Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females

Apolipoprotein E (apoE) mediates the redistribution of lipids among cells and is expressed at highest levels in brain and liver. Human apoE exists in three major isoforms encoded by distinct alleles (\u3b52, \u3b53, and \u3b54). Compared with APOE \u3b52 and \u3b53, APOE \u3b54 increases the risk of cognitive impairments, lowers the age of onset of Alzheimer's disease (AD), and decreases the response to AD treatments. Besides age, inheritance of the APOE \u3b54 allele is the most important known risk factor for the development of sporadic AD, the most common form of this illness. Although numerous hypotheses have been advanced, it remains unclear how APOE \u3b54 might affect cognition and increase AD risk. To assess the effects of distinct human apoE isoforms on the brain, we have used the neuron-specific enolase (NSE) promoter to express human apoE3 or apoE4 at similar levels in neurons of transgenic mice lacking endogenous mouse apoE. Compared with NSE-apoE3 mice and wild-type controls, NSE-apoE4 mice showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age and were seen primarily in females. These findings demonstrate that human apoE isoforms have differential effects on brain function in vivo and that the susceptibility to apoE4-induced deficits is critically influenced by age and gender. These results could be pertinent to cognitive impairments observed in human APOE \u3b54 carriers. NSE-apoE mice and similar models may facilitate the preclinical assessment of treatments for apoE-related cognitive deficits

Most Probable Number Rapid Viability PCR Method to Detect Viable Spores of Bacillus anthracis in Swab Samples

This note presents a comparison of Most-Probable-Number Rapid Viability (MPN-RV) PCR and traditional culture methods for the quantification of Bacillus anthracis Sterne spores in macrofoam swabs generated by the Centers for Disease Control and Prevention (CDC) for a multi-center validation study aimed at testing environmental swab processing methods for recovery, detection, and quantification of viable B. anthracis spores from surfaces. Results show that spore numbers provided by the MPN RV-PCR method were in statistical agreement with the CDC conventional culture method for all three levels of spores tested (10{sup 4}, 10{sup 2}, and 10 spores) even in the presence of dirt. In addition to detecting low levels of spores in environmental conditions, the MPN RV-PCR method is specific, and compatible with automated high-throughput sample processing and analysis protocols

Antimicrobial Peptides Pom-1 and Pom-2 from Pomacea poeyana Are Active against Candida auris, C. parapsilosis and C. albicans Biofilms

Recently two peptides isolated from the Cuban freshwater snail Pomacea poeyana (Pilsbry, 1927) were described to have antimicrobial activity against bacterial pathogens. Here we show considerable activities of Pom-1 and Pom-2 to reduce the viability of C. albicans, C. parapsilosis and the less common species C. auris measured as the decrease of metabolic activity in the resazurin reduction assay for planktonic cells. Although these activities were low, Pom-1 and Pom-2 turned out to be highly potent inhibitors of biofilm formation for the three Candida species tested. Whereas Pom-1 was slightly more active against C. albicans and C. parapsilosis as representatives of the more common Candida species Pom-2 showed no preference and was fully active also against biofilms of the more uncommon species C. auris. Pom-1 and Pom-2 may represent promising lead structures for the development of a classical peptide optimization strategy with the realistic aim to further increase antibiofilm properties and other pharmacologic parameters and to generate finally the first antifungal drug with a pronounced dedication against Candida biofilms

Developing Health-Based Pre-Planning Clearance Goals for Airport Remediation Following Chemical Terrorist Attack: Introduction and Key Assessment Considerations

In the event of a chemical terrorist attack on a transportation hub, post-event remediation and restoration activities necessary to attain unrestricted facility reuse and re-entry could require hours to multiple days. While restoration timeframes are dependent on numerous variables, a primary controlling factor is the level of pre-planning and decision-making completed prior to chemical terrorist release. What follows is the first of a two-part analysis identifying key considerations, critical information, and decision criteria to facilitate post-attack and post-decontamination consequence management activities. A conceptual site model and human health-based exposure guidelines are developed and reported as an aid to site-specific pre-planning in the current absence of U.S. state or Federal values designated as compound-specific remediation or re-entry concentrations, and to safely expedite facility recovery to full operational status. Chemicals of concern include chemical warfare nerve and vesicant agents and the toxic industrial compounds phosgene, hydrogen cyanide, and cyanogen chloride. This work has been performed as a national case study conducted in partnership with the Los Angeles International Airport and The Bradley International Terminal. All recommended guidelines have been selected for consistency with airport scenario release parameters of a one-time, short-duration, finite airborne release from a single source followed by compound-specific decontamination

Membrane-Bound TNF Induces Protective Immune Responses to M. bovis BCG Infection: Regulation of memTNF and TNF Receptors Comparing Two memTNF Molecules

Several activities of the transmembrane form of TNF (memTNF) in immune responses to intracellular bacterial infection have been shown to be different from those exerted by soluble TNF. Evidence is based largely on studies in transgenic mice expressing memTNF, but precise cellular mechanisms are not well defined and the importance of TNF receptor regulation is unknown. In addition, memTNF activities are defined for a particular modification of the extracellular domain of TNF but a direct comparison of different mutant memTNF molecules has not been done in vivo

The Polyamine Inhibitor Alpha-Difluoromethylornithine Modulates Hippocampus-Dependent Function after Single and Combined Injuries

Exposure to uncontrolled irradiation in a radiologic terrorism scenario, a natural disaster or a nuclear battlefield, will likely be concomitantly superimposed on other types of injury, such as trauma. In the central nervous system, radiation combined injury (RCI) involving irradiation and traumatic brain injury may have a multifaceted character. This may entail cellular and molecular changes that are associated with cognitive performance, including changes in neurogenesis and the expression of the plasticity-related immediate early gene Arc. Because traumatic stimuli initiate a characteristic early increase in polyamine metabolism, we hypothesized that treatment with the polyamine inhibitor alpha-difluoromethylornithine (DFMO) would reduce the adverse effects of single or combined injury on hippocampus structure and function. Hippocampal dependent cognitive impairments were quantified with the Morris water maze and showed that DFMO effectively reversed cognitive impairments after all injuries, particularly traumatic brain injury. Similar results were seen with respect to the expression of Arc protein, but not neurogenesis. Given that polyamines have been found to modulate inflammatory responses in the brain we also assessed the numbers of total and newly born activated microglia, and found reduced numbers of newly born cells. While the mechanisms responsible for the improvement in cognition after DFMO treatment are not yet clear, the present study provides new and compelling data regarding the potential use of DFMO as a potential countermeasure against the adverse effects of single or combined injury

Swallowing dysfunction in cancer patients

Purpose Dysphagia (swallowing dysfunction) is a debilitating, depressing, and potentially life-threatening complication in cancer patients that is likely underreported. The present paper is aimed to review relevant dysphagia literature between 1990 and 2010 with a focus on assessment tools, prevalence, complications, and impact on quality of life in patients with a variety of different cancers, particularly in those treated with curative chemoradiation for head and neck cancer. Methods The literature search was limited to the English language and included both MEDLINE/PubMed and EMBASE. The search focused on papers reporting dysphagia as a side effect of cancer and cancer therapy. We identified relevant literature through the primary literature search and by articles identified in references. Results A wide range of assessment tools for dysphagia was identified. Dysphagia is related to a number of factors such as direct impact of the tumor, cancer resection, chemotherapy, and radiotherapy and to newer therapies such as epidermal growth factor receptor inhibitors. Concomitant oral complications such as xerostomia may exacerbate subjective dysphagia. Most literature focuses on head and neck cancer, but dysphagia is also common in other types of cancer. Conclusions Swallowing impairment is a clinically relevant acute and long-term complication in patients with a wide variety of cancers. More prospective studies on the course of dysphagia and impact on quality of life from baseline to long-term follow-up after various treatment modalities, including targeted therapies, are needed

Prevalence and Risk Factors for Hyposalivation and Xerostomia in Childhood Cancer Survivors Following Different Treatment Modalities-A Dutch Childhood Cancer Survivor Study Late Effects 2 Clinical Study (DCCSS LATER 2)

Simple Summary Salivary gland dysfunction is an underestimated late effect in childhood cancer survivors (CCS). The objective of this cross-sectional study, part of the multidisciplinary multicenter Dutch Childhood Cancer Survivor Study Late Effects 2 (DCCSS LATER 2), was to assess the prevalence of and risk factors for hyposalivation and xerostomia in CCS with a long-term follow-up exceeding 15 years. From February 2016 until March 2020, 292 CCS were included. The prevalence of hyposalivation was 32% and the prevalence of xerostomia was 9.4%. Hyposalivation and xerostomia did not correlate significantly. Risk factors for hyposalivation were female gender and a higher dose of radiotherapy (>12 Gy) to the salivary glands. Screening for hyposalivation during long-term follow-up in CCS is recommended in order to provide optimal oral supportive care aimed to improve oral health. Background: Limited data are available on the risk factors of salivary gland dysfunction in long-term childhood cancer survivors (CCS). The objective of this cross-sectional study, part of the multidisciplinary multicenter Dutch CCS Study Late Effects 2 (DCCSS LATER 2), was to assess the prevalence of and risk factors for hyposalivation and xerostomia in CCS. Methods: From February 2016 until March 2020, 292 CCS were included. Data with regard to gender, age at study, diagnosis, age at diagnosis, and treatment characteristics were collected, as well as the unstimulated (UWS) and stimulated whole salivary flow rate (SWS). Xerostomia was assessed with the Xerostomia Inventory (XI) questionnaire. Multivariable Poisson regression analyses were used to evaluate the association between potential risk factors and the occurrence of hyposalivation. Results: The minimum time between diagnosis and study enrollment was 15 years. The prevalence of hyposalivation was 32% and the prevalence of xerostomia was 9.4%. Hyposalivation and xerostomia were not significantly correlated. Risk factors for hyposalivation were female gender and a higher dose of radiotherapy (>12 Gy) to the salivary gland region. Conclusion: Considering the importance of saliva for oral health, screening for hyposalivation in CCS is suggested in order to provide optimal oral supportive care aimed to improve oral health

Early detection of urothelial premalignant lesions using hexaminolevulinate fluorescence cystoscopy in high risk patients

<p>Abstract</p> <p>Background</p> <p>To evaluate fluorescence cystoscopy with hexaminolevulinate (HAL) in the early detection of dysplasia (DYS) and carcinoma in situ (CIS) in select high risk patients.</p> <p>Methods</p> <p>We selected 30 consecutive bladder cancer patients at high risk for progression. After endoscopic resection, all patients received (a) induction BCG schedule when needed, and (b) white light and fluorescence cystoscopy after 3 months. HAL at doses of 85 mg (GE Healthcare, Buckinghamshire, United Kingdom) dissolved in 50 ml of solvent to obtain an 8 mmol/L solution was instilled intravesically with a 12 Fr catheter into an empty bladder and left for 90 minutes. The solution was freshly prepared immediately before instillation. Cystoscopy was performed within 120 minutes of bladder emptying. Standard and fluorescence cystoscopy was performed using a double light system (Combilight PDD light source 5133, Wolf, Germany) which allowed an inspection under both white and blue light.</p> <p>Results</p> <p>The overall incidence was 43.3% dysplasia, 23.3% CIS, and 13.3% superficial transitional cell cancer. In 21 patients, HAL cystoscopy was positive with one or more fluorescent flat lesions. Of the positive cases, there were 4 CIS, 10 DYS, 2 association of CIS and DYS, 4 well-differentiated non-infiltrating bladder cancers, and 1 chronic cystitis. In 9 patients with negative HAL results, random biopsies showed 1 CIS and 1 DYS. HAL cystoscopy showed 90.1% sensitivity and 87.5% specificity with 95.2% positive predictive value and 77.8% negative predictive value.</p> <p>Conclusion</p> <p>Photodynamic diagnosis should be considered a very important tool in the diagnosis of potentially evolving flat lesions on the bladder mucosa such as DYS and CIS. Moreover, detection of dysplasic lesions that are considered precursors of CIS may play an important role in preventing disease progression. In our opinion, HAL cystoscopy should be recommended in the early follow-up of high risk patients.</p