Catherine M. McGrath

Direct measurement of the high-spin and low-spin bond lengths and the spin state population in mixed spin state systems: an Fe K-edge XAFS study of iron(III) dithiocarbamate complexes

Abstract A combination of Fe K-edge XAFS and advanced data analysis methods has been used to determine the Fe–S distances and spin state population in iron(III) dithiocarbamate spin crossover complexes. This new approach allows for the first direct determination of Fe–S bond lengths (2.44(2) A high-spin, 2.30(2) A low-spin) for both spin state isomers in mixed spin systems in contrast to single crystal X-ray crystallographic determinations where only the weighted average of the HS and LS values is observed. The agreement between XAFS and magnetic susceptibility derived values of the spin state populations is very good.

Pathomx: an interactive workflow-based tool for the analysis of metabolomic data

BackgroundMetabolomics is a systems approach to the analysis of cellular processes through small-molecule metabolite profiling. Standardisation of sample handling and acquisition approaches has contributed to reproducibility. However, the development of robust methods for the analysis of metabolomic data is a work-in-progress. The tools that do exist are often not well integrated, requiring manual data handling and custom scripting on a case-by-case basis. Furthermore, existing tools often require experience with programming environments such as MATLAB® or R to use, limiting accessibility. Here we present Pathomx, a workflow-based tool for the processing, analysis and visualisation of metabolomic and associated data in an intuitive and extensible environment.ResultsThe core application provides a workflow editor, IPython kernel and a HumanCyc™-derived database of metabolites, proteins and genes. Toolkits provide reusable tools that may be linked together to create complex workflows. Pathomx is released with a base set of plugins for the import, processing and visualisation of data. The IPython backend provides integration with existing platforms including MATLAB® and R, allowing data to be seamlessly transferred. Pathomx is supplied with a series of demonstration workflows and datasets. To demonstrate the use of the software we here present an analysis of 1D and 2D 1H NMR metabolomic data from a model system of mammalian cell growth under hypoxic conditions.ConclusionsPathomx is a useful addition to the analysis toolbox. The intuitive interface lowers the barrier to entry for non-experts, while scriptable tools and integration with existing tools supports complex analysis. We welcome contributions from the community.

Lipid and Metabolic Changes in Rheumatoid Arthritis

While the most obvious manifestations of rheumatoid arthritis (RA) involve inflammation and damage in the synovial joints, the systemic effects of the condition are widespread and life-threatening. Of particular interest is the ‘lipid paradox’ of RA, where patients with a numerically equivocal starting lipid profile have a significantly raised risk of cardiovascular (CV) events and response to therapy results in a ‘normalization’ of lipid levels and reduction in events. Changes in lipids can be seen before overt disease manifestations which suggest that they are closely linked to the more widespread inflammation-driven metabolic changes associated with tumour necrosis factor (TNF). Cachexia involves a shift in body mass from muscle to fat, which may or may not directly increase the cardiovascular risk. However, since TNF inhibition is associated with reduction in cardiovascular events, it does suggest that these widespread metabolic changes involving lipids are of importance. Analysis of single lipids or metabolites have been used to identify some of the key changes, but more recently, metabolomic and lipidomic approaches have been applied to identify a broad spectrum of small molecule changes and identify potentially altered metabolic pathways. Further work is needed to understand fully the metabolic changes in lipid profiles and identify novel ways of targeting desired profile changes, but work so far does suggest that a better understanding may allow management of patients to downregulate the systemic effects of their disease that puts them at risk of cardiovascular complications.

Synthesis of the first lanthanide complexes of dialkyl α-hydroxyiminophosphonates; ambivalent ligand bonding in the PrIII and NdIII complexes of diisopropyl α-hydroxyiminopropylphosphonate (L1), [PrL13Cl3] and [NdL12(NO3)3(H2O)]

Lanthanide complexes of dialkyl α-hydroxyiminophosphonates (RO)2P(O)C(R′)N(OH)(L1–L3), where R = Et or Pri and R′= Me or Et, have been prepared for the first time; the crystal structures of two complexes of L1(R = Pri, R′= Et) have been determined, showing nine-co-ordination geometry in both cases with asymmetric bidentate ligands in [PrL13Cl3] and monodentate bonding in [NdL12(NO3)3(H2O)] demonstrating that the ambivalent nature of the new ligands allow formation of neutral complexes.

Metabolomics in rheumatology

The musculoskeletal system is a highly active metabolic system. Energy consumption is driven by the combined demands of skeletal muscle, turnover and remodelling of bone, cartilage and other structural components in response to changing levels of loading. The high-energy respiratory chain is estimated to result in the turnover of 65 kg/day of adenosine triphosphate for the whole body, increasing during periods of activity [1]. With skeletal muscle accounting for 30% of body mass in a postmenopausal woman (and more in men), it is perhaps not surprising then that changes in metabolic activity are observed in musculoskeletal disease. Overall resting energy use is increased by 8% in RA patients and, interestingly, a similar increase in metabolic activity is seen in patients who smoke, a well-established risk factor for the development of RA [2]. The mechanism underlying this increase in energy metabolism is unclear, but the active role of the immune system in the inflammatory processes in RA suggests that immune cell activation and turnover may contribute. There are also significant changes in liver metabolism as a result of the acute phase response and large shifts in systemic metabolism as a result of rheumatoid cachexia, where muscle degradation occurs along with the related increase in the mass of body fat. Many of these metabolic changes can pre-date obvious joint symptoms, and metabolic pathways may change in response to therapy. It is not surprising therefore that there is increasing interest in using altered metabolites as biomarkers of disease activity and response to therapy. These studies may also provide novel insights into the pathological processes driving complex musculoskeletal diseases. RA was first associated with altered levels of individual metabolites in a report from 1962 describing changes in the metabolism of tryptophan [3]. In recent years a more broad-ranging approach, metabolomics, has been applied to assessment of the disease. Metabolomics is the new kid on the omics block and comparable in scope to genomics, transcriptomics and proteomics. Through the study of small molecules (<1500 Da) within specific or multiple compartments (blood, urine, joints, saliva, eyes, tears, cerebrospinal fluid, intact cells), metabolite profiles or fingerprints, each containing thousands of metabolites, can be identified. In individuals at risk due to genetics, their environment or both, disruptive pathological processes can result in altered metabolite profiles long before overt signs and symptoms of disease appear. The metabolites themselves can be identified and quantified using NMR spectroscopy or mass spectrometry. Metabolite identification is done by reference to metabolite databases or by direct metabolite assay. The Human Metabolome Database lists >41 000 metabolite entries in the latest version, however, just 3000 have been linked with diseases to date [4]. In common with other omics approaches, metabolomics experiments generate prodigious amounts of data, but this is amenable to multivariate analysis techniques, including principal components analysis, partial least squares discriminant analysis, regression methods and genetic algorithms. Metabolomics studies have been reported for virtually all of the main rheumatologic diseases, although notably none yet for SSc [5]. Our own group has demonstrated the use of urinary metabolic fingerprint analysis to predict responses to anti-TNF [6], and we have suggested that metabolites resulting from TNF-driven cachexia are among the useful predictive biomarkers. Serum metabolic profiling can differentiate four types of human arthritis [7], and we have shown the predictive value of the serum metabolite profile in early synovitis patients, with differences between those with self-limiting disease and those who went on to develop persistent RA [8]. The value of combining omics approaches has been demonstrated in a study using proteomics and metabolomics to show alterations in both vitamin D3 metabolites and proteins in patients with AS [9]. The combination of genetic and metabolomic data [10] has shown the potential to identify genotype-influenced metabotypes in a number of chronic diseases. Different cells types vary in their energy and metabolic requirements, with cells undergoing proliferation being very different from those in a stable steady state. This applies to tissue cells such as synovial stroma and to immune cells including macrophages and T lymphocytes. Thus the state of immune activation and tissue hyperplasia may be strongly reflected in the metabolic profiles observed in tissues and in biofluids from patients, providing useful insights into the state of the disease and its aetiopathology. Comprehensive clinical assessment approaches used by BILAG and SLEDAI offer a clinical approach to individualized systems medicine by objectively quantifying components in a disease. Transcriptomics, proteomics and metabolomics are the biological equivalents of these clinical assessments. However, the sole analysis of tissues from the specific site of disease will miss the systemic changes commonly associated with complex diseases that may be responsible for driving the persistence and much of the associated co-morbidity.

Addressing DRESS (drug reaction with eosinophilia and systemic symptoms)

SummaryThe syndrome of drug reaction with eosinophilia and systemic symptoms (DRESS) is the manifestation of a severe idiosyncratic drug-induced reaction with variable latency period. DRESS occurs in one in 1000 to one in 10 000 of drug exposures with high rates of long-term sequelae and mortality of around 10%. There are several classes of drugs historically associated with DRESS – aromatic antiepileptics such as carbamazepine and related compounds, nonsteroidal anti-inflammatory drugs, antiretroviral drugs and antibiotics as well as drugs such as sulfasalazine, allopurinol and dapsone. There is growing recognition of the role of genetic predisposition. Implicated alleles can sometimes be used for predrug screening. DRESS can be associated with reactivation of human herpes viruses, which may be important in a prolonged and severe disease course. Prompt recognition of DRESS, withdrawal of the suspect drug under clinical supervision and supportive care are vital.

A study of the soft X-ray photoreduction of [NiIV(S2CNEt2)3][BF4] and soft X-ray photoisomerisation of [PPh4][NiII(S2COEt)3] at the Ni L-edge†

A detailed study of the soft X-ray photochemistry occurring in some nickel dithiocarbamate and xanthate complexes has shown that soft X-ray induced photoreduction of [NiIV(S2CNEt2)3][BF4] results in a NiII square-planar species and the rate is dependent on photon flux, photon energy and ligand set, but is essentially independent of temperature. Also, it has been demonstrated that [PPh4][NiII(S2COEt)3] is photoisomerised to a NiII square-planar species on exposure to soft X-rays. The implication for experiments on third generation synchrotron sources is discussed briefly.

First structural characterisation of an amino phosphonate monoester metal complex

A new type of tetradentate amino phosphonate monoester has been synthesized by alkaline hydrolysis of the parent phosphonate diester; the crystal structure of its copper complex reveals a monoester ligand-bridged centrosymmetric dimeric five-co-ordinate copper(II) complex.

49. Schnitzler syndrome: a case of chronic urticaria and monoclonal gammopathy

extremityof the lower limb. Inourcase,only the footandankle regionwas affected, with both feet being affected at different points of time. Recurrence of episodes have been described in the literature, and can affect different anatomical sites. This was the case for our patient, but specifically affected the distal limb on each occasion rather than more commonproximalsites.Episodeshadbeenrelatively frequentalso inour patient,withmultipleepisodesover thepreceding1tenyears -whichalso appears to be an atypical phenomenon.Due to the location of symptoms atthepatient’s feet,her recurrentepisodeshadbeenessentiallymisdiagnosed as prolonged gout flares, thus leading to delayed diagnosis. Unfortunately,basedon the literature, this isamore commonexperience in patients with foot involvement due to its lower frequency and nonspecificnature.Assuch,patientsareatriskofpersistentbonepainsymptomswhichcanaffect functionandsubsequentqualityof life. Key Learning Points: Bone marrow oedema syndrome is a rare condition that can often be missed. Symptoms can be transient in nature with patients not presenting, or being misdiagnosed with alternative conditions. In our described case, the patient’s episode was prolonged thus allowing appropriate investigation. Cases are generally managed conservatively, however gradual resolution can take weeks to months to occur. Literature is limited in regarding medical therapy, however use of bisphosphonates has been described and was utilised in this case. Our patient isundergoingcontinuedfollowupwithin thecommunityunder the rheumatologyteamtomonitorhergradual recovery. Disclosure: S. El-Ghazali: None. K. Bhamra: None. A. Khan: None. M. Burden:None. I.Patel:None.

13. Progress of Pregnancies in a Patient with Previously Treated Thrombotic Thrombocytopaenic Purpura and Lupus

and had gone through two successful pregnancies previously with no problems. Case description: 34 year old patient presented to us through the combined Medical and Obstetric clinic and the Respiratory team when she presented acutely short of breath during 22nd week of her third pregnancy. She had previously had two children 18 and 14 years of age and hadnomajorproblems through thosepregnancies.ShehadaCTPAsuspecting pulmonary embolism which showed no evidence of PE but enlarged pulmonary arteries. This lead to an Echocardiogram which showedevidenceofPulmonaryHypertensionwithdilatedrightheart indicating decompensation. The estimated pulmonary artery pressure was 60mmHg. She was managed as probable primary pulmonary hypertensionanddeliveredtwinsspontaneouslyat28weeks.Herbreathingimprovedpost-partum,butshecontinuedtobeshortofbreathonexertion. This prompted further investigation and a Rheumatology referral. Further questioning revealedhistoryofRaynauds,paraesthesiaof fingers andtoes,markedalopecia,familyhistoryofotherautoimmuneconditions. ANA revealed positive RNP and she was treated as probable MCTD or RNPvariant lupus.Possibilityofmyocarditisandpulmonaryhypertension with rapid progression prompted aggressive treatment with IV Cyclophosphamide, steroids and Iloprost. Unfortunately over a period of time her pulmonary hypertension worsened and she was referred to Pulmonary Vascular centre at Newcastle. After a period of IV Iloprost, she was added to the lung transplant list. She had successful bilateral lung transplant in 2013. Her pulmonary artery pressure improved dramatically and though she developed multiple other complications following the transplantherprimaryproblemimprovedsignificantly. Discussion: This case was a very interesting one that we would like to share with our Rheumatology colleagues due to the rapidity of development of pulmonary hypertension in a patient with very limited symptoms otherwise. The rapid progression and need for lung transplant was also a significantfeatureofthecase. Key learning points: The key learning points were the importance of looking for signs and symptoms of CTD in acute presentation of pulmonary hypertension especially during pregnancy. Management of these patientsandthepotential requirementof lung transplant in thesepatients isanimportant learningpointaswell.