Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease.

Mycobacterium ulcerans infection causes a neglected tropical disease known as Buruli ulcer that is now found in poor rural areas of West Africa in numbers that sometimes exceed those reported for another significant mycobacterial disease, leprosy, caused by M. leprae. Unique among mycobacterial diseases, M. ulcerans produces a plasmid-encoded toxin called mycolactone (ML), which is the principal virulence factor and destroys fat cells in subcutaneous tissue. Disease is typically first manifested by the appearance of a nodule that eventually ulcerates and the lesions may continue to spread over limbs or occasionally the trunk. The current standard treatment is 8 weeks of daily rifampin and injections of streptomycin (RS). The treatment kills bacilli and wounds gradually heal. Whether RS treatment actually stops mycolactone production before killing bacilli has been suggested by histopathological analyses of patient lesions. Using a mouse footpad model of M. ulcerans infection where the time of infection and development of lesions can be followed in a controlled manner before and after antibiotic treatment, we have evaluated the progress of infection by assessing bacterial numbers, mycolactone production, the immune response, and lesion histopathology at regular intervals after infection and after antibiotic therapy. We found that RS treatment rapidly reduced gross lesions, bacterial numbers, and ML production as assessed by cytotoxicity assays and mass spectrometric analysis. Histopathological analysis revealed that RS treatment maintained the association of the bacilli with (or within) host cells where they were destroyed whereas lack of treatment resulted in extracellular infection, destruction of host cells, and ultimately lesion ulceration. We propose that RS treatment promotes healing in the host by blocking mycolactone production, which favors the survival of host cells, and by killing M. ulcerans bacilli

Stress-Induced Heat Shock Protein 40 and Immune Function in Altered Gravity

In space, astronauts are more susceptible to pathogens, viral reactivation and immunosuppression, which poses limits to their health and the mission. Interestingly, during space flight, stress-inducible heat shock proteins (HSP) are robustly induced, and the overexpression of HSPs have been implicated in immune dysregulation, therefore HSPs may be critically involved in regulating immune homeostasis. HSP40/DNAJ1 plays a major role in proper protein translation and folding. Its loss of function has been implicated in susceptibility to microbial infection, while its overexpression has been implicated in autoimmunity, collectively suggesting its complicated, but necessary, role in maintaining immunological function. To determine the role of HSP40 during stress-induced altered gravity conditions, wild-type and Hsp40 mutant Drosophila melanogaster were exposed to ground-based chronic hypergravity conditions, followed by quantitative PCR (qPCR) analysis of immune gene expression. In addition, larval hemocytes were collected to determine the functional output in response to E. coli bioparticle phagocytosis. Preliminary data indicates a required role for Hsp40 in strengthening immune function during stress-induced spaceflight in flies. In short, a critical need to evaluate the relationship between HSPs and immune suppression during space flight is necessary. Since space travel may become available to the general public in the not too distant future, and for the possibility of long-term space missions, a more comprehensive evaluation of the molecules responsible for immune dysfunction observed during space flight is required

Impact of Preoperative Anemia in Patients Undergoing Peripheral Vascular Intervention

Objectives: Transcarotid artery revascularization (TCAR) is an emerging novel approach to carotid intervention, adopted and well-suited for high-risk patients. Our objective was to assess the outcomes of TCAR and determine its impact on the volume of carotid endarterectomy (CEA) and non-TCAR carotid artery stenting (CAS) in a single-state experience. Methods: A large statewide quality consortium registry was queried. The indications and outcomes of TCAR compared with CEA and non-TCAR CAS from January 2018 to October 2019 were reviewed. Non-TCAR CAS included transfemoral, transbrachial stenting and transcarotid stenting without the flow reversal technique. We also assessed the impact of TCAR on the trend of CEA and non-TCAR CAS performed, analyzing data from 2012 to 2019. Outcome comparisons were performed using the χ 2 and Mann-Whitney U tests, depending on the distribution of the outcomes. Results: A total of 438 TCARs were performed by 39 physicians in 16 hospitals; 60% of the patients were asymptomatic and 40% symptomatic. The TCAR indication was physiologic high risk for 369 patients (84%) and restenosis for 69 patients (16%), with most occurring after prior CEA (94%). Of the non-TCAR CAS cases, 94% were performed via transfemoral access. The patients undergoing non-TCAR CAS had the highest 30-day mortality ( P \u3c .001) and the highest incidence of 30-day new neurologic deficits ( P = .008) compared with the patients undergoing CEA and TCAR. CEA had the lowest myocardial infarction rate ( P = .015; Table). The number of TCAR procedures performed and the number of physicians and hospitals performing them increased during the 2-year period. Since the introduction of TCAR, no significant frequency decrease has occurred in the number of non-TCAR CAS or CEA cases by hospitals or physicians (Fig). However, a significant negative trend was found in the number of CEAs performed by physicians since 2012 ( P \u3c .001; Fig). Conclusions: TCAR is a safe method of carotid revascularization and is becoming an increasingly used method. TCAR has not affected the CEA hospital or physician volume since its introduction. CEA volumes and physician usage are declining, which could have future credentialing implications. In the present single-state experience, TCAR compared favorably with CEA and non-TCAR CAS might be less appealing because of its higher neurologic event rate

Nanotools for Neuroscience and Brain Activity Mapping

Neuroscience is at a crossroads. Great effort is being invested into deciphering specific neural interactions and circuits. At the same time, there exist few general theories or principles that explain brain function. We attribute this disparity, in part, to limitations in current methodologies. Traditional neurophysiological approaches record the activities of one neuron or a few neurons at a time. Neurochemical approaches focus on single neurotransmitters. Yet, there is an increasing realization that neural circuits operate at emergent levels, where the interactions between hundreds or thousands of neurons, utilizing multiple chemical transmitters, generate functional states. Brains function at the nanoscale, so tools to study brains must ultimately operate at this scale, as well. Nanoscience and nanotechnology are poised to provide a rich toolkit of novel methods to explore brain function by enabling simultaneous measurement and manipulation of activity of thousands or even millions of neurons. We and others refer to this goal as the Brain Activity Mapping Project. In this Nano Focus, we discuss how recent developments in nanoscale analysis tools and in the design and synthesis of nanomaterials have generated optical, electrical, and chemical methods that can readily be adapted for use in neuroscience. These approaches represent exciting areas of technical development and research. Moreover, unique opportunities exist for nanoscientists, nanotechnologists, and other physical scientists and engineers to contribute to tackling the challenging problems involved in understanding the fundamentals of brain function

CyPPA, a Positive SK3/SK2 Modulator, Reduces Activity of Dopaminergic Neurons, Inhibits Dopamine Release, and Counteracts Hyperdopaminergic Behaviors Induced by Methylphenidate1

Dopamine (DA) containing midbrain neurons play critical roles in several psychiatric and neurological diseases, including schizophrenia and attention deficit hyperactivity disorder, and the substantia nigra pars compacta neurons selectively degenerate in Parkinson’s disease. Pharmacological modulation of DA receptors and transporters are well established approaches for treatment of DA-related disorders. Direct modulation of the DA system by influencing the discharge pattern of these autonomously firing neurons has yet to be exploited as a potential therapeutic strategy. Small conductance Ca2+-activated K+ channels (SK channels), in particular the SK3 subtype, are important in the physiology of DA neurons, and agents modifying SK channel activity could potentially affect DA signaling and DA-related behaviors. Here we show that cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA), a subtype-selective positive modulator of SK channels (SK3 > SK2 > > > SK1, IK), decreased spontaneous firing rate, increased the duration of the apamin-sensitive afterhyperpolarization, and caused an activity-dependent inhibition of current-evoked action potentials in DA neurons from both mouse and rat midbrain slices. Using an immunocytochemically and pharmacologically validated DA release assay employing cultured DA neurons from rats, we show that CyPPA repressed DA release in a concentration-dependent manner with a maximal effect equal to the D2 receptor agonist quinpirole. In vivo studies revealed that systemic administration of CyPPA attenuated methylphenidate-induced hyperactivity and stereotypic behaviors in mice. Taken together, the data accentuate the important role played by SK3 channels in the physiology of DA neurons, and indicate that their facilitation by CyPPA profoundly influences physiological as well as pharmacologically induced hyperdopaminergic behavior

Proceedings of the Tenth Annual Beef Cattle Short Course.

91 p

Global importance of Indigenous Peoples, their lands, and knowledge systems for saving the world's primates from extinction

Publisher Copyright: Copyright © 2022 The Authors, some rights reserved.Primates, represented by 521 species, are distributed across 91 countries primarily in the Neotropic, Afrotropic, and Indo-Malayan realms. Primates inhabit a wide range of habitats and play critical roles in sustaining healthy ecosystems that benefit human and nonhuman communities. Approximately 68% of primate species are threatened with extinction because of global pressures to convert their habitats for agricultural production and the extraction of natural resources. Here, we review the scientific literature and conduct a spatial analysis to assess the significance of Indigenous Peoples' lands in safeguarding primate biodiversity. We found that Indigenous Peoples' lands account for 30% of the primate range, and 71% of primate species inhabit these lands. As their range on these lands increases, primate species are less likely to be classified as threatened or have declining populations. Safeguarding Indigenous Peoples' lands, languages, and cultures represents our greatest chance to prevent the extinction of the world's primates.Peer reviewe