The Productivity of Pharmaceuticals in Improving Health: An Analysis of the OECD Health Data

Although a number of studies have been conducted on health production functions, little attention has been given to pharmaceuticals as a separate input into the production of health. Building upon existing published work, this paper uses an alternative specification and more recent data to estimate the effect of pharmaceutical expenditures on levels of health in the member countries of the Organization for Economic Cooperation and Development (OECD). In a sample of developed countries, we found that pharmaceutical consumption, as measured by per capita drug expenditures, has a positive effect on life expectancy at advanced ages. The marginal effect of pharmaceutical consumption is consistent with estimates that have been reported previously but appears to decline with increasing age. Over the past few years, the substantial and disproportionate growth of pharmaceutical expenditures for public and private payers in the U.S. has led to calls for regulatory intervention (e.g., price controls). However, our research suggests that increases in drug spending may yield further increases in life expectancy.Health production, life expectancy, pharmaceuticals, OECD, ecological studies

Autoregulation of Connexin43 Gap Junction Formation by Internally Translated Isoforms

SummaryDuring each heartbeat, intercellular electrical coupling via connexin43 (Cx43) gap junctions enables synchronous cardiac contraction. In failing hearts, impaired Cx43 trafficking reduces gap junction coupling, resulting in arrhythmias. Here we report that internal translation within Cx43 (GJA1) mRNA occurs, resulting in truncated isoforms that autoregulate Cx43 trafficking. We find that at least four truncated Cx43 isoforms occur in the human heart, with a 20 kDa isoform predominating. In-frame AUG codons within GJA1 mRNA are the translation initiation sites and their ablation arrests trafficking of full-length Cx43. The 20 kDa isoform is sufficient to rescue this trafficking defect in trans, suggesting it as a trafficking chaperone for Cx43. Limiting cap-dependent translation through inhibition of mTOR enhances truncated isoform expression, increasing Cx43 gap junction size. The results suggest that internal translation is a mechanism of membrane protein autoregulation and a potent target for therapies aimed at restoring normal electrical coupling in diseased hearts

The presence of valine at residue 129 in human prion protein accelerates amyloid formation

The polymorphism at residue 129 of the human PRNP gene modulates disease susceptibility and the clinicopathological phenotypes in human transmissible spongiform encephalopathies. The molecular mechanisms by which the effect of this polymorphism are mediated remain unclear. It has been shown that the folding, dynamics and stability of the physiological, alpha-helix-rich form of recombinant PrP are not affected by codon 129 polymorphism. Consistent with this, we have recently shown that the kinetics of amyloid formation do not differ between protein containing methionine at codon 129 and valine at codon 129 when the reaction is initiated from the a-monomeric PrPC-like state. In contrast, we have shown that the misfolding pathway leading to the formation of beta-sheet-rich, soluble oligomer waS favoured by the presence of methionine, compared with valine, at position 129. In the present work, we examine the effect of this polymorphism on the kinetics of an alternative misfolding pathway, that of amyloid formation using partially folded PrP allelomorphs. We show that the valine 129 allelomorph forms amyloids with a considerably shorter lag phase than the methionine 129 allelomorph both under spontaneous conditions and when seeded with pre-formed amyloid fibres. Taken together, our studies demonstrate that the effect of the codon 129 polymorphism depends on the specific misfolding pathway and on the initial conformation of the protein. The inverse propensities of the two allelomorphs to misfold in vitro through the alternative oligomeric and amyloidogenic pathways could explain some aspects of prion diseases linked to this polymorphism such as age at onset and disease incubation time. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved

Indications for liver transplantation in the cyclosporine era

One hundred seventy orthotopic liver transplants were performed under conventional immunosuppression with azathioprine and steroids with 1- and 5-year survivals of 32.9% and 20.0%, respectively. Since the introduction of cyclosporine-prednisone therapy in March 1980, 313 primary orthotopic liver transplants have been performed. Actuarial survivals at 1 and 5 years have improved to 69.7% and 62.8%, respectively. Biliary atresia is now the most common indication for liver replacement. In adults, primary biliary cirrhosis and sclerosing cholangitis have become more common indications for transplantation, and alcoholic cirrhosis and primary liver malignancy as indications have declined. Early enthusiasm for liver transplantation in patients with hepatic cancer has been tempered by the finding that recurrence is both common and rapid. An increasing number of patients with inborn errors of metabolism originating in the liver are receiving transplants, including patients with Wilson's disease, tyrosinemia, alpha-1-antitrypsin deficiency, glycogen storage disease, familial hypercholesterolemia, and hemochromatosis. Survival in this group of patients has been excellent (74.4% at 1 and 5 years). A hemophiliac who received a transplant for postnecrotic cirrhosis has survived and may have been cured of his hemophilia. About 20% of patients require retransplantation for rejection, technical failure, or primary graft failure. Only 4 of the patients receiving retransplants under conventional immunosuppression survived beyond 6 months, and all died within 14 months of retransplantation. Sixty-eight patients have received retransplants under cyclosporine-prednisone. Thirty-one patients are surviving, all for at least 1 year. Six of the 12 patients requiring a third transplant are alive 2 to 3 years after the primary operation. An aggressive approach to retransplantation in the patient with a failed graft is justified

Using Color in Machine Vision Systems for Wood Processing

Color information, already shown to be valuable in distinguishing wood surface features, should prove especially useful for future applications of machine vision in the wood products industry. This review provides investigators interested in such applications with the information necessary for understanding the benefits-and associated difficulties-of using color. Various standard color-measurement systems ("color spaces") are discussed. No one system has been completely successful, at least partly because simple physical measurements are difficult to correlate with a human observer's complex perception of color. Color video camera systems, designed with human viewers in mind, have the potential for machine vision applications, but certain system "features" (white balance, gamma or contour correction) could cause problems. Future applications, including detecting and classifying hard-to-identify defects and matching colors of wood components, will require careful choice of lighting geometry and source, camera system, and color space for the purpose at hand

Analysis of Genetic Variants Associated with Levels of Immune Modulating Proteins for Impact on Alzheimer’s Disease Risk Reveal a Potential Role for SIGLEC14

Genome-wide association studies (GWAS) have identified immune-related genes as risk factors for Alzheimer’s disease (AD), including TREM2 and CD33, frequently passing a stringent false-discovery rate. These genes either encode or signal through immunomodulatory tyrosine-phosphorylated inhibitory motifs (ITIMs) or activation motifs (ITAMs) and govern processes critical to AD pathology, such as inflammation and amyloid phagocytosis. To investigate whether additional ITIM and ITAM-containing family members may contribute to AD risk and be overlooked due to the stringent multiple testing in GWAS, we combined protein quantitative trait loci (pQTL) data from a recent plasma proteomics study with AD associations in a recent GWAS. We found that pQTLs for genes encoding ITIM/ITAM family members were more frequently associated with AD than those for non-ITIM/ITAM genes. Further testing of one family member, SIGLEC14 which encodes an ITAM, uncovered substantial copy number variations, identified an SNP as a proxy for gene deletion, and found that gene expression correlates significantly with gene deletion. We also found that SIGLEC14 deletion increases the expression of SIGLEC5, an ITIM. We conclude that many genes in this ITIM/ITAM family likely impact AD risk, and that complex genetics including copy number variation, opposing function of encoded proteins, and coupled gene expression may mask these AD risk associations at the genome-wide level

Areal geology of the Illinois fluorspar district : Part III, Herod and Shetlerville Quadrangles

Ope

Combustion of two-component miscible droplets in reduced gravity

This research focuses on the combustion of binary miscible droplets initially in the mm size range. Experiments are performed using the NASA Lewis 2.2 sec drop tower in Cleveland, Ohio, where mixtures of alkanes and/or alcohols are studied. The fuel components are selected to have significantly different volatilities. Initial oxygen mole fractions from about 0.15-0.5 and initial pressures from 0.2-2 atm are employed. Different inerts are used (He, CO2, Ar, N2) to change burning rates and sooting behaviors. Objectives are to observe the following: (1) Transient droplet diameters (including three-staged combustion behaviors and microexplosion; (2) Transient flow behaviors (sudden flame contraction, luminosity, extinction); and (3) Behaviors of observable soot particles. theoretical and computational research in support of this program has also been undertaken. This research includes analytical studies to determine the effects of small but nonzero gravitational levels on droplet gasification, analytical studies of hydrodynamic stability of spherically-symmetrical droplet gasification (to address the question as to whether spherically-symmetrical droplet gasification may be destabilized from capillary, i.e., Marangoni effects), and computational modeling of effects of capillary stresses on droplet gasification

Taiwanese Version of the EQ-5D: Validation in a Representative Sample of the Taiwanese Population

Background/PurposeWe know of no validated Taiwanese-language instrument to measure a utility of the patient's health. Our aim was to evaluate the reliability and validity of a Taiwanese version of the EuroQol instrument (EQ-5D) in a Taiwanese population.MethodsQuestionnaires containing the Taiwanese versions of the EQ-5D and the Short-Form 12 Health Survey (SF-12) were sent to 12,923 people in Taiwan in December 2002. Concurrent validity of the EQ-5D was analyzed by assuming that subjects with problems in any EQ-5D dimensions had decreased SF-12 scores. Discriminant validity of the EQ-5D was analyzed by assuming that subjects with the following characteristics had lowered EQ-5D indexes and scores on the EQ-5D visual analog scale (VAS): more chronic diseases than others, serious illness, more hospitalizations in the past year than others, poor general health, and more outpatient visits than others. Test—retest reliability was analyzed in a subgroup of respondents who were evaluated twice within a month by using the intraclass correlation coefficient and the k method.ResultsThe general survey response rate was 12.7% (1644 of 12,923). SF-12 scores were lower in subjects reporting problems on EQ-5D dimensions than in others without such problems (p < 0.01). Subjects with more health problems than others had lower EQ-5D indexes and VAS scores (p < 0.01). The physical dimension of the EQ-5D was more strongly correlated with the SF-12 Physical Component Summary than with the Mental Component Summary; this finding satisfied the a priori hypothesis. For test—retest reliability of items on the EQ-5D, k values ranged from 0.49 to 1 (p < 0.001).ConclusionThe Taiwanese EQ-5D instrument appears to be a moderately valid and reliable tool for measuring the health status of the general population in Taiwan