Binge-Like Alcohol Exposure During Adolescence Disrupts Dopaminergic Neurotransmission in the Adult Prelimbic Cortex

Repeated binge-like exposure to alcohol during adolescence has been reported to perturb prefrontal cortical development, yet the mechanisms underlying these effects are unknown. Here we report that adolescent intermittent ethanol exposure induces cellular and dopaminergic abnormalities in the adult prelimbic cortex (PrL-C). Exposing rats to alcohol during early-mid adolescence (PD28–42) increased the density of long/thin dendritic spines of layer 5 pyramidal neurons in the adult PrL-C. Interestingly, although AIE exposure did not alter the expression of glutamatergic proteins in the adult PrL-C, there was a pronounced reduction in dopamine (DA) D1 receptor modulation of both intrinsic firing and evoked NMDA currents in pyramidal cells, whereas D2 receptor function was unaltered. Recordings from fast-spiking interneurons also revealed that AIE reduced intrinsic excitability, glutamatergic signaling, and D1 receptor modulation of these cells. Analysis of PrL-C tissue of AIE-exposed rats further revealed persistent changes in the expression of DA-related proteins, including reductions in the expression of tyrosine hydroxylase and catechol-O-methyltransferase (COMT). AIE exposure was associated with hypermethylation of the COMT promoter at a conserved CpG site in exon II. Taken together, these findings demonstrate that AIE exposure disrupts DA and GABAergic transmission in the adult medial prefrontal cortex (mPFC). As DA and GABA work in concert to shape and synchronize neuronal ensembles in the PFC, these alterations could contribute to deficits in behavioral control and decision-making in adults who abused alcohol during adolescence

Better than nothing? Patient-delivered partner therapy and partner notification for chlamydia: the views of Australian general practitioners

<p>Abstract</p> <p>Background</p> <p>Genital chlamydia is the most commonly notified sexually transmissible infection (STI) in Australia and worldwide and can have serious reproductive health outcomes. Partner notification, testing and treatment are important facets of chlamydia control. Traditional methods of partner notification are not reaching enough partners to effectively control transmission of chlamydia. Patient-delivered partner therapy (PDPT) has been shown to improve the treatment of sexual partners. In Australia, General Practitioners (GPs) are responsible for the bulk of chlamydia testing, diagnosis, treatment and follow up. This study aimed to determine the views and practices of Australian general practitioners (GPs) in relation to partner notification and PDPT for chlamydia and explored GPs' perceptions of their patients' barriers to notifying partners of a chlamydia diagnosis.</p> <p>Methods</p> <p>In-depth, semi-structured telephone interviews were conducted with 40 general practitioners (GPs) from rural, regional and urban Australia from November 2006 to March 2007. Topics covered: GPs' current practice and views about partner notification, perceived barriers and useful supports, previous use of and views regarding PDPT.</p> <p>Transcripts were imported into NVivo7 and subjected to thematic analysis. Data saturation was reached after 32 interviews had been completed.</p> <p>Results</p> <p>Perceived barriers to patients telling partners (patient referral) included: stigma; age and cultural background; casual or long-term relationship, ongoing relationship or not. Barriers to GPs undertaking partner notification (provider referral) included: lack of time and staff; lack of contact details; uncertainty about the legality of contacting partners and whether this constitutes breach of patient confidentiality; and feeling both personally uncomfortable and inadequately trained to contact someone who is not their patient. GPs were divided on the use of PDPT - many felt concerned that it is not best clinical practice but many also felt that it is better than nothing.</p> <p>GPs identified the following factors which they considered would facilitate partner notification: clear clinical guidelines; a legal framework around partner notification; a formal chlamydia screening program; financial incentives; education and practical support for health professionals, and raising awareness of chlamydia in the community, in particular amongst young people.</p> <p>Conclusions</p> <p>GPs reported some partners do not seek medical treatment even after they are notified of being a sexual contact of a patient with chlamydia. More routine use of PDPT may help address this issue however GPs in this study had negative attitudes to the use of PDPT. Appropriate guidelines and legislation may make the use of PDPT more acceptable to Australian GPs.</p

Protocol for a randomised controlled trial of a decision aid for the management of pain in labour and childbirth [ISRCTN52287533]

BACKGROUND: Women report fear of pain in childbirth and often lack complete information on analgesic options prior to labour. Preferences for pain relief should be discussed before labour begins. A woman's antepartum decision to use pain relief is likely influenced by her cultural background, friends, family, the media, literature and her antenatal caregivers. Pregnant women report that information about analgesia was most commonly derived from hearsay and least commonly from health professionals. Decision aids are emerging as a promising tool to assist practitioners and their patients in evidence-based decision making. Decision aids are designed to assist patients and their doctors in making informed decisions using information that is unbiased and based on high quality research evidence. Decision aids are non-directive in the sense that they do not aim to steer the user towards any one option, but rather to support decision making which is informed and consistent with personal values. METHODS/DESIGN: We aim to evaluate the effectiveness of a Pain Relief for Labour decision aid, with and without an audio-component, compared to a pamphlet in a three-arm randomised controlled trial. Approximately 600 women expecting their first baby and planning a vaginal birth will be recruited for the trial. The primary outcomes of the study are decisional conflict (uncertainty about a course of action), knowledge, anxiety and satisfaction with decision-making and will be assessed using self-administered questionnaires. The decision aid is not intended to influence the type of analgesia used during labour, however we will monitor health service utilisation rates and maternal and perinatal outcomes. This study is funded by a competitive peer-reviewed grant from the Australian National Health and Medical Research Council (No. 253635). DISCUSSION: The Pain Relief for Labour decision aid was developed using the Ottawa Decision Support Framework and systematic reviews of the evidence about the benefits and risks of the non-pharmacological and pharmacological methods of pain relief for labour. It comprises a workbook and worksheet and has been developed in two forms – with and without an audio-component (compact disc). The format allows women to take the decision aid home and discuss it with their partner

Chronic Alcohol Exposure Alters Behavioral and Synaptic Plasticity of the Rodent Prefrontal Cortex

In the present study, we used a mouse model of chronic intermittent ethanol (CIE) exposure to examine how CIE alters the plasticity of the medial prefrontal cortex (mPFC). In acute slices obtained either immediately or 1-week after the last episode of alcohol exposure, voltage-clamp recording of excitatory post-synaptic currents (EPSCs) in mPFC layer V pyramidal neurons revealed that CIE exposure resulted in an increase in the NMDA/AMPA current ratio. This increase appeared to result from a selective increase in the NMDA component of the EPSC. Consistent with this, Western blot analysis of the postsynaptic density fraction showed that while there was no change in expression of the AMPA GluR1 subunit, NMDA NR1 and NRB subunits were significantly increased in CIE exposed mice when examined immediately after the last episode of alcohol exposure. Unexpectedly, this increase in NR1 and NR2B was no longer observed after 1-week of withdrawal in spite of a persistent increase in synaptic NMDA currents. Analysis of spines on the basal dendrites of layer V neurons revealed that while the total density of spines was not altered, there was a selective increase in the density of mushroom-type spines following CIE exposure. Examination of NMDA-receptor mediated spike-timing-dependent plasticity (STDP) showed that CIE exposure was associated with altered expression of long-term potentiation (LTP). Lastly, behavioral studies using an attentional set-shifting task that depends upon the mPFC for optimal performance revealed deficits in cognitive flexibility in CIE exposed mice when tested up to 1-week after the last episode of alcohol exposure. Taken together, these observations are consistent with those in human alcoholics showing protracted deficits in executive function, and suggest these deficits may be associated with alterations in synaptic plasticity in the mPFC

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Chronic intermittent ethanol (CIE) increases the density of mature dendritic spines in layer V mPFC pyramidal neurons and produces a transient increase in NMDARs.

<p>A) Representative blots of NMDAR and AMPAR subunits in control and CIE exposed mice. B) CIE significantly increased expression of NR1 and NR2B subunits of NMDARs in a PSD-enriched fraction (n = 6–8 mice/group; two-tailed t-tests; *p<0.05) in tissue obtained immediately after the last episode of alcohol exposure. The levels of NR1 and NR2B had returned to baseline after 1- week of withdrawal (WD). C) Representative image of the basal dendrites and dendritic spines of a layer V pyramidal neuron in the mPFC (arrow shows cell body and arrowhead denotes axon). D) Representative images of diolistic labeling of basal dendrites from control and CIE exposed mice. Also shown is automated filament detection and classification of the dendritic shaft (grey) and spines (n = 5–6 mice/group; stubby = red, long = blue, mushroom = green, filopodia = pink). E, G) Total spine density was not altered between control and CIE exposed mice at 0 d or 7 d WD (SAS Proc Mixed model; p>0.05). F, H) The density of mushroom spines was increased by CIE exposure at both time point (SAS Proc Mixed model; *p<0.05).</p

Chronic intermittent ethanol (CIE) exposure alters the time course of STDP.

<p>EPSPs were induced by focal stimulation close to basal dendrites of the recorded neuron in layers V/VI. Pairing an EPSP with a burst of postsynaptic action potentials lead to consistent increases in all 3 treatment groups (control, CIE no withdrawal, and CIE followed by 7 days of withdrawal) at 20–30 minutes post pairing. However, at 50–60 minutes post-pairing the EPSP amplitude in CIE exposed mice was significantly increased relative to controls in both the no-withdrawal and one-week withdrawal group. Induction of STDP was NMDAR-dependent: In the presence of the NMDAR antagonist APV the burst of postsynaptic action potentials did not result in a significant change from baseline in slices prepared from control animals. The bar graph shows the relative increase in EPSP amplitude relative to the 10 minutes baseline at 2 different time points (20–30 min and 50–60 min post STDP induction, respectively) for the 4 groups. At 20–30 min, the EPSP amplitude was significantly increased over baseline in all groups. The relative amount of LTP at 50–60 minutes post-pairing was significantly different between control and CIE mice. This was due both to a decrease in potentiation at the late time-point and to the continued increase in LTP in both CIE-exposed groups of mice. *p<0.5 significantly different from baseline (20–30 min) or the vehicle control group (50–60 min), respectively (Repeated measures ANOVA and post-hoc analysis using unpaired Student's t-tests).</p

Chronic intermittent ethanol exposure (CIE) increases the ratio of NMDA to AMPA currents independent of alterations in synaptic glutamate release.

<p>A) Examples of EPSCs from neurons of a control and CIE-exposed mouse. Left: The NMDA/AMPA ratio was significantly larger in slices from control versus CIE exposed mice. Right: Changes in the amplitude of the NMDAR current was not accompanied by increases in the decay time constant. B) CIE exposure did not affect the frequency or average amplitude of mEPSCs. The top left shows representative traces of pharmacologically isolated mEPSCs in a slice from a control mouse. The right insert shows averaged mEPSCs from a control (black) and CIE (no-withdrawal) mouse, respectively. *p<0.5 significantly different from the vehicle control group (ANOVA and post-hoc analysis using unpaired Student's t-tests). C) Histogram of the amplitude distribution of mEPSCs from all cells over 10 min of recording (control, black; CIE no-withdrawal, blue; CIE 7 days withdrawal, red). The insert shows the same data replotted as cumulative frequency distribution to show that the relative amplitude distribution of synaptic events did also not change.</p

Schematic of the prefrontal cortex (PFC) demonstrating location of tissue punches and neurons used for electrophysiology experiments and morphological analysis.

<p><i>Top:</i> Tissue punches used for western blot analysis centered on the prelimbic (PrL) PFC. Shown are sections of the mouse brain at Bregma 2.00 mm. <i>Bottom</i>: The box shows a bright-field image of a biocytin-labeled layer V pyramidal neuron in the PrL PFC. The inserts show a typical arrangement of the recording and theta-glass stimulation electrode, which was placed within the same layer as the recorded neuron near the basal dendrites.</p

Chronic intermittent ethanol (CIE) exposure reduces the ability of mice to shift attention towards previously unrewarded stimuli in order to learn a new response strategy.

<p>A) CIE does not interfere with the ability to reverse a response discrimination in a T-maze. Mice were trained on a response discrimination (Response) that required them to always turn towards one side to obtain food reward. After 3 cycles of CIE or air exposure and 3 days of withdrawal, mice were retested (Retest) using the same turn discrimination. Animals in both groups showed a small improvement in performance on Retest day, indicating that CIE did not impair the retention of the previously learned strategy. On the following day, mice were required to reverse their strategy (Reversal) and turn towards the opposite arm to obtain the reward. The bar graph in A1 shows the total number of trials to criterion on the 3 test days for mice in the control (n = 8) and CIE (n = 8) groups. Data in A2 shows the number of reinforcers earned (i.e. the number of correct choices) during training (Response and Retest Day). No differences were observed between the treatment groups on any test day. B, C) Attentional Set-shifting is impaired in CIE exposed mice. Mice were trained on a response discrimination task as described in <i>A</i> with the addition of a visual cue (Response). After 3 cycles of CIE or air exposure and 3 or 7 days of withdrawal, mice were retested on the Response Discrimination (Retest). On the following day, mice were trained to shift attention to the visual cue to obtain food reward (Shift to Visual Cue). B1) CIE exposed mice required significantly more trials to reach performance criterion on Reversal Day. B2) Changes on Reversal Day were not due to differences in association strength established during training. The number of reinforcers earned (i.e. the number of correct choices) was not different in all treatment groups. C) Analysis of the types of errors committed on Reversal Day revealed that CIE exposed mice made significantly more perseverative errors than mice in the control group. Other types of errors did not differ significantly, indicating that once the new strategy was acquired, the mice had no difficulty in maintaining the new response strategy. All data are expressed as means ± SEM. **p<0.01 and *p<0.05 significantly different from the vehicle control group (ANOVA and post-hoc analysis using unpaired Student's t-tests).</p