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In this cross sectional study from a large UK centre, screening for mental illness in individuals with psoriasis has demonstrated a high burden of depression and anxiety. 85% of the cohort report that their psoriasis had affected their quality of life. Quality of life scores correlate with depression scores, emphasing the importance of managing individual's mental health alongside their psoriasis to improve overall quality of life.

BackgroundThe COVID-19 pandemic disrupted healthcare and may have impacted ethnic inequalities in healthcare. We aimed to describe the impact of pandemic-related disruption on ethnic differences in clinical monitoring and hospital admissions for non-COVID conditions in England.MethodsWe conducted a cohort study using OpenSAFELY (2018-2022). We grouped ethnicity (exposure), into five categories: White, South Asian, Black, Other, Mixed. We used interrupted time-series regression to estimate ethnic differences in clinical monitoring frequency (e.g., blood pressure measurements) before and after 23rd March 2020. We used multivariable Cox regression to quantify ethnic differences in hospitalisations related to: diabetes, cardiovascular disease, respiratory disease, and mental health before and after 23rd March 2020.FindingsOf 14,930,356 adults in 2020 with known ethnicity (92% of sample): 86.6% were White, 7.3% Asian, 2.6% Black, 1.4% Mixed ethnicity, and 2.2% Other ethnicities. Clinical monitoring did not return to pre-pandemic levels for any ethnic group. Ethnic differences were apparent pre-pandemic, except for diabetes monitoring, and remained unchanged, except for blood pressure monitoring in those with mental health conditions where differences narrowed during the pandemic. For those of Black ethnicity, there were seven additional admissions for diabetic ketoacidosis per month during the pandemic, and relative ethnic differences narrowed during the pandemic compared to White. There was increased admissions for heart failure during the pandemic for all ethnic groups, though highest in White ethnicity. Relatively, ethnic differences narrowed for heart failure admission in those of Asian and Black ethnicity compared to White. For other outcomes the pandemic had minimal impact on ethnic differences.InterpretationOur study suggests ethnic differences in clinical monitoring and hospitalisations remained largely unchanged during the pandemic for most conditions. Key exceptions were hospitalisations for diabetic ketoacidosis and heart failure, which warrant further investigation to understand the causes.FundingLSHTM COVID-19 Response Grant (DONAT15912).Research in contextEvidence before this studyWe searched MEDLINE from inception to 7th September 2022, for articles published in English, including the title/abstract search terms (healthcare disruption OR indirect impact OR miss* diagnos* OR delayed diagnos* OR service disruption) AND (sars-cov-2 OR covid-19 OR pandemic OR lockdown) AND (ethnic*). Of the seven studies identified, two broadly investigated the indirect impacts of the pandemic on non-COVID outcomes and reported ethnic differences. However, these two only included data until January 2021 at the latest. Other studies investigated just one disease area such as dementia or diabetes and frequently did not have the power to investigate specific ethnic groups.Added value of this studyThis is one of the largest studies to describe how the pandemic impacted ethnic differences in clinical monitoring at primary care and hospital admissions for non-COVID conditions (across four disease areas: cardiovascular disease, diabetes mellitus, respiratory disease and mental health) in England. A study population of nearly 15 million people, allowed the examination of five ethnic groups, and data until April 2022 allowed the evaluation of impacts for a longer period than previous studies.We showed that clinical monitoring had still not returned to pre-pandemic levels even by April 2022. Ethnic differences in clinical monitoring were seen pre-pandemic, though not in diabetes measures, these differences were either not impacted or reduced during the pandemic. We also showed that there were ethnic differences in hospital admissions, for many outcomes the pandemic did not impact these differences but there were some exceptions, in particular for diabetic ketoacidosis admissions in those of Black ethnicity and heart failure admissions for those of Black and Asian ethnicities.Implications of all the available evidenceWe found that the pandemic reduced ethnic inequalities for some outcomes (in hospitalisations for diabetic ketoacidosis and heart failure). However, these were driven by greater absolute increases in admissions for black and asian groups (diabetic ketoacidosis) and white groups (heart failure), which warrant further investigation to understand the underlying causes.

ObjectivesTo investigate alcohol use recording in people with newly diagnosed depression in English primary care and individual characteristics associated with the recording of alcohol use.DesignA population-based cross-sectional study.SettingPrimary care data from English practices contributing to the UK Clinical Practice Research Datalink.ParticipantsWe included adults (18+ years) diagnosed with depression between 1 January 2011 and 1 January 2017 without previous antidepressant use and at least 1 year of registration before diagnosis.Primary and secondary outcome measuresWe described the proportion of individuals with alcohol use and level of alcohol use recorded at four time points (the date of depression diagnosis, 3 months before or after depression diagnosis, 12 months before or after depression diagnosis and any point pre or postdepression diagnosis). We used logistic regression to investigate individual characteristics associated with alcohol use recording in the 3 months before or after depression diagnosis.ResultsWe identified 36 424 adults with depression. 538 (2%) had alcohol use recorded in the 3 months before or after depression diagnosis using formal validated methods such as the Alcohol Use Disorders Identification Test and its abbreviated versions. At each time point, most individuals with alcohol use recorded were low risk drinkers. Alcohol use recording in the 3 months before or after depression diagnosis was associated with male sex (OR=1.38, 95% CI 1.29 to 1.48) and several other individual-level factors.ConclusionsOur study shows low levels of alcohol use recording in the 3 months before or after depression diagnosis. Levels of alcohol use recording varied depending on individual characteristics. Incentivised recording of alcohol use will increase completeness, which could improve clinical management and reduce missed opportunities for care in people with depression.

Background Many patients with bronchiectasis have recurrent hospitalisations for infective exacerbations. Acute kidney injury (AKI) is known to be associated with increased in-hospital mortality. This study examined the frequency of AKI, associated risk-factors, and the association of AKI with in-hospital mortality among patients with bronchiectasis. Methods Anonymised data of patients with non-cystic fibrosis bronchiectasis from the UK Clinical Practice Research Datalink, linked to Hospital Episode Statistics, were used to identify hospitalisations with a primary diagnosis of lower respiratory tract infection (LRTI), from 2004 to 2013. After estimating the proportion of AKI diagnoses, a multivariable logistic regression model was constructed to investigate which background factors were associated with AKI. In-hospital mortality was compared between hospitalisations with and without an AKI diagnosis, with subsequent logistic regression analyses carried out for the association between AKI and in-hospital mortality. Results Of 7804 hospitalisations due to LRTI observed in 3477 patients with bronchiectasis, 230 hospitalisations involved an AKI diagnosis, an average of 2.9 %. However, the percentage increased from less than 2 % in 2004 to nearly 5 % in 2013. After taking this temporal change into account, AKI was independently associated with older age, male sex, decreased baseline kidney function, previous history of AKI, and a diagnosis of sepsis. In-hospital mortality was 33.0 % (76/230) and 6.8 % (516/7574), in hospitalisations with and without AKI, respectively (P

Heme oxygenase (HO) catalyzes the catabolism of heme to biliverdin, CO, and a free iron through three successive oxygenation steps. The third oxygenation, oxidative degradation of verdoheme to biliverdin, has been the least understood step despite its importance in regulating HO activity. We have examined in detail the degradation of a synthetic verdoheme IXα complexed with rat HO-1. Our findings include: 1) HO degrades verdoheme through a dual pathway using either O2 or H2O2; 2) the verdoheme reactivity with O2 is the lowest among the three O2 reactions in the HO catalysis, and the newly found H2O2 pathway is ∼40-fold faster than the O2-dependent verdoheme degradation; 3) both reactions are initiated by the binding of O2 or H2O2 to allow the first direct observation of degradation intermediates of verdoheme; and 4) Asp140 in HO-1 is critical for the verdoheme degradation regardless of the oxygen source. On the basis of these findings, we propose that the HO enzyme activates O2 and H2O2 on the verdoheme iron with the aid of a nearby water molecule linked with Asp140. These mechanisms are similar to the well established mechanism of the first oxygenation, meso-hydroxylation of heme, and thus, HO can utilize a common architecture to promote the first and third oxygenation steps of the heme catabolism. In addition, our results infer the possible involvement of the H2O2-dependent verdoheme degradation in vivo, and potential roles of the dual pathway reaction of HO against oxidative stress are proposed.

Heme oxygenase catalyzes the regiospecific oxidation of hemin to biliverdin IXalpha with concomitant liberation of CO and iron by three sequential monooxygenase reactions. The alpha-regioselectivity of heme oxygenase has been thought to result from the regioselective oxygenation of the heme alpha-meso position at the first step, which leads to the reaction pathway via meso-hydroxyheme IXalpha and verdoheme IXalpha intermediates. However, recent reports concerning heme oxygenase forming biliverdin isomers other than biliverdin IXalpha raise a question whether heme oxygenase can degrade meso-hydroxyhemin and isomers other than the alpha-isomers. In this paper, we investigated the stereoselectivity of each of the two reaction steps from meso-hydroxyhemin to verdoheme and verdoheme to biliverdin by using a truncated form of rat heme oxygenase-1 and the chemically synthesized four isomers of meso-hydroxyhemin and verdoheme. Heme oxygenase-1 converted all four isomers of meso-hydroxyhemin to the corresponding isomers of verdoheme. In contrast, only verdoheme IXalpha was converted to the corresponding biliverdin IXalpha. We conclude that the third step, but not the second, is stereoselective for the alpha-isomer substrate. The present findings on regioselectivities of the second and the third steps have been discussed on the basis of the oxygen activation mechanisms of these steps.

Aggregation of the protein alpha-synuclein has been identified in the pathogenesis of Parkinson’s disease and is initiated by the folding of the protein monomer into an amyloid form of insoluble fibrils. The neurotransmitters dopamine and norepinephrine have been shown to both inhibit the formation of these fibrils and disaggregate existing fibrils, yielding the more toxic oligomeric form of α-synuclein. This study characterizes the stable oligomers formed through the aggregation and disaggregation processes in the presence of these catecholamines, and suggests differences in oligomer formation depending on the extent of oxidation of the neurotransmitter at the time of oligomerization. Unique oligomers are also stabilized, likely formed from the aggregation of monomeric α-synuclein and a proteolytic fragment of α-synuclein; however, proteolytic fragments do not form as readily in the presence of these neurotransmitters. These findings suggest novel pathways for the formation of α-synuclein oligomers in the presence of neurotransmitters, particularly oxidized forms.

Heme oxygenase is a key enzyme in the oxygen-dependent heme catabolism pathway. In order to clarify the role of highly conserved His132 in heme oxygenase isoform-1, we have prepared 30 kDa truncated rat heme oxygenase mutants in which His132 has been replaced by Ala, Gly, and Ser. The expressed recombinant mutant proteins were isolated in inclusion bodies and were recovered from the lysis pellet by dissolution in urea followed by dialysis. The solubilized fraction obtained, however, was composed of a mixture of a functional enzyme and an inactive fraction. The inactive fraction was removed by Sephadex G-75 gel filtration column chromatography, as it eluted out of the column at the void volume. The gel filtration-purified heme oxygenase mutants have spectroscopic and enzymatic properties identical to those of wild type. The hemin complex of the H132A mutant exhibits a transition between a high-spin acid form and a low-spin alkaline form with a pKa value of 7.6 identical to that in the wild-type complex. These results demonstrate that His132 in heme oxygenase does not link to the coordinated water molecule and is not an essential residue for the enzyme activity. These results are in accordance with our previous preliminary results [Ito-Maki, M., Ishikawa, K., Mansfield Matera, K., Sato, M., Ikeda-Saito, M., & Yoshida, T. (1995) Arch. Biochem. Biophys. 317, 253-258] but contradict a recent report that His132 is the distal base linked to the coordinated water molecule and an important residue for enzyme catalysis [Wilks, A., Ortiz de Montellano, P. R., Sun, J., & Loehr, T. M. (1996) Biochemistry 35, 930-936]. Prolonged storage of the solubilized fraction from the inclusion bodies of the mutants, H132S in particular, results in an increase in the void volume fraction with a concomitant decrease of the 30 kDa fraction. We infer that His132 plays a structural role in stabilization of the heme oxygenase protein.

Heme oxygenase is a central enzyme of heme degradation and associated carbon monoxide biosynthesis. We have prepared the alpha-hydroxyheme-heme oxygenase complex, which is the first intermediate in the catalytic reaction. The active site structure of the complex was examined by optical absorption, EPR, and resonance Raman spectroscopies. In the ferric form of the enzyme complex, the heme iron is five coordinate high spin and the alpha-hydroxyheme group in the complex assumes a structure of an oxophlorin where the alpha-meso hydroxy group is deprotonated. In the ferrous form, the alpha-hydroxy group is protonated and consequently the prosthetic group assumes a porphyrin structure. The alpha-hydroxyheme group undergoes a redox-linked conversion between a keto and an enol form. The ferric alpha-hydroxyheme reacts with molecular oxygen to form a radical species. Reaction of the radical species with a reducing equivalent yields the verdoheme-heme oxygenase complex. Reaction of the ferrous alpha-hydroxyheme-heme oxygenase complex with oxygen also yields the verdoheme-enzyme complex. We conclude that the catalytic conversion of ferric alpha-hydroxyheme to verdoheme by heme oxygenase requires molecular oxygen and one reducing equivalent.

Recombinant human microsomal heme oxygenase-2 was expressed in Escherichia coli. Tryptic digestion of the membrane fraction, in which the wild-type enzyme was localized, yielded a soluble tryptic peptide of 28 kDa, which retained the ability to accept electrons from NADPH-cytochrome P-450 reductase and the enzymatic activity for conversion of heme to biliverdin. The tryptic fragment, when purified to apparent homogeneity, bound one equivalent of heme to form a substrateenzyme complex that had spectroscopic properties characteristic of heme proteins, such as myoglobin and hemoglobin. Optical absorption, Raman scattering, and EPR studies of the heme-tryptic fragment complex revealed that the ferric heme was six coordinate high spin at neutral pH and six coordinate low spin at alkaline pH, with a pKο value of 8.5. EPR and Raman scattering studies indicated that a neutral imidazole of a histidine residue served as the proximal ligand in the heme-heme oxygenase-2 fragment complex. The reaction with hydrogen peroxide converted the heme of the heme oxygenase-2 fragment complex into a verdoheme-like intermediate, while the reaction with m-chloroperbenzoic acid yielded a oxoferryl species. These spectroscopic properties are similar to those obtained for heme oxygenase-1, and thus the catalytic mechanism of heme oxygenase-2 appears to be similar to that of heme oxygenase-1.

A truncated, soluble rat heme oxygenase-1 lacking its C-terminal, membrane-anchoring segment, and its His25 → Ala and His132 → Ala mutants have been prepared by site-directed mutagenesis and expression in Escherichia coli. We found that wild-type enzyme can degrade heme to biliverdin, but its specific activity was about one-fifth that of the native, full-length enzyme, suggesting that the C-terminal segment is important for accepting electrons from NADPH cytochrome P450 reductase. His132 → Ala mutant had an enzyme activity comparable to that of the wild-type enzyme; hence, the highly conserved His132 is not essential for the display of the heme oxygenase activity. In contrast, His25 → Ala mutation completely abolished the enzyme′s catalytic activity. A five-coordinate type ferrous NO EPR spectrum was observed for the heme-heme oxygenase H25A complex. Hence, we conclude that His25 is the proximal axial ligand of the heme iron and is essential for the heme degradation activity of the enzyme.

Oxidation of low density lipoproteins (LDL) in the presence of myeloperoxidase and subsequent uptake of the oxidized LDL by specialized receptors on macrophages has been suggested as an initiating event of atherosclerosis. Oxidized fatty acid chains within the glycerophospholipids of LDL have been implicated as the recognition feature by the receptors. The ability of three fatty acids (oleic, linoleic, and arachidonic acids) typically contained in the lipid portion of the glycerophospholipids to bind and be oxidized by myeloperoxidase was measured by spectroscopically observing interactions of the lipids with the heme prosthetic group of the enzyme. As unsaturation increases in the lipid chain, myeloperoxidase binds and oxidizes the fatty acid more readily, as measured by K(D), K(M), and k(cat). A possible mechanism of the free radical oxidation by myeloperoxidase is discussed.

Heme oxygenase (HO) catalyzes the catabolism of heme to biliverdin, CO, and a free iron through three successive oxygenation steps. The third oxygenation, oxidative degradation of verdoheme to biliverdin, has been the least understood step despite its importance in regulating HO activity. We have examined in detail the degradation of a synthetic verdoheme IXalpha complexed with rat HO-1. Our findings include: 1) HO degrades verdoheme through a dual pathway using either O(2) or H(2)O(2); 2) the verdoheme reactivity with O(2) is the lowest among the three O(2) reactions in the HO catalysis, and the newly found H(2)O(2) pathway is approximately 40-fold faster than the O(2)-dependent verdoheme degradation; 3) both reactions are initiated by the binding of O(2) or H(2)O(2) to allow the first direct observation of degradation intermediates of verdoheme; and 4) Asp(140) in HO-1 is critical for the verdoheme degradation regardless of the oxygen source. On the basis of these findings, we propose that the HO enzyme activates O(2) and H(2)O(2) on the verdoheme iron with the aid of a nearby water molecule linked with Asp(140). These mechanisms are similar to the well established mechanism of the first oxygenation, meso-hydroxylation of heme, and thus, HO can utilize a common architecture to promote the first and third oxygenation steps of the heme catabolism. In addition, our results infer the possible involvement of the H(2)O(2)-dependent verdoheme degradation in vivo, and potential roles of the dual pathway reaction of HO against oxidative stress are proposed.

Heme oxygenase catalyzes the regiospecific oxidative degradation of iron protoporphyrin IX (heme) to biliverdin, CO and Fe, utilizing molecular oxygen and electrons donated from the NADPH-cytochrome P-450 reductase. The catalytic conversion of heme proceeds through two known heme derivatives, alpha-hydroxyheme and verdoheme. In order to assess the requirement of reducing equivalents in the second stage of heme degradation, from alpha-hydroxyheme to verdoheme, we have prepared the alpha-hydroxyheme complex with rat heme oxygenase isoform-1 and examined its reactivity with molecular oxygen in the absence of added electrons. Upon reaction with oxygen, the majority of the alpha-hydroxyheme in heme oxygenase is altered to a species which exhibits an optical absorption spectrum with a broad Soret band, along with the minority which is converted to verdoheme. The major product species, which is electron paramagnetic resonace-silent, can be recovered to the original alpha-hydroxyheme by addition of sodium dithionite. We have also found that oxidation of the alpha-hydroxyheme-heme oxygenase complex by ferricyanide or iridium(IV) chloride yields a species which exhibits an optical absorption spectrum and reactivity similar to those of the main product of the oxygen reaction. We infer that the oxygen reaction with the ferric alpha-hydroxyheme-heme oxygenase complex forms a ferric-porphyrin cation radical. We conclude that in the absence of reducing agents, the oxygen molecule functions mainly as an oxidant for the porphyrin ring and has no role in the oxygenation of alpha-hydroxyheme. This result corroborates our previous conclusion that the catalytic conversion of alpha-hydroxyheme to verdoheme by heme oxygenase requires one reducing equivalent along with molecular oxygen.

A truncated, soluble, and enzymatically active form of human heme oxygenase-2 (DeltaHHO2) was expressed in Escherichia coli. To identify the axial heme ligand of HO-2, His-45 to Ala (DeltaH45A) and His-152 to Ala (DeltaH152A) mutants have been prepared using this expression system. DeltaH45A could form a 1:1 complex with hemin but was completely devoid of the heme degradation activity. A 5-coordinate-type ferrous NO EPR spectrum was observed for the heme-DeltaH45A complex. The DeltaH152A mutant was expressed as an inclusion body and was recovered from the lysis pellet by dissolution in urea followed by dialysis. The solubilized fraction obtained, however, was composed of a mixture of a functional enzyme and an inactive fraction. The inactive fraction was removed by Sephadex G-75 column chromatography since it eluted out of the column at the void volume. The gel filtration-purified DeltaH152A exhibited spectroscopic and enzymatic properties identical to those of wild-type. We conclude, in contrast to the previous reports (McCoubrey and Maines (1993) Arch. Biochem. Biophys. 302, 402-408; McCoubrey, W. K., Jr., Huang, T. J., and Maines, M. (1997) J. Biol. Chem. 272, 12568-12574), that His-45, but not His-152, in heme oxygenase isoform-2 is the proximal ligand of the heme and is essential for the heme degradation activity of the enzyme. His-152 appears to play a structural role in stabilization of the heme oxygenase protein.

The O2 and CO reactions with the heme, alpha-hydroxyheme, and verdoheme complexes of heme oxygenase have been studied. The heme complexes of heme oxygenase isoforms-1 and -2 have similar O2 and CO binding properties. The O2 affinities are very high, KO2 = 30-80 microM-1, which is 30-90-fold greater than those of mammalian myoglobins. The O2 association rate constants are similar to those for myoglobins (kO2' = 7-20 microM-1 s-1), whereas the O2 dissociation rates are remarkably slow (kO2 = 0.25 s-1), implying the presence of very favorable interactions between bound O2 and protein residues in the heme pocket. The CO affinities estimated for both isoforms are only 1-6-fold higher than the corresponding O2 affinities. Thus, heme oxygenase discriminates much more strongly against CO binding than either myoglobin or hemoglobin. The CO binding reactions with the ferrous alpha-hydroxyheme complex are similar to those of the protoheme complex, and hydroxylation at the alpha-meso position does not appear to affect the reactivity of the iron atom. In contrast, the CO affinities of the verdoheme complexes are10,000 times weaker than those of the heme complexes because of a 100-fold slower association rate constant (kCO' approximately 0. 004 microM-1 s-1) and a 300-fold greater dissociation rate constant (kCO approximately 3 s-1) compared with the corresponding rate constants of the protoheme and alpha-hydroxyheme complexes. The positive charge on the verdoporphyrin ring causes a large decrease in reactivity of the iron.

Herne oxygenase (HO) catalyzes the regiospecific degradation of heure to biliverdin-α by using O2 and electrons donated by NADPH cytochrome P-450 reductase. The enzyme binds one equivalent of heure to form the heure-enzyme complex, and electron donation initiates the three stepwise oxygenase reactions through the two novel heure derivatives, α-hydroxyheme and verdoheme, during which CO and iron-biliverdin-α are produced; heure participates both as a prosthetic group and as a substrate. Electronic states, coordination structures, and reactivities of the HO complexes with heure, α-hydroxyheme, and verdoheme have been studied. The proximal iron ligand has been identified as a neutral imidazole of His-25 and the presence of a distal base has been established. Conversion to α-hydroxyheme is the step responsible for the regiospecificity. α-Hydroxyheme reveals its ferrous neutral radical state as a key property of its reactivity. Requirement of O2 and one reducing equivalent for the conversion of ferric α-hydroxyheme to verdoheme has been determined. The positive charge on the macrocycle causes unique characteristics of the verdoheme complex. Combination of the novel characteristics of the catalytic intermediates and the protein environment appears to be responsible for the unique HO enzyme function.

Heme oxygenase (HO) is the microsomal enzyme that catalyzes the oxidative degradation of protoheme (iron protoporphyrin IX) and the generation of carbon monoxide. The enzyme converts protoheme into biliverdin through two known heme derivatives, alpha-hydroxyheme and verdoheme. To gain insight into the degradation mechanisms of the two intermediates, the resonance Raman spectra were observed for alpha-hydroxyheme and verdoheme complexes of HO and compared with those of apomyoglobin (apo-Mb) complexes. The ferrous alpha-hydroxyheme complexed with both HO and apo-Mb shows a resonance Raman spectral pattern similar to that of the protoheme complexes. On the contrary, the ferric alpha-hydroxyheme and ferrous verdoheme complexes of HO and apo-Mb show atypical Raman patterns, which are interpreted as the result of the symmetry lowering of the porphyrin-conjugated pi-electron system. The comparison of the resonance Raman spectra of the verdoheme complexed with HO and apo-Mb with those of the five- and six-coordinate model complexes of verdoheme shows that the ferrous forms of the verdoheme-protein complexes are six-coordinate. The Fe-CO and Fe-CN stretching frequencies of ferrous verdoheme compounds are distinct from those of ferrous heme compounds. It is inferred that the positive charge of the verdoheme ring possesses some of the charge density on the iron atom, causing unique characteristics of the iron ligand stretching vibrations and altered ligand binding properties.