Spatial contextual recognition memory updating is modulated by dopamine release in the dorsal hippocampus from the locus coeruleus.

Detecting novelty is critical to consolidate declarative memories, such as spatial contextual recognition memory. It has been shown that stored memories, when retrieved, are susceptible to modification, incorporating new information through an updating process. Catecholamine release in the hippocampal CA1 region consolidates an object location memory (OLM). This work hypothesized that spatial contextual memory updating could be changed by decreasing catecholamine release in the hippocampal CA1 terminals from the locus coeruleus (LC). In a mouse model expressing Cre-recombinase under the control of the tyrosine hydroxylase (TH) promoter, memory updating was impaired by photoinhibition of the CA1 catecholaminergic terminals from the LC (LC-CA1) but not from the ventral tegmental area (VTA-CA1). In vivo microdialysis confirmed that the extracellular concentration of both dopamine (DA) and noradrenaline (NA) decreased after photoinhibition of the LC-CA1 terminals (but not VTA-CA1) during the OLM update session. Furthermore, DA D1/D5 and beta-adrenergic receptor antagonists disrupted behavior, but only the former impaired memory updating. Finally, photoinhibition of LC-CA1 terminals suppressed long-term potentiation (LTP) induction in Schaffer's collaterals as a plausible mechanism for memory updating. These data will help understand the underpinning mechanisms of DA in spatial contextual memory updating.

A Method for Variant Agnostic Detection of SARS-CoV-2, Rapid Monitoring of Circulating Variants, and Early Detection of Emergent Variants Such as Omicron.

The rapid emergence of SARS-CoV-2 variants raised public health questions concerning the capability of diagnostic tests to detect new strains, the efficacy of vaccines, and how to map the geographical distribution of variants to understand transmission patterns and loads on healthcare resources. Next-generation sequencing (NGS) is the primary method for detecting and tracing new variants, but it is expensive, and it can take weeks before sequence data are available in public repositories. This article describes a customizable reverse transcription PCR (RT-PCR)-based genotyping approach which is significantly less expensive, accelerates reporting, and can be implemented in any lab that performs RT-PCR. Specific single-nucleotide polymorphisms (SNPs) and indels were identified which had high positive-percent agreement (PPA) and negative-percent agreement (NPA) compared to NGS for the major genotypes that circulated through September 11, 2021. Using a 48-marker panel, testing on 1,031 retrospective SARS-CoV-2 positive samples yielded a PPA and NPA ranging from 96.3 to 100% and 99.2 to 100%, respectively, for the top 10 most prevalent World Health Organization (WHO) lineages during that time. The effect of reducing the quantity of panel markers was explored, and a 16-marker panel was determined to be nearly as effective as the 48-marker panel at lineage assignment. Responding to the emergence of Omicron, a genotyping panel was developed which distinguishes Delta and Omicron using four highly specific SNPs. The results demonstrate the utility of the condensed panel to rapidly track the growing prevalence of Omicron across the US in December 2021 and January 2022.

Adjunctive treatments for the management of septic shock - a narrative review of the current evidence.

Septic shock is a leading cause of death and morbidity worldwide. The cornerstones of management include prompt identification of sepsis, early initiation of antibiotic therapy, adequate fluid resuscitation and organ support. Over the past two decades, there have been considerable improvements in our understanding of the pathophysiology of sepsis and the host response, including regulation of inflammation, endothelial disruption and impaired immunity. This has offered opportunities for innovative adjunctive treatments such as vitamin C, corticosteroids and beta-blockers. Some of these approaches have shown promising results in early phase trials in humans, while others, such as corticosteroids, have been tested in large, international, multicentre randomised controlled trials. Contemporary guidelines make a weak recommendation for the use of corticosteroids to reduce mortality in sepsis and septic shock. Vitamin C, despite showing initial promise in observational studies, has so far not been shown to be clinically effective in randomised trials. Beta-blocker therapy may have beneficial cardiac and non-cardiac effects in septic shock, but there is currently insufficient evidence to recommend their use for this condition. The results of ongoing randomised trials are awaited. Crucial to reducing heterogeneity in the trials of new sepsis treatments will be the concept of enrichment, which refers to the purposive selection of patients with clinical and biological characteristics that are likely to be responsive to the intervention being tested.

Zika Virus Infects Human Fetal Brain Microglia and Induces Inflammation.

BACKGROUND: The unprecedented reemergence of Zika virus (ZIKV) has startled the world with reports of increased microcephaly in Brazil. ZIKV can infect human neural progenitors and impair brain growth. However, direct evidence of ZIKV infection in human fetal brain tissues remains elusive. METHODS: Investigations were performed with brain cell preparations obtained from 9 donors. Virus infectivity was assessed by detection of virus antigen by flow cytometry together with various hematopoietic cell surface markers. Virus replication was determined by viral RNA quantification. Cytokine levels in supernatant obtained from virus-infected fetal brain cells were measured simultaneously in microbead-based immunoassays. RESULTS: We also show that ZIKV infection was particularly evident in hematopoietic cells with microglia, the brain-resident macrophage population being one of the main targets. Infection induces high levels of proinflammatory immune mediators such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), interleukin 1ß (IL-1ß), and monocyte chemotactic protein 1 (MCP-1). CONCLUSIONS: Our results highlight an important role for microglia and neuroinflammation during congenital ZIKV pathogenesis.

Attenuated psychosis symptoms are related to working alliance between therapist and service user.

AIM: Many trials have demonstrated the efficacy of specific therapy modalities for individuals with attenuated psychosis symptoms (APS). Less is known regarding mechanisms behind positive outcomes, including the role of nonspecific therapeutic factors. This study explored working alliance (WA) in a clinic serving individuals with APS to see how WA changed across the course of treatment and its relation to APS. METHODS: Session level APS and WA data was available for 12 individuals of diverse racial and gender identity, (M = 48 sessions each). Multilevel models with random intercepts tested change in WA and APS over time, and cross-sectional and prospective relations. RESULTS: WA increased and APS decreased over time. Cross sectionally, WA and APS were inversely related. Prospective relations were non-significant. CONCLUSION: When symptoms increase, therapists for individuals with APS should be attentive to potential disruptions in WA, though strong WA may be a cross-sectional protective factor.

Fluorescent probes for investigation of isoprenoid configuration and size discrimination by bactoprenol-utilizing enzymes.

Undecaprenyl Pyrophosphate Synthase (UPPS) is an enzyme critical to the production of complex polysaccharides in bacteria, as it produces the crucial bactoprenol scaffold on which these materials are assembled. Methods to characterize the systems associated with polysaccharide production are non-trivial, in part due to the lack of chemical tools to investigate their assembly. In this report, we develop a new fluorescent tool using UPPS to incorporate a powerful fluorescent anthranilamide moiety into bactoprenol. The activity of this analogue in polysaccharide biosynthesis is then tested with the initiating hexose-1-phosphate transferases involved in Capsular Polysaccharide A biosynthesis in the symbiont Bacteroides fragilis and the asparagine-linked glycosylation system of the pathogenic Campylobacter jejuni. In addition, it is shown that the UPPS used to make this probe is not specific for E-configured isoprenoid substrates and that elongation by UPPS is required for activity with the downstream enzymes.

Anomalous intrinsic viscosity of octadecylamine-functionalised carbon nanotubes in suspension.

Single walled carbon nanotubes, SWCNTs, are used as a model cylinder of nanoscopic dimensions for testing rheological theories of how addition of cylindrical particles affects the viscosity of a suspension of such particles. Using the rate of growth of the accompanying induced linear dichroism following application of an applied electric field, the dynamics of carbon nanotube alignment is studied in suspensions of octadecylamine functionalised single walled carbon nanotubes, ODA-SWCNTs, in 1,2 dichloroethane. From such measurements the viscosity of the suspension is measured as the concentration of the suspension is varied. While working within the dilute limit the viscosity is found to increase linearly with concentration and the intrinsic viscosity of the suspension is found to be 8000. This anomalously high intrinsic viscosity is compared with the predictions of various models for a rigid cylinder and found to be incompatible with any of the current models. Some suggestions are made as to the way this ODA-SWCNT result may be eventually accommodated within other models.

Efficacy of computed tomographic scans in the evaluation of patients with esophageal foreign bodies.

OBJECTIVES: This study aimed to determine whether computed tomographic (CT) scans on which foreign body impaction cannot be detected can be relied upon to decide whether a patient requires further investigation by esophagoscopy. This information might minimize unnecessary esophagoscopy without incurring the risk of a missed impacted foreign body. METHODS: In a retrospective chart review of all patients admitted to National University Hospital, Singapore, over the period 2004 to 2011 for an ingested foreign body, case files of patients who underwent preoperative CT scanning followed by esophagoscopy were identified and reviewed. The results of the CT scan and the findings of esophagoscopy in these patients were analyzed. RESULTS: A total of 376 patients underwent rigid esophagoscopy for an ingested foreign body during this period. Of these, 119 patients had CT scans performed before the endoscopy. Based on our analysis, the sensitivity of CT scanning was 100%, and the specificity was 70.6%. The positive predictive value was 89.5%, and the negative predictive value was 100%. None of the patients who had CT scans with no detectable foreign body had complications on follow-up. CONCLUSIONS: CT scanning appeared to be sensitive and specific in investigation of patients with an ingested foreign body. It also has a high negative predictive value, which may allow it to be the only preliminary investigation in these patients. Based on these data, a prospective study with close monitoring of patients who have CT scans with no detectable foreign body can be designed to accrue more patients to answer this query.

Cardiovascular and renal outcomes following percutaneous coronary intervention in a population with renal disease: a case-control study.

BACKGROUND: Patients with renal disease are less likely to undergo percutaneous coronary intervention (PCI) due to concerns about poor outcomes. AIM: We describe outcomes following PCI in individuals with chronic kidney disease (CKD), as compared with matched controls with comparable CKD who did not undergo PCI. We also identified factors predictive of poor outcomes following PCI amongst patients with CKD. DESIGN: Retrospective observational case-control study. METHODS: Cases were individuals with CKD (stages 1-5) undergoing PCI between 2008 and 2014. Controls were age, gender and creatinine-matched individuals not requiring PCI. We compared mortality between groups using Kaplan-Meier curves and Cox regression modelling. We assessed changes in serum creatinine using Wilcoxon Rank testing. We explored the relationship between biochemical and haematological measures (baseline creatinine, calcium, phosphate, calcium-phosphate product, parathyroid hormone, white cell count, haemoglobin, platelet count, c-reactive protein and total cholesterol) and post-PCI mortality, using logistic regression. RESULTS: We identified 144 cases and 144 controls. Mortality was significantly lower amongst cases compared with controls [hazard ratio 0.46 (95% confidence intervals 0.31, 0.69)]. PCI did not result in a significant change in renal function (P=0.52). Amongst cases, serum creatinine and calcium-phosphate product were predictors of mortality following PCI. CONCLUSION: Cases undergoing PCI had lower mortality, and PCI was not associated with accelerated CKD progression. On this data, PCI should not be deferred as a treatment option in patients with CKD. Serum creatinine and calcium-phosphate product predict mortality following PCI in this cohort, and may be useful in risk-stratifying patients with CKD being considered for PCI.

The identification of vertical velocity profiles using an inertial sensor to investigate pre-impact detection of falls.

This study investigates distinguishing falls from normal Activities of Daily Living (ADL) by thresholding of the vertical velocity of the trunk. Also presented is the design and evaluation of a wearable inertial sensor, capable of accurately measuring these vertical velocity profiles, thus providing an alternative to optical motion capture systems. Five young healthy subjects performed a number of simulated falls and normal ADL and their trunk vertical velocities were measured by both the optical motion capture system and the inertial sensor. Through vertical velocity thresholding (VVT) of the trunk, obtained from the optical motion capture system, at -1.3 m/s, falls can be distinguished from normal ADL, with 100% accuracy and with an average of 323 ms prior to trunk impact and 140 ms prior to knee impact, in this subject group. The vertical velocity profiles obtained using the inertial sensor, were then compared to those obtained using the optical motion capture system. The signals from the inertial sensor were combined to produce vertical velocity profiles using rotational mathematics and integration. Results show high mean correlation (0.941: Coefficient of Multiple Correlations) and low mean percentage error (6.74%) between the signals generated from the inertial sensor to those from the optical motion capture system. The proposed system enables vertical velocity profiles to be measured from elderly subjects in a home environment where as this has previously been impractical.

Major Egr3 isoforms are generated via alternate translation start sites and differ in their abilities to activate transcription.

In previous studies, we detected a major, unidentified Egr response element (ERE) binding complex in brain extracts. We now report that this complex contains a truncated isoform of Egr3 generated by use of an alternate translation start site at methionine 106. Furthermore, the ERE binding complex previously thought to contain full-length Egr3 includes several isoforms generated by initiation at other internal methionines. Full-length and truncated (missing residues 1 to 105) Egr3 isoforms differ in the ability to stimulate transcription directed by a tandem repeat of two EREs but not by a single ERE. Taken together, our results indicate that alternative translation start sites are used to generate Egr3 isoforms with distinct transcriptional properties.

The EGR family of transcription-regulatory factors: progress at the interface of molecular and systems neuroscience.

The EGR family of transcription regulatory factors, which is implicated in orchestrating the changes in gene expression that underlie neuronal plasticity, has attracted the attention of both molecular and systems neuroscientists. In this article, the advances made in both these fields of research are reviewed. Recent systems-based studies underscore the remarkable sensitivity and specificity of the induction of the expression of genes encoding EGR-family members in naturally occurring plasticity paradigms. However, they also challenge conventional views of the role of this family in plasticity. Recent molecular studies have identified the gonadotropin subunit, luteinizing hormone beta, as an EGR1-regulated gene in vivo and uncovered an essential role for EGR3 in muscle-spindle development. In addition, the discovery of novel proteins that are capable of suppressing EGR-mediated transcription cast doubt over the prevalent assumption that changes in EGR mRNA or protein levels provide an accurate measure of EGR-driven transcriptional activity.

Equity of access to dialysis facilities in Wales.

BACKGROUND: Demand for dialysis, particularly, in-centre haemodialysis (HD), is growing, and more units will be needed. Travel time to treatment is consistently a major area of concern for patients. AIM: To analyse access to current dialysis facilities in Wales, and use the data to help plan for new dialysis units. METHODS: We analysed a combination of UK Renal Registry, Welsh population census data, the Welsh Index of Multiple Deprivation 2005 (WIMD), travel time and geographical information systems. RESULTS: Prevalence of HD fell significantly with increasing travel time from units. This was not influenced by the WIMD. Prior to the opening of a new HD unit in Aberystwyth, prevalence in the surrounding area was significantly lower than for Wales as whole, but within 2 years, prevalence had risen to approximate national levels. In Haverfordwest, an area >30 min drive from any current facility, prevalence is consistently and significantly lower than for Wales as a whole, and has not shown the growth seen elsewhere in the country. DISCUSSION: The ability to combine data has enabled modelling of the likely immediate impact of opening a new unit in Haverfordwest, and also provided an estimate of its required capacity. This multidisciplinary approach to demand analysis should help to highlight areas of under-provision, and facilitate the planning of the sites and sizes of new dialysis units in Wales.

Clonal rearrangement of chromosome band 6p21 in the mesenchymal component of pulmonary chondroid hamartoma.

Pulmonary chondroid hamartomas (PCH) are biphasic benign tumors that contain both mesenchymal and epithelial populations. In this report we describe two PCH in which clonal translocations at chromosome band 6p21 were demonstrated in mesenchymal cells. One of these had a unique translocation, t(6;14)(p21;q24), that was also found in one of two PCH karyotyped previously. The t(6;14) has not been described in other varieties of benign or malignant neoplasia. The 6p21 aberrations are of particular interest because break points in this chromosomal region appear to be characteristic of endometrial polyps. Endometrial polyps, like PCH, are biphasic benign tumors in which mesenchymal clonality has been demonstrated.

Drug delivery into the cochlear apex: Improved control to sequentially affect finely spaced regions along the entire length of the cochlear spiral.

BACKGROUND: Administering pharmaceuticals to the scala tympani of the inner ear is a common approach to study cochlear physiology and mechanics. We present here a novel method for in vivo drug delivery in a controlled manner to sealed ears. NEW METHOD: Injections of ototoxic solutions were applied from a pipette sealed into a fenestra in the cochlear apex, progressively driving solutions along the length of scala tympani toward the cochlear aqueduct at the base. Drugs can be delivered rapidly or slowly. In this report we focus on slow delivery in which the injection rate is automatically adjusted to account for varying cross sectional area of the scala tympani, therefore driving a solution front at uniform rate. RESULTS: Objective measurements originating from finely spaced, low- to high-characteristic cochlear frequency places were sequentially affected. Comparison with existing methods(s): Controlled administration of pharmaceuticals into the cochlear apex overcomes a number of serious limitations of previously established methods such as cochlear perfusions with an injection pipette in the cochlear base: The drug concentration achieved is more precisely controlled, drug concentrations remain in scala tympani and are not rapidly washed out by cerebrospinal fluid flow, and the entire length of the cochlear spiral can be treated quickly or slowly with time. CONCLUSIONS: Controlled administration of solutions into the cochlear apex can be a powerful approach to sequentially effect objective measurements originating from finely spaced cochlear regions and allows, for the first time, the spatial origin of CAPs to be objectively defined.

Blockade of NGF-induced neurite outgrowth by a dominant-negative inhibitor of the egr family of transcription regulatory factors.

Although it is well established that members of the Egr family of transcription regulatory factors are induced in many neuronal plasticity paradigms, it is still unclear what role, if any, they play in this process. Because NGF stimulation of pheochromocytoma 12 cells elicits a robust induction of Egr family members, we have investigated their role in mediating long-term effects elicited by NGF in these cells by using the Egr zinc finger DNA-binding domain as a selective antagonist of Egr family-mediated transcription. We report that expression of this Egr inhibitor construct suppresses neurite outgrowth elicited by NGF but not by dibutyryl cAMP. To check that this Egr inhibitor construct does not act by blocking the MEK/ERK pathway, which is known to mediate NGF-induced neurite outgrowth, we confirmed that the Egr inhibitor construct does not block NGF activation of Elk1-mediated transcription, a response that is dependent on this pathway. Conversely, inhibition of MEK does not impair Egr family-mediated transcription. Thus, we conclude (1) that induction of Egr family members and activation of the MEK/ERK pathway by NGF are mediated by separate signaling pathways and (2) that both are required to trigger neurite outgrowth induced by NGF.

Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, p21(waf1/cip1), and erythropoietin.

Iron chelators are pluripotent neuronal antiapoptotic agents that have been shown to enhance metabolic recovery in cerebral ischemia models. The precise mechanism(s) by which these agents exert their effects remains unclear. Recent studies have demonstrated that iron chelators activate a hypoxia signal transduction pathway in non-neuronal cells that culminates in the stabilization of the transcriptional activator hypoxia-inducible factor-1 (HIF-1) and increased expression of gene products that mediate hypoxic adaptation. We examined the hypothesis that iron chelators prevent oxidative stress-induced death in cortical neuronal cultures by inducing expression of HIF-1 and its target genes. We report that the structurally distinct iron chelators deferoxamine mesylate and mimosine prevent apoptosis induced by glutathione depletion and oxidative stress in embryonic cortical neuronal cultures. The protective effects of iron chelators are correlated with their ability to enhance DNA binding of HIF-1 and activating transcription factor 1(ATF-1)/cAMP response element-binding protein (CREB) to the hypoxia response element in cortical cultures and the H19-7 hippocampal neuronal cell line. We show that mRNA, protein, and/or activity levels for genes whose expression is known to be regulated by HIF-1, including glycolytic enzymes, p21(waf1/cip1), and erythropoietin, are increased in cortical neuronal cultures in response to iron chelator treatment. Finally, we demonstrate that cobalt chloride, which also activates HIF-1 and ATF-1/CREB in cortical cultures, also prevents oxidative stress-induced death in these cells. Altogether, these results suggest that iron chelators exert their neuroprotective effects, in part, by activating a signal transduction pathway leading to increased expression of genes known to compensate for hypoxic or oxidative stress.

Measuring quality of life in cancer patients.

The diagnosis and management of cancer can have a major impact on every aspect of a patient's quality of life. Despite its importance, quality of life is rarely a reported outcome in randomized clinical trials in cancer patients. Failure to collect quality-of-life information may reflect a lack of information among researchers and clinicians about the adequacy and relative merits of measures available for assessing quality of life. We reviewed the adequacy of the 17 existing scales for assessing quality of life in cancer patients against characteristics needed for an adequate measure. None of the existing measures met all of the criteria. Recommendations about the relative adequacy of existing scales were made.