Differential regulation of bladder pain and voiding function by sensory afferent populations revealed by selective optogenetic activation

Bladder-innervating primary sensory neurons mediate reflex-driven bladder function under normal conditions, and contribute to debilitating bladder pain and/or overactivity in pathological states. The goal of this study was to examine the respective roles of defined subtypes of afferent neurons in bladder sensation and function in vivo via direct optogenetic activation. To accomplish this goal, we generated transgenic lines that express a Channelrhodopsin-2-eYFP fusion protein (ChR2-eYFP) in two distinct populations of sensory neurons: TRPV1-lineage neurons (Trpv1Cre;Ai32, the majority of nociceptors) and Nav1.8+ neurons (Scn10aCre;Ai32, nociceptors and some mechanosensitive fibers). In spinal cord, eYFP+ fibers in Trpv1Cre;Ai32 mice were observed predominantly in dorsal horn (DH) laminae I-II, while in Scn10aCre;Ai32 mice they extended throughout the DH, including a dense projection to lamina X. Fiber density correlated with number of retrogradely-labeled eYFP+ dorsal root ganglion neurons (82.2% Scn10aCre;Ai32 vs. 62% Trpv1Cre;Ai32) and degree of DH excitatory synaptic transmission. Photostimulation of peripheral afferent terminals significantly increased visceromotor responses to noxious bladder distension (30–50 mmHg) in both transgenic lines, and to non-noxious distension (20 mmHg) in Scn10aCre;Ai32 mice. Depolarization of ChR2+ afferents in Scn10aCre;Ai32 mice produced low- and high-amplitude bladder contractions respectively in 53% and 27% of stimulation trials, and frequency of high-amplitude contractions increased to 60% after engagement of low threshold (LT) mechanoreceptors by bladder filling. In Trpv1Cre;Ai32 mice, low-amplitude contractions occurred in 27% of trials before bladder filling, which was pre-requisite for light-evoked high-amplitude contractions (observed in 53.3% of trials). Potential explanations for these observations include physiological differences in the thresholds of stimulated fibers and their connectivity to spinal circuits

A novel platform for isotype-specific testing of autoantibodies.

The objective of this study was to test if a novel platform could be used for isotype-specific autoantibody testing in humans. Further, we evaluated if testing with this novel platform enables earlier detection of insulin autoantibodies in individuals that have first-degree relatives with type-1 diabetes than currently used approaches. Longitudinal serum samples from participants were collected before and after they converted to become positive for insulin autoantibodies by the current standardly used assays. Using a novel plasmonic gold chip platform, we tested these samples for IgM isotype-specific autoantibodies. Serial serum samples from individuals without diabetes were also tested as a comparison control cohort. Our results demonstrate proof-of-concept that a plasmonic gold chip can specifically detect the IgM insulin autoantibody. Five out of the six individuals that converted to being positive for insulin autoantibodies by standard testing had significant IgM autoantibodies on the plasmonic chip platform. The plasmonic chip platform detected IgM autoantibodies earlier than standard testing by up to 4 years. Our results indicate that the plasmonic gold platform can specifically detect the IgM isotype autoantibodies and suggest that combining isotype-specific testing with currently used approaches enables earlier detection of insulin autoantibodies in individuals that have first-degree relatives with type 1 diabetes

A parametric shell analysis of the shuttle 51-L SRB AFT field joint

Following the Shuttle 51-L accident, an investigation was conducted to determine the cause of the failure. Investigators at the Langley Research Center focused attention on the structural behavior of the field joints with O-ring seals in the steel solid rocket booster (SRB) cases. The shell-of-revolution computer program BOSOR4 was used to model the aft field joint of the solid rocket booster case. The shell model consisted of the SRB wall and joint geometry present during the Shuttle 51-L flight. A parametric study of the joint was performed on the geometry, including joint clearances, contact between the joint components, and on the loads, induced and applied. In addition combinations of geometry and loads were evaluated. The analytical results from the parametric study showed that contact between the joint components was a primary contributor to allowing hot gases to blow by the O-rings. Based upon understanding the original joint behavior, various proposed joint modifications are shown and analyzed in order to provide additional insight and information. Finally, experimental results from a hydro-static pressurization of a test rocket booster case to study joint motion are presented and verified analytically

Lawyers\u27 Negligence Liability to Non-Clients: A Texas Viewpoint.

Courts should examine the relationship of a non-client to a negligent lawyer to determine whether a lawyer is liable to a non-client despite lack of privity. In most jurisdictions, attorneys enjoy the privity of contract requirement which limits their duty to exercise reasonable care. As a result, lawyers are normally immune to negligent malpractice actions brought by non-clients. Courts should examine the relationship between the attorney and the non-client to determine whether the requirement of privity is an overly restrictive limit on the lawyer’s scope of duty. These relationships can be classified into three categories. The first category involves plaintiffs who are the intended beneficiaries of the attorney’s work for a client. The second category includes plaintiffs who rely on negligent misrepresentations made by the attorney. The third category includes plaintiffs who are in an adversary relationship to the lawyer and his client. Attorney liability should extend to a non-client, intended beneficiary despite lack of privity. The main function of the privity requirement is to prevent unlimited liability. In this category of cases, however, the plaintiffs who may have legitimate claims are certain and foreseeable. Attorneys should also be liable for negligent misrepresentations made to plaintiffs foreseen to rely on the information. The Restatement (Second) of Torts provides a proper standard of the law for this category of cases and does not impose an undue burden on the legal profession since no unforeseen plaintiffs would recover. Lastly, the adverse plaintiff should not recover against the opposing attorney for negligence in bringing or handling his client’s suit. The dangers of creating a conflict of interest and of inhibiting a lawyer in performing his duty of zealously advocating his client’s position are too great to allow liability for less than intentional or malicious conduct

Lawyers\u27 Negligence Liability to Non-Clients: A Texas Viewpoint.

Courts should examine the relationship of a non-client to a negligent lawyer to determine whether a lawyer is liable to a non-client despite lack of privity. In most jurisdictions, attorneys enjoy the privity of contract requirement which limits their duty to exercise reasonable care. As a result, lawyers are normally immune to negligent malpractice actions brought by non-clients. Courts should examine the relationship between the attorney and the non-client to determine whether the requirement of privity is an overly restrictive limit on the lawyer’s scope of duty. These relationships can be classified into three categories. The first category involves plaintiffs who are the intended beneficiaries of the attorney’s work for a client. The second category includes plaintiffs who rely on negligent misrepresentations made by the attorney. The third category includes plaintiffs who are in an adversary relationship to the lawyer and his client. Attorney liability should extend to a non-client, intended beneficiary despite lack of privity. The main function of the privity requirement is to prevent unlimited liability. In this category of cases, however, the plaintiffs who may have legitimate claims are certain and foreseeable. Attorneys should also be liable for negligent misrepresentations made to plaintiffs foreseen to rely on the information. The Restatement (Second) of Torts provides a proper standard of the law for this category of cases and does not impose an undue burden on the legal profession since no unforeseen plaintiffs would recover. Lastly, the adverse plaintiff should not recover against the opposing attorney for negligence in bringing or handling his client’s suit. The dangers of creating a conflict of interest and of inhibiting a lawyer in performing his duty of zealously advocating his client’s position are too great to allow liability for less than intentional or malicious conduct

A blinded determination of H0H_0 from low-redshift Type Ia supernovae, calibrated by Cepheid variables

Presently a ${>}3\sigma$ tension exists between values of the Hubble constant $H_0$ derived from analysis of fluctuations in the Cosmic Microwave Background by Planck, and local measurements of the expansion using calibrators of type Ia supernovae (SNe Ia). We perform a blinded reanalysis of Riess et al. 2011 to measure $H_0$ from low-redshift SNe Ia, calibrated by Cepheid variables and geometric distances including to NGC 4258. This paper is a demonstration of techniques to be applied to the Riess et at. 2016 data. Our end-to-end analysis starts from available CfA3 and LOSS photometry, providing an independent validation of Riess et al. 2011. We obscure the value of $H_0$ throughout our analysis and the first stage of the referee process, because calibration of SNe Ia requires a series of often subtle choices, and the potential for results to be affected by human bias is significant. Our analysis departs from that of Riess et al. 2011 by incorporating the covariance matrix method adopted in SNLS and JLA to quantify SN Ia systematics, and by including a simultaneous fit of all SN Ia and Cepheid data. We find $H_0 = 72.5 \pm 3.1$ (stat) $\pm 0.77$ (sys) km s$^{-1}$ Mpc$^{-1}$ with a three-galaxy (NGC 4258+LMC+MW) anchor. The relative uncertainties are 4.3% statistical, 1.1% systematic, and 4.4% total, larger than in Riess et al. 2011 (3.3% total) and the Efstathiou 2014 reanalysis (3.4% total). Our error budget for $H_0$ is dominated by statistical errors due to the small size of the supernova sample, whilst the systematic contribution is dominated by variation in the Cepheid fits, and for the SNe Ia, uncertainties in the host galaxy mass dependence and Malmquist bias.Comment: 38 pages, 13 figures, 13 tables; accepted for publication in MNRA

Making Continuous Improvement a Reality: Achieving High Performance in the Ottawa County, Michigan, Circuit and Probate Courts

Today, a well-functioning court is expected to resolve large volumes of work in a fair and orderly way within demanding time frames. The overall goal is quality administration in all phases of court operations, yet achieving this goal in practice means navigating the shoals of tight budgets, workplace politics, and the heavy press of daily business. Courts are under enormous stress these days, and as a result it should come as no surprise that too many courts are infected with pessimistic court leadership. Winston Churchill is often reported to have said, “The pessimist sees difficulty in every opportunity, the optimist sees the opportunity in every difficulty.”1 A high-performance court makes the effort to reject pessimism as it looks to improve its administrative practices, even in tough times. To seize the opportunity for continuous improvement and rally support throughout the court, though, takes coordinated planning and follow-through. The bottom line is that court leaders need to work together at organizational change. In two recent articles in Court Review, we emphasized the necessity of judicial involvement and commitment if administrative improvement is to take hold and thrive. One point was that developing shared, court-wide agreement among judges on how court personnel should work together requires accepting two primary responsibilities: the role each judge has in making decisions and the administrative role judges have in making the system work. Judges benefit from orderly and stable court administration because it helps enhance preparation of all parties, augments the understanding of outstanding issues, and clarifies future procedural events necessary to bring final resolution. However, in any courthouse, making effective administrative practices a reality is a team effort; it requires conscious effort to organize work processes in a way that clarifies and engages the joint contributions of judges and court staff.