George H. Elder

Bio: George H. Elder is an academic researcher from University Hospital of Wales. The author has contributed to research in topics: Porphyria & Uroporphyrinogen III decarboxylase. The author has an hindex of 42, co-authored 136 publications receiving 5237 citations. Previous affiliations of George H. Elder include University of Wales & Cardiff University.

Porphyria cutanea tarda.

Abstract: Porphyria cutanea tarda (PCT) is a skin disease that results from decreased activity of uroporphyrinogen decarboxylase (UROD) About 80% of patients have the sporadic (type I) form in which UROD deficiency is restricted to the liver Others have familial (type II) PCT in which mutations in the UROD gene are inherited in an autosomal dominant pattern with low clinical penetrance PCT may also follow exposure to porphyrogenic chemicals Clinically overt PCT (types I and II) is provoked by liver cell injury, particularly when associated with alcohol abuse, hepatitis C infection, or estrogens Hepatic iron overload is common, depletion of iron stores produces remission, and their replenishment leads to relapse In PCT, hepatic UROD is inactivated by a process targeted at its catalytic site, which is iron-dependent, requires a heme precursor, and may be accelerated by induction of cytochrome P450s Susceptibility to develop PCT in response to common causes of liver injury may be determined by co-inheritance of genes that regulate components of this inactivation process

C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload

Abstract: All reported mutations in ALAS2, which encodes the rate-regulating enzyme of erythroid heme biosynthesis, cause X-linked sideroblastic anemia. We describe eight families with ALAS2 deletions, either c.1706-1709 delAGTG (p.E569GfsX24) or c.1699-1700 delAT (p.M567EfsX2), resulting in frameshifts that lead to replacement or deletion of the 19–20 C-terminal residues of the enzyme. Prokaryotic expression studies show that both mutations markedly increase ALAS2 activity. These gain-of-function mutations cause a previously unrecognized form of porphyria, X-linked dominant protoporphyria, characterized biochemically by a high proportion of zinc-protoporphyrin in erythrocytes, in which a mismatch between protoporphyrin production and the heme requirement of differentiating erythroid cells leads to overproduction of protoporphyrin in amounts sufficient to cause photosensitivity and liver disease.

The incidence of inherited porphyrias in Europe.

Abstract: Retrospective estimates of the prevalence of porphyrias have been reported but there has been no large scale prospective study of their incidence. The European Porphyria Network collected information prospectively over a 3 year period about the number of newly diagnosed symptomatic patients with an inherited porphyria (335 patients from 11 countries). Prevalence was calculated from the incidence and mean disease duration. The incidence of hepato-cellular carcinoma (HCC) in acute hepatic porphyria and the prevalence of patients with recurrent acute attacks of porphyria were also investigated. The incidence of symptomatic acute intermittent porphyria (AIP) was similar in all countries (0.13 per million per year; 95 % CI: 0.10 – 0.14) except Sweden (0.51; 95 % CI: 0.28–0.86). The incidence ratio for symptomatic AIP: variegate porphyria: hereditary coproporphyria was 1.00:0.62: 0.15. The prevalence of AIP (5.4 per million; 95 % CI: 4.5–6.3) was about half that previously reported. The prevalence of erythropoietic protoporphyria (EPP) was less uniform between countries and, in some countries, exceeded previous estimates. Fourteen new cases of HCC (11 from Sweden) were reported in patients with acute porphyria. Sixty seven patients (3 VP; 64 AIP: 53 females, 11 males) with recurrent attacks of acute porphyria were identified. The estimated percentage of patients with AIP that will develop recurrent acute attacks was 3–5 %. In conclusion, the prevalence of symptomatic acute porphyria may be decreasing, possibly due to improved management, whereas the prevalence of EPP may be increasing due to improved diagnosis and its greater recognition as a cause of photosensitivity.

Toxic cyanobacteria in water: a guide to their public health consequences, monitoring and management.

Abstract: This book describes the present state of knowledge regarding the impact of cyanobacteria on health through the use of water. It considers aspects of risk management and details the information needed for protecting drinking water sources and recreational water bodies from the health hazards caused by cyanobacteria and their toxins. It also outlines the state of knowledge regarding the principal considerations in the design of programmes and studies for monitoring water resources and supplies and describes the approaches and procedures used. The development of this publication was guided by the recommendations of several expert meetings concerning drinking water (Geneva, December 1995; Bad Elster, June 1996) and recreational water (Bad Elster, June 1996; St Helier, May 1997). An expert meeting in Bad Elster, April 1997, critically reviewed the literature concerning the toxicity of cyanotoxins and developed the scope and content of this book. A draft manuscript was reviewed at an editorial meeting in November 1997, and a further draft was reviewed by the working group responsible for updating the Guidelines for Drinkingwater Quality in March 1998.

Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation

Abstract: Jaundice occurs in most newborn infants. Most jaundice is benign, but because of the potential toxicity of bilirubin, newborn infants must be monitored to identify those who might develop severe hyperbilirubinemia and, in rare cases, acute bilirubin encephalopathy or kernicterus. The focus of this guideline is to reduce the incidence of severe hyperbilirubinemia and bilirubin encephalopathy while minimizing the risks of unintended harm such as maternal anxiety, decreased breastfeeding, and unnecessary costs or treatment. Although kernicterus should almost always be preventable, cases continue to occur. These guidelines provide a framework for the prevention and management of hyperbilirubinemia in newborn infants of 35 or more weeks of gestation. In every infant, we recommend that clinicians 1) promote and support successful breastfeeding; 2) perform a systematic assessment before discharge for the risk of severe hyperbilirubinemia; 3) provide early and focused follow-up based on the risk assessment; and 4) when indicated, treat newborns with phototherapy or exchange transfusion to prevent the development of severe hyperbilirubinemia and, possibly, bilirubin encephalopathy (kernicterus).

Listening to silence and understanding nonsense: exonic mutations that affect splicing

Abstract: Point mutations in the coding regions of genes are commonly assumed to exert their effects by altering single amino acids in the encoded proteins. However, there is increasing evidence that many human disease genes harbour exonic mutations that affect pre-mRNA splicing. Nonsense, missense and even translationally silent mutations can inactivate genes by inducing the splicing machinery to skip the mutant exons. Similarly, coding-region single-nucleotide polymorphisms might cause phenotypic variability by influencing splicing accuracy or efficiency. As the splicing mechanisms that depend on exonic signals are elucidated, new therapeutic approaches to treating certain genetic diseases can begin to be explored.

Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs).

Abstract: Halogenated aromatic compounds, typified by the polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), biphenyls (PCBs), and diphenylethers (PCDEs), are industrial compounds or byproducts which have been widely identified in the environment and in chemical-waste dumpsites. Halogenated aromatics are invariably present in diverse analytes as highly complex mixtures of isomers and congeners and this complicates the hazard and risk assessment of these compounds. Several studies have confirmed the common receptor-mediated mechanism of action of toxic halogenated aromatics and this has resulted in the development of structure-activity relationships for this class of chemicals. The most toxic halogenated aromatic is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and based on in vivo and in vitro studies the relative toxicities of individual halogenated aromatics have been determined relative to TCDD (i.e., toxic equivalents). The derived toxic equivalents can be used for hazard and risk assessment of halogenated aromatic mixtures; moreover, for more complex mixtures containing congeners for which no standards are available (e.g., bromo/chloro mixtures), several in vitro or in vivo assays can be utilized for hazard or risk assessment.

Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and related compounds : environmental and mechanistic considerations with support the development of toxic equivalency factors (TEFs)

Abstract: Halogenated aromatic compounds, typified by the polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), biphenyls (PCBs), and diphenylethers (PCDEs), are industrial compounds or byproducts which have been widely identified in the environment and in chemical-waste dumpsites. Halogenated aromatics are invariably present in diverse analytes as highly complex mixtures of isomers and congeners and this complicates the hazard and risk assessment of these compounds. Several studies have confirmed the common receptor-mediated mechanism of action of toxic halogenated aromatics and this has resulted in the development of structure-activity relationships for this class of chemicals. The most toxic halogenated aromatic is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and based on in vivo and in vitro studies the relative toxicities of individual halogenated aromatics have been determined relative to TCDD (i.e., toxic equivalents). The derived toxic equivalents can be used for hazard and risk assessment of halogenated aromatic mixtures; moreover, for more complex mixtures containing congeners for which no standards are available (e.g., bromo/chloro mixtures), several in vitro or in vivo assays can be utilized for hazard or risk assessment.