Liver Transplantation to Provide Low-Density-Lipoprotein Receptors and Lower Plasma Cholesterol in a Child with Homozygous Familial Hypercholesterolemia

A six-year-old girl with severe hypercholesterolemia and atherosclerosis had two defective genes at the low-density-lipoprotein (LDL) receptor locus, as determined by biochemical studies of cultured fibroblasts. One gene, inherited from the mother, produced no LDL receptors; the other gene, inherited from the father, produced a receptor precursor that was not transported to the cell surface and was unable to bind LDL. The patient degraded intravenously administered 125I-LDL at an extremely low rate, indicating that her high plasma LDL-cholesterol level was caused by defective receptor-mediated removal of LDL from plasma. After transplantation of a liver and a heart from a normal donor, the patient's plasma LDL-cholesterol level declined by 81 per cent, from 988 to 184 mg per deciliter. The fractional catabolic rate for intravenously administered 125I-LDL, a measure of functional LDL receptors in vivo, increased by 2.5-fold. Thus, the transplanted liver, with its normal complement of LDL receptors, was able to remove LDL cholesterol from plasma at a nearly normal rate. We conclude that a genetically determined deficiency of LDL receptors can be largely reversed by liver transplantation. These data underscore the importance of hepatic LDL receptors in controlling the plasma level of LDL cholesterol in human beings. (N Engl J Med 1984; 311: 1658–64.). © 1984, Massachusetts Medical Society. All rights reserved

Self-Policing: Dissemination and Adoption of Police Eyewitness Policies in Virginia

Professional policing organizations emphasize the importance of the adoption of sound police policies and procedures, but traditionally doing so has been left to individual agencies. State and local government typically does not closely regulate police, and neither federal constitutional rulings nor state law typically sets out in any detail the practices that police should follow. Thus, law enforcement agencies must themselves draft and disseminate policy. This paper presents the results of studies used to assess the adoption of eyewitness identification policies by law enforcement agencies in Virginia. Policymakers were focused on this problem because Virginia experienced a series of DNA exonerations in cases involving eyewitness misidentifications. In 2005, lawmakers enacted a law that required agencies to have some written policy in place. However, there was little guidance on what that policy should be. To remedy this problem, the state law enforcement policy agency, the Virginia Department of Criminal Justice Services (DCJS) promulgated, in 2011, a detailed model policy on eyewitness procedure. Nevertheless, as reported in a 2013 study, those model practices were only haltingly adopted. In particular, many agencies did not use blind or blinded lineups, in which the administrator does not know which photo is that of a suspect or cannot view which photo the eyewitness is examining. In Fall 2018, all of the over-three hundred law enforcement agencies in Virginia had their policies on this subject requested, using the state freedom of information law. The results show that there has now been widespread adoption of the DCJS model policy. Improved eyewitness identification practices have been adopted by the vast majority of agencies, including large and small agencies. This Article concludes by asking what contributed to the extensive dissemination of a model police policy, and what its implications are for improving police policy and practice without the use of regulation

Three-Dimensional Model for the Human Cl−/HCO3− Exchanger, AE1, by Homology to the E. coli ClC Protein

AbstractAE1 mediates electroneutral 1:1 exchange of bicarbonate for chloride across the plasma membrane of erythrocytes and type A cells of the renal collecting duct. No high-resolution structure is available for the AE1 membrane domain, which alone is required for its transport activity. A recent electron microscopy structure of the AE1 membrane domain was proposed to have a similar protein fold to ClC chloride channels. We developed a three-dimensional homology model of the AE1 membrane domain, using the Escherichia coli ClC channel structure as a template. This model agrees well with a long list of biochemically established spatial constraints for AE1. To investigate the AE1 transport mechanism, we created point mutations in regions corresponding to E. coli ClC transport mechanism residues. When expressed in HEK293 cells, several mutants had Cl−/HCO3− exchange rates significantly different from that of wild-type AE1. When further assessed in Xenopus laevis oocytes, there were significant changes in the transport activity of several AE1 point mutants as assessed by changes in pH. None of the mutants, however, added an electrogenic component to AE1 transport activity. This indicates that the AE1 point mutants altered the transport activity of AE1, without changing its electrogenicity and stoichiometry. The homology model successfully identified residues in AE1 that are critical to AE1 transport activity. Thus, we conclude that AE1 has a similar protein fold to ClC chloride channels

Psychometric characteristics of daily diaries for the Patient-Reported Outcomes Measurement Information System (PROMIS®): a preliminary investigation

Purpose - The Patient-Reported Outcomes (PRO) Measurement Information System (PROMIS®) has developed assessment tools for numerous PROs, most using a 7-day recall format. We examined whether modifying the recall period for use in daily diary research would affect the psychometric characteristics of several PROMIS measures. Methods - Daily versions of short-forms for three PROMIS domains (pain interference, fatigue, depression) were administered to a general population sample (n = 100) for 28 days. Analyses used multilevel item response theory (IRT) models. We examined differential item functioning (DIF) across recall periods by comparing the IRT parameters from the daily data with the PROMIS 7-day recall IRT parameters. Additionally, we examined whether the IRT parameters for day-to-day within-person changes are invariant to those for between-person (cross-sectional) differences in PROs. Results - Dimensionality analyses of the daily data suggested a single dimension for each PRO domain, consistent with PROMIS instruments. One-third of the daily items showed uniform DIF when compared with PROMIS 7-day recall, but the impact of DIF on the scale level was minor. IRT parameters for within-person changes differed from between-person parameters for 3 depression items, which were more sensitive for measuring change than between-person differences, but not for pain interference and fatigue items. Notably, mean scores from daily diaries were significantly lower than the PROMIS 7-day recall norms. Conclusions - The results provide initial evidence supporting the adaptation of PROMIS measures for daily diary research. However, scores from daily diaries cannot be directly interpreted on PROMIS norms established for 7-day recall

Functional assessment of SLC4A11, an integral membrane protein mutated in corneal dystrophies

SLC4A11, a member of the SLC4 family of bicarbonate transporters, is a widely expressed integral membrane protein, abundant in kidney and cornea. Mutations of SLC4A11 cause some cases of the blinding corneal dystrophies, congenital hereditary endothelial dystrophy, and Fuchs endothelial corneal dystrophy. These diseases are marked by fluid accumulation in the corneal stroma, secondary to defective fluid reabsorption by the corneal endothelium. The role of SLC4A11 in these corneal dystrophies is not firmly established, as SLC4A11 function remains unclear. To clarify the normal function(s) of SLC4A11, we characterized the protein following expression in the simple, low-background expression system Xenopus laevis oocytes. Since plant and fungal SLC4A11 orthologs transport borate, we measured cell swelling associated with accumulation of solute borate. The plant water/borate transporter NIP5;1 manifested borate transport, whereas human SLC4A11 did not. SLC4A11 supported osmotically driven water accumulation that was electroneutral and Na⁺ independent. Studies in oocytes and HEK293 cells could not detect Na⁺⁻ coupled HCO3⁻ transport or Cl⁻/HCO3⁻ exchange by SLC4A11. SLC4A11 mediated electroneutral NH3 transport in oocytes. Voltagedependent OH⁻ or H⁺ movement was not measurable in SLC4A11- expressing oocytes, but SLC4A11-expressing HEK293 cells manifested low-level cytosolic acidification at baseline. In mammalian cells, but not oocytes, OH⁻/H⁺ conductance may arise when SLC4A11 activates another protein or itself is activated by another protein. These data argue against a role of human SLC4A11 in bicarbonate or borate transport. This work provides additional support for water and ammonia transport by SLC4A11. When expressed in oocytes, SLC4A11 transported NH3, not NH3/H⁺.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Effects of Ohio Opioid Prescribing Policy on Postsurgical Prescriptions Following Sports Procedures

Background: Prescribed opioid medication after orthopedic sports surgery has been shown to exceed patient requirements. In 2017, as a response to the opioid epidemic, Ohio passed Opioid Prescribing Guidelines (OPG) limiting narcotic prescriptions for acute pain. This study sought to evaluate the effects of the OPG on prescribing behavior of orthopedists following knee arthroscopy (KA), shoulder arthroscopy (SA), and anterior cruciate ligament reconstruction (ACLR). Methods: An institutional database was queried to calculate morphine equivalent dose (MED) prescribed at discharge, acute follow-up (\u3c90 days), and chronic follow-up (\u3e90 days) and compare MED pre- and post-OPG. Cases were identified over a 2-year period starting 1 year prior to OPG implementation. Individual surgeon data were tracked to control for inter-surgeon variability. Results: A total of 1663 patients were included in the analysis. Demographic variables were similar pre- and post-OPG for each procedure group. With all surgeons included, average discharge MED decreased significantly for all procedures from pre- to post-OPG. Surgeons qualified for individual analysis if they had at least 10 surgeries pre- and post-OPG. Of qualifying providers, 80% of KA, 25% of SA, and 0% of ACLR surgeons reduced discharge MED prescribed post-OPG. MED prescribed during follow-up was largely unaffected by implementation of the OPG. Conclusion: Average discharge morphine equivalent dose (MED) prescribed after SA, KA, and ACLR decreased following the implementation of the OPG. The MED reduction effect of the OPG was the greatest in magnitude after SA, and SA was the only surgery that showed MED reductions that persisted during acute follow up. Opioid prescriptions beyond 90 days postoperatively were unchanged by the OPG for all surgeries. Policy that restricts postoperative opioid prescriptions can be an effective, but incomplete method to address the opioid crisis