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ABSTRACT Calciphylaxis is a rare life-threatening form of skin necrosis. Although traditionally observed in patients with end-stage renal disease and/or hyperparathyroidism, calciphylaxis has also been reported to occur in 'non-traditional' patients with normal renal and parathyroid function. We report a case of warfarin-induced calciphylaxis treated successfully with sodium thiosulphate and discuss the role of Vitamin K2 as a potential therapeutic option in the management of warfarin-induced calciphylaxis. [ABSTRACT FROM AUTHOR]

Dietary consumption of lysine in humans leads to the biosynthesis of Δ 1 -piperideine-6-carboxylic acid (P6C), with elevated levels linked to the neurological disorder epilepsy. Here we demonstrate that P6C biosynthesis is also a critical component of lysine catabolism in Arabidopsis thaliana. P6C regulates vitamin B6 homeostasis, and increased P6C levels deplete B6 vitamers, resulting in compromised plant immunity. We further establish a key role for pyridoxal and pyridoxal-5-phosphate biosynthesis in plant immunity. Our analysis indicates that P6C metabolism probably evolved through combining select lysine and proline metabolic enzymes horizontally acquired from diverse bacterial sources at different points during evolution. More generally, certain enzymes from the lysine and proline metabolic pathways were probably recruited in evolution as potential guardians of B6 vitamers and for semialdehyde detoxification., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

For either healthy or diseased organisms, lipids are key components for cellular membranes; they play important roles in numerous cellular processes including cell growth, proliferation, differentiation, energy storage and signaling. Exercise and disease development are examples of cellular environment alterations which produce changes in these networks. There are indications that alterations in lipid metabolism contribute to the development and progression of a variety of cancers. Measuring such alterations and understanding the pathways involved is critical to fully understand cellular metabolism. The demands for this information have led to the emergence of lipidomics, which enables the large-scale study of lipids using mass spectrometry (MS) techniques. Mass spectrometry has been widely used in lipidomics and allows us to analyze detailed lipid profiles of cancers. In this article, we discuss emerging strategies for lipidomics by mass spectrometry; targeted, as opposed to global, lipid analysis provides an exciting new alternative method. Additionally, we provide an introduction to lipidomics, lipid categories and their major biological functions, along with lipidomics studies by mass spectrometry in cancer samples. Further, we summarize the importance of lipid metabolism in oncology and tumor microenvironment, some of the challenges for lipodomics, and the potential for targeted approaches for screening pharmaceutical candidates to improve the therapeutic efficacy of treatment in cancer patients.

Acute inflammation is the body's first defense in response to pathogens or injury that is partially governed by a novel genus of endogenous lipid mediators that orchestrate the resolution of inflammation, coined specialized pro-resolving mediators (SPMs). SPMs, derived from omega-3-polyunstaturated fatty acids (PUFAs), include the eicosapentaenoic acid-derived and docosahexaenoic acid-derived Resolvins, Protectins, and Maresins. Herein, we review their biosynthesis, structural characteristics, and therapeutic effectiveness in various diseases such as ischemia, viral infections, periodontitis, neuroinflammatory diseases, cystic fibrosis, lung inflammation, herpes virus, and cancer, especially focusing on therapeutic effectiveness in respiratory inflammation and ischemia-related injuries. Resolvins are sub-nanomolar potent agonists that accelerate the resolution of inflammation by reducing excessive neutrophil infiltration, stimulating macrophage functions including phagocytosis, efferocytosis, and tissue repair. In addition to regulating neutrophils and macrophages, Resolvins control dendritic cell migration and T cell responses, and they also reduce the pro-inflammatory cytokines, proliferation, and metastasis of cancer cells. Importantly, several lines of evidence have demonstrated that Resolvins reduce tumor progression in melanoma, oral squamous cell carcinoma, lung cancer, and liver cancer. In addition, Resolvins enhance tumor cell debris clearance by macrophages in the tumor's microenvironment. Resolvins, with their unique stereochemical structure, receptors, and biosynthetic pathways, provide a novel therapeutical approach to activating resolution mechanisms during cancer progression., Competing Interests: Dr.Paul Norris are employees of SCIEX. The paper reflects the views of the scientists, and not the company. The authors declare no conflict of interest.

T cells are often absent from human cancer tissues during both spontaneously induced immunity and therapeutic immunotherapy, even in the presence of a functional T cell-recruiting chemokine system, suggesting the existence of T cell exclusion mechanisms that impair infiltration. Using a genome-wide in vitro screening platform, we identified a role for phospholipase A2 group 10 (PLA2G10) protein in T cell exclusion. PLA2G10 up-regulation is widespread in human cancers and is associated with poor T cell infiltration in tumor tissues. PLA2G10 overexpression in immunogenic mouse tumors excluded T cells from infiltration, resulting in resistance to anti-PD-1 immunotherapy. PLA2G10 can hydrolyze phospholipids into small lipid metabolites, thus inhibiting chemokine-mediated T cell mobility. Ablation of PLA2G10's enzymatic activity enhanced T cell infiltration and sensitized PLA2G10-overexpressing tumors to immunotherapies. Our study implicates a role for PLA2G10 in T cell exclusion from tumors and suggests a potential target for cancer immunotherapy.

A novel thermoacidophilic archeaon, strain J1 T (=DSM 112778 T ,=JCM 34702 T ), was isolated from a hot pool in a volcanic area of Java, Indonesia. Cells of the strain were irregular, motile cocci of 1.0-1.2 µm diameter. Aerobic, organoheterotrophic growth with casamino acids was observed at an optimum temperature of 70 °C in a range of 55-78 °C and at an optimum pH of 3 in a range of 1.5 to 5. Various organic compounds were utilized, including a greater variety of sugars than has been reported for growth of other species of the genus. Chemolithoautotrophic growth was observed with reduced sulphur compounds, including mineral sulphides. Ferric iron was reduced during anaerobic growth with elemental sulphur. Cellular lipids were calditoglycerocaldarchaeol and caldarchaeol with some derivates. The organism contained the respiratory quinone caldariellaquinone. On the basis of phylogenetic and chemotaxonomic comparison with its closest relatives, it was concluded that strain J1 T represents a novel species, for which the name Metallosphaera javensis is proposed. Low DNA-DNA relatedness values (16S rRNA gene <98.4%, average nucleotide identity (ANI) <80.1%) distinguished J1 T from other species of the genus Metallosphaera and the DNA G+C content of 47.3% is the highest among the known species of the genus.

Facial transplants represent the current exemplar in the reconstruction of severely damaged faces, whereas conventional free flap reconstruction has its limitations in restoring both function and surface cover., Methods: In a retrospective study over 6 years (2014-2020), 5 cases (n = 5) of vascularized nerve flaps (VNFs) were performed by our team. These involved three acute and two late reconstructions. The mean age was 41 years with a maximum of 6-year follow-up. To objectify the different permutations and combinations, we categorized composite, chimeric, and hybrid VNFs into types I, IIa-c, and III, each with a unique characteristic. Postoperative function was evaluated using the validated Sunnybrook and Terzis scores for facial nerve palsy; masticatory function was assessed using dental impression studies., Results: There was a 100% flap survival rate, with no instances of flap necrosis and only one complication: hematoma at 24 hours postoperative. Sunnybrook and Terzis scores showed a statistically significant improvement postoperatively, indicating both improved repose and facial expressions (paired student t test, P < 0.05). Given that each VNF was specifically customized for a particular patient, each type of VNF in this cohort was unique, thereby illustrating each type succinctly., Conclusions: VNFs are separate entities from standard free flaps, as they require extensive preoperative planning to allow the deconstructing of composite blocks of tissue into separate vascularized entities and amalgamating them into a new conglomerate. This allows VNFs to fill a niche area in facial reconstructive surgery between face transplants and conventional free tissue transfers, with enormous potential., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

The chronic neuro-inflammatory character of multiple sclerosis (MS) suggests that the natural process to resolve inflammation is impaired. This protective process is orchestrated by specialized pro-resolving lipid mediators (SPMs), but to date, the role of SPMs in MS remains largely unknown. Here, we provide in vivo evidence that treatment with the SPM lipoxin A 4 (LXA 4 ) ameliorates clinical symptoms of experimental autoimmune encephalomyelitis (EAE) and inhibits CD4 + and CD8 + T cell infiltration into the central nervous system (CNS). Moreover, we show that LXA 4 potently reduces encephalitogenic Th1 and Th17 effector functions, both in vivo and in isolated human T cells from healthy donors and patients with relapsing-remitting MS. Finally, we demonstrate that LXA 4 affects the spinal cord lipidome by significantly reducing the levels of pro-inflammatory lipid mediators during EAE. Collectively, our findings provide mechanistic insight into LXA 4 -mediated amelioration of neuro-inflammation and highlight the potential clinical application of LXA 4 for MS., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The COVID-19 pandemic has caused unprecedented disruption to the routine operations of healthcare services across the world. As the potential duration of the pandemic remains uncertain, the need to develop strategies to continue urgent elective services has received increasing attention. A solution adopted in the Kent, Sussex and Surrey area of England has been to create COVID-19-protected cancer hubs. The Queen Victoria Hospital is the designated hub for head and neck cancer services in the area. We report on the evolution of the head and neck cancer care pathway and standard operating protocols put in place and how these have combined both national guidelines and local problem solving. It is hoped that our experience can help guide other centres as they re-establish head and neck cancer services during the ongoing pandemic., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Chronic inflammation is a key pathological hallmark of multiple sclerosis (MS) and suggests that resolution of inflammation, orchestrated by specialized pro-resolving lipid mediators (LM), is impaired. Here, through targeted-metabololipidomics in peripheral blood of patients with MS, we revealed that each disease form was associated with distinct LM profiles that significantly correlated with disease severity. In particular, relapsing and progressive MS patients were associated with high eicosanoids levels, whereas the majority of pro-resolving LM were significantly reduced or below limits of detection and correlated with disease progression. Furthermore, we found impaired expression of several pro-resolving LM biosynthetic enzymes and receptors in blood-derived leukocytes of MS patients. Mechanistically, differentially expressed mediators like LXA 4 , LXB 4 , RvD1 and PD1 reduced MS-derived monocyte activation and cytokine production, and inhibited inflammation-induced blood-brain barrier dysfunction and monocyte transendothelial migration. Altogether, these findings reveal peripheral defects in the resolution pathway in MS, suggesting pro-resolving LM as novel diagnostic biomarkers and potentially safe therapeutics., (Copyright© 2020 Ferrata Storti Foundation.)

Ferrous iron- and sulfur-oxidizing Acidihalobacter species and similar so far unclassified bacteria have been isolated from the islands of Vulcano (Italy) and Milos (Greece), specifically from where seawater was acidified at sulfide-rich geothermal sites. Acidithiobacillus species which tolerated concentrations of chloride that inhibit most Acidithiobacillus spp. were also isolated from sites on both islands: these were At. thiooxidans strains and an unclassified species, Acidithiobacillus sp. strain V1. The potential of salt-tolerant acidophiles for industrial application in promoting copper extraction from mineral sulfides where chloride is naturally present at concentrations which would inhibit most acidophiles, or where seawater rather than fresh water is available, appears to be limited by the sensitivity of ferrous-iron oxidizing Acidihalobacter spp. to copper. However, tolerance of copper and chloride shown by At. thiooxidans strain A7 suggests it could oxidize sulfur and benefit acid leaching if ferric iron or copper was provided as the primary oxidant of sulfide ores.

Strain MG, isolated from an acidic pond sediment on the island of Milos (Greece), is proposed as a novel species of ferrous iron- and sulfur-oxidizing Acidithiobacillus. Currently, four of the eight validated species of this genus oxidize ferrous iron, and strain MG shares many key characteristics with these four, including the capacities for catalyzing the oxidative dissolution of pyrite and for anaerobic growth via ferric iron respiration. Strain MG also grows aerobically on hydrogen and anaerobically on hydrogen coupled to ferric iron reduction. While the 16S rRNA genes of the iron-oxidizing Acidi-thiobacillus species (and strain MG) are located in a distinct phylogenetic clade and are closely related (98-99% 16S rRNA gene identity), genomic relatedness indexes (ANI/dDDH) revealed strong genomic divergence between strain MG and all sequenced type strains of the taxon, and placed MG as the first cultured representative of an ancestral phylotype of iron oxidizing acidithiobacilli. Strain MG is proposed as a novel species, Acidithiobacillus ferrianus sp. nov. The type strain is MG T (= DSM 107098 T  = JCM 33084 T ). Similar strains have been found as isolates or indicated by cloned 16S rRNA genes from several mineral sulfide mine sites.

Background: Cysteinyl leukotrienes (CysLTs) are potent prophlogistic mediators in asthmatic patients; however, inhibition of CysLT receptor 1 is not a consistently effective treatment, suggesting additional regulatory mechanisms. Other cysteinyl-containing lipid mediators (LMs) derived from docosahexaenoic acid, namely maresin conjugates in tissue regeneration (MCTRs), were recently discovered. Therefore their production and actions in the lung are of considerable interest., Objective: We sought to determine MCTR production, bioactions, and mechanisms in the human lung and in patients with experimental allergic airway inflammation., Methods: LM metabololipidomic profiling of the lung was performed by using liquid chromatography with tandem mass spectrometry. Donor-derived human precision-cut lung slices were exposed to leukotriene (LT) D 4 , MCTRs, or both before determination of airway contraction. The actions of exogenous MCTRs on murine allergic host responses were determined in the setting of ovalbumin- and house dust mite-induced lung inflammation., Results: Lipidomic profiling showed that the most abundant cysteinyl LMs in healthy human lungs were MCTRs, whereas CysLTs were most prevalent in patients with disease. MCTRs blocked LTD 4 -initiated airway contraction in human precision-cut lung slices. In mouse allergic lung inflammation MCTRs were present with temporally regulated production. With ovalbumin-induced inflammation, MCTR1 was most potent for promoting resolution of eosinophils, and MCTR3 potently decreased airway hyperreactivity to methacholine, bronchoalveolar lavage fluid albumin, and serum IgE levels. MCTR1 and MCTR3 inhibited lung eosinophilia after house dust mite-induced inflammation., Conclusion: These results identified lung MCTRs that blocked human LTD 4 -induced airway contraction and promoted resolution of murine allergic airway responses when added exogenously. Together, these findings uncover proresolving mechanisms for lung responses that can be disrupted in patients with disease., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: Recently, we observed that the specialized proresolving mediator (SPM) entity resolvin D1 activates lipoxin A 4 /formyl peptide receptor 2 (ALX/FPR2), which facilitates cardiac healing and persistent inflammation is a hallmark of impaired cardiac repair in aging. Splenic leukocyte-directed SPMs are essential for the safe clearance of inflammation and cardiac repair after injury; however, the target of SPMs remains undefined in cardiac healing and repair., Methods: To define the mechanistic basis of ALX/FPR2 as a resolvin D1 target, ALX/FPR2-null mice were examined extensively. The systolic-diastolic heart function was assessed using echocardiography, leukocytes were phenotyped using flow cytometry, and SPMs were quantitated using mass spectrometry. The presence of cardiorenal syndrome was validated using histology and renal markers., Results: Lack of ALX/FPR2 led to the development of spontaneous obesity and diastolic dysfunction with reduced survival with aging. After cardiac injury, ALX/FPR2 -/- mice showed lower expression of lipoxygenases (-5, -12, -15) and a reduction in SPMs in the infarcted left ventricle and spleen, indicating nonresolving inflammation. Reduced SPM levels in the infarcted heart and spleen are suggestive of impaired cross-talk between the injured heart and splenic leukocytes, which are required for the resolution of inflammation. In contrast, cyclooxygenases (-1 and -2) were over amplified in the infarcted heart. Together, these results suggest interorgan signaling in which the spleen acts as both an SPM biosynthesizer and supplier in acute heart failure. ALX/FPR2 dysfunction magnified obesogenic cardiomyopathy and renal inflammation (↑NGAL, ↑TNF-α, ↑CCL2, ↑IL-1β) with elevated plasma creatinine levels in aging mice. At the cellular level, ALX/FPR2 -/- mice showed impairment of macrophage phagocytic function ex-vivo with expansion of neutrophils after myocardial infarction., Conclusions: Lack of ALX/FPR2 induced obesity, reduced the life span, amplified leukocyte dysfunction, and facilitated profound interorgan nonresolving inflammation. Our study shows the integrative and indispensable role of ALX/FPR2 in lipid metabolism, cardiac inflammation-resolution processes, obesogenic aging, and renal homeostasis., (Copyright © 2019 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Deep vein thrombosis (DVT) is a common cardiovascular disease with a major effect on quality of life, and safe and effective therapeutic measures to efficiently reduce existent thrombus burden are scarce. Using a comprehensive targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics approach, we established temporal clusters of endogenously biosynthesized specialized proresolving mediators (SPMs) and proinflammatory and prothrombotic lipid mediators during DVT progression in mice. Administration of resolvin D4 (RvD4), an SPM that was enriched at the natural onset of thrombus resolution, significantly reduced thrombus burden, with significantly less neutrophil infiltration and more proresolving monocytes in the thrombus, as well as an increased number of cells in an early apoptosis state. Moreover, RvD4 promoted the biosynthesis of other D-series resolvins involved in facilitating resolution of inflammation. Neutrophils from RvD4-treated mice were less susceptible to an ionomycin-induced release of neutrophil extracellular traps (NETs), a meshwork of decondensed chromatin lined with histones and neutrophil proteins critical for DVT development. These results suggest that delivery of SPMs, specifically RvD4, modulates the severity of thrombo-inflammatory disease in vivo and improves thrombus resolution., (© 2019 by The American Society of Hematology.)

Targeting hypoxia-sensitive pathways in immune cells is of interest in treating diseases. Here, we demonstrate that physiologic hypoxia (1% O 2 ), as encountered in bone marrow and spleen, accelerates human M2 macrophage efferocytosis of apoptotic-neutrophils and senescent erythrocytes via lipolysis-dependent biosynthesis of specialized pro-resolving mediators (SPMs), i.e. resolvins, protectins, maresins and lipoxin. SPM-production was enhanced via hypoxia in M2 macrophages interacting with neutrophils and erythrocytes enabling structural elucidation of a novel eicosapentaenoic acid (EPA)-derived resolvin, resolvin E4 (RvE4) that stimulates efferocytosis of senescent erythrocytes and more potently than aspirin in mouse hemorrhagic exudates. In hypoxia, glycolysis inhibition enhanced neutrophil RvE4-SPM biosynthesis. Human macrophage-erythrocyte co-incubations in physiologic hypoxia produced RvE4-SPM from erythrocyte stores of omega-3 fatty acids. These results indicate that hypoxic environments, including bone marrow and spleen as well as sites of inflammation, activate SPM-biosynthetic circuits that in turn stimulate resolution and clearance of senescent erythrocytes and apoptotic neutrophils., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Changes in the intestinal lymphatic vascular system, such as lymphatic obstruction, are characteristic features of inflammatory bowel diseases. The lymphatic vasculature forms a conduit to enable resolution of inflammation; this process is driven by specialized endogenous proresolving mediators (SPMs). To evaluate contributions of lymphatic obstruction to intestinal inflammation and to study profiles of SPMs, we generated a novel animal model of lymphatic obstruction using African green monkeys. Follow-up studies were performed at 7, 21, and 61 days. Inflammation was determined by histology. Luminex assays were performed to evaluate chemokine and cytokine levels. In addition, lipid mediator metabololipidomic profiling was performed to identify SPMs. After 7 days, lymphatic obstruction resulted in a localized inflammatory state, paralleled by an increase in inflammatory chemokines and cytokines, which were found to be up-regulated after 7 days but returned to baseline after 21 and 61 days. At the same time, a distinct pattern of SPMs was profiled, with an increase for D-series resolvins, protectins, maresins, and lipoxins at 61 days. These results indicate that intestinal lymphatic obstruction can lead to an acute inflammatory state, accompanied by an increase in proinflammatory mediators, followed by a phase of resolution, paralleled by an increase and decrease of respective SPMs., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Resolvins (Rvs), endogenous lipid mediators, play a key role in the resolution of inflammation. Sickle cell disease (SCD), a genetic disorder of hemoglobin, is characterized by inflammatory and vaso-occlusive pathologies. We document altered proresolving events following hypoxia/reperfusion in humanized SCD mice. We demonstrate novel protective actions of 17 R -resolvin D1 (17 R- RvD1; 7 S , 8 R , 17 R -trihydroxy-4 Z , 9 E , 11 E , 13 Z , 15 E , 19 Z -docosahexaenoic acid) in reducing ex vivo human SCD blood leukocyte recruitment by microvascular endothelial cells and in vivo neutrophil adhesion and transmigration. In SCD mice exposed to hypoxia/reoxygenation, oral administration of 17 R - RvD1 reduces systemic/local inflammation and vascular dysfunction in lung and kidney. The mechanism of action of 17 R -RvD1 involves (1) enhancement of SCD erythrocytes and polymorphonuclear leukocyte efferocytosis, (2) blunting of NF-κB activation, and (3) a reduction in inflammatory cytokines, vascular activation markers, and E-selectin expression. Thus, 17 R -RvD1 might represent a new therapeutic strategy for the inflammatory vasculopathy of SCD., (© 2019 by The American Society of Hematology.)

Specialized pro-resolving mediator(s) (SPMs) are produced from the endogenous ω-3 polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and accelerate resolution of acute inflammation. We identified specific clusters of SPM in human plasma and serum using LC-MS/MS based lipid mediator (LM) metabololipidomics in two separate laboratories for inter-laboratory validation. The human plasma cluster consisted of resolvin (Rv)E1, RvD1, lipoxin (LX)B 4 , 18-HEPE, and 17-HDHA, and the human serum cluster consisted of RvE1, RvD1, AT-LXA 4 , 18-HEPE, and 17-HDHA. Human plasma and serum SPM clusters were increased after ω-3 supplementation (triglyceride dietary supplements or prescription ethyl esters) and low dose intravenous lipopolysaccharide (LPS) challenge. These results were corroborated by parallel determinations with the same coded samples in a second, separate laboratory using essentially identical metabololipidomic operational parameters. In these healthy subjects, two ω-3 supplementation protocols (Study A and Study B) temporally increased the SPM cluster throughout the endotoxin-challenge time course. Study A and Study B were randomized and Study B also had a crossover design with placebo and endotoxin challenge. Endotoxin challenge temporally regulated lipid mediator production in human serum, where pro-inflammatory eicosanoid (prostaglandins and thromboxane) concentrations peaked by 8 hours post-endotoxin and SPMs such as resolvins and lipoxins initially decreased by 2 h and were then elevated at 24 hours. In healthy adults given ω-3 supplementation, the plasma concentration of the SPM cluster (RvE1, RvD1, LXB 4 , 18-HEPE, and 17-HDHA) peaked at two hours post endotoxin challenge. These results from two separate laboratories with the same samples provide evidence for temporal production of specific pro-resolving mediators with ω-3 supplementation that together support the role of SPM in vivo in inflammation-resolution in humans.

Resolution of infection and inflammation is governed by innate immune cells. The resolvin family of n-3 mediators produced by resolving exudates stimulates clearance of neutrophils and attenuates pro-inflammatory signals. Using metabololipidomics, endogenous resolvin D3 (RvD3) was identified in self-resolving exudates during active E. coli infection. Through a new, independent synthetic route for RvD3, we matched endogenous and synthetic RvD3 and determined that RvD3 (ng doses) potently reduced the resolution interval (R i ) by ~4.5h during E. coli peritonitis after administration at peak inflammation (T max =12h) and increased leukocyte phagocytosis of E. coli and neutrophils as well as reduced proinflammatory cytokines, chemokines, MMP-2 and MMP-9. At pM-nM concentrations, RvD3 also enhanced human macrophage efferocytosis and bacterial phagocytosis, increased neutrophil bacterial phagocytosis and intracellular ROS generation, and reduced human platelet-PMN aggregation. These results provide additional evidence for potent RvD3 immunoresolvent actions in host defense, host protection and antimicrobial defense., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Metabolomics enables a systems approach to interrogate the bioactive mediators, their pathways and further metabolites involved in the physiology and pathophysiology of human and animal tissues. New metabololipidomic approaches with mass spectrometry presented in this brief review can now be utilized for the identification and profiling of lipid mediator networks that control inflammation-resolution in human blood and healthy and diseased solid tissues. Coagulation of blood is a protective response that prevents excessive bleeding on injury of blood vessels. Here, we review novel approaches to understand the relationship(s) between coagulation and resolution of inflammation and infection. To determine whether coagulation is involved in host-protective actions by lipid mediators, we used a metabololipidomic-based profiling approach with human whole blood (WB) during coagulation. We identified recently temporal clusters of endogenously produced pro-thrombotic and proinflammatory lipid mediators (eicosanoids), as well as specialized proresolving mediators (SPMs) in this vital process. In addition to the classic eicosanoids (prostaglandins, thromboxanes and leukotrienes), a specific SPM cluster was identified that consists of resolvin E1 (RvE1), RvD1, RvD5, lipoxin B 4 , and maresin 1, each of which present at bioactive concentrations (0.1-1 nM). The removal of adenosine from coagulating blood samples significantly enhances SPM amounts and unleashes the biosynthesis of RvD3, RvD4, and RvD6 evident following rapid snap freezing with centrifugation before extraction and LC-MS-MS. The classic cyclooxygenase inhibitors, celecoxib and indomethacin, that block thromboxanes and prostanoids do not block production of the clot-driven SPM cluster. Unbiased mass cytometry analysis demonstrated that the SPM cluster produced in human blood targets leukocytes at the single-cell level, directly activating extracellular signaling in human neutrophils and monocytes. Human whole blood treated with the components of this SPM cluster enhanced both phagocytosis and killing of Escherichia coli by leukocytes. Thus, we identified a pro-resolving lipid mediator circuit and specific SPM cluster that promotes host defense. This new lipid mediator (LM)-SPM metabololipidomic approach now provides accessible metabolomic profiles in healthy and diseased human tissues, including cancer, for precision and personalized medicine., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Anabasum is a synthetic analog of Δ 8 -tetrahydrocannabinol (THC)-11-oic acid that in preclinical models of experimental inflammation exerts potent anti-inflammatory actions with minimal central nervous system (CNS) cannabimimetic activity. Here we used a novel model of acute inflammation driven by i.d. UV-killed E. coli in healthy humans and found that anabasum (5 mg) exerted a potent anti-inflammatory effect equivalent to that of prednisolone in terms of inhibiting neutrophil infiltration, the hallmark of acute inflammation. These effects arose from the inhibition of the neutrophil chemoattractant LTB 4 , while the inhibition of antiphagocytic prostanoids (PGE 2 , TxB 2 , and PGF 2 α) resulted in enhanced clearance of inflammatory stimulus from the injected site. Anabasum at the higher dose of 20 mg possessed the additional properties of triggering the biosynthesis of specialized pro-resolving lipid mediators including LXA 4 , LXB 4 , RvD1, and RvD3. Collectively, we demonstrate for the first time a striking anti-inflammatory and pro-resolution effects of a synthetic analog of THC in healthy humans., (© 2017 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Psoriasis (PSO) is an immune-mediated inflammatory disease associated with metabolic and cardiovascular comorbidities. It is now known that resolution of inflammation is an active process locally controlled by specialized proresolving mediators (SPMs), named resolvins (Rvs), protectins, and maresins., Objective: It is unknown whether these potent lipid mediators (LMs) are involved in PSO pathophysiology and if the skin and blood have disease-specific SPMs phenotype profiles., Methods: We used liquid chromatography-tandem mass spectrometry-based LM metabololipidomics to obtain skin and peripheral blood LM profiles from PSO compared to healthy subjects. Some LMs were tested in cell culture experiments with corresponding gene expression and protein concentration analyses., Results: The levels of several LM were significantly elevated in lesional PSO skin compared to nonlesional and skin from healthy subjects. Particularly, RvD5, protectins Dx, and aspirin-triggered forms of lipoxin were present only in lesional PSO skin, whereas protectin D1 was present in nonlesional PSO skin. To determine specific roles of SPMs on skin-related inflammatory cytokines, RvD1 and RvD5 were incubated with human keratinocytes. RvD1 and RvD5 reduced the expression levels of interleukin 24 and S100A12, whereas only RvD1 significantly abrogated interleukin-24 production by keratinocytes., Conclusions: These findings suggest that an imbalance between locally produced proresolution and proinflammatory LMs identified in PSO skin and blood compartments might play a role in PSO pathophysiology. Moreover, some of the PSO-related cytokines can be modified by specific SPMs and involved mechanisms support investigation of targeting novel proresolving lipid mediators as a therapy for PSO., (Published by Elsevier Inc.)

Resolvin conjugates in tissue regeneration (RCTRs) are new chemical signals that accelerate resolution of inflammation, infection, and tissue regeneration. Herein, using liquid chromatography-tandem mass spectrometry-based metabololipidomics, we identified RCTRs in human spleen, lymph node, bone marrow, and brain. In human spleen incubated with Staphylococcus aureus, endogenous RCTRs were increased along with conversion of deuterium-labeled docosahexaenoic acid, conferring pathway activation. Physical and biological properties of endogenous RCTRs were matched with those prepared by total organic synthesis. The complete stereochemical assignment of bioactive RCTR1 is 8R-glutathionyl-7S,17S-dihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid, RCTR2 is 8R-cysteinylglycinyl-7S,17S-dihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid, and RCTR3 is 8R-cysteinyl-7S,17S-dihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid. These stereochemically defined RCTRs stimulated human macrophage phagocytosis, efferocytosis, and planaria tissue generation. Proteome profiling demonstrated that RCTRs regulated both proinflammatory and anti-inflammatory cytokines with human macrophages. In microfluidic chambers, the three RCTRs limited human polymorphonuclear cell migration. In hind-limb ischemia-reperfusion-initiated organ injury, both RCTR2 and RCTR3 reduced polymorphonuclear cell infiltration into lungs. In infectious peritonitis, RCTR1 shortened the resolution intervals. Each RCTR (1 nmol/L) accelerated planaria tissue regeneration by approximately 0.5 days, with direct comparison to both maresin and protectin CTRs. Together, these results identify a new bioactive RCTR (ie, RCTR3) in human tissues and establish the complete stereochemistry and rank-order potencies of three RCTRs in vivo. Moreover, RCTR1, RCTR2, and RCTR3 each exert potent anti-inflammatory and proresolving actions with human leukocytes., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The mineral sulfide-oxidising Acidithiobacillus ferrooxidans has been extensively studied over many years but some fundamental aspects of its metabolism remain uncertain, particularly with regard to its anaerobic oxidation of sulfur. This label-free, liquid chromatography-electron spray ionisation-mass spectrometry-based proteomic analysis estimated relative protein abundance during aerobic and anaerobic growth of At. ferrooxidans. One of its two bc1 complexes, that encoded by the petII operon, was strongly implicated in anaerobic ferric iron-coupled sulfur oxidation, probably in conjunction with two cytochromes. These two cytochromes are homologs of the Cyc2 and Cyc1 proteins that are involved in ferrous iron oxidation. The previously undetected cytochromes apparently associated with anaerobic growth in At. ferrooxidans appear to be absent in many other ferrous iron-oxidising acidophiles that can also reduce ferric iron, which suggests a diversity in the ferric-iron-coupled sulfur oxidation pathways. For aerobic growth of At. ferrooxidans, this analysis was consistent with the generally accepted mechanism for its oxidation of ferrous iron. Unexpectedly, proteins encoded by the petI operon were not abundant and generally not detected in the proteomic analyses of cells grown aerobically on sulfur, although there was some expression of genes of the petI and petII operons in these cells.

Local production and downstream metabolism of specialized proresolving lipid mediators (SPMs) are pivotal in regulating their biological actions during resolution of inflammation. Resolvin D4 (RvD4: 4S,5R,17S-trihydroxydocosa-6E,8E,10Z,13Z,15E,19Z hexaenoic acid) is one of the more recently elucidated SPMs with complete stereochemistry biosynthesized from docosahexaenoic acid . Here, we report a new multimilligram commercial synthesis that afforded enough material for matching, validation, and further evaluation of RvD4 functions. Using LC-MS-MS profiling, RvD4 was identified at bioactive amounts in human (1 pg/mL) and mouse bone marrow (12 pg/femur and tibia). In mouse bone marrow, ischemia increased the formation of RvD4 > 37-fold (455 pg/femur and tibia). Two separate mouse ischemic injury models were used, where RvD4 reduced second organ reperfusion lung injury > 50%, demonstrating organ protection. Structure-function relationships of RvD4 demonstrated > 40% increase in neutrophil and monocyte phagocytic function in human whole blood in comparison with 2 separate trans-containing double bond isomers that were inactive. These 2 isomers were prepared by organic synthesis: 4S,5R,17S-trihydroxydocosa-6E,8E,10E,13Z,15E,19Z-hexaenoic acid (10-trans-RvD4), a natural isomer, and 4S,5R,17S-trihydroxydocosa-6E,8E,10E,13E,15E,19Z-hexaenoic acid (10,13-trans-RvD4), a rogue isomer. Compared to leukotriene B 4 , D-series resolvins (RvD1, RvD2, RvD3, RvD4, or RvD5) did not stimulate human neutrophil chemotaxis monitored via real-time microfluidics chambers. A novel 17-oxo-containing-RvD4 product of eicosanoid oxidoreductase was identified with human bone marrow cells. Comparison of 17-oxo-RvD4 to RvD4 demonstrated that with human leukocytes 17-oxo-RvD4 was inactive. Together, these provide commercial-scale synthesis that permitted a second independent validation of RvD4 complete stereochemical structure as well as evidence for RvD4 regulation in tissues and its stereoselective phagocyte responses., (©2018 Society for Leukocyte Biology.)

Proinflammatory eicosanoids (prostaglandins and leukotrienes) and specialized pro-resolving mediators (SPM) are temporally regulated during infections. Here we show that human macrophage phenotypes biosynthesize unique lipid mediator signatures when exposed to pathogenic bacteria. E. coli and S. aureus each stimulate predominantly proinflammatory 5-lipoxygenase (LOX) and cyclooxygenase pathways (i.e., leukotriene B 4 and prostaglandin E 2 ) in M1 macrophages. These pathogens stimulate M2 macrophages to produce SPMs including resolvin D2 (RvD2), RvD5, and maresin-1. E. coli activates M2 macrophages to translocate 5-LOX and 15-LOX-1 to different subcellular locales in a Ca 2+ -dependent manner. Neither attenuated nor non-pathogenic E. coli mobilize Ca 2+ or activate LOXs, rather these bacteria stimulate prostaglandin production. RvD5 is more potent than leukotriene B 4 at enhancing macrophage phagocytosis. These results indicate that M1 and M2 macrophages respond to pathogenic bacteria differently, producing either leukotrienes or resolvins that further distinguish inflammatory or pro-resolving phenotypes.

Rationale: Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a major public health concern with high mortality and morbidity. Although inflammatory responses triggered by infection are crucial for host defense against invading microbes, the excessive inflammation often causes tissue damage leading to organ dysfunction. Resolution of inflammation, an active immune process mediated by endogenous lipid mediators (LMs), is important to maintain host homeostasis., Objectives: We sought to determine the role of the nucleotide-binding domain, leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3) inflammasome in polymicrobial sepsis and regulation of LM biosynthesis., Methods: We performed cecal ligation and puncture (CLP) using mice lacking NLRP3 inflammasome-associated molecules to assess mortality. Inflammation was evaluated by using biologic fluids including plasma, bronchoalveolar, and peritoneal lavage fluid. Local acting LMs in peritoneal lavage fluid from polymicrobacterial septic mice were assessed by mass spectrometry-based metabololipidomics., Measurements and Main Results: Genetic deficiency of NLRP3 inhibited inflammatory responses and enhanced survival of CLP-induced septic mice. NLRP3 deficiency reduced proinflammatory LMs and increased proresolving LM, lipoxin B 4 (LXB 4 ) in septic mice, and in macrophages stimulated with LPS and ATP. Activation of the NLRP3 inflammasome induced caspase-7 cleavage and pyroptosis. Caspase-7 deficiency similarly reduced inflammation and mortality in CLP-induced sepsis, and increased LXB 4 production in vivo and in vitro. Exogenous application of LXB 4 reduced inflammation, pyroptosis, and mortality of mice after CLP., Conclusions: Genetic deficiency of NLRP3 promoted resolution of inflammation in polymicrobial sepsis by relieving caspase-7-dependent repression of LXB 4 biosynthesis, and increased survival potentially via LXB 4 production and inhibition of proinflammatory cytokines.

Specialized pro-resolving mediators (SPM), e.g. Resolvin D1, Protectin D1, Lipoxin A₄, and Resolvin E1 have each shown to be active in ocular models reducing inflammation. In general, SPMs have specific agonist functions that stimulate resolution of infection and inflammation in animal disease models. The presence and quantity of SPM in human emotional tears is of interest. Here, utilizing a targeted LC-MS-MS metabololipidomics based approach we document the identification of pro-inflammatory (Prostaglandins and Leukotriene B₄) and pro-resolving lipid mediators (D-series Resolvins, Protectin D1, and Lipoxin A₄) in human emotional tears from 12 healthy individuals. SPMs from the Maresin family (Maresin 1 and Maresin 2) were not present in these samples. Principal Component Analysis (PCA) revealed gender differences in the production of specific mediators within these tear samples as the SPMs were essentially absent in these female donors. These results indicate that specific SPM signatures are present in human emotional tears at concentrations known to be bioactive. Moreover, they will help to further appreciate the mechanisms of production and action of SPMs in the eye, as well as their physiologic roles in human ocular disease resolution., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Pulmonary arterial (PA) stiffness is associated with increased mortality in patients with pulmonary hypertension (PH); however, the role of PA stiffening in the pathogenesis of PH remains elusive. Here, we show that distal vascular matrix stiffening is an early mechanobiological regulator of experimental PH. We identify cyclooxygenase-2 (COX-2) suppression and corresponding reduction in prostaglandin production as pivotal regulators of stiffness-dependent vascular cell activation. Atomic force microscopy microindentation demonstrated early PA stiffening in experimental PH and human lung tissue. Pulmonary artery smooth muscle cells (PASMC) grown on substrates with the stiffness of remodeled PAs showed increased proliferation, decreased apoptosis, exaggerated contraction, enhanced matrix deposition, and reduced COX-2-derived prostanoid production compared with cells grown on substrates approximating normal PA stiffness. Treatment with a prostaglandin I 2 analog abrogated monocrotaline-induced PA stiffening and attenuated stiffness-dependent increases in proliferation, matrix deposition, and contraction in PASMC. Our results suggest a pivotal role for early PA stiffening in PH and demonstrate the therapeutic potential of interrupting mechanobiological feedback amplification of vascular remodeling in experimental PH.

Analysis of phylogenomic metrics of a recently released draft genome sequence of the halotolerant, acidophile 'Thiobacillus prosperus' DSM 5130 indicates that it is not a member of the genus Thiobacillus within the class Betaproteobacteria as originally proposed. Based on data from 16S rRNA gene phylogeny, and analyses of multiprotein phylogeny and average nucleotide identity (ANI), we show that it belongs to a new genus within the family Ectothiorhodospiraceae, for which we propose the name Acidihalobacter gen. nov. In accordance, it is proposed that 'Thiobacillus prosperus' DSM 5130 be named Acidihalobacter prosperus gen. nov., sp. nov. DSM 5130T ( = JCM 30709T) and that it becomes the type strain of the type species of this genus.

Unlabelled: Pharmacologic and global gene deletion studies demonstrate that cyclooxygenase-2 (PTGS2/COX-2) plays a critical role in DMBA/TPA-induced skin tumor induction. Although many cell types in the tumor microenvironment express COX-2, the cell types in which COX-2 expression is required for tumor promotion are not clearly established. Here, cell type-specific Cox-2 gene deletion reveals a vital role for skin epithelial cell COX-2 expression in DMBA/TPA tumor induction. In contrast, myeloid Cox-2 gene deletion has no effect on DMBA/TPA tumorigenesis. The infrequent, small tumors that develop on mice with an epithelial cell-specific Cox-2 gene deletion have decreased proliferation and increased cell differentiation properties. Blood vessel density is reduced in tumors with an epithelial cell-specific Cox-2 gene deletion, compared with littermate control tumors, suggesting a reciprocal relationship in tumor progression between COX-2-expressing tumor epithelial cells and microenvironment endothelial cells. Lipidomics analysis of skin and tumors from DMBA/TPA-treated mice suggests that the prostaglandins PGE2 and PGF2α are likely candidates for the epithelial cell COX-2-dependent eicosanoids that mediate tumor progression. This study both illustrates the value of cell type-specific gene deletions in understanding the cellular roles of signal-generating pathways in complex microenvironments and emphasizes the benefit of a systems-based lipidomic analysis approach to identify candidate lipid mediators of biologic responses., Implications: Cox-2 gene deletion demonstrates that intrinsic COX-2 expression in initiated keratinocytes is a principal driver of skin carcinogenesis; lipidomic analysis identifies likely prostanoid effectors., (©2014 American Association for Cancer Research.)

Background: Intralymphatic histiocytosis (IH) is a rare condition often associated with systemic disease. A benign condition, clinical presentations can vary greatly and its cause is largely unknown. Histologically, there are macrophages within distended lymphatic vessels, although this can be an incidental finding or the primary abnormality., Objective: We present a series of 7 cases of IH with and without disease associations, and a review of the literature. We propose IH as either primary (without associated conditions) or secondary (associated with systemic disease)., Methods: This was a retrospective collection of patients whose skin biopsy specimens revealed intralymphatic collections of histiocytes. We reviewed their clinical presentation, disease associations, and staining of slides with CD68 in all cases, D2-40 in 5 cases, and HLA-DR in 4 cases., Results: Clinical features were highly variable, and not all cases were associated with systemic disease. One case had admixed reactive angioendotheliomatosis. All 4 cases stained for HLA-DR showed strong expression by the intralymphatic macrophages., Limitations: Retrospective analysis and limited numbers are limitations., Conclusion: IH is not always associated with systemic disease although macrophage activation nevertheless implies immune activation., (Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Macrophages are central to essential physiological processes including the regulation of innate and adaptive immunity, but they are also central to a number of inflammatory disease states. These immune cells also possess remarkable plasticity and display various shades of functionalities based on changes in the surrounding molecular environment. Macrophage biology has defined various phenotypes and roles in inflammation based primarily on cytokine and chemokine profiles of cells in different activation states. Importantly, macrophages are elite producers of eicosanoids and other related lipid mediators during inflammation, but specific roles of these molecules have not generally been incorporated into the larger context of macrophage biology. In this review, we discuss the current classification of macrophage types and their roles in inflammation and disease, along with the practical challenges of studying biologically relevant phenotypes ex vivo. Using the latest advances in eicosanoid lipidomics, we highlight several key studies from our laboratory that provide a comprehensive understanding of how eicosanoid metabolism differs between macrophage phenotypes, along with how this metabolism is altered by changes in membrane fatty acid distribution and varied durations of Toll-like receptor (TLR) priming. In conclusion, we summarize several examples of the benefit of macrophage plasticity to develop accurate cellular mechanisms of lipid metabolism, and insights from lipidomic analyses about the differences in eicosanoid pathway enzyme activity in vitro vs. in cells ex vivo. Examples of new techniques to further understand the role of macrophage eicosanoid signaling in vivo are also discussed., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The deep circumflex iliac artery (DCIA) flap is often used for mandibular reconstruction but it is bulky and causes additional donor-site morbidity because of the inclusion of an "obligatory internal oblique muscle". Large composite segmental mandibular resections that consist of floor of mouth, subtotal tongue, and adjacent facial skin are a challenge in terms of reconstruction. They often require 2 free flaps or a free scapular flap and both have disadvantages. The deep circumflex iliac artery perforator (DCIAP) flap with a cutaneous component overcomes the disadvantages. We describe reconstructions with DCIAP flaps in 3 patients with large mandibular composite segmental defects. We report our experience of the flap and discuss some of the difficulties we encountered and the points we learned perioperatively., (Copyright © 2013. Published by Elsevier Ltd.)

Some novel actinobacteria from geothermal environments were shown to grow autotrophically with sulfur as an energy source. These bacteria have not been formally named and are referred to here as "Acidithiomicrobium" species, as the first of the acidophilic actinobacteria observed to grow on sulfur. They are related to Acidimicrobium ferrooxidans with which they share a capacity for ferrous iron oxidation. Ribulose bisphosphate carboxylase/oxygenase (RuBisCO) is active in CO(2) fixation by Acidimicrobium ferrooxidans, which appears to have acquired its RuBisCO-encoding genes from the proteobacterium Acidithiobacillus ferrooxidans or its ancestor. This lateral transfer of RuBisCO genes between a proteobacterium and an actinobacterium would add to those noted previously among proteobacteria, between proteobacteria and cyanobacteria and between proteobacteria and plastids. "Acidithiomicrobium" has RuBisCO-encoding genes which are most closely related to those of Acidimicrobium ferrooxidans and Acidithiobacillus ferrooxidans, and has additional RuBisCO genes of a different lineage. 16S rRNA gene sequences from "Acidithiomicrobium" species dominated clone banks of the genes extracted from mixed cultures of moderate thermophiles growing on copper sulfide and polymetallic sulfide ores in ore leaching columns.

Malakoplakia that presents in the head and neck is rare. We describe a case in a man who presented with a fungating mass in the periauricular skin that was thought to be a malignant tumour. Histopathological and microbiological investigations established a diagnosis of malakoplakia., (Copyright 2009 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Drospirenone (DRSP) is a novel progestin with aldosterone receptor antagonist activity developed for hormone therapy as DRSP /17-beta estradiol (DRSP/E2). Because of a significant aldosterone antagonist activity, we studied the effects of DRSP/E2 on serum potassium (K) and blood pressure (BP) in hypertensive postmenopausal women with and without diabetes mellitus., Methods: This was a multicenter trial in postmenopausal women 44 to 70 years of age, either with type 2 diabetes mellitus (n = 82) or without type 2 diabetes mellitus (n = 148) and using an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist. Patients were randomized to 28 days of DRSP/E2 or placebo. Study endpoints were the number and percentage subjects who developed hyperkalemia (K >or= 5.5 mEq/L) and changes from baseline in clinic systolic and diastolic BP. To increase the likelihood of unmasking hyperkalemia, the nondiabetic group was also administered ibuprofen for 5 days., Results: There were no statistical differences in the overall number and percentage of subjects with hyperkalemia for DRSP/E2 versus placebo. No subject had symptoms or electrocardiographic changes related to hyperkalemia. Blood pressure was reduced by -8.6/-5.8 mm Hg in patients receiving DRSP/E2 versus -3.7/-2.9 mm Hg in those receiving placebo (P < .01 for both SBP and DBP)., Conclusions: In hypertensive postmenopausal women, treatment with DRSP/E2 was not associated with a greater incidence of hyperkalemia than with placebo in patients with and without type 2 diabetes mellitus and concomitant use of ACE inhibitors, angiotensin receptor antagonists, or ibuprofen. Furthermore, DRSP/E2 was found to have a significant antihypertensive effect in this high-risk population.

Modernisation has brought down outpatient waits and did-not-attends at Addenbrooke Hospital's dermatology department. A 360-degree review of services has led to continuous service Improvement. GPs and hospital nurses have received specialist training, freeing up consultant time and enabling more consultants to be seen.

A new species of ferrous-iron-oxidizing, moderately thermophilic, acidophilic bacteria, Acidimicrobium ferrooxidans , has been described. Two isolates of the species differed only in the tendency of one, previously known as strain TH3, to grow in filaments. The chromosomal DNA base composition is between 67 and 69 mol% G + C. The capacity of this species to fix CO 2 from air was greater than that of iron-oxidizing thermoacidophiles of the genus Sulfobacillus , which required an enhanced CO 2 concentration for optimum autotrophic growth. Under air, ferrous iron oxidation in mixed cultures of A. ferrooxidans with either Sulfobacillus thermosulfidooxidans or Sulfobacillus acidophilus was more extensive than in pure cultures of these three strains. The greater part of ferrous iron oxidation in mixed cultures probably resulted from activity of the Sulfobacillus species, which possess a greater tolerance of ferric iron, and which presumably grew mixotrophically utilizing organic compounds from A. ferrooxidans .

Several isolates of Gram-positive, acidophilic, moderately thermophilic, ferrous-iron- and mineral-sulphide-oxidizing bacteria were examined to establish unequivocally the characteristics of Sulfobacillus-like bacteria. Two species were evident: Sulfobacillus thermosulfidooxidans with 48-50 mol% G+C and Sulfobacillus acidophilus sp. nov. with 55-57 mol% G+C. Both species grew autotrophically and mixotrophically on ferrous iron, on elemental sulphur in the presence of yeast extract, and heterotrophically on yeast extract. Autotrophic growth on sulphur was consistently obtained only with S. acidophilus.