bluuebunny/crossref_metadata_2025 huggingface dataset:
Barriers to Energy Efficiency: More Than Just Market Failure
Authors: Eyre Nick
Published: January 2017

The importance to environmental policy of improving energy efficiency is now widely agreed. It is also well established that levels of energy efficiency are below the optimum for economic efficiency, i.e. there are market barriers to energy efficiency. Neo-c1assical economic theory provides a taxonomy of the barriers in terms of market failure and can evaluate short term policy options to address them. However, this paradigm does not explain the underlying causes or why all the market failures act in the direction of lower energy efficiency. Economic analysis alone cannot identify long term, sustainable approaches to removing the barriers; input is needed from other disciplines. A review of the multi-disciplinary literature identifies some common elements in the nature of the barriers: a dichotomy between producers and consumers, centralisation in energy supply and planning, a commodity view of energy, and complexity of energy efficiency markets. It is concluded that these are fundamental characteristics of energy use in a modem economy. They constitute a meta-barrier - a framework in which the other barriers can be described. Barriers to energy efficiency therefore remain deeply entrenched and, in the short term, optimisation of energy efficiency is unlikely. However, future changes in technology, market structures and institutions may open new opportunities to address the fundamental problems in the longer term.
A Win-Win Strategy for Economic Wealth and Climate Protection – Equally Important for the First and the Third World
Authors: Bach Wilfrid
Published: January 2017

Reduction targets for a desired degree of climate protection are negotiated at the international circuit. Concrete measures for reaching such targets are implemented at the national and city levels. Demonstrated here for electricity use in the commercial sector of the City of Muenster is a “Win-Win Strategy” which, if correctly done will result only in winners. Specifically, it is shown that electricity use between 1990 and 2005 in a Trend Scenario would increase by ca. 25 %, while in the Climate Protection Scenario it could decrease by ca. 23 % due to savings and substitution measures. The benefits, costs, and net gains are computed for different price developments. For a favored variant, the net gain to customers is ca. 66 M DM and that of the city utility – acting as an investor/contractor – is ca. 44 M DM over the period 1996–2021. The monetary savings are calculated by individual uses and user categories. The calculated benefit-loss developments show favorable payback times ranging from 11 to 14 years for the total commercial sector or 2 to 5 years for individual objects. Rough estimates show that over the next 10 years the “Win Win Strategy” could provide 256 additional jobs in the commercial electricity sector of Muenster, and about 700 000 new jobs when projected for Germany as a whole. Additionally, studies show that implementing the electricity efficiency potential in five Western European countries by 2020 could save between 20 and 50 Bil.(billion) ECU, whilst the need for some 90 additional 1000 MW power plants could be avoided. If current commercially available efficiency technologies were used to reach a standard of living equal to that in W. Europe in the late 1970s, the Third World final energy demand would be ca. 1 kW/cap, and in the First World perhaps a little greater. The energetic limit of the ecosphere is estimated to be ca. 1.5 kW/cap at the current world population. Finally, the policy options discussed here can help tap this huge available energy efficiency gold mine by the North and the South alike. The function of the “Win Win Strategy” is to help supply the funds for paving the way toward a sustainable future.
Agricultural Waste to Energy – A UK Perspective
Authors: Griffiths A. J. , Hicks W.
Published: January 2017

The UK has a potential to utilise agricultural waste and energy crops to generate significant portion of its electrical power supplying 2.21 millions homes and saving the equivalent of 13 million tonnes of coal per year. Stimulated by the Non fossil Fuel Obligation orders, suppliers and other contractors have installed about 1200 MW of the Governments 1500 MW target for renewable power generation by the year 2000. Under the first order of 1990, 25.48 MW of generating capacity was installed using biomass and its associated wastes. Under the 1993 order this had increased to 122.78 MW using a variety of different technologies and a more diverse range of wastes and energy crops. The regional potential for both dry and wet waste arisings have been analysed and both the potential, economics and favoured technologies identified.
Myocardial elements content and cardiac function after repeated i.v. administration of DMPS in rabbits
Authors: Hrdina Radomír , Geršl Vladimír , Vávrová Jaroslava , Holečková Magdalena , Palička Vladimír , Voglová Jaroslava , Mazurová Yvona , Bajgar Jiří
Published: January 2017

1 A dithiol chelating agent-2,3-dimercapto-1-propane-sulphonate (DMPS)- may be administered in acute or chronic intoxication with certain heavy metals (e.g. cadmium, cobalt, lead) that may cause cardiotoxicity. 2 DMPS can act as a depleter of physiologically important elements (e.g. potassium, magnesium, calcium) in various tissues including cardiac one. The possibility of subsequent alteration in cardiac function cannot be excluded.

3 Changes in the myocardial concentration of the abovementioned elements at the end of the experiment and cardiac function were studied during repeated I.V. administration of DMPS as single doses of 50 mg/kg/ week for 10 weeks in rabbits. Biochemical, haemato-logical and histological examinations were also performed.

4 Most of the measured parameters were not affected by the repeated administration of DMPS. A significant decrease in magnesium and a near significant decrease in calcium in cardiac muscle was not accompanied by functional or morphological changes.

It is still suggested, however, that care should be taken in using DMPS for treating patients with cardiotoxicity as a result of poisoning with heavy metals.
Incorporating hormesis in the routine testing of hazards
Authors: Bailer A John , Oris James T
Published: January 2017

The phenomenon of subtoxic stimulation of organism response is not uncommon in aquatic toxicology experiments. We describe the presence of hormesis in both growth and reproduction experiments in aquatic toxicology where these responses are observed in both animals and plants and at different trophic levels of an ecosystem. The implications of ignoring hormetic responses in the analysis of toxicity data are discussed. In particular, we note that specification of models that explicitly cannot accommodate or remove potential effects of hormesis may lead to biased potency estimates. Further, the presence of hormesis has implications for the design of toxicology experiments, with the spacing of concentration test conditions being critical.
Implications of hormesis on the bioassay and hazard assessment of chemical carcinogens
Authors: Teeguarden Justin G , Dragan Yvonne P , Pitot Henry C
Published: January 2017

Hormesis has been defined as a dose-response relationship which depicts improvement in some endpoint (increased metabolic rates, reduction in tumor incidence, etc.) at low doses of a toxic compound followed by a decline in the endpoint at higher doses. The existence of hormetic responses to carcinogenic agents has several implications for the bioassay and hazard assessment of carcinogens. To be capable of detecting and statistically testing for hormetic or other nonlinear dose-response functions, current study designs must be modified to include lower doses and sufficiently large numbers of animals. In addition, improved statistical methods for testing nonlinear dose-response relationships will have to be developed. Research integrating physiologically-based pharmacokinetic model descriptions of target dose with mechanistic data holds the greatest promise for improving the description of the dose-response curve at low doses. The 1996 Proposed Carcinogen Risk Assessment Guidelines encourage the use of mechanistic data to improve the descriptions of the dose-response curve at low doses, but do not distinguish between the types of nonlinear dose-response curves. Should this refined approach lead to substantial support for hormesis in carcinogenic processes, future guidelines will need to provide guidance on establishing safe doses and communicating the results to the public.
A protein disulfide-thiol interchange protein with NADH: protein disulfide reductase (NADH oxidase) activity as a molecular target for low levels of exposure to organic solvents in plant growth
Authors: Morré D J
Published: January 2017

A number of solvents including ethyl, amyl, butyl, octyl and benzyl alcohols, ethylene glycol, ethyl acetate, acetone, diethyl ether, propylene oxide, r-dioxane, benzene, xylene, chloroform and carbon tetrachloride stimulate the growth of plants or plant parts at low concentrations and inhibit at high concentrations. These same solvents, at low dilutions, stimulate the activity of a growth-related protein disulfide-thiol interchange protein (TIP) with NADH: protein disulfide reductase (NADH oxidase) (NOX) activity with plasma membrane vesicles isolated from elongating regions cut from dark grown seedlings of soybeans. Based on these and other findings, we suggest the TIP/NOX protein to be the molecular target of the biological effects of low levels of exposure (hormesis) involved in the stimulation of plant growth.
Neurotoxicity risk assessment of MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) as a synthetic impurity of drugs
Authors: Kramer Peter Juergen , Caldwell John , Hofmann Andreas , Tempel Peter , Weisse Guenter
Published: January 2017

1-Methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) induces symptoms indistinguishable from those of Parkinson's disease. It selectively destroys dopaminergic neurons in the substantia nigra and the globus pallidus. Death of these same neurons is apparently the cause of idiopathic Parkinson's disease. As phenyl-1,2,3,6 tetrahydropyridine is a commonly encountered subunit in heterocyclic drugs and because MPTP was found as a minor impurity in early batches of a candidate drug at Merck KGaA, it may be assumed that MPTP will also be present as an as yet undiscovered minor impurity in various existing drugs. A neurotoxicity risk assessment on MPTP has been conducted to define the risk of MPTP as an impurity in drugs that are used orally. This risk assessment has shown that compounds containing less than 5.0 p.p.m. MPTP administered orally will not cause a neurotoxicological health risk to patients treated with such a drug.
Uptake by man of aluminium in a public water supply
Authors: Priest N D , Talbot R J , Newton D , Day J P , King S J , Fifield L K
Published: January 2017

1 After overnight fasting, two young male adults each received a single oral dose of 100 Bq 26Al in tap water. Coincidence gamma-ray spectrometry and accelerator mass spectrometry were used to determine the 26Al content of excretion collections and of blood samples.

2 Close to 100% of the intake was recovered in faeces during the first 7 days. Gastro-intestinal uptake, determined by comparing urinary excretion with patterns previously established following intravenous administration of 26Al, averaged 0.22% in the two subjects.

3 Uptake fractions based on comparisons of blood concentration following ingestion and injection were much lower, but were judged to be unreliable. It is concluded that aluminium present in most water supplies is unlikely to contribute as much as 1% of a typical daily uptake of 10 mg from food.
Urinary cadmium as indicator of renal cadmium in humans: an autopsy study
Authors: Orlowski Czeslaw , Piotrowski Jerzy K , Subdys Joanna K , Gross Adam
Published: January 2017

Objective: To estimate the equivalent cadmium levels in renal cortex and in urine, as based on autopsy analysis of subjects not exposed to cadmium occupationally.

Methods: The levels of Cd were determined in renal cortex, liver, urine and urinary bladder of 39 subjects deceased at the age 42+14 years. Flame atomic absorption spectrometry (kidneys, liver) and flameless AAS (urine, bladder) were used.

Results: The urinary cadmium level determined post mortem is strongly correlated with the renal Cd levels. Eliminating cases with high urinary proteins and extrapolating from sets of data with elevated urinary protein concentration to its normal range yielded a value of 1.7 mg/g creatinine as equivalent to the renal level of 50 mg/g w.w.

Conclusions: It seems possible to use monitoring data for cadmium in urine and in renal cortex in a coherent way.
Oral aluminum administration to rats with normal renal function. 1. Impairment of erythropoiesis
Authors: Garbossa Graciela , Gálvez Gladys , Castro María E , Nesse Alcira
Published: January 2017

Aluminum (Al) toxicity has been mainly investigated in uremic patients although healthy subjects and patients without renal insufficiency are not exempt from its potential deleterious effects. This experimental study aims to elucidate the action of different doses of Al citrate on in vivo erythropoiesis and find out whether the metal exerts a local toxic effect upon the bone marrow late erythroid progenitor cells. The groups in the first experimental series were: C1 (n=5) controls and TAl-1 (n=5) rats receiving 1 mmol Al citrate/g body weight/day by gavage. Colony-forming units-erythroid (CFU-E) development was inhibited in the TAl-1 group, but the median osmotic fragility (MOF) and hematocrit (Ht) values were similar to those of the C1 group. The groups in the second series were C2 (n=5) controls and TAl-2 (n=5) rats receiving Al citrate in drinking water (100 mmol/l). The TAl-2 group showed decreased Ht, hemoglobin concentration, MOF and red blood-cell life-span values (P50.05), and a marked inhibition of the CFU-E development (P50.01). Serum and bone Al concentrations were increased in both Al-treated groups (P50.01). There was a dose-dependent increase in bone Al levels (P50.01) and a dose-dependent decrease of CFU-E development (P50.05). The CFU-E development was inversely correlated with the bone Al content (r=70.79; P50.05). The results demonstrate that even very low doses of Al citrate impair erythropoiesis in vivo and higher doses exert a deleterious action on both CFU-E and mature erythrocytes. This might show a local effect of Al on CFU-E caused by the bone sensitivity to the metal accumulation.
Oral aluminum administration to rats with normal renal function. 2. Body distribution
Authors: Garbossa Graciela , Gálvez Gladys , Pérez Gladys , Stripeikis Jorge , Tudino Mabel , Nesse Alcira
Published: January 2017

Aluminum (Al) has no known physiological function and is not considered an essential dietary compound. Nowadays, it is recognized as an element that can produce adverse effects on biological systems. The present study determined Al partitioning in the body compartments of rats that have been orally exposed for 15 weeks. Three experimental groups were studied: Controls (C, n=19), TAl-1 (n=10) rats receiving daily doses of Al citrate (1.0 mmol/g body weight) by gavage and TA1-2 (n=13), receiving Al citrate with the drinking water (100 mmol/ l). At the end of the experimental period, the Al contents of organs and sera were determined. Results are expressed as median and range values. Comparing the TAl-2 rats with the control ones, remarkable Al accumulation could be observed in serum (4.8/2.7 - 16.3 vs 0.4/0.2 - 1.2 mmol/l, P50.001), bone (3.33/1.78 - 4.85 vs 1.00/0.48 - 1.59 mmol/ g, P50.001), kidney (2.33/0.96 - 3.15 vs 0.52/0.22 - 2.07 mmol/g, P50.001), spleen (2.22/0.70 - 4.19 vs 0.27/ 0.11 - 0.36 mmol/g, P50.001) and liver (0.60/0.42 - 0.91 vs 0.24/0.14 - 0.78 mmol/g, P50.01) while brain Al content was not significantly increased. Aluminum levels were raised in the TAl-1 group only in serum (2.8/1.3 - 10.4 mmol/ g, P50.001), bone (1.85/1.00 - 3.41 mmol/g, P50.001) and kidney (1.74/0.96 - 2.07 mmol/g, P50.01). Bone Al concentration increased in a dose-dependent manner (TAl-2 vs TAl-1, P50.001). The results demonstrate different tissue Al accumulation in rats chronically exposed to Al citrate, irrespective of their intact renal function.
Nephrotoxic effects of di-(2-ethylhexyl)phthalate (DEHP) hydrolysis products on cultured kidney epithelial cells
Authors: Rothenbacher Klaus-Peter , Kimmel Reiner , Hildenbrand Sibylle , Schmahl Friedrich W , Dartsch Peter C
Published: January 2017

1 Di-(2-ethylhexyl)-phthalate (DEHP) possesses a great industrial value as a plasticizing agent and has become an ubiquitous environmental contaminant. In most species it is rapidly metabolized to mono-(2-ethylhexyl)-phthalate (MEHP) and 2-ethylhexanoic acid (2- EHA). Evaluation of toxicity of DEHP and its primary metabolites has been focussed on reproductive toxicity and hepatocarcinogenic properties. The aim of this study was to determine the nephrotoxic potential of both DEHP metabolites by use of cultured kidney epithelial cells (Opossum kidney cells; OK cells).

2 For this purpose, OK cells were exposed for 3 days to MEHP and 2-EHA at concentrations ranging from 0.1 -500 mmol/L and the toxicity as well as the effects on migratory activity and intracellular cytoskeleton were studied by cell biological, morphological and morpho-metric methods.

3 When compared with corresponding controls, treatment of OK cells with MEHP and 2-EHA, respectively, showed marked differences in cell viability between both DEHP metabolites. MEHP caused a dose-depen-dent decrease in cell viability (ED50 =25 mmol/L) accompanied by a moderate swelling of the cells at concentrations up to 25 mmol/L. MEHP concentrations higher than 25 mmol/L caused a dose-dependent shrinkage of the cells and the occurrence of a high amount of cell debris as a result of cell lysis. 2-EHA did not cause a reduced viability or an altered cell volume. The migratory activity of OK cells was not significantly influenced by both metabolites. Moreover, MEHP toxicity resulted in a largely reduced and altered organization of F-actin (stress fibers), but not of myosin, microtubules and vimentin.

4 The study indicates that cultured epithelial cells can be used as a prescreening system to assess the nephrotoxicity of hazardous substances such as DEHP. As demonstrated in this study, only MEHP, but not 2-EHA, has a marked nephrotoxic effect in vitro.
Prognostic implications of hyperkalemia in toad toxin intoxication
Authors: Chi Huan-Teng , Hung Dong-Zong , Hu Wei-Hsiung , Yang Dar-Yu
Published: January 2017

The toad possesses several toxic substances. Toad toxin poisoning manifests itself primarily with digitalis-like, cardioactive effects which results in bradycardia, varying degrees of atrio-ventricular block, ventricular tachycardia, ventricular fibrillation and sudden death. We report a cluster poisoning in a family who became intoxicated after ingestion of cooked toad soup for a skin problem. The youngest one (15 months old) died of refractory bradydyarrhythmias soon after arriving at our hospital. A second child (20 months old), who survived, arrived in shock with hyperkalemia (potassium 7.3 mEq/ L) and varying degrees of atrio-ventricular block. She was successfully treated with atropine, lidocaine, and cardio-version, and had a transvenous temporary pacemaker implanted for 1 day. The third boy (16 years old) had hyperkalemia (potassium 6.3 mEq/L) and bradycardia. The remaining three adults had only mild symptoms of nausea, vomiting, watery diarrhea and a sensation of numbness over their oral mucosa.

We found that the level of serum potassium had prognostic implications in toad intoxication. Determination of serum potassium level is readily available in almost every hospital and is therefore more convenient to measure than serum digoxin level. We conclude that if hyperkalemia develops, the treatment of toad intoxication must be more aggressive to prevent mortality.
The pharmacokinetics and metabolism of 14C/13C-labeled ortho-phenylphenol formation following dermal application to human volunteers
Authors: Timchalk C , Selim S , Sangha G , Bartels M J
Published: January 2017

1. The pharmacokinetics and metabolism of uniformly labeled 14C/13C-ortho-phenylphenol (OPP) were followed in six human male volunteers given a single 8 h dermal dose of 6 mg OPP/kg body weight formulated as a 0.4% (w/v) solution in isopropyl alcohol. The application site was covered with a non-occlusive dome allowing free movement of air, but preventing the loss of radioactivity due to physical contact. At 8 h post-exposure the non-occlusive dome was removed, the dose site was wiped with isopropyl alcohol containing swabs and the skin surface repeatedly stripped with tape. Blood specimens, urine, and feces were collected from each volunteer over a 5 day post-exposure period and were analyzed for radioactivity and metabolites (urine only).

2. Following dermal application, peak plasma levels of radioactivity were obtained within 4 h post-exposure and rapidly declined with virtually all of the absorbed dose rapidly excreted into the urine within 24 h post-exposure. A one-compartment pharmacokinetic model was used to describe the time-course of OPP absorption and clearance in male human volunteers. Approximately 43% of the dermally applied dose was absorbed through the skin with an average absorption half-life of 10 h. Once absorbed the renal clearance of OPP was rapid with an average half-life of 0.8 h. The rate limiting step for renal clearance was the relatively slower rate of dermal absorption; therefore the pharmacokinetics of OPP in humans was described by a `flip-flop' single compartment model. Overall, the pharmacokinetics were similar between individuals, and the model parameters were in excellent agreement with the experimental data.

3. Approximately 73% of the total urinary radioactivity was accounted for as free OPP, OPP-sulfate and OPP-glucuronide conjugates. The sulfate conjugate was the major metabolite (*69%). Therefore, total urinary OPP equivalents (acid-labile conjugates+free OPP) can be used to estimate the systemically absorbed dose of OPP.

4. The rapid excretion of OPP and metabolites into the urine following dermal exposure indicates that OPP is unlikely to accumulate in humans upon repeated exposure. Based on these data, blood and/or urinary OPP concentration (acid-labile conjugates) could be utilized to quantify the amount of OPP absorbed by humans under actual use conditions.
Medicinal herb, Thonningia sanguinea protects against aflatoxin B1 acute hepatotoxicity in Fischer 344 rats
Authors: Gyamfi Maxwell Afari , Aniya Yoko
Published: January 2017

1. Thonningia sanguinea, a plant used prophylactically against bronchial asthma in Ghana was recently found to have antioxidative and hepatoprotective actions in our laboratory.

2. In this study, the effect of T. sanguinea extract on certain biochemical indices in serum and liver of Fischer 344 rats given a single intraperitoneal (i.p.) dose (1 mg/kg) of aflatoxin B1 (AFB1) was investigated.

3. Administration of AFB1 resulted in significant increases in serum alanine aminotransferase (ALT) and glutathione S-transferase (GST) levels and a signifi-cant decrease in aniline hydroxylase activity in liver microsomes. When T. sanguinea (5 ml/kg) was intraperitoneally administered to rats 12 h and 1 h before AFB1, liver injury was significantly reduced as seen in the decreased levels of serum ALT and serum GST. However, the decrease in aniline hydroxylase activity by AFB1 was not recovered but enhanced by T. sanguinea pre-treatment.

4. Kinetic analysis of cytochrome P450 activity of rat liver microsomes in vitro demonstrated that T. sanguinea inhibited aniline hydroxylase non-competitively suggesting depression of biotransformation of AFB1 to toxic metabolites.

5. The data indicate a hepatoprotective action of T. sanguinea against AFB1-induced liver injury.
Effect of single neonatal vitamin D3 treatment (hormonal imprinting) on the bone mineralization of adult non-treated and dexamethasone treated rats
Authors: Karabélyos Cs , Horváth Cs , Holló I , Csaba G
Published: January 2017

Hormonal imprinting (the first encounter between the hormone and receptor after birth) is needed for the normal development of receptor. Presence of the appropriate hormone in excess, or its absence, as well as presence of hormone-like molecules able to bind to the maturing receptor in this time, can cause faulty imprinting. In this experiment the effect of neonatal treatment with a single dose of 0.05 mg cholecalciferol (vitamin D3) was studied by bone densitometry. The treatment caused significant decrease of body weight in 3-month old females and also significant reduction of bone mineral density (BMD) and bone mineral content (BMC) in males. Dexamethasone treatment of 3-month old rats for 10 days increased BMD in males and BMC in females without affecting body weight. The double treatment (vitamin D neonatally and dexamethasone when adult) decreased the body weight of both sexes and increased BMD in males, and BMC, BMD/bw and BMC/bw in both sexes, related to the control or the only vitamin D treated groups. Considering the hormonal imprinting effect of neonatal vitamin D treatment at glucocorticoid receptorial level in other experiments, similar effects also can be supposed for vitamin D itself, manifested in the changes of bone mineralization.
Molecular analyses of adaptive survival responses (ASRs): role of ASRs in radiotherapy
Authors: Boothman David A , Odegaard Eric , Yang Chin-Rang , Hosley Kelly , Mendonca Marc S
Published: January 2017

Adaptive survival responses (ASRs), whereby cells demonstrate a survival advantage when exposed to very low doses of ionizing radiation (IR) 4-24 h prior to a high dose challenge, were first reported over 15 years ago. These responses were linked to hormesis, which implied that exposure to low levels of IR may be beneficial to the cell. We postulate that increased survival does not necessarily mean that the treatment is beneficial.

Studies at the molecular level indicate that ASRs are the result of misregulated cell cycle checkpoint responses, occurring in the G1 phase of the cell cycle after IR. Specific gene products (i.e., PCNA, cyclin D1, cyclin A, XIP8, xip5 and xip13) appear to control these cell cycle checkpoint responses. Certain neoplastic cells show potent ASRs because they bypass checkpoints which would otherwise lead to apoptosis or other forms of cell death (possibly necrosis), and/or these cancer cells lack genetic factors, such as specific caspases (cysteine aspartate-specific proteases), that control apoptosis. Alterations in these cell cycle checkpoints or apoptotic responses may also occur during IR-induced stress responses in normal cells, at critical times (10-18 days posttreatment) following IR. One IR-induced protein, XIP8, may be a critical controlling factor at this point where delayed-onset apoptosis occurs. Additionally, we have shown that the presence or absence (i.e., SCID cells) of nonhomologous DNA double strand break repair did not seem to influence ASRs, suggesting that ASRs may be caused by signal transduction stress responses.

ASRs may be beneficial to survival, however, the consequence(s) of that survival may be dire. For example, many neoplastic cells exhibited far greater ASRs than normal cells. Additionally, ASRs were induced by as little as 1 cGy and and were enhanced by repeated exposures of low level radiation. The implications for radiotherapy are that when a patient arrives for port film imaging during the course of therapy, the dose-rate, overall level of exposure, and time between port film exposure and high dose IR treatment become potentially important factors for improved efficacy of treatment of certain cancers. Further research is warranted to determine what molecular factors are most important for ASRs, and current work is focusing on XIP8.
Hormesis - Implications for risk assessment caloric intake (body weight) as an exemplar
Authors: Turturro Angelo , Hass Bruce , Hart Ronald W
Published: January 2017

Hormesis can be considered as a parameter which has a non-monotonic relationship with some endpoint. Since caloric intake is such a parameter, and the impact of this parameter on risk assessment has been fairly well characterized, it can provide clues as to how to integrate the information from a hormetic parameter into risk assessments for toxicants. Based on the work with caloric intake, one could: (a) define a biomarker for hormetic effect; (b) integrate specific information on when in the animals lifespan the parameter is active to influence parameters such as survival; (c) evaluate component effects of the overall hormetic response; and (d) address the consequences of a non-monotonic relationship between the hormetic parameter and endpoints critical for risk assessment.

These impacts on risk assessments have been characterized for chronic tests, but are also true for short-term tests. A priority is the characterization of the dose-response curves for hormetic parameters. This quantification will be critical in utilizing them in risk assessment. With this information, one could better quantitatively address the changes one expects to result from the hormetic parameter, and limit the uncertainty and variability which occurs in toxicity testing.
Second degree atrio-ventricular block and cardiotoxicity secondary to envenomation by the scorpion Leiurus quinquestriatus (`Yellow Scorpion') - an indication for serotherapy?
Authors: Shapira Michael Y , Haviv Yosef S , Sviri Sigal
Published: January 2017

Tachyarrhythmia following scorpion envenomation might be an indication for anti venin therapy. We present a case of an unusual cardiotoxic response to Leiurus quinquestriatus (`yellow scorpion') venom - second degree atrio-ventricular block (Mobitz type 1). We review the biological activities of L. quinquestriatus' venom and the arrhythmia's possible pathophysiology. The question arising from this case is the therapeutic approach to cardiotoxicity and bradyarrhythmias induced by scorpion envenomation - mainly, the indication for anti serum therapy.
Functional responses of human neutrophils to sodium sulfite (Na2SO3) in vitro
Authors: Labbé Pierrette , Pelletier Martin , Omara Felix O , Girard Denis
Published: January 2017

An influx of neutrophils into the airways is a common feature observed during pulmonary inflammation induced by air pollutants, including sulfur dioxide and sulfates. In the present study focusing on the in vitro interactions of sodium sulfite (Na2SO3) with human neutrophils, we confirm results indicating that this sulfite induces superoxide production (O27) by itself. We demonstrated that this response can occur more rapidly than previously reported (within 5 min), and that Na2SO3 can act as a priming agent, in a concentration-dependent fashion, to the bacterial tripeptide N-formyl-methionineleucine-phenylalanine (fMLP) by increasing O27 production. In addition, our results show that Na2SO3 induces gene expression in human neutrophils in a concentration-dependent manner as assessed by incorporation of 5-[3H] uridine into total RNA. However, it does not induce cell shape changes. We also demonstrated that Na2SO3 does not modulate neutrophil apoptosis nor reverse the well-known delaying effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on apoptosis. We conclude that Na2SO3 acts rapidly on neutrophil physiology, within a few minutes with respect to superoxide production, and a few hours (4 h) with respect to gene expression without altering a biological process such as the rate of apoptosis evaluated after a long period of incubation (20 h). We further conclude that Na2SO3-induced production of O27 does not drive neutrophils to undergo apoptosis, a mechanism known to occur in other conditions. Therefore, the potential toxicity of Na2SO3 during pulmonary inflammation or lung-associated diseases may be related to its ability to induce superoxide production without altering neutrophil apoptosis rate.
Attributable fractions: fundamental concepts and their visualization
Authors: Eide Geir Egil , Heuch Ivar
Published: January 2017

A general methodology for visualizing attributable fractions in epidemiology is described. The methodology applies to the multifactorial exposure situation and embraces various types of attributable fractions including adjusted, sequential and average attributable fractions. The concept of the scaled Venn diagram plays a central role, illustrating total disease risk and excess disease risk attributable to the exposures as areas in a unit square. This forms the ground for making simple pie charts of attributable fractions summing to 1 (or 100%). The potential applications extend from cohort and cross-sectional data to data from case-control studies. The methodology is illustrated by theoretical as well as empirical examples including the risk of motor fatalities attributable to driver’s blood alcohol concentration and age, and the prevalence of chronic cough attributable to smoking habits, occupational exposure to dust or gas, and residence. A total of 40 figures illustrate the methodology.
A review of adjusted estimators of attributable risk
Authors: Benichou Jacques
Published: January 2017

This paper reviews adjusted methods of estimation of attributable risk ( AR), that is methods that allow one to obtain estimates of AR while controlling for other factors. Estimability and basic principles of AR estimation are first considered and the rationale for adjusted AR estimators is discussed. Then, adjusted AR estimators are reviewed focusing on cross-sectional, cohort and case-control studies. Two inconsistent adjusted estimators are briefly commented upon. Next, adjusted estimators based on stratification, namely the weighted-sum and Mantel-Haenszel (MH) approaches, are reviewed and contrasted. It appears that the weighted-sum approach, which allows for full interaction between exposure and adjustment factors, can be affected by small-sample bias. By contrast, the MH approach, which rests on the assumption of no interaction between exposure and adjustment factors may be misleading if interaction between exposure and adjustment factors is present. Model-based adjusted estimators represent a more general and flexible approach that includes both stratification approaches as special cases and offers intermediate options. Bruzzi et al.’s and Greenland and Drescher’s estimators are reviewed and contrasted. Finally, special problems of adjusted estimation are considered, namely estimation from case-cohort data, estimation for risk factors with multiple levels, for multiple risk factors, for recurrent events, estimation of the prevented and preventable fractions, and estimation of the generalized impact fraction. Comments on future directions are presented.
The application of methods to quantify attributable risk in medical practice
Authors: Uter W , Pfahlberg A
Published: January 2017

Several epidemiological parameters have been introduced for quantifying the population impact of a certain exposure on morbidity on a population level, termed ‘attributable risk’ (AR). Of these definitions, the AR as suggested by Levin in 1953 or some algebraic transformations of it are most commonly used. A structured literature search, based on the Medline database, identified 334 original epidemiological studies dealing with this AR published between 1966 and 1996 (mostly case-control studies). A considerable increase in the number of published studies incorporating some quantification of the exposure impact on the population level in terms of the AR was observed in the last decade. However, in 64.5% of these studies no exact definition of the AR used was given. Adjustment procedures necessary in multifactorial situations were performed by only 37.5%, confidence intervals for the AR were given by only 19.3% of authors. Thus, although the increasing popularity of this important epidemiological measure is encouraging, its correct application and comprehensive reporting in medical practice should be promoted further.
Multilevel analysis with messy data
Authors: Longford N T
Published: January 2017

This paper reviews applications of the method of multiple imputation to dealing with multilevel data that have several kinds of imperfections. These are classified into two broad categories: missing values and imprecise measurement (corrupted recording). The role of the model describing the data imperfections is emphasized. With multiple imputation, these imperfections and information about the processes underlying them can be taken into account. The inferences drawn exploit all the collected information and appropriately reflect the information contained in the data.
The EM algorithm and medical studies: a historical linik
Authors: Meng Xiao-Li
Published: January 2017

Anderson Gray McKendrick's 1926 paper, `Applications of mathematics to medical problems', was the earliest reference cited in Dempster et al.'s 1977 paper that defined and popularized the EM algorithm. McKendrick's paper was prominently featured by Joseph Oscar Irwin in his 1962 inaugural address as the President of the Royal Statistical Society (in the UK), entitled `The place of mathematics in medical and biological statistics'. The link of McKendrick's work to the EM algorithm is due to an improvement made by Irwin on a novel method McKendrick used for estimating an infection rate when the observed data do not distinguish between those individuals who are not susceptible to the infection and those who are susceptible, but do not develop symptoms. This article examines this link, along the way illustrating the central ideas underlying the EM algorithm as well as its properties; the examination also suggests a profiling strategy for speeding up EM, which may be worthy of general investigation. McKendrick's data on an epidemic of cholera are used for illustration and to compare EM with Irwin's method as well as the Newton-Raphson algorithm. Issues beyond computation are also discussed whenever appropriate.
Uses of the EM algorithm in the analysis of data on HIV/AIDS and other infectious diseases
Authors: Becker Niels G
Published: January 2017

The analysis of data on infectious diseases is a natural setting for applications of the EM algorithm, because the infection process is only partially observable. Difficulties in determining the expectation at the E step have been side-stepped by adopting pragmatic models which reflect only part of the mechanism that generates the data. In the HIV/AIDS context the EM algorithm has helped in the reconstruction of the unobserved HIV infection curve, the so-called backprojection problem, as well as in the estimation of the distribution for the incubation period until AIDS, in estimating the infectivity of HIV in partnerships and in estimating parameters describing the decline in the immune system. There is a need for smooth estimates of functions in these applications, suggesting the use of the EMS algorithm or use of the EM algorithm to maximize a penalized likelihood. For data on other infectious diseases the application of the EM algorithm has so far been restricted to analyses of data on the size of outbreaks in a sample of households.
EM algorithms without missing data
Authors: Becker Mark P , Yang Ilsoon , Lange Kenneth
Published: January 2017

Most problems in computational statistics involve optimization of an objective function such as a loglikelihood, a sum of squares, or a log posterior function. The EM algorithm is one of the most effective algorithms for maximization because it iteratively transfers maximization from a complex function to a simple, surrogate function. This theoretical perspective clarifies the operation of the EM algorithm and suggests novel generalizations. Besides simplifying maximization, optimization transfer usually leads to highly stable algorithms with well-understood local and global convergence properties. Although convergence can be excruciatingly slow, various devices exist for accelerating it. Beginning with the EM algorithm, we review in this paper several optimization transfer algorithms of substantial utility in medical statistics.
The EM algorithm in medical imaging
Authors: Kay Jim
Published: January 2017

This article outlines the statistical developments that have taken place in the use of the EM algorithm in emission and transmission tomography during the past decade or so. We discuss the statistical aspects of the modelling of the projection data for both the emission and transmission cases and define the relevant probability models. This leads to the use of the method of maximum likelihood as a means of estimating the relevant unknown parameters within a given region of a patient's body and to the use of the EM algorithm to compute the reconstruction. Various different types of EM algorithm are discussed, including the SAGE algorithms of Fessler and Hero. The limitations of the EM algorithm, per se, are covered and the need for regularization is stressed. A number of different methods for penalizing the likelihood are described and a number of algorithms for the computation of the penalized EM reconstruction are discussed.
On the EM algorithm for overdispersed count data
Authors: McLachlan G J
Published: January 2017

In this paper, we consider the use of the EM algorithm for the fitting of distributions by maximum likelihood to overdispersed count data. In the course of this, we also provide a review of various approaches that have been proposed for the analysis of such data. As the Poisson and binomial regression models, which are often adopted in the first instance for these analyses, are particular examples of a generalized linear model (GLM), the focus of the account is on the modifications and extensions to GLMs for the handling of overdispersed count data.
Clinical trials in psychiatry: background and statistical perspective
Authors: Johnson Tony
Published: January 2017

There have been many hundreds of studies which have examined the efficacy of different forms of treatment of psychiatric disorders over the past 40 years. This paper presents some background to these studies for statisticians, illustrating and discussing some of the difficult problems which arise in this specialty of medicine. It also demonstrates a major requirement for statisticians to influence both the design and presentation of clinical trials and provides some suggestions about how this may be done.
Psychiatric epidemiology
Authors: Pickles Andrew
Published: January 2017

Statisticians working in psychiatric epidemiology regularly confront a variety of problems that are rare in other branches of epidemiology. These problems range from the frequent absence of ‘objective’ biological markers and consequent reliance on informant and self-reports of considerable fallability, to the perhaps corresponding frequent use of multivariate statistical methods such as latent variable modelling. Equally, such difficulties can be regarded as challenges that offer the statistician a critical role.
The use of multivariate statistical methods in psychiatry
Authors: Everitt B S , Landau S
Published: January 2017

Multivariate methods such as factor analysis and cluster analysis have been used for many years by psychiatric researchers primarily for investigating the problems of psychiatric diagnosis. In more recent times, the range of multivariate techniques used has been extended as has the number of areas in which they are being applied.
Statistical methods in psychiatric genetics
Authors: Sham Pak C
Published: January 2017

Most psychiatric disorders are determined by the complex interplay between genetic and environmental factors. Aetiological research into these complex disorders raises many different questions which require a variety of statistical methods. These include survival analysis for the estimation of morbid risk, structural equation models for the partitioning of phenotypic variances and covariances into genetic and other components, complex segregation analysis to detect loci of major effect, and linkage and association analysis for the localisation and identification of susceptibility genes. Future developments in psychiatric genetics will involve the integration of genetic and epidemiological statistics in order to study the interplay between genetic and environmental factors in the complex pathways which lead to mental disorders.
Measurement reliability and agreement in psychiatry
Authors: Shrout Patrick E
Published: January 2017

Psychiatric research has benefited from attention to measurement theories of reliability, and reliability/agreement statistics for psychopathology ratings and diagnoses are regularly reported in empirical reports. Nevertheless, there are still controversies regarding how reliability should be measured, and the amount of resources that should be spent on studying measurement quality in research programs. These issues are discussed in the context of recent theoretical and technical contributions to the statistical analysis of reliability. Special attention is paid to statistical studies published since Kraemer's 1992 review of reliability methods in this journal.
Multiple imputation: a primer
Authors: Schafer Joseph L
Published: January 2017

In recent years, multiple imputation has emerged as a convenient and flexible paradigm for analysing data with missing values. Essential features of multiple imputation are reviewed, with answers to frequently asked questions about using the method in practice.
Applications of multiple imputation in medical studies: from AIDS to NHANES
Authors: Barnard John , Meng Xiao-Li
Published: January 2017

Rubin's multiple imputation is a three-step method for handling complex missing data, or more generally, incomplete-data problems, which arise frequently in medical studies. At the first step, m (> 1) completed-data sets are created by imputing the unobserved data m times using m independent draws from an imputation model, which is constructed to reasonably approximate the true distributional relationship between the unobserved data and the available information, and thus reduce potentially very serious nonresponse bias due to systematic difference between the observed data and the unobserved ones. At the second step, m complete-data analyses are performed by treating each completed-data set as a real complete-data set, and thus standard complete-data procedures and software can be utilized directly. At the third step, the results from the m complete-data analyses are combined in a simple, appropriate way to obtain the so-called repeated-imputation inference, which properly takes into account the uncertainty in the imputed values. This paper reviews three applications of Rubin's method that are directly relevant for medical studies. The first is about estimating the reporting delay in acquired immune deficiency syndrome (AIDS) surveillance systems for the purpose of estimating survival time after AIDS diagnosis. The second focuses on the issue of missing data and noncompliance in randomized experiments, where a school choice experiment is used as an illustration. The third looks at handling nonresponse in United States National Health and Nutrition Examination Surveys (NHANES). The emphasis of our review is on the building of imputation models (i.e. the first step), which is the most fundamental aspect of the method.
Parametric models for incomplete continuous and categorical longitudinal data
Authors: Kenward M G , Molenberghs G
Published: January 2017

This paper reviews models for incomplete continuous and categorical longitudinal data. In terms of Rubin's classification of missing value processes we are specifically concerned with the problem of nonrandom missingness. A distinction is drawn between the classes of selection and pattern-mixture models and, using several examples, these approaches are compared and contrasted. The central roles of identifiability and sensitivity are emphasized throughout.