Cellular iron uptake, trafficking and metabolism: Key molecules and mechanisms and their roles in disease.

Iron is a crucial transition metal for virtually all life. Two major destinations of iron within mammalian cells are the cytosolic iron-storage protein, ferritin, and mitochondria. In mitochondria, iron is utilized in critical anabolic pathways, including: iron-storage in mitochondrial ferritin, heme synthesis, and iron-sulfur cluster (ISC) biogenesis. Although the pathways involved in ISC synthesis in the mitochondria and cytosol have begun to be characterized, many crucial details remain unknown. In this review, we discuss major aspects of the journey of iron from its initial cellular uptake, its modes of trafficking within cells, to an overview of its downstream utilization in the cytoplasm and within mitochondria. The understanding of mitochondrial iron processing and its communication with other organelles/subcellular locations, such as the cytosol, has been elucidated by the analysis of certain diseases e.g., Friedreich's ataxia. Increased knowledge of the molecules and their mechanisms of action in iron processing pathways (e.g., ISC biogenesis) will shape the investigation of iron metabolism in human health and disease.

The association between paramedic service system hospital offload time and response time.

OBJECTIVE: To address an important care issue in Canada, we tested the association between paramedic system hospital offload and response time, while considering the impact of other system-level factors. METHODS: Data from Calgary, Alberta (2014-2017), included median offload (exposure) and response (outcome) time aggregated by hour, with covariates paramedic system episodes of care-dispatch and arrival of a response unit-and hospital transport arrivals (collectively called volume), time of day, and season. Analyses used linear regression and modified Poisson models. RESULTS: 301,105 EMS episodes of care over 26,193 1-h periods were included. For any given 1-h period, the median (IQR) across all episodes of care for offload time, response time, episodes of care, and hospital transport arrivals were 55.3 (45.7, 66.3) min, 8.6 (7.6, 9.8) min, 12 (8, 16) episodes, and 8 (5, 10) hospital arrivals, respectively. Multivariable modelling revealed a complex association differing over levels of exposure and covariates, requiring description using "light stress" and "heavy stress" system scenarios. The light scenario was defined as median offload of 30 min and volume < 10th percentile (six episodes and four hospital arrivals), in the summer, and the heavy scenario as median offload of 90 min and volume > 90th percentile (17 episodes and 13 hospital arrivals), in the winter. An increase is reported in minutes:seconds for median hourly response time between scenarios by time of day: 1:04-4:16 (0000-0559 h.), 0:42-2:05 (0600-1159 h.), 0:57-3:01 (1200-1759 h.), and 0:18-2:21 (1800-2359 h.). CONCLUSIONS: Increasing offload is associated with increased response time; however the relationship is complex, with a greater impact on response time noted in select situations such as high volume in the winter. These observations illustrate the interdependence of paramedic, ED, and inpatient systems and provide high-yield targets for polices to mitigate the risk to community availability of paramedic resources at times of high offload delay/system stress.

ABSTRAIT: OBJECTIF: Afin de régler un problème important de soins au Canada, nous avons testé l'association entre le déchargement du système paramédical et le temps de réponse, tout en tenant compte de l'incidence d'autres facteurs au niveau du système. MéTHODES: Les données de Calgary, en Alberta (2014-2017) incluent le temps médian de déchargement (exposition) et de réponse (résultat) agrégé par heure, qui s'agit co-variables épisodes de soins du système paramédical - répartition et arrivée d'une unité d'intervention - et arrivées de transport hospitalier (collectivement appelé volume), l'heure et la saison. Les analyses ont utilisé la régression linéaire et des modèles de Poisson modifiés. RéSULTATS: 301105 épisodes de soins médicaux d'urgence sur 26193 périodes d'une heure ont été inclus. Pour une période d'une heure donnée, la médiane (QRI) pour tous les épisodes de soins pour le temps de déchargement, le temps de réponse, les épisodes de soins et les arrivées par transport à l'hôpital était de 55,3 (45,7, 66,3) minutes, 8,6 (7,6, 9,8) minutes, 12 (8, 16) épisodes et 8 (5, 10) arrivées à l'hôpital, respectivement. La modélisation multi-variable a révélé une association complexe qui varie selon les niveaux d'exposition et les co-variables, et qui nécessite une description à l'aide de scénarios de systèmes de « stress léger ¼ et de « stress lourd ¼. Le scénario léger a été défini comme un déchargement médian de 30 minutes, volume inférieur au 10e percentile (six épisodes et quatre arrivées à l'hôpital), pendant l'été. Le scénario lourd comme déchargement médian de 90 minutes, volume > 90e percentile (17 épisodes et 13 arrivées à l'hôpital), en hiver. Une augmentation est rapportée en minutes: secondes pour le temps de réponse horaire médian entre des scénarios par heure du jour : 1:04-4:16 (0000-0559 h.), 0:42-2:05 (0600-1159 h.), 0:57-3:01 (1200-1759 h.), et 0:18-2:21 (1800-2359 h.). CONCLUSIONS: L'augmentation du déchargement est associée à une augmentation du temps de réponse, mais la relation est complexe, avec un impact plus important sur le temps de réponse noté dans certaines situations, comme un volume élevé en hiver. Ces observations illustrent l'interdépendance des systèmes paramédicaux, des services d'urgence et des services aux patients hospitalisés et fournissent des cibles à haut rendement pour les politiques afin d'atténuer le risque pour la disponibilité des ressources paramédicales dans la collectivité en période de retard élevé ou de stress systémique.

Decadal stability in coral cover could mask hidden changes on reefs in the East Asian Seas.

Coral reefs in the Central Indo-Pacific region comprise some of the most diverse and yet threatened marine habitats. While reef monitoring has grown throughout the region in recent years, studies of coral reef benthic cover remain limited in spatial and temporal scales. Here, we analysed 24,365 reef surveys performed over 37 years at 1972 sites throughout East Asia by the Global Coral Reef Monitoring Network using Bayesian approaches. Our results show that overall coral cover at surveyed reefs has not declined as suggested in previous studies and compared to reef regions like the Caribbean. Concurrently, macroalgal cover has not increased, with no indications of phase shifts from coral to macroalgal dominance on reefs. Yet, models incorporating socio-economic and environmental variables reveal negative associations of coral cover with coastal urbanisation and sea surface temperature. The diversity of reef assemblages may have mitigated cover declines thus far, but climate change could threaten reef resilience. We recommend prioritisation of regionally coordinated, locally collaborative long-term studies for better contextualisation of monitoring data and analyses, which are essential for achieving reef conservation goals.

Analysis of hydrothermal vent-associated symbionts by ribosomal RNA sequences.

Ribosomal RNA (rRNA) sequences were used to establish the phylogenetic affiliations of symbioses in which prokaryotes appear to confer sulfur-based chemoautotrophy on their invertebrate hosts. Two submarine hydrothermal vent animals, the vestimentiferan tube worm Riftia pachyptila and the clam Calyptogena magnifica, and a tidal-flat bivalve, Solemya velum, were inspected. 5S rRNA's were extracted from symbiont-bearing tissues, separated into unique forms, and their nucleotide sequences determined and related to other 5S rRNA's in a phylogenetic tree analysis. The prokaryotic symbionts are related to one another and affiliated with the same narrow phylogenetic grouping as Escherichia coli and Pseudomonas aeruginosa. The sequence comparisons suggest that Riftia is more closely related to the bivalves than their current taxonomic status would suggest.

Molecular phylogeny of the animal kingdom.

A rapid sequencing method for ribosomal RNA was applied to the resolution of evolutionary relationships among Metazoa. Representatives of 22 classes in 10 animal phyla were used to infer phylogenetic relationships, based on evolutionary distances determined from pairwise comparisons of the 18S ribosomal RNA sequences. The classical Eumetazoa are divided into two groups. Cnidarians arose from a protist ancestry different from the second group, the Bilateria. Within the Bilateria, an early split gave rise to Platyhelminthes (flatworms) and the coelomate lineage. Coelomates are thus monophyletic, and they radiated rapidly into four groups: chordates, echinoderms, arthropods, and eucoelomate protostomes.

Should ipratropium bromide be added to beta-agonists in treatment of acute severe asthma?

In a double-blind randomized trial, 40 patients with acute severe asthma were given either nebulized salbutamol, 5 mg, or salbutamol, 5 mg mixed with ipratropium bromide 500 micrograms, on admission to hospital and again two hours later. There was no significant difference between the mean peak flows of the two treatment groups at any time. However, two hours after each treatment, there were fewer subjects in the ipratropium and salbutamol group whose peak flow rates had fallen back toward baseline levels than in the salbutamol only treatment group. Thus, although ipratropium did not improve the overall maximal bronchodilator response, it may have prolonged the duration of the response, which would be a clinically useful effect.

Ear involvement in the yellow nail syndrome.

Recognized features of the yellow nail syndrome include yellow nails, lymphedema, and pleural effusions. We report a patient with the additional feature of keratosis obturans, which may be a manifestation of this syndrome in the external ear.

Ponto-bulbar palsy with deafness (Brown-Vialetto-Van Laere syndrome).

The authors describe the clinical and electrophysiological features in 2 cases of ponto-bulbar palsy with deafness, and the clinical course and post-mortem findings in a sibling of one of these, who died in infancy, and who appears to have suffered from the same disease. The cases are compared with 17 previously published cases, and the disease is discussed in relation to other progressive neurological diseases of childhood.

The lure of a LYR: The logistics of iron sulfur cluster delivery.

How are nascent iron-sulfur (Fe-S) clusters directed to specific recipient proteins? In this issue of Cell Metabolism, Maio et al. (2014) show that the mitochondrial Fe-S cochaperone protein HSC20 guides nascent Fe-S clusters based on a highly conserved motif, LYR, that exists in target proteins in different molecular contexts.

Fixing frataxin: 'ironing out' the metabolic defect in Friedreich's ataxia.

The metabolically active and redox-active mitochondrion appears to play a major role in the cellular metabolism of the transition metal, iron. Frataxin, a mitochondrial matrix protein, has been identified as playing a key role in the iron metabolism of this organelle due to its iron-binding properties and is known to be essential for iron-sulphur cluster formation. However, the precise function of frataxin remains elusive. The decrease in frataxin expression, as seen in the inherited disorder Friedreich's ataxia, markedly alters cellular and mitochondrial iron metabolism in both the mitochondrion and the cell. The resulting dysregulation of iron trafficking damages affects tissues leading to neuro- and cardiodegeneration. This disease underscores the importance of iron homeostasis in the redox-active environment of the mitochondrion and the molecular players involved. Unravelling the mechanisms of altered iron metabolism in Friedreich's ataxia will help elucidate a biochemical function for frataxin. Consequently, this will enable the development of more effective and rationally designed treatments. This review will focus on the emerging function of frataxin in relation to the observed alterations in mitochondrial iron metabolism in Friedreich's ataxia. Tissue-specific alterations due to frataxin loss will also be discussed, as well as current and emerging therapeutic strategies.

Glutathione S-transferase and MRP1 form an integrated system involved in the storage and transport of dinitrosyl-dithiolato iron complexes in cells.

Nitrogen monoxide (NO) is vital for many essential biological processes as a messenger and effector molecule. The physiological importance of NO is the result of its high affinity for iron in the active sites of proteins such as guanylate cyclase. Indeed, NO possesses a rich coordination chemistry with iron and the formation of dinitrosyl-dithiolato iron complexes (DNICs) is well documented. In mammals, NO generated by cytotoxic activated macrophages has been reported to play a role as a cytotoxic effector against tumor cells by binding and releasing intracellular iron. Studies from our laboratory have shown that two proteins traditionally involved in drug resistance, namely multidrug-resistance protein 1 and glutathione S-transferase, play critical roles in intracellular NO transport and storage through their interaction with DNICs (R.N. Watts et al., Proc. Natl. Acad. Sci. USA 103:7670-7675, 2006; H. Lok et al., J. Biol. Chem. 287:607-618, 2012). Notably, DNICs are present at high concentrations in cells and are biologically available. These complexes have a markedly longer half-life than free NO, making them an ideal "common currency" for this messenger molecule. Considering the many critical roles NO plays in health and disease, a better understanding of its intracellular trafficking mechanisms will be vital for the development of new therapeutics.

A steroid sparing effect of ketotifen in steroid-dependent asthmatics.

In a multicentre, double-blind trial, the steroid sparing effect of a new anti-anaphylactic agent ketotifen was assessed against placebo in eighty-six steroid-dependent asthmatics. Mean reduction in total daily prednisolone dosage in patients on ketotifen was 4.0 +/- 3.6 mg compared to 1.7 +/- 2.8 mg on placebo, a result significantly in favour of the active drug (P < 0.01). This suggests that ketotifen has a place similar to that of disodium cromoglycate or steroid aerosols in the managment of steroid-dependent asthmatics. It has the advantage of requiring only twice-daily oral administration.

Changes in blood gas tensions and functional residual capacity chronic asthmatics treated with disodium cromoglycate.

Twenty chronic asthmatic subjects were treated with disodium cromoglycate in open trial. Although in the group as a whole spirometric findings improved, some patients showed a significant increase in arterial oxygen tension or a significant fall in functional residual capacity without any appreciable changes in spirometry. These changes may partly explain the clinical efficacy of this drug.