and effectively apply appropriate philosophical dimensions, knowledge and theories in practice and critically evaluate these areas with respect to assessment of the postoperative patient, thus aiming for a holistic assessment of the patient.