Summary In patients with neurodegenerative diseases, there is a spectrum of smell dysfunction ranging from severe loss, as seen in Alzheimer's disease and Parkinson's disease, to relatively little ...loss, as seen in progressive supranuclear palsy. Given the ubiquitous but varying degrees of olfactory dysfunction among such diseases, it is conceivable that differential disruption of a common primordial neuropathological substrate causes these differences in olfactory function. For example, the amount of damage to forebrain neurotransmitter and neuromodulator circuits, most notably those involving cholinergic transmission, appears to be correlated with quantitative smell test scores across a wide range of neurodegenerative diseases. Thus, a key question is whether damage to such a substrate is the basis for the perceptual differences in olfaction or whether disease-specific or other entities, such as respiratory infections or pollution, are responsible. In light of the early preclinical onset of smell deficits in many neurodegenerative diseases, the answer to this question might provide crucial insight into the cause of disease pathology at its earliest stages of development.
Using a simple approach for coding pain severity, the present study describes self-reported pain in U.S. adults. Data are included for 8,781 adults who completed the Functioning and Disability ...Supplement of the 2012 National Health Interview Survey. An internationally piloted pain severity coding system was used to group participants into 5 discrete ordered pain categories based on their pain persistence (days with pain in the last 3 months) and bothersomeness (little, a lot, somewhere in between): pain free and categories 1 (low) to 4 (high). It is estimated that 126.1 million adults reported some pain in the previous 3 months, with 25.3 million adults (11.2%) suffering from daily (chronic) pain and 23.4 million (10.3%) reporting a lot of pain. Based on the persistence and bothersomeness of their pain, 14.4 million adults (6.4%) were classified as having the highest level of pain, category 4, with an additional 25.4 million adults (11.3%) experiencing category 3 pain. Individuals with category 3 or 4 pain were likely to have worse health status, to use more health care, and to suffer from more disability than those with less severe pain. Associations were seen between pain severity and selected demographic variables including race, ethnicity, preferred language, sex, and age.
U.S. estimates of pain prevalence are presented using a simple approach for assigning pain severity developed by the Washington Group on Disability Statistics. Concurrent validity is assessed. Although this approach is promising, additional work is required to determine the usefulness of the Washington Group pain categories for pain research or clinical practice.
Human skin contains an abundant and diverse population of microbial organisms. Many of these microbes inhabit follicular structures of the skin. Furthermore, numerous studies have shown that the ...interaction of some members of the skin microbiome with host cells will result in changes in cell function. However, estimates of the potential for the microbiome to influence human health through skin have ignored the inner follicular surface, and therefore vastly underestimated the potential of the skin microbiome to have a systemic effect on the human body. By calculating the surface area of follicular and the interfollicular epithelial surface it is shown that skin provides a vast interface for interactions with the microbiome.
The study of synaptic plasticity and specifically LTP and LTD is one of the most active areas of research in neuroscience. In the last 25 years we have come a long way in our understanding of the ...mechanisms underlying synaptic plasticity. In 1988, AMPA and NMDA receptors were not even molecularly identified and we only had a simple model of the minimal requirements for the induction of plasticity. It is now clear that the modulation of the AMPA receptor function and membrane trafficking is critical for many forms of synaptic plasticity and a large number of proteins have been identified that regulate this complex process. Here we review the progress over the last two and a half decades and discuss the future challenges in the field.
Studies of LTP and LTD have been models for how the combination of classic electrophysiology and molecular methodologies can open the door for mechanistic insights into neuronal function. Rick Huganir and Roger Nicoll review the recent history and debates around the mechanisms of LTP and LTD and future directions for the field.
Induced pluripotent stem cell derived hepatocytes (IPSC-Heps) have the potential to reduce the demand for a dwindling number of primary cells used in applications ranging from therapeutic cell ...infusions to in vitro toxicology studies. However, current differentiation protocols and culture methods produce cells with reduced functionality and fetal-like properties compared to adult hepatocytes. We report a culture method for the maturation of IPSC-Heps using 3-Dimensional (3D) collagen matrices compatible with high throughput screening. This culture method significantly increases functional maturation of IPSC-Heps towards an adult phenotype when compared to conventional 2D systems. Additionally, this approach spontaneously results in the presence of polarized structures necessary for drug metabolism and improves functional longevity to over 75 days. Overall, this research reveals a method to shift the phenotype of existing IPSC-Heps towards primary adult hepatocytes allowing such cells to be a more relevant replacement for the current primary standard.
Changes in the properties and postsynaptic abundance of AMPA-type glutamate receptors (AMPARs) are major mechanisms underlying various forms of synaptic plasticity, including long-term potentiation ...(LTP), long-term depression (LTD), and homeostatic scaling. The function and the trafficking of AMPARs to and from synapses is modulated by specific AMPAR GluA1–GluA4 subunits, subunit-specific protein interactors, auxiliary subunits, and posttranslational modifications. Layers of regulation are added to AMPAR tetramers through these different interactions and modifications, increasing the computational power of synapses. Here we review the reliance of synaptic plasticity on AMPAR variants and propose “the AMPAR code” as a conceptual framework. The AMPAR code suggests that AMPAR variants will be predictive of the types and extent of synaptic plasticity that can occur and that a hierarchy exists such that certain AMPARs will be disproportionally recruited to synapses during LTP/homeostatic scaling up, or removed during LTD/homeostatic scaling down.
Changes in the number and properties of postsynaptic AMPARs are a fundamental mechanism of synaptic plasticity. Diering and Huganir discuss how AMPAR subunits, posttranslational modifications, and protein binding partners form combinatorial molecular codes relevant for understanding synapse function and plasticity.
Decreased smell function is related to brain health, future mortality, and quality of life. Most people inflicted with the SARS-CoV-2 virus evidence some measurable smell dysfunction during its acute ...phase, although many are unaware of the loss. Long-term deficits occur in up to 30% of COVID-19 cases, although total anosmia is relatively rare. This review explores what is presently known about the nature and pathophysiology of olfactory dysfunction due to the SARS-CoV-2 virus, including reversible inflammation within the olfactory cleft, downregulation of olfactory receptor proteins, and long-lasting peripheral and central damage to olfactory structures. It also addresses the question as to whether long-term smell loss might increase the likelihood of future development of cognitive and neurological deficits.
COVID-19 has brought to public attention the importance of the sense of smell in everyday life, with untold numbers of patients seeking treatment for decreased ability to smell, which, in many cases, may be permanent.The neuroepithelium that harbors the olfactory receptor cells is directly exposed to the outside environment, making it susceptible to damage from toxic agents and a host of viruses, most notably SARS-CoV-2, the cause of COVID-19.SARS-CoV-2 invades nearly all types of cells within the olfactory neuroepithelium, but does not appear to significantly invade olfactory receptor cells, which lack the primary entry receptor, angiotensin-converting enzyme II (ACE2). However, other entry receptors may also be involved.The degree to which SARS-CoV-2 impacts central olfactory processing centers or leads to later neurological disorders has yet to be determined.
Abstract Olfactory dysfunction is an early ‘pre-clinical’ sign of Parkinson's disease (PD). The present review is a comprehensive and up-to-date assessment of such dysfunction in PD and related ...disorders. The olfactory bulb is implicated in the dysfunction, since only those syndromes with olfactory bulb pathology exhibit significant smell loss. The role of dopamine in the production of olfactory system pathology is enigmatic, as overexpression of dopaminergic cells within the bulb's glomerular layer is a common feature of PD and most animal models of PD. Damage to cholinergic, serotonergic, and noradrenergic systems is likely involved, since such damage is most marked in those diseases with the most smell loss. When compromised, these systems, which regulate microglial activity, can influence the induction of localized brain inflammation, oxidative damage, and cytosolic disruption of cellular processes. In monogenetic forms of PD, olfactory dysfunction is rarely observed in asymptomatic gene carriers, but is present in many of those that exhibit the motor phenotype. This suggests that such gene-related influences on olfaction, when present, take time to develop and depend upon additional factors, such as those from aging, other genes, formation of α-synuclein- and tau-related pathology, or lowered thresholds to oxidative stress from toxic insults. The limited data available suggest that the physiological determinants of the early changes in PD-related olfactory function are likely multifactorial and may include the same determinants as those responsible for a number of other non-motor symptoms of PD, such as dysautonomia and sleep disturbances.
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