Prion-like propagation of tau aggregation might underlie the stereotyped progression of neurodegenerative tauopathies. True prions stably maintain unique conformations (“strains”) in vivo that link ...structure to patterns of pathology. We now find that tau meets this criterion. Stably expressed tau repeat domain indefinitely propagates distinct amyloid conformations in a clonal fashion in culture. Reintroduction of tau from these lines into naive cells reestablishes identical clones. We produced two strains in vitro that induce distinct pathologies in vivo as determined by successive inoculations into three generations of transgenic mice. Immunopurified tau from these mice recreates the original strains in culture. We used the cell system to isolate tau strains from 29 patients with 5 different tauopathies, finding that different diseases are associated with different sets of strains. Tau thus demonstrates essential characteristics of a prion. This might explain the phenotypic diversity of tauopathies and could enable more effective diagnosis and therapy.
•Tau stably propagates multiple amyloid conformations (strains) in dividing cells•Strains induce unique pathologies in transgenic mice•Strains can be passaged through multiple generations of mice and back to cells•Different tauopathies are associated with different sets of strains
Prions stably propagate unique conformations (strains) that produce different pathologies. Sanders et al. now report that tau acts as a prion in cells and in vivo by this criterion and find that different tauopathies are associated with unique tau strains.
Multiple neurodegenerative diseases are characterized by single-protein dysfunction and aggregation. Treatment strategies for these diseases have often targeted downstream pathways to ameliorate ...consequences of protein dysfunction; however, targeting the source of that dysfunction, the affected protein itself, seems most judicious to achieve a highly effective therapeutic outcome. Antisense oligonucleotides (ASOs) are small sequences of DNA able to target RNA transcripts, resulting in reduced or modified protein expression. ASOs are ideal candidates for the treatment of neurodegenerative diseases, given numerous advancements made to their chemical modifications and delivery methods. Successes achieved in both animal models and human clinical trials have proven ASOs both safe and effective. With proper considerations in mind regarding the human applicability of ASOs, we anticipate ongoing in vivo research and clinical trial development of ASOs for the treatment of neurodegenerative diseases.
In this review, Schoch and Miller describe the preclinical research that is developing and has advanced the application of antisense oligonucleotides (ASOs) to human clinical trials for neurodegenerative diseases. Recent clinical successes are highlighted and support the use of ASOs as a viable therapeutic strategy.
Pathological evidence for selective four-repeat (4R) tau deposition in certain dementias and exon 10-positioned MAPT mutations together suggest a 4R-specific role in causing disease. However, direct ...assessments of 4R toxicity have not yet been accomplished in vivo. Increasing 4R-tau expression without change to total tau in human tau-expressing mice induced more severe seizures and nesting behavior abnormality, increased tau phosphorylation, and produced a shift toward oligomeric tau. Exon 10 skipping could also be accomplished in vivo, providing support for a 4R-tau targeted approach to target 4R-tau toxicity and, in cases of primary MAPT mutation, eliminate the disease-causing mutation.
•Antisense oligonucleotide-mediated MAPT splicing is successful in vivo•Increasing 4R-tau induces tau phosphorylation and exacerbates seizures•Reducing 4R-tau is effective in human tau-expressing mouse models
Schoch et al. employ antisense oligonucleotide technology to manipulate tau isoforms, demonstrating that increased four-repeat tau drives toxic changes in a human tau mouse model. Reducing four-repeat tau was also achieved, suggesting application in human tauopathies.
The Johnson Thermoelectric Converter (JTEC) operates as an approximation of an Ericsson cycle thermodynamic heat engine with no moving parts. During operation, hydrogen flows from a high-temperature ...high-pressure region to a low-pressure region by way of a membrane-electrode assembly. In passing through the assembly, the hydrogen is stripped of its electrons which flow through the circuit and reform with protons to the recover hydrogen on the low-pressure side. Some of the electrical power extracted is used to electrochemically “pump” the hydrogen back to the low-temperature high-pressure side and sustain the pressure differential. The objective of the work presented here was to mathematically characterize a JTEC system and to develop the coupled relationships between design goals like efficiency, net power production, and power density; and design parameters like high versus low operating temperatures and pressures, device geometry, and thermophysical properties of the device materials and working fluid. Power production is related to the operating pressure ratio, the ratio of high to low device operating temperatures, the high operating temperature, and the effective heat transfer area of the hot end. The efficiency is related to several non-dimensional and dimensional number groups (especially the recuperator effectiveness). The power density or volume of the device is related to a different recuperator parameter, the high temperature of the heat addition source, the cold temperature of the thermal rejection source, and the internal device geometry. Even with reasonable simplifications and assumptions, the design space contains a large number of variable parameters. The model equations were exercised over the large parametric trade space.
•Parametric study of a solid state Ericsson heat engine was performed.•Good recuperator design was the greatest contributor to cycle efficiency.•Power was most impacted by ratio of device surface area to ion exchange thickness.
Optimal perioperative fluid management is an important component of Enhanced Recovery After Surgery (ERAS) pathways. Fluid management within ERAS should be viewed as a continuum through the ...preoperative, intraoperative, and postoperative phases. Each phase is important for improving patient outcomes, and suboptimal care in one phase can undermine best practice within the rest of the ERAS pathway. The goal of preoperative fluid management is for the patient to arrive in the operating room in a hydrated and euvolemic state. To achieve this, prolonged fasting is not recommended, and routine mechanical bowel preparation should be avoided. Patients should be encouraged to ingest a clear carbohydrate drink two to three hours before surgery. The goals of intraoperative fluid management are to maintain central euvolemia and to avoid excess salt and water. To achieve this, patients undergoing surgery within an enhanced recovery protocol should have an individualized fluid management plan. As part of this plan, excess crystalloid should be avoided in all patients. For low-risk patients undergoing low-risk surgery, a “zero-balance” approach might be sufficient. In addition, for most patients undergoing major surgery, individualized goal-directed fluid therapy (GDFT) is recommended. Ultimately, however, the additional benefit of GDFT should be determined based on surgical and patient risk factors. Postoperatively, once fluid intake is established, intravenous fluid administration can be discontinued and restarted only if clinically indicated. In the absence of other concerns, detrimental postoperative fluid overload is not justified and “permissive oliguria” could be tolerated.
Tauopathies are neurodegenerative disorders that affect distinct brain regions, progress at different rates, and exhibit specific patterns of tau accumulation. The source of this diversity is ...unknown. We previously characterized two tau strains that stably maintain unique conformations in vitro and in vivo, but did not determine the relationship of each strain to parameters that discriminate between tauopathies such as regional vulnerability or rate of spread. We have now isolated and characterized 18 tau strains in cells based on detailed biochemical and biological criteria. Inoculation of PS19 transgenic tau (P301S) mice with these strains causes strain-specific intracellular pathology in distinct cell types and brain regions, and induces different rates of network propagation. In this system, strains alone are sufficient to account for diverse neuropathological presentations, similar to those that define human tauopathies. Further study of these strains can thus establish a structural logic that governs these biological effects.
•Tau forms multiple, unique prion strains with distinct biochemical properties•Tau strains induce diverse pathological phenotypes in vitro and in vivo•Tau strains target different brain regions and propagate pathology at unique rates•We present a framework to understand the diversity of human tauopathies
Kaufman et al. observe that tau forms multiple self-propagating amyloid strains. The introduction of each into transgenic mouse brain creates a distinct pathology that targets different brain regions and induces unique rates of spread. Thus, strain variation can account for the diversity of human tauopathies.
Abstract
Objective:
During the past two decades, professional associations, accrediting bodies, and payors have made post-surgical pain treatment a high priority. In light of the disappointing ...findings in previous surveys, a survey was conducted to assess patient perceptions and characterize patient experiences/levels of satisfaction with post-surgical pain management.
Research design and methods:
Survey included a random sample of US adults who had undergone surgery within 5 years from the survey date. Participants were asked about their concerns before surgery, severity of perioperative pain, pain treatments, perceptions about post-surgical pain and pain medications, and satisfaction with treatments they received.
Results:
Of the 300 participants, ∼86% experienced pain after surgery; of these, 75% had moderate/extreme pain during the immediate post-surgical period, with 74% still experiencing these levels of pain after discharge. Post-surgical pain was the most prominent pre-surgical patient concern, and nearly half reported they had high/very high anxiety levels about pain before surgery. Approximately 88% received analgesic medications to manage pain; of these, 80% experienced adverse effects and 39% reported moderate/severe pain even after receiving their first dose.
Study limitations:
Key study limitations include the relatively small population size, potential for recall bias associated with the 14-month average time delay from surgery date to survey date, and the inability to account for influences of type of surgery and intraoperative anesthetic/analgesic use on survey results.
Conclusions:
Despite heightened awareness and clinical advancements in pain management, there has been little improvement in post-surgical analgesia as measured by this survey of post-surgical patients.
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