ABSTRACT
Methyl-coenzyme M reductase (MCR) catalyzes both the synthesis and the anaerobic oxidation of methane (AOM). Its catalytic site contains Ni at the core of cofactor F430. The Ni ion, in its low-valent Ni(I) state, lights the fuse leading to homolysis of the C-S bond of methyl-coenzyme M (methyl-SCoM) to generate a methyl radical, which abstracts a hydrogen atom from coenzyme B (HSCoB) to generate methane and the mixed disulfide CoMSSCoB. Direct reversal of this reaction activates methane to initiate anaerobic methane oxidation. On the basis of the crystal structures, which reveal a Ni-thiol interaction between Ni(II)-MCR and inhibitor CoMSH, a Ni(I)-thioether complex with substrate methyl-SCoM has been transposed to canonical MCR mechanisms. Similarly, a Ni(I)-disulfide with CoMSSCoB is proposed for the reverse reaction. However, this Ni(I)-sulfur interaction poses a conundrum for the proposed hydrogen-atom abstraction reaction because the >6 Å distance between the thiol group of SCoB and the thiol of SCoM observed in the structures appears to be too long for such a reaction. The spectroscopic, kinetic, structural, and computational studies described here establish that both methyl-SCoM and CoMSSCoB bind to the active Ni(I) state of MCR through their sulfonate groups, forming a hexacoordinate Ni(I)-N/O complex, not Ni(I)-S. These studies rule out direct Ni(I)-sulfur interactions in both substrate-bound states. As a solution to the mechanistic conundrum, we propose that both the forward and the reverse MCR reactions emanate through long-range electron transfer from the Ni(I)-sulfonate complexes with methyl-SCoM and CoMSSCoB, respectively.
Subject(s)
Nickel/chemistry , Nickel/metabolism , Oxidoreductases/chemistry , Oxidoreductases/metabolism , Sulfonic Acids/chemistry , Electron Transport , Kinetics , Substrate SpecificityABSTRACT
Juvenile dermatomyositis (JDM) is an extremely heterogeneous orphan disease with limited amount of dedicated research on the subject matter. Recent research suggests that JDM may not just be the classic antibody driven complements mediated microangiopathy as was thought to be in the past. The etiopathogenesis of JDM also involves inappropriate stimulation of innate immune system followed by dysregulation of the adaptive immune response through dendritic cells. Many variable immune factors such as genetics, major histocompatibility complex expressions, immunohistochemical variabilities, and diversity in specific and associated autoantibodies may make individual IIM and JDM cases unique. The diversity in IIM and JDM also explains individual variability in response to specific therapies. Classifying and matching the right patients to the right treatment is crucial to the successful treatment of these patients with better outcomes. Sub-type specific biologic therapy may be the best current treatment that can match the patient to the best treatment options. A PubMed search was performed to find all the available cases of refractory myositis patients treated with biologics up to July 2020. Using this search this article reviews all the current biologic treatment options and experiences for both adults and children in the context of recent basic science to assist pediatric rheumatologists in choosing the optimal biologic therapy for a child with recalcitrant JDM.
Subject(s)
Myositis , Adult , Autoantibodies , Biological Products/therapeutic use , Child , Dermatomyositis/drug therapy , Humans , Immunologic Factors , Myositis/drug therapyABSTRACT
OBJECTIVE: Complement-mediated vasculopathy of muscle and skin are clinical features of juvenile dermatomyositis (JDM). We assess gene copy-number variations (CNVs) for complement C4 and its isotypes, C4A and C4B, in genetic risks and pathogenesis of JDM. METHODS: The study population included 105 patients with JDM and 500 healthy European Americans. Gene copy-numbers (GCNs) for total C4, C4A, C4B and HLA-DRB1 genotypes were determined by Southern blots and qPCRs. Processed activation product C4d bound to erythrocytes (E-C4d) was measured by flow cytometry. Global gene-expression microarrays were performed in 19 patients with JDM and seven controls using PAXgene-blood RNA. Differential expression levels for selected genes were validated by qPCR. RESULTS: Significantly lower GCNs and differences in distribution of GCN groups for total C4 and C4A were observed in JDM versus controls. Lower GCN of C4A in JDM remained among HLA DR3-positive subjects (p=0.015). Homozygous or heterozygous C4A-deficiency was present in 40.0% of patients with JDM compared with 18.2% of controls (OR=3.00 (1.87 to 4.79), p=8.2×10(-6)). Patients with JDM had higher levels of E-C4d than controls (p=0.004). In JDM, C4A-deficient subjects had higher levels of E-C4d (p=0.0003) and higher frequency of elevated levels of multiple serum muscle enzymes at diagnosis (p=0.0025). Microarray profiling of blood RNA revealed upregulation of type I interferon-stimulated genes and lower abundance of transcripts for T-cell and chemokine function genes in JDM, but this was less prominent among C4A-deficient or DR3-positive patients. CONCLUSIONS: Complement C4A deficiency appears to be an important factor for the genetic risk and pathogenesis of JDM, particularly in patients with a DR3-positive background.
Subject(s)
Complement C4/genetics , Complement C4a/deficiency , DNA Copy Number Variations , Dermatomyositis/genetics , Genetic Predisposition to Disease , Immunologic Deficiency Syndromes/genetics , Adolescent , Case-Control Studies , Child , Child, Preschool , Complement C4/deficiency , Complement C4a/genetics , Complement C4b/genetics , Female , Genotype , HLA-DRB1 Chains/genetics , Hereditary Complement Deficiency Diseases , Humans , Male , Receptors, Tumor Necrosis Factor, Member 25/blood , Receptors, Tumor Necrosis Factor, Member 25/genetics , Risk Factors , White People/geneticsABSTRACT
Objectives: Juvenile systemic sclerosis is a rare childhood disease. Three disease activity indices have been published for adult patients with systemic sclerosis: the European Scleroderma Study Group Index, a modified version of the European Scleroderma Study Group Index and the revised European Scleroderma Trials and Research index. The objective of this study was to determine the feasibility and performance of the three disease activity indices in a prospectively followed cohort of patients with juvenile systemic sclerosis. Methods: The analysis cohort was selected from the prospective international inception cohort enrolling juvenile systemic sclerosis patients. The correlation of the disease activity indices with the physicians' and the patients' global assessment of disease activity was determined. The disease activity indices were compared between patients with active and inactive disease. Sensitivity to change between 6- and 12-month follow-up was investigated by mixed models. Results: Eighty percent of the 70 patients had a diffuse cutaneous subtype. The revised European Scleroderma Trials and Research index was highly correlated with the physician-reported global disease activity/parents-reported global disease activity (r = 0.74/0.64), followed by the European Scleroderma Study Group activity index (r = 0.61/0.55) and the modified version of the European Scleroderma Study Group activity index (r = 0.51/0.43). The disease activity indices significantly differed between active and inactive patients. The disease activity indices showed sensitivity to change between 6- and 12-month follow-up among patients who improved or worsened according to the physician-reported global disease activity and the parents-reported global disease activity. Conclusion: Overall, no disease activity score is superior to the other, and all three scores have limitations in the application in juvenile systemic sclerosis patients. Furthermore, research on the concept of disease activity and suitable scores to measure disease activity in patients with juvenile systemic sclerosis is necessary in future.
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Objective: To compare organ involvement and disease severity between male and female patients with juvenile onset systemic sclerosis. Methods: Demographics, organ involvement, laboratory evaluation, patient-reported outcomes and physician assessment variables were compared between male and female juvenile onset systemic sclerosis patients enrolled in the prospective international juvenile systemic sclerosis cohort at their baseline visit and after 12 months. Results: One hundred and seventy-five juvenile onset systemic sclerosis patients were evaluated, 142 females and 33 males. Race, age of onset, disease duration, and disease subtypes (70% diffuse cutaneous) were similar between males and females. Active digital ulceration, very low body mass index, and tendon friction rubs were significantly more frequent in males. Physician global assessment of disease severity and digital ulcer activity was significantly higher in males. Composite pulmonary involvement was also more frequent in males, though not statistically significantly. After 12 months, they are the pattern of differences changed female patients had significantly more frequent pulmonary involvement. Conclusion: In this cohort, juvenile onset systemic sclerosis had a more severe course in males at baseline and but the pattern changed after 12 months. Some differences from adult findings persisted, there is no increased signal of pulmonary arterial hypertension or heart failure in male pediatric patients. While monitoring protocols of organ involvement in juvenile onset systemic sclerosis need to be identical for males and females.
ABSTRACT
Methyl-Coenzyme M Reductase (MCR) catalyzes the biosynthesis of methane in methanogenic archaea, using a catalytic Ni-centered Cofactor F430 in its active site. It also catalyzes the reverse reaction, that is, the anaerobic activation and oxidation, including the cleavage of the CH bond in methane. Because methanogenesis is the major source of methane on earth, understanding the reaction mechanism of this enzyme can have massive implications in global energy balances. While recent publications have proposed a radical-based catalytic mechanism as well as novel sulfonate-based binding modes of MCR for its native substrates, the structure of the active state of MCR, as well as a complete characterization of the reaction, remain elusive. Previous attempts to structurally characterize the active MCR-Ni(I) state have been unsuccessful due to oxidation of the redox- sensitive catalytic Ni center. Further, while many cryo structures of the inactive Ni(II)-enzyme in various substrates-bound forms have been published, no room temperature structures have been reported, and the structure and mechanism of MCR under physiologically relevant conditions is not known. In this study, we report the first room temperature structure of the MCRred1-silent Ni(II) form using an X-ray Free-Electron Laser (XFEL), with simultaneous X-ray Emission Spectroscopy (XES) and X-ray Diffraction (XRD) data collection. In celebration of the seminal contributions of inorganic chemist Dick Holm to our understanding of nickel-based catalysis, we are honored to announce our findings in this special issue dedicated to this remarkable pioneer of bioinorganic chemistry.
Subject(s)
Lasers , Methane , Crystallography, X-Ray , Methane/chemistry , Oxidation-Reduction , Oxidoreductases , TemperatureABSTRACT
OBJECTIVE: Utilizing data obtained from a prospective, international, juvenile systemic sclerosis (SSc) cohort, the present study was undertaken to determine if pulmonary screening with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLco) is sufficient to assess the presence of interstitial lung disease (ILD) in comparison to high-resolution computed tomography (HRCT) in juvenile SSc. METHODS: The juvenile SSc cohort database was queried for patients enrolled from January 2008 to January 2020 with recorded pulmonary function tests (PFTs) parameters and HRCT to determine the discriminatory properties of PFT parameters, FVC, and DLco in detecting ILD. RESULTS: Eighty-six juvenile SSc patients had both computed tomography imaging and FVC values for direct comparison. Using findings on HRCT as the standard measure of ILD presence, the sensitivity of FVC in detecting ILD in juvenile SSc was only 40%, the specificity was 77%, and area under the curve (AUC) was 0.58. Fifty-eight juvenile SSc patients had both CT imaging and DLco values for comparison. The sensitivity of DLco in detecting ILD was 76%, the specificity was 70%, and AUC was 0.73. CONCLUSION: The performance of PFTs in juvenile SSc to detect underlying ILD was quite limited. Specifically, the FVC, which is one of the main clinical parameters in adult SSc to detect and monitor ILD, would miss ~60% of children who had ILD changes on their accompanying HRCT. The DLco was more sensitive in detecting potential abnormalities on HRCT, but with less specificity than the FVC. These results support the use of HRCT in tandem with PFTs for the screening of ILD in juvenile SSc.
Subject(s)
Lung Diseases, Interstitial/complications , Scleroderma, Systemic/complications , Adolescent , Child , Female , Humans , Lung Diseases, Interstitial/diagnostic imaging , Lung Diseases, Interstitial/pathology , Male , Missed Diagnosis , Prospective Studies , ROC Curve , Tomography, X-Ray Computed , Vital CapacityABSTRACT
OBJECTIVE: To evaluate the baseline clinical characteristics of juvenile systemic sclerosis (SSc) patients in the international juvenile SSc inception cohort, and to compare these characteristics between the classically defined juvenile diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) subtypes and among those with overlap features. METHODS: A cross-sectional study was performed using baseline visit data. Information on demographic characteristics, organ system evaluation, treatment, and patient- and physician-reported outcomes was extracted and summary statistics applied. Comparisons between juvenile dcSSc and lcSSc subtypes and patients with and without overlap features were performed using chi-square and Mann-Whitney U tests. RESULTS: At data extraction, 150 juvenile SSc patients were enrolled across 42 centers; 83% were White, 80% were female, juvenile dcSSc predominated (72%), and 17% of the cohort had overlap features. Significant differences were found between juvenile dcSSc and juvenile lcSSc regarding modified Rodnan skin thickness score, the presence of Gottron's papules, digital tip ulceration, results of the 6-minute walk test, and composite pulmonary and cardiac involvement. All of these were more frequent in dcSSc except for cardiac involvement. Juvenile dcSSc patients had significantly worse scores for physician-rated disease activity and damage. A significantly higher occurrence of Gottron's papules and musculoskeletal and composite pulmonary involvement, and a significantly lower frequency of Raynaud's phenomenon, were seen in those with overlap features. CONCLUSION: Results from a large international juvenile SSc cohort demonstrate significant differences between juvenile dcSSc and juvenile lcSSc patients, including more globally severe disease and increased frequency of interstitial lung disease in juvenile dcSSc patients, while those with lcSSc have more frequent cardiac involvement. Those with overlap features had an unexpected higher frequency of interstitial lung disease.
Subject(s)
Lung Diseases, Interstitial , Scleroderma, Diffuse , Scleroderma, Systemic , Skin Ulcer , Cross-Sectional Studies , Female , Humans , Male , Scleroderma, Diffuse/diagnosis , Scleroderma, Localized , Scleroderma, Systemic/diagnosis , Scleroderma, Systemic/epidemiologyABSTRACT
The novel coronavirus SARS-CoV-2 (COVID-19) has infected people across the world, including an increasing number of children in the United States (U.S.). The epidemiology of pediatric infection in the U.S. and how it influences clinical outcomes is still being characterized. In this study, we describe a cohort of 989 children with laboratory-confirmed SARS-CoV-2 infection. Children under age 20 in a statewide health system with SARS-CoV-2 infection, defined by positive PCR testing, between February 1 and August 30, 2020 were included in this observational cohort study. Data extracted from the medical record included age, demographic information, clinical illness severity, hospital stay, and comorbidities. Analysis included descriptive statistics and Chi-square as appropriate. Nine hundred and eighty-children met inclusion criteria for this study, ranging from 1 month to 20 years in age. Most children (62.4%) were asymptomatic at the time of diagnosis and children over the age of 2 were significantly more likely to be asymptomatic at diagnosis than younger children (P < .05). Hispanic children were significantly more likely to be symptomatic at the time of diagnosis (56.3% asymptomatic; P < .05). The high proportion of children with asymptomatic infection emphasizes the importance of understanding the unique role of children in the pandemic. Older children are more likely to be asymptomatic, but also more likely to experience severe or critical illness when symptoms do develop. Hispanic children were more likely to be symptomatic at diagnosis, highlighting the importance of culturally specific outreach to vulnerable communities.
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Background In the midst of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, a lot more chaos could be anticipated in the flu season due to the coexistence of SARS-CoV-2 and influenza with almost similar epidemiologic and clinical features. Could this become a "twindemic" or "syndemic" if there is any viral interference occurs? We investigated the effect of influenza and pneumococcal vaccines on the disease course of SARS-CoV-2 in the pediatric population and the possibility of viral interference. Material and methods After approval from Institutional Review Board, a retrospective electronic chart review on 20 years and younger SARS-CoV-2 polymerase chain reaction (PCR) positive patients who visited Arkansas Children's Hospital System between February 1 to August 30, 2020, was performed. The clinical data was collected along with influenza and pneumococcal vaccination status of these patients. Results The results showed that viral interference may have played a role in the current flu and coronavirus disease 2019 (COVID-19) twindemic. SARS-CoV-2 and influenza may have significantly affected each other's epidemiological features. Conclusion Understanding the relationship and co-existence of other viruses alongside SARS-CoV-2 and knowing the vaccination status of the host population may help in deploying the right strategies to get the best outcomes.
ABSTRACT
Juvenile dermatomyositis (JDM) has a wide spectrum of clinical presentations. In the last decade, several myositis-specific antibodies have been identified in patients with JDM and connected with specific organ involvement or specific clinical picture. It has been published that the presence of anti-NXP2 autoantibodies presents a risk for calcinosis in patients with JDM. We aimed to investigate the prevalence of calcinosis and response to the treatment in JDM patients with anti-NXP2. In a retrospective, multinational, multicenter study, data on 26 JDM (19 F, 7 M) patients with positive anti-NXP2 were collected. The mean age at disease presentation was 6.5 years (SD 3.7), the median diagnosis delay was 4 months (range 0.5-27 months). Patients were divided into two groups (A and B) based on the presence of calcinosis, which occurred in 42% of anti-NXP2 positive JDM patients (group A). Four patients already had calcinosis at presentation, one developed calcinosis after 4 months, and 6 developed calcinosis later in the disease course (median 2 years, range 0.8-7.8). The differences in laboratory results were not statistically significant between the groups. The mean age at disease presentation (5.2/7.5 years) trended toward being younger in group A. Children with calcinosis were treated with several combinations of drugs. In four cases, rituximab and, in one case, anti-TNF alpha agents were used successfully. Disease outcome (by evaluation of the treating physician) was excellent in four, good in two, stable in two, and poor in three patients. None of the patients from group B had a poor disease outcome. In conclusion, JDM patients with anti-NXP2 are prone to develop calcinosis, especially if they present with the disease early, before 5 years of age. The development of calcinosis is associated with worse disease outcomes. The combination of several immunomodulatory drugs and biologic drugs can stop calcinosis progression; however, there are no evidence-based therapies for treating calcinosis in JDM patients.
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BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is a once in a lifetime public health catastrophe that has driven the world not only into a medical crisis but has pushed to the brink of economic collapse. Prevention of transmission of the replication-competent virus to the susceptible host is the key to the control of COVID-19. The phenomenon of "sustained-positivity," "reinfections," and their role in disease transmission are poorly understood in adults and not even recognized in the pediatric population yet. This information is crucial for ascertaining the quarantine/isolation period for test-positive patients. Most of the time, adult studies' results are extrapolated and applied to children, but severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has treated children differently than adults. MATERIAL AND METHODS: The Institutional Review Board (IRB) approval has been obtained. A retrospective electronic chart review of 989 SARS-CoV-2 polymerase chain reaction (PCR)/reverse transcription-PCR (RT-PCR) positive pediatric patients was performed. The aim was to look at the existence of sustained positivity and SARS -CoV-2 reinfection in the pediatric population, as was reported in the adults. Results: We present our retrospective observational study on 989 SARS-CoV-2 positive pediatric patients; 172 of these had repeated multiple testings, 68 had multiple consecutive positive tests over time, and 27 qualified for sustained-positive status. We also report on four pediatric COVID-19 reinfections. CONCLUSION: This is the first report on pediatric SARS-CoV-2 reinfection, one of very few on pediatric SARS-CoV-2 sustained positivity and reinfection. These two phenomena occur in children also as reported in adults but have several differences. The reinfection is possible within one to three weeks of becoming negative as against adults who have been reported to become positive in a minimum of 45-90 days from becoming negative. More extensive reporting is essential to ascertain the accurate quarantine/isolation recommendation in children.
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The understanding of etiology and pathogenesis of idiopathic immune myositis is fast evolving, and so is the classification of myositis subtypes. The diversity in genetics, major histocompatibility complex expressions, immunohistochemical, and specific and associated autoantibodies not only explains the individual variability in response to therapies but also begs for subtype-specific treatments. With the evolution of the new biological therapies, the treatment of idiopathic immune myositis (IIM) has greatly transformed in recent years. This article appraises the current therapeutic value of intravenous immunoglobulin (IVIg) in idiopathic immune myopathy patients in the era of transformed treatment options. This article argues why the IVIg therapy still retains its value as an unreplaceable treatment option in certain specific subtypes of idiopathic immune myositis patients as well as in certain specific clinical idiopathic immune myositis scenarios.
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PURPOSE: In the recent climate of consumerism and consumer focused care, health and social care needs to be more responsive than ever before. Consumer needs and preferences can be elicited with accepted validity and reliability only by strict methodological control, customerisation of the questionnaire and skilled interpretation. To construct, conduct, interpret and implement improved service provision, requires a trained work force and infrastructure. This article aims to appraise various aspects of consumer surveys and to assess their value as effective service improvement tools. DESIGN/METHODOLOGY/APPROACH: The customer is the sole reason organisations exist. Consumer surveys are used worldwide as service and quality of care improvement tools by all types of service providers including health service providers. The article critically appraises the value of consumer surveys as service improvement tools in health services tool and its future applications. FINDINGS: No one type of survey is the best or ideal. The key is the selection of the correct survey methodology, unique and customised for the particular type/aspect of care being evaluated. The method used should reflect the importance of the information required. RESEARCH LIMITATIONS/IMPLICATIONS: Methodological rigor is essential for the effectiveness of consumer surveys as service improvement tools. Unfortunately so far there is no universal consensus on superiority of one particular methodology over another or any benefit of one specific methodology in a given situation. More training and some dedicated resource allocation is required to develop consumer surveys. More research is needed to develop specific survey methodology and evaluation techniques for improved validity and reliability of the surveys as service improvement tools. Measurement of consumer preferences/priorities, evaluation of services and key performance scores, is not easy. PRACTICAL IMPLICATIONS: Consumer surveys seem impressive tools as they provide the customer a voice for change or modification. However, from a scientific point-of-view their credibility in service improvement in terms of reproducibility, reliability and validity, has remained debatable. ORIGINALITY/VALUE: This artcile is a critical appraisal of the value of consumer surveys as a service improvement tool in health services--a lesson which needs to be learnt.
Subject(s)
Data Collection/methods , Patient Satisfaction , Quality Indicators, Health Care , Humans , Quality Assurance, Health CareABSTRACT
Juvenile idiopathic arthritis (JIA) is the most common but extremely heterogeneous group of rheumatic diseases of childhood. There are no reliable, well-researched and published biomarkers for diagnosis or monitoring in juvenile idiopathic arthritis as there are for rheumatoid arthritis (RA) in adults. Biomarkers are not utilized in classifying JIA as they are in adult RA, making the JIA classifications less clinically effective and informative. The situation presents a lost opportunity for early aggressive therapy in JIA patients. Various researchers have used diverse biomarkers anecdotally in JIA and more systematically in RA patients and have drawn inferences on their utility from their experiences. The experience with biomarkers from RA patients cannot necessarily be extrapolated for JIA patients because they are dissimilar diseases. This article reconnoiters the comparative utility of various arthritis biomarkers in adult as well as in JIA patients. In contrast to RA, JIA is in itself a diverse group of arthritis with clinically overlapping subgroups with diverse etiology. The difference in the etiopathogenesis of arthritis subgroups demands identifying subgroup-specific biomarkers for diagnosis/monitoring and subgroup-specific therapies for management. The diagnostic/prognostic value of the individual biomarker could be different in different types of arthritis and in different types of hosts. Understanding the utility of individual biomarkers and careful selection of the assay are important to achieve the best disease outcomes.
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INTRODUCTION: The COPA syndrome is a newly recognized monogenic, autosomal dominant autoimmune disease presenting mostly presenting in childhood. Clinical features include inflammation of the lungs, kidneys, and joints. Approximately twenty-six patients with COPA syndrome worldwide have been investigated all originating from eight families. Patients with this syndrome exhibit heterozygous monogenic missense mutations in the WD40 domain. This domain is a functionally-significant area of the alpha subunit of coatomer-associated protein (COPα) which encodes the coat protein complex I (COPI). The COPI dysfunction is also associated with autoantibody expansion. We report two patients with COPA syndrome. METHODS: All testing and molecular genetic analysis were performed after obtaining the informed consent of both the patient and parents. A retrospective chart review was carried out on both the patients. Demographic, clinical and laboratory findings were abstracted from outpatient and inpatient encounters. Pulmonary function tests (PFTs), chest computed tomography (CT) scans, and lung biopsy histopathology reports were also reviewed and summarized. RESULTS: The index case and the father of the child both demonstrated a unique inflammatory pulmonary, arthritis, and renal disease triad starting in early childhood including pulmonary hemorrhage. The two patients had a novel COPA mutation previously undescribed. CONCLUSIONS: To date, only four pathological, genetic mutations have been reported that are compatible with COPA syndrome. We here report two patients with COPA syndrome within the same family with a novel COPA gene mutation different than the heterozygous monogenic missense mutations in the WD40 domain and distinct from the clinical phenotypes reported in the literature so far.
Subject(s)
Autoimmune Diseases/genetics , Coatomer Protein/genetics , Mutation, Missense/genetics , Adult , Arthritis/genetics , Child , Heterozygote , Humans , Lung Diseases, Interstitial/genetics , Male , Nephritis/genetics , Pedigree , Pneumonia/genetics , SyndromeABSTRACT
The idiopathic inflammatory myopathies (IIM) until recently have been considered a heterogeneous broad group of six autoimmune muscle diseases. Initially, autoantibodies in IIM (including JDM) and CD8+ T cell-induced cytotoxicity (PM and IBM) were the predominant recognized etiopathology mechanisms used to classify myopathies. In the early late 1990's to 2000's, evolving understanding of the molecules such as interleukin (IL), tumor necrosis factor (TNF), interferon (IFN), and other cytokines as well as differences in response to therapies, has led IIM researchers to look beyond previous disease mechanisms. For decades the overexpression of Th1- associated cytokines (TNF-α, IFN-γ and IL-12) in the areas of inflammation in skin and muscle in IIM pointed to Th1 as the primary pathway for inflammation in myositis.However, in the last decade overexpression and elevated level of Th17-associated cytokines (IL-17, IL-22, and IL-6) were identified in the blood and the inflamed muscles of myositis patients. We also do not know how Th1 and Th2 cytokines work differently in diverse hosts, in different concentrations, in different inflammatory milieus, and in the presence or absence of each other or other adhesion/co-stimulatory molecules such as NF-κB. Also, several autoantibodies to intracellular organelles have been identified in myositis.In this review, we will discuss the most recent advances in IIM research and how that might bring new biologic therapies to market in the next 5-15 years to assist in the care of our most difficult IIM and JDM patients.
Subject(s)
Biological Products/therapeutic use , Myositis/drug therapy , Adult , Antibodies, Monoclonal, Humanized/therapeutic use , Child , Chronic Disease , Clinical Trials as Topic , Dermatomyositis/drug therapy , Forecasting , Humans , Immunosuppressive Agents/therapeutic use , Therapies, Investigational/trendsABSTRACT
PURPOSE: Pressure to change is politically driven owing to escalating healthcare costs and an emphasis on efficiency gains, value for money and improved performance proof in terms of productivity and recently to some extent by demands from less satisfied patients and stakeholders. In a background of newly immerging expensive techniques and drugs, there is an increasing consumer expectation, i.e. quality services. At the same time, health system managers and practitioners are finding it difficult to cope with demand and quality expectations. Clinicians are frustrated because they are not recognised for their contribution. Managers are frustrated because meaningful dialogue with clinicians is lacking, which has intensified the need for change to a more efficient system that satisfies all arguments about cost effectiveness and sustainable quality services. Various strategies, originally developed by management quality "gurus" for engineering industries, have been applied to health industries with variable success, which largely depends on the type of health care system to which they are applied. DESIGN/METHODOLOGY/APPROACH: Business process re-engineering is examined as a quality management tool using past and recent publications. FINDINGS: The paper finds that applying business process re-engineering in the right circumstances and selected settings for quality improvement is critical for its success. It is certainly "not for everybody". ORIGINALITY/VALUE: The paper provides a critical appraisal of business process re-engineering experiences in UK healthcare. Lessons learned regarding selecting organisations and agreeing realistic expectations are addressed. Business process re-engineering has been evaluated and reviewed since 1987 in US managed health care, with no clear lessons learned possibly because unit selection and simultaneous comparison between two units virtually performing at opposite ends has never been done before. Two UK pilot studies, however, add useful insights.
Subject(s)
Health Care Reform/organization & administration , Quality Assurance, Health Care/organization & administration , State Medicine/organization & administration , Environment , Humans , Patient Satisfaction , Total Quality Management/organization & administration , United KingdomABSTRACT
STUDY OBJECTIVES: We hypothesized that alterations in cardiac hemodynamics associated with obstructive sleep apnea-hypopnea (OSAH) would be reflected in higher natriuretic peptide levels. We examined the association of OSAH with natriuretic peptides in a community-based sample. DESIGN: Cross-sectional, retrospective, observational study. SETTING: Framingham Heart Study Offspring Cohort and Sleep Heart Health Study. PARTICIPANTS: Community-based sample of 623 individuals. MEASUREMENTS: Full-montage home polysomnography was used to determine apnea-hypopnea index (AHI) and percentage of time with an oxyhemoglobin saturation < 90% (PctLt90). Sensitive immunoradiometric assays were used to measure plasma B-type (BNP) and N-terminal pro-atrial natriuretic peptide (NT-ANP). Multivariable regression was used to examine the relations between natriuretic peptides and indicators of OSAH, adjusting for age, sex, body mass index, and clinical covariates. RESULTS: No statistically significant relations between OSAH indices and BNP were observed in the multivariable model. Compared with an AHI < 5, relative levels of 1.20, 0.88, and 0.91 were observed forAHI categories 5-15, 15-30, >30 events per hour, respectively. For NT-ANP, no significant relations were seen with AHI in the multivariable model (relative levels of 0.98, 0.91, and 0.90). An inverse association was observed between NT-ANP and PctLt90 in age- and sex-adjusted models (relative levels of 0.93, 0.87, and 0.80), although this association became statistically nonsignificant after adjusting for body mass index. CONCLUSION: Lack of association of natriuretic peptides with OSAH indices suggests that undiagnosed OSAH may not be associated with major alterations in left ventricular function, as reflected in morning natriuretic peptide levels.
Subject(s)
Natriuretic Peptides/blood , Sleep Apnea, Obstructive/blood , Atrial Fibrillation/epidemiology , Body Mass Index , Cohort Studies , Female , Humans , Hypertension/epidemiology , Male , Middle Aged , Myocardial Infarction/epidemiology , Obesity/diagnosis , Obesity/epidemiology , Polysomnography , Prevalence , Residence Characteristics , Severity of Illness Index , Sleep Apnea, Obstructive/diagnosis , Sleep Apnea, Obstructive/epidemiologyABSTRACT
This report describes a male baby with primary hyperoxaluria type-1, presenting at 5 hours of age with cyanotic episodes, hypotonia, unexplained techypnea and tachycardia. This infant also had renal calcinosis, and middle cerebral arterial infarct with unilateral enlargement of ventricle and left porencephalic cyst on CT scan. The infant improved with diuretics, water supplementation, pyridoxine, and Albright solution.