X-linked anaemia of mice: An hereditary disorder of iron absorption

The X-linked anaemia of mice (gone symbol, sla) is hypoehroxato and microcytic in character. Typically, the mean corpuscular haemoglobin concentration, the mean cell volume and the mean cell diameter are reduced. Anaemia is moderately severe in young hemizygous male and homozygous female mice, and regresses spontaneously with age. Heterozygous female animals show little or no haematological abnormality, and duality of the red cell population is not seen. The iron stores of anaemic mice, as determined both chemically and histochemically, are depleted at all ages. The clearance of iron from the plasma le rapid and the appearance of radio-iron in the red cells, after parenteral injection, is both greater and more rapid than normal. The serum iron concentration is low and the total serum iron binding capacity is elevated, as is the free erythrocyte protoporphyrin concentration. The anaemia responds well to parenteral iron dextran. Together, these findings are characteristic of iron deficiency. In contrast to the usual situation in iron deficiency in man and other mammals, intestinal iron absorption is not increased in X-linked anaemia of mice; indeed a significantly-low level of absorption of inorganic iron at three dose levels (0.1, 1.0 and 10 mug) has been found. Histo-chemical studies reveal abnormal accumulation of stainable iron in the mucosal epithelium of the small bowel of anaemic and heterozygous mice. These findings imply that the deficiency of iron is a consequence of malabsorption of iron by the small bowel, probably as a result of a primary, genetically controlled, fault in the metabolic processes of iron transfer from the mucosa cell to the plasma. The histochomical findings in the mucosa epithelium of heterozygous carriers are consistent with, although they do not constitute proof of the provisions of the Lyon hypothesis of X-chromosome inactivation. X-linked mouse anaemia does not, at present, seem to be a model for any known form of heritable human anaemia, but is potentially a useful tool in the investigation of the still mysterious processes whereby iron is transferred from the mucosal epithelium to the plasma. A hypothetical model explaining known features of iron absorption, and incorporating possible sites of action of the sla gene, is presented and discussed. It is postulated that the sla gene controls the production either of an enzyme ("iron transferase") necessary for the transfer of iron to the plasma from the mucosal epithelial cell of the small bowel, or of a carrier substance ("cytoferrin") to which iron must be bound for this transfer to be achieved

El servicio de transfusión del ejército republicano durante la Guerra Civil Española y su influencia en Gran Bretaña en la Segunda Guerra Mundial

By the end of the First World War, the value of blood transfusion was widely recognized, but it was not until the Spanish Civil War (1936-1939) that large civilian blood donor organizations were created to provide preserved (citrated) blood for transfusion, for both civilian and military patients. Indirect transfusion techniques were developed to administer this blood, with easy-to-use instruments, capable of being carried out anywhere and by any medical personnel with experience in the administration of intravenous injections. Efficient transportation and distribution systems were also established in order to adequately supply the sanitary facilities that served the moving battle fronts. This pioneering work enabled the creation, for the first time in history, of military blood transfusion services. While this was the case for both the insurgent (Nationalist) forces and those of the Spanish Republican Government, it is the latter that forms the focus of this particular study. This is made possible by the publications of Catalan hematologist Frederic Duran Jordà, creator and director of the Republican Blood Transfusion Service, who details the techniques and procedures developed during the war for the collection, testing, distribution and transfusion of blood. Further insight - especially with regard to the practical application of front-line transfusion - can be gleaned from the various writings of Dr Reginald Saxton, British volunteer with the Republican Sanidad Militar. It is the intention, here, to demonstrate that the British authorities benefitted greatly from the Spanish experience in the development of plans for transfusion services that would prove crucial in treating civilian and military casualties during World War II (1939-1945). Frederic Duran Jordà, and Reginald Saxton were key advisers, together with others returning from Spain, including renowned British hematologist, Janet Vaughan. Moreover, the principles developed in Spain (1936-39) for delivery of military blood transfusion practice still support current measures in battlefield casualty resuscitation.Al final de la Primera Guerra Mundial, el valor de la transfusión sanguínea era ampliamente reconocido, pero no fue hasta la Guerra Civil Española (1936-1939) cuando se crearon grandes organizaciones civiles de donantes de sangre para proporcionar sangre conservada (citratada) para la transfusión en pacientes civiles y militares en ambos bandos. Se desarrollaron técnicas de transfusión indirecta para administrar esta sangre, con instrumental de fácil manejo, capaz de ser llevado a cabo en cualquier lugar y por cualquiera con experiencia en la administración de inyecciones endovenosas. También se establecieron sistemas eficaces de transporte y distribución, a fin de abastecer adecuadamente las instalaciones sanitarias que prestaban servicio en los frentes de batalla en movimiento. Este trabajo pionero permitió la creación, por primera vez en la historia, de servicios militares de transfusión de sangre. Si bien este fue el caso tanto de las fuerzas insurgentes (nacionalistas) como del Gobierno republicano español, es este último el que constituye el foco de estudio aquí. Esto es posible gracias a las publicaciones del hematólogo catalán Frederic Duran Jordà, creador y director del Servicio Republicano de Transfusión de Sangre, que detallan las técnicas y procedimientos desarrollados durante la guerra para la recogida, análisis, distribución y transfusión de sangre. Esta información se amplía, especialmente con respecto a la aplicación práctica de la transfusión en primera línea, gracias a diferentes publicaciones del Dr. Reginald Saxton, voluntario británico integrado en la Sanidad Militar de la Republica. Es nuestra intención demostrar que las autoridades británicas se beneficiaron de la experiencia española en vísperas del estallido de la Segunda Guerra Mundial en 1939. Les ayudó a desarrollar planes para los servicios de transfusión que resultarían cruciales en el tratamiento de bajas civiles y militares durante la contienda. Frederic Duran Jordà y Reginald Saxton fueron asesores clave, junto con otros que regresaban de España, incluyendo a la reconocida hematóloga británica, Janet Vaughan. Además, los principios desarrollados en España (1936-39) para la práctica militar de transfusiones de sangre siguen respaldando las medidas actuales de reanimación de heridos en el campo de batalla

Consistent Pulmonary and Systemic Responses from Inhalation of Fine Concentrated Ambient Particles: Roles of Rat Strains Used and Physicochemical Properties

Several studies have reported health effects of concentrated ambient particles (CAP) in rodents and humans; however, toxicity end points in rodents have provided inconsistent results. In 2000 we conducted six 1-day exposure studies where spontaneously hypertensive (SH) rats were exposed to filtered air or CAPs (≤ 2.5 μm, 1,138–1,765 μg/m(3)) for 4 hr (analyzed 1–3 hr afterward). In seven 2-day exposure studies in 2001, SH and Wistar Kyoto (WKY) rats were exposed to filtered air or CAP (≤ 2.5 μm, 144–2,758 μg/m(3)) for 4 hr/day × 2 days (analyzed 1 day afterward). Despite consistent and high CAP concentrations in the 1-day exposure studies, no biologic effects were noted. The exposure concentrations varied among the seven 2-day exposure studies. Except in the first study when CAP concentration was highest, lavageable total cells and macrophages decreased and neutrophils increased in WKY rats. SH rats demonstrated a consistent increase of lavage fluid γ -glutamyltransferase activity and plasma fibrinogen. Inspiratory and expiratory times increased in SH but not in WKY rats. Significant correlations were found between CAP mass (microgram per cubic meter) and sulfate, organic carbon, or zinc. No biologic effects correlated with CAP mass. Despite low chamber mass in the last six of seven 2-day exposure studies, the levels of zinc, copper, and aluminum were enriched severalfold, and organic carbon was increased to some extent when expressed per milligram of CAP. Biologic effects were evident in those six studies. These studies demonstrate a pattern of rat strain–specific pulmonary and systemic effects that are not linked to high mass but appear to be dependent on CAP chemical composition

FeCycle: Attempting an iron biogeochemcial budget from a mesoscale SF 6 tracer experiment in unpertutbed low iron waters

An improved knowledge of iron biogeochemistry is needed to better understand key controls on the functioning of high-nitrate low-chlorophyll (HNLC) oceanic regions. Iron budgets for HNLC waters have been constructed using data from disparate sources ranging from laboratory algal cultures to ocean physics. In summer 2003 we conducted FeCycle, a 10-day mesoscale tracer release in HNLC waters SE of New Zealand, and measured concurrently all sources (with the exception of aerosol deposition) to, sinks of iron from, and rates of iron recycling within, the surface mixed layer. A pelagic iron budget (timescale of days) indicated that oceanic supply terms (lateral advection and vertical diffusion) were relatively small compared to the main sink (downward particulate export). Remote sensing and terrestrial monitoring reveal 13 dust or wildfire events in Australia, prior to and during FeCycle, one of which may have deposited iron at the study location. However, iron deposition rates cannot be derived from such observations, illustrating the difficulties in closing iron budgets without quantification of episodic atmospheric supply. Despite the threefold uncertainties reported for rates of aerosol deposition (Duce et al., 1991), published atmospheric iron supply for the New Zealand region is ∼50-fold (i.e., 7-to 150-fold) greater than the oceanic iron supply measured in our budget, and thus was comparable (i.e., a third to threefold) to our estimates of downward export of particulate iron. During FeCycle, the fluxes due to short term (hours) biological iron uptake and regeneration were indicative of rapid recycling and were tenfold greater than for new iron (i.e. estimated atmospheric and measured oceanic supply), giving an "fe" ratio (uptake of new iron/ uptake of new + regenerated iron) of 0.17 (i.e., a range of 0.06 to 0.51 due to uncertainties on aerosol iron supply), and an "Fe" ratio (biogenic Fe export/uptake of new + regenerated iron) of 0.09 (i.e., 0.03 to 0.24)

Modelling the impact and cost-effectiveness of the HIV intervention programme amongst commercial sex workers in Ahmedabad, Gujarat, India.

BACKGROUND: Ahmedabad is an industrial city in Gujarat, India. In 2003, the HIV prevalence among commercial sex workers (CSWs) in Ahmedabad reached 13.0%. In response, the Jyoti Sangh HIV prevention programme for CSWs was initiated, which involves outreach, peer education, condom distribution, and free STD clinics. Two surveys were performed among CSWs in 1999 and 2003. This study estimates the cost-effectiveness of the Jyoti Sangh HIV prevention programme. METHODS: A dynamic mathematical model was used with survey and intervention-specific data from Ahmedabad to estimate the HIV impact of the Jyoti Sangh project for the 51 months between the two CSW surveys. Uncertainty analysis was used to obtain different model fits to the HIV/STI epidemiological data, producing a range for the HIV impact of the project. Financial and economic costs of the intervention were estimated from the providers perspective for the same time period. The cost per HIV-infection averted was estimated. RESULTS: Over 51 months, projections suggest that the intervention averted 624 and 5,131 HIV cases among the CSWs and their clients, respectively. This equates to a 54% and 51% decrease in the HIV infections that would have occurred among the CSWs and clients without the intervention. In the absence of intervention, the model predicts that the HIV prevalence amongst the CSWs in 2003 would have been 26%, almost twice that with the intervention. Cost per HIV infection averted, excluding and including peer educator economic costs, was USD 59 and USD 98 respectively. CONCLUSION: This study demonstrated that targeted CSW interventions in India can be cost-effective, and highlights the importance of replicating this effort in other similar settings.Published versio

Perinatal Tobacco Smoke Exposure Increases Vascular Oxidative Stress and Mitochondrial Damage in Non-Human Primates

Epidemiological studies suggest that events occurring during fetal and early childhood development influence disease susceptibility. Similarly, molecular studies in mice have shown that in utero exposure to cardiovascular disease (CVD) risk factors such as environmental tobacco smoke (ETS) increased adult atherogenic susceptibility and mitochondrial damage; however, the molecular effects of similar exposures in primates are not yet known. To determine whether perinatal ETS exposure increased mitochondrial damage, dysfunction and oxidant stress in primates, archived tissues from the non-human primate model Macaca mulatta (M. mulatta) were utilized. M. mulatta were exposed to low levels of ETS (1 mg/m3 total suspended particulates) from gestation (day 40) to early childhood (1 year), and aortic tissues were assessed for oxidized proteins (protein carbonyls), antioxidant activity (SOD), mitochondrial function (cytochrome oxidase), and mitochondrial damage (mitochondrial DNA damage). Results revealed that perinatal ETS exposure resulted in significantly increased oxidative stress, mitochondrial dysfunction and damage which were accompanied by significantly decreased mitochondrial antioxidant capacity and mitochondrial copy number in vascular tissue. Increased mitochondrial damage was also detected in buffy coat tissues in exposed M. mulatta. These studies suggest that perinatal tobacco smoke exposure increases vascular oxidative stress and mitochondrial damage in primates, potentially increasing adult disease susceptibility

The SOLAS air-sea gas exchange experiment (SAGE) 2004

Author Posting. © The Author(s), 2010. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Deep Sea Research Part II: Topical Studies in Oceanography 58 (2011): 753-763, doi:10.1016/j.dsr2.2010.10.015.The SOLAS air-sea gas exchange experiment (SAGE) was a multiple-objective study investigating gas-transfer processes and the influence of iron fertilisation on biologically driven gas exchange in high-nitrate low-silicic acid low-chlorophyll (HNLSiLC) Sub-Antarctic waters characteristic of the expansive Subpolar Zone of the southern oceans. This paper provides a general introduction and summary of the main experimental findings. The release site was selected from a pre-voyage desktop study of environmental parameters to be in the south-west Bounty Trough (46.5°S 172.5°E) to the south-east of New Zealand and the experiment conducted between mid-March and mid-April 2004. In common with other mesoscale iron addition experiments (FeAX’s), SAGE was designed as a Lagrangian study quantifying key biological and physical drivers influencing the air-sea gas exchange processes of CO2, DMS and other biogenic gases associated with an iron-induced phytoplankton bloom. A dual tracer SF6/3He release enabled quantification of both the lateral evolution of a labelled volume (patch) of ocean and the air-sea tracer exchange at the 10’s of km’s scale, in conjunction with the iron fertilisation. Estimates from the dual-tracer experiment found a quadratic dependency of the gas exchange coefficient on windspeed that is widely applicable and describes air-sea gas exchange in strong wind regimes. Within the patch, local and micrometeorological gas exchange process studies (100 m scale) and physical variables such as near-surface turbulence, temperature microstructure at the interface, wave properties, and wind speed were quantified to further assist the development of gas exchange models for high-wind environments. There was a significant increase in the photosynthetic competence (Fv/Fm) of resident phytoplankton within the first day following iron addition, but in contrast to other FeAX’s, rates of net primary production and column-integrated chlorophyll a concentrations had only doubled relative to the unfertilised surrounding waters by the end of the experiment. After 15 days and four iron additions totalling 1.1 tonne Fe2+, this was a very modest response compared to the other mesoscale iron enrichment experiments. An investigation of the factors limiting bloom development considered co- limitation by light and other nutrients, the phytoplankton seed-stock and grazing regulation. Whilst incident light levels and the initial Si:N ratio were the lowest recorded in all FeAX’s to date, there was only a small seed-stock of diatoms (less than 1% of biomass) and the main response to iron addition was by the picophytoplankton. A high rate of dilution of the fertilised patch relative to phytoplankton growth rate, the greater than expected depth of the surface mixed layer and microzooplankton grazing were all considered as factors that prevented significant biomass accumulation. In line with the limited response, the enhanced biological draw-down of pCO2 was small and masked by a general increase in pCO2 due to mixing with higher pCO2 waters. The DMS precursor DMSP was kept in check through grazing activity and in contrast to most FeAX’s dissolved dimethylsulfide (DMS) concentration declined through the experiment. SAGE is an important low-end member in the range of responses to iron addition in FeAX’s. In the context of iron fertilisation as a geoengineering tool for atmospheric CO2 removal, SAGE has clearly demonstrated that a significant proportion of the low iron ocean may not produce a phytoplankton bloom in response to iron addition.SAGE was jointly funded through the New Zealand Foundation for Research, Science and Technology (FRST) programs (C01X0204) "Drivers and Mitigation of Global Change" and (C01X0223) "Ocean Ecosystems: Their Contribution to NZ Marine Productivity." Funding was also provided for specific collaborations by the US National Science Foundation from grants OCE-0326814 (Ward), OCE-0327779 (Ho), and OCE 0327188 OCE-0326814 (Minnett) and the UK Natural Environment Research Council NER/B/S/2003/00282 (Archer). The New Zealand International Science and Technology (ISAT) linkages fund provided additional funding (Archer and Ziolkowski), and the many collaborator institutions also provided valuable support

Translational toxicology in setting occupational exposure limits for dusts and hazard classification – a critical evaluation of a recent approach to translate dust overload findings from rats to humans

Background We analyze the scientific basis and methodology used by the German MAK Commission in their recommendations for exposure limits and carcinogen classification of “granular biopersistent particles without known specific toxicity” (GBS). These recommendations are under review at the European Union level. We examine the scientific assumptions in an attempt to reproduce the results. MAK’s human equivalent concentrations (HECs) are based on a particle mass and on a volumetric model in which results from rat inhalation studies are translated to derive occupational exposure limits (OELs) and a carcinogen classification. Methods We followed the methods as proposed by the MAK Commission and Pauluhn 2011. We also examined key assumptions in the metrics, such as surface area of the human lung, deposition fractions of inhaled dusts, human clearance rates; and risk of lung cancer among workers, presumed to have some potential for lung overload, the physiological condition in rats associated with an increase in lung cancer risk. Results The MAK recommendations on exposure limits for GBS have numerous incorrect assumptions that adversely affect the final results. The procedures to derive the respirable occupational exposure limit (OEL) could not be reproduced, a finding raising considerable scientific uncertainty about the reliability of the recommendations. Moreover, the scientific basis of using the rat model is confounded by the fact that rats and humans show different cellular responses to inhaled particles as demonstrated by bronchoalveolar lavage (BAL) studies in both species. Conclusion Classifying all GBS as carcinogenic to humans based on rat inhalation studies in which lung overload leads to chronic inflammation and cancer is inappropriate. Studies of workers, who have been exposed to relevant levels of dust, have not indicated an increase in lung cancer risk. Using the methods proposed by the MAK, we were unable to reproduce the OEL for GBS recommended by the Commission, but identified substantial errors in the models. Considerable shortcomings in the use of lung surface area, clearance rates, deposition fractions; as well as using the mass and volumetric metrics as opposed to the particle surface area metric limit the scientific reliability of the proposed GBS OEL and carcinogen classification.International Carbon Black Associatio

Track E Implementation Science, Health Systems and Economics

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138412/1/jia218443.pd