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Metabotropic glutamate receptor 5 (mGlu5) plays a fundamental role in synaptic plasticity, potentially serving as a therapeutic target for various neurodevelopmental and psychiatric disorders. Previously, we have shown that mGlu5 can also signal from intracellular membranes in the cortex, hippocampus, and striatum. Using cytoplasmic Ca2+ indicators, we showed that activated cell surface mGlu5 induced a transient Ca2+ increase, whereas the activation of intracellular mGlu5 mediated a sustained Ca2+ elevation in striatal neurons. Here, we used the newly designed ER-targeted Ca2+ sensor, ER-GCaMP6-150, as a robust, specific approach to directly monitor mGlu5-mediated changes in ER Ca2+ itself. Using this sensor, we found that the activation of cell surface mGlu5 led to small declines in ER Ca2+, whereas the activation of ER-localized mGlu5 resulted in rapid, more pronounced changes. The latter could be blocked by the Gq inhibitor FR9000359, the PLC inhibitor U73122, as well as IP3 and ryanodine receptor blockers. These data demonstrate that like cell surface and nuclear mGlu5, ER-localized receptors play a pivotal role in generating and shaping intracellular Ca2+ signals.

Pre-exposure prophylaxis (PrEP) is a valued component of HIV prevention and increasing attention is focusing on women’s PrEP use. Common HIV prevention options (e.g., condoms) remain underused and fail to consider the context of intimate partner violence (IPV). PrEP presents an opportunity to expand viable options for women. A systematic rapid review using key word searches of PubMed and proceedings from six national and international conferences related to HIV, women’s health, or interpersonal violence identified nine studies which met set inclusion criteria. Studies were coded using a structured abstraction form and summarized according to relevant themes. IPV was found to have implications on women’s interest and willingness to use PrEP, partner interference or interruptions in PrEP use, and adherence. Findings indicate a dearth of research on women’s PrEP use and IPV and highlight the urgency for research, public heath practice, and policy attention around the HIV risk context and needs of women who experience IPV.

Pre-exposure prophylaxis (PrEP) presents an opportunity to expand prevention options for women at risk for HIV infection. Yet, women’s PrEP use remains low and relatively little is known about PrEP acceptability and attitudes among a sub-population of women at risk for HIV—those experiencing intimate partner violence (IPV). A cross-sectional survey included closed and open-ended questions to assess IPV, PrEP acceptability, and attitudes about PrEP use among women seeking care at an urban family planning clinic in Pittsburgh, Pennsylvania (N = 145). Approximately 70% of women reported being willing to use PrEP with the key reasons for potential use including previous STI diagnosis, inconsistent condom use, and lack of or dishonest conversations with partners. Among women reporting recent IPV (41%), potential barriers to PrEP included concerns around drug effects, access/affordability, and adherence. Over half of women reporting recent IPV reported concerns around partner reaction impacting potential PrEP use. Results from this mixed-methods study highlight the need for a woman-centered PrEP intervention that uniquely includes awareness raising and understanding of PrEP for women, as well as reflects the context of IPV in decision-making and care.

Spinal mGluR5 is a key mediator of neuroplasticity underlying persistent pain. Although brain mGluR5 is localized on cell surface and intracellular membranes, neither the presence nor physiological role of spinal intracellular mGluR5 is established. Here we show that in spinal dorsal horn neurons >80% of mGluR5 is intracellular, of which ∼60% is located on nuclear membranes, where activation leads to sustained Ca 2+ responses. Nerve injury inducing nociceptive hypersensitivity also increases the expression of nuclear mGluR5 and receptor-mediated phosphorylated-ERK1/2, Arc/Arg3.1 and c- fos . Spinal blockade of intracellular mGluR5 reduces neuropathic pain behaviours and signalling molecules, whereas blockade of cell-surface mGluR5 has little effect. Decreasing intracellular glutamate via blocking EAAT-3, mimics the effects of intracellular mGluR5 antagonism. These findings show a direct link between an intracellular GPCR and behavioural expression in vivo . Blockade of intracellular mGluR5 represents a new strategy for the development of effective therapies for persistent pain. mGluR5 has been shown to play a role in chronic pain regulation. Here, the authors use membrane permeable and non-transported, impermeable mGluR5 antagonists to show that spinal analgesic effects in vivo are mediated by intracellular rather than cell surface mGluR5.

Purpose Extension of adjuvant endocrine therapy beyond five years confers only modest survival benefit in breast cancer patients and carries risk of toxicities. This systematic review investigates the role of biomarker tests in predicting the clinical response to an extension of endocrine therapy. Methods We searched Ovid MEDLINE, Ovid Embase, Global Index Medicus, and the Cochrane Central Register of Controlled Trials using an iterative approach to identify full-text articles related to breast cancer, endocrine therapy, and biomarkers. Results Of the 1,217 unique reports identified, five studies were deemed eligible. Four investigated the Breast Cancer Index (BCI) assay in three distinct study populations. These studies consistently showed that BCI score was predictive of response to extended endocrine therapy among 1,946 combined patients, who were predominately non-Hispanic white and postmenopausal. Conclusions Evidence in the setting of predictive tests for extended endocrine therapy is sparse. Most relevant studies investigated the use of BCI, but these study populations were largely restricted to a single age, race, and ethnicity group. Future studies should evaluate a variety of biomarkers in diverse populations. Without sufficient evidence, physicians and patients face a difficult decision in balancing the benefits and risks of endocrine therapy extension.

6-hydroxydopamine (6-OHDA) is one of the most commonly used toxins for modeling degeneration of dopaminergic (DA) neurons in Parkinson's disease. 6-OHDA also causes axonal degeneration, a process that appears to precede the death of DA neurons. To understand the processes involved in 6-OHDA-mediated axonal degeneration, a microdevice designed to isolate axons fluidically from cell bodies was used in conjunction with green fluorescent protein (GFP)-labeled DA neurons. Results showed that 6-OHDA quickly induced mitochondrial transport dysfunction in both DA and non-DA axons. This appeared to be a general effect on transport function since 6-OHDA also disrupted transport of synaptophysin-tagged vesicles. The effects of 6-OHDA on mitochondrial transport were blocked by the addition of the SOD1-mimetic, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), as well as the anti-oxidant N-acetyl-cysteine (NAC) suggesting that free radical species played a role in this process. Temporally, microtubule disruption and autophagy occurred after transport dysfunction yet before DA cell death following 6-OHDA treatment. The results from the study suggest that ROS-mediated transport dysfunction occurs early and plays a significant role in inducing axonal degeneration in response to 6-OHDA treatment.

The group 1 metabotropic glutamate receptor, mGluR5, is found on the cell surface as well as on intracellular membranes where it can mediate both overlapping and unique signaling effects. Previously we have shown that glutamate activates intracellular mGluR5 by entry through sodium-dependent transporters and/or cystine glutamate exchangers. Calibrated antibody labelling suggests that the glutamate concentration within neurons is quite high (~10 mM) raising the question as to whether intracellular mGluR5 is maximally activated at all times or whether a different ligand might be responsible for receptor activation. To address this issue, we used cellular, optical and molecular techniques to show that intracellular glutamate is largely sequestered in mitochondria; that the glutamate concentration necessary to activate intracellular mGluR5 is about ten-fold higher than what is necessary to activate cell surface mGluR5; and uncaging caged glutamate within neurons can directly activate the receptor. Thus these studies further the concept that glutamate itself serves as the ligand for intracellular mGluR5.

Background Dental caries in the expanding elderly, predominantly-dentate population is an emerging public health concern. Elderly individuals with heavily restored dentitions represent a clinical challenge and significant financial burden for healthcare systems, especially when their physical and cognitive abilities are in decline. Prescription of higher concentration fluoride toothpaste to prevent caries in older populations is expanding in the UK, significantly increasing costs for the National Health Services (NHS) but the effectiveness and cost benefit of this intervention are uncertain. The Reflect trial will evaluate the effectiveness and cost benefit of General Dental Practitioner (GDP) prescribing of 5000 ppm fluoride toothpaste and usual care compared to usual care alone in individuals 50 years and over with high-risk of caries. Methods/design A pragmatic, open-label, randomised controlled trial involving adults aged 50 years and above attending NHS dental practices identified by their dentist as having high risk of dental caries. Participants will be randomised to prescription of 5000 ppm fluoride toothpaste (frequency, amount and duration decided by GDP) and usual care only. 1200 participants will be recruited from approximately 60 dental practices in England, Scotland and Northern Ireland and followed up for 3 years. The primary outcome will be the proportion of participants receiving any dental treatment due to caries. Secondary outcomes will include coronal and root caries increments measured by independent, blinded examiners, patient reported quality of life measures, and economic outcomes; NHS and patient perspective costs, willingness to pay, net benefit (analysed over the trial follow-up period and modelled lifetime horizon). A parallel qualitative study will investigate GDPs’ practises of and beliefs about prescribing the toothpaste and patients’ beliefs and experiences of the toothpaste and perceived impacts on their oral health-related behaviours. Discussion The Reflect trial will provide valuable information to patients, policy makers and clinicians on the costs and benefits of an expensive, but evidence-deficient caries prevention intervention delivered to older adults in general dental practice. Trial registration ISRCTN: 2017-002402-13 registered 02/06/2017, first participant recruited 03/05/2018. Ethics Reference No: 17/NE/0329/233335. Funding Body: Health Technology Assessment funding stream of National Institute for Health Research. Funder number: HTA project 16/23/01. Trial Sponsor: Manchester University NHS Foundation Trust, Oxford Road, Manchester, M13 9WL. The Trial was prospectively registered.

Background Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN), resulting in tremor, rigidity, and bradykinesia. Although the etiology is unknown, insight into the disease process comes from the dopamine (DA) derivative, 6-hydroxydopamine (6-OHDA), which produces PD-like symptoms. Studies show that 6-OHDA activates stress pathways, such as the unfolded protein response (UPR), triggers mitochondrial release of cytochrome-c, and activates caspases, such as caspase-3. Because the BH3-only protein, Puma ( p 53- u pregulated m ediator of a poptosis), is activated in response to UPR, it is thought to be a link between cell stress and apoptosis. Results To test the hypothesis that Puma serves such a role in 6-OHDA-mediated cell death, we compared the response of dopaminergic neurons from wild-type and Puma -null mice to 6-OHDA. Results indicate that Puma is required for 6-OHDA-induced cell death, in primary dissociated midbrain cultures as well as in vivo . In these cultures, 6-OHDA-induced DNA damage and p53 were required for 6-OHDA-induced cell death. In contrast, while 6-OHDA led to upregulation of UPR markers, loss of ATF3 did not protect against 6-OHDA. Conclusions Together, our results indicate that 6-OHDA-induced upregulation of Puma and cell death are independent of UPR. Instead, p53 and DNA damage repair pathways mediate 6-OHDA-induced toxicity.

Key Points Establishes that there is considerable variation between different guideline recommendations, indicating differences in interpretation of the evidence. Encourages more discussion about the frequency and timing of bitewing radiographs with a view to obtaining a consensus of opinion throughout the profession. Provides an objective appraisal of guideline quality. Objectives To identify guidelines on when and how frequently bitewing radiographs should be used in dentistry for the diagnosis of caries, and to provide an objective appraisal of their quality. Data sources MEDLINE (OVID), US National Guideline Clearinghouse ( www.guideline.gov ) and the Royal College of Surgeons of England ( https://www.rcseng.ac.uk/fds/publications-clinical-guidelines/clinical_guidelines ) websites were searched using a variety of relevant search terms (2 August 2016). Data selection Publications were included if they made recommendations on the issue of when and how frequently radiographs should be used in any dentally-related specialty pertaining to the diagnosis of caries; and/or if they were aimed at the individual practitioner (any health professional working within dentistry) and/or patients. Data analysis Thirteen published guidelines were included and assessed using the AGREE II instrument. Conclusions There was a significant variation amongst the guidelines in the recommendations at what age radiography should be undertaken. There was also disagreement on the frequency of repeat radiographs and how this is influenced by the age of the patient and their caries risk.