Subject(s)
Complement Factor B , Hematologic Agents , Hemoglobinuria, Paroxysmal , Adult , Female , Humans , Male , Administration, Oral , Complement Factor B/antagonists & inhibitors , Hematologic Agents/administration & dosage , Hematologic Agents/adverse effects , Hematologic Agents/therapeutic use , Hemoglobinuria, Paroxysmal/drug therapy , Hemoglobinuria, Paroxysmal/complicationsSubject(s)
Complement Factor B , Hematologic Agents , Hemoglobinuria, Paroxysmal , Humans , Administration, Oral , Complement Factor B/antagonists & inhibitors , Hematologic Agents/administration & dosage , Hematologic Agents/adverse effects , Hematologic Agents/therapeutic use , Hemoglobinuria, Paroxysmal/drug therapy , Hemoglobinuria, Paroxysmal/complicationsSubject(s)
Complement Factor B , Hematologic Agents , Hemoglobinuria, Paroxysmal , Adult , Female , Humans , Male , Administration, Oral , Hemoglobinuria, Paroxysmal/drug therapy , Hemoglobinuria, Paroxysmal/complications , Complement Factor B/antagonists & inhibitors , Hematologic Agents/administration & dosage , Hematologic Agents/adverse effects , Hematologic Agents/therapeutic useABSTRACT
The complement system plays a crucial role in orchestrating the activation and regulation of inflammation within the human immune system. Three distinct activation pathways-classical, lectin, and alternative-converge to form the common lytic pathway, culminating in the formation of the membrane-attacking complex that disrupts the structure of pathogens. Dysregulated complement system activity can lead to tissue damage, autoimmune diseases, or immune deficiencies. In this study, the antimicrobial activity of human serum was investigated by using a bioluminescent microbe probe, Escherichia coli (pEGFPluxABCDEamp). This probe has previously been used to determine the antimicrobial activity of complement system and the polymorphonuclear neutrophils. In this study, blocking antibodies against key serum activators and components, including IgG, complement component 1q, factor B, and properdin, were utilized. The influence of body temperature and acute phase proteins, such as C reactive protein (CRP) and serum amyloid alpha (SAA), on the complement system was also examined. The study reveals the critical factors influencing complement system activity and pathway function. Alongside crucial factors like C1q and IgG, alternative pathway components factor B and properdin played pivotal roles. Results indicated that the alternative pathway accounted for approximately one third of the overall serum antimicrobial activity, and blocking this pathway disrupted the entire complement system. Contrary to expectations, elevated body temperature during inflammation did not enhance the antimicrobial activity of human serum. CRP demonstrated complement activation properties, but at higher physiological concentrations, it exhibited antagonistic tendencies, dampening the response. On the other hand, SAA enhanced the serum's activity. Overall, this study sheds a light on the critical factors affecting both complement system activity and pathway functionality, emphasizing the importance of a balanced immune response.
Subject(s)
Body Temperature , C-Reactive Protein , Complement Activation , Complement C1q , Complement Factor B , Properdin , Serum Amyloid A Protein , Humans , C-Reactive Protein/metabolism , C-Reactive Protein/immunology , Complement C1q/immunology , Complement C1q/metabolism , Serum Amyloid A Protein/metabolism , Serum Amyloid A Protein/immunology , Properdin/immunology , Properdin/metabolism , Complement Factor B/metabolism , Complement Factor B/immunology , Body Temperature/immunology , Escherichia coli/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunologyABSTRACT
Iptacopan, the first orally available small-molecule complement factor B inhibitor, was developed by Novartis AG of Switzerland. Iptacopan for the treatment of PNH was just approved by the FDA in December 2023. Other indications for treatment are still in phase III clinical trials. Iptacopan is a small-molecule inhibitor targeting complement factor B, showing positive therapeutic effects in the treatment of PNH, C3 glomerulonephritis, and other diseases. Although Iptacopan is already on the market, there has been no detailed synthesis process or specific parameter report on the intermediates during the synthesis of its compounds except for the original research patent. In this study, a practical synthesis route for Iptacopan was obtained through incremental improvement while a biosynthesis method for ketoreductase was used for the synthesis of the pivotal intermediate 12. Moreover, by screening the existing enzyme library of our research group on the basis of random as well as site-directed mutagenesis methods, an enzyme (M8) proven to be of high optical purity with a high yield for biocatalectic reduction was obtained. This enzyme was used to prepare the compound benzyl (2S,4S)-4-hydroxy-2-(4-(methoxycarbonyl)-phenyl)-piperidine-1-carboxylate) white powder (36.8 g HPLC purity: 98%, ee value: 99%). In the synthesis of intermediate 15, the reaction was improved from two-step to one-step, which indicated that the risk of chiral allosterism was reduced while the scale was expanded. Finally, Iptacopan was synthesized in a seven-step reaction with a total yield of 29%. Since three chiral intermediate impurities were synthesized directionally, this paper lays a solid foundation for the future of pharmaceutical manufacturing.
Subject(s)
Complement Factor B , Molecular Structure , Complement Factor B/antagonists & inhibitorsABSTRACT
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal, complement-mediated hemolytic anemia with a variety of manifestations. Currently, the methods for treating PNH include anti-C5 treatments (eculizumab and ravulizumab) and pegcetacoplan (a targeted C3 inhibitor). On December 5, 2023, the US FDA approved a factor B inhibitor called Fabhalta® (iptacopan), previously known as LNP023, for the treatment of adult patients with PNH, including those who have previously received anti-C5 therapy. The main objective of this review was to elucidate the clinical efficacy and safety of the newly approved factor B inhibitor, iptacopan. Iptacopan plays a proximal role in the alternative complement pathway to control extravascular hemolysis mediated by C3b and intravascular hemolysis mediated by terminal complement. The recommended dosage is 200 mg orally twice daily. The 24-week results of the pivotal phase III open-label trial, APPLY-PNH, demonstrated that among PNH patients who had previously received anti-C5 therapy, 51/60 (estimated percentages 82%) of patients in the iptacopan group showed an increase in hemoglobin of ≥2 g/dL compared to 0/35 (estimated percentages 2%) in the standard treatment group, also, 69% of iptacopan-treated patients achieved hemoglobin levels ≥12 g/dL, while no patients in the standard treatment group reached this level (both p < 0.001). The 48-week results were similar to those observed at 24 weeks. The most common adverse events were headache, infection and diarrhea. There were almost no clinical breakthrough hemolysis. Trials evaluating the long-term safety and efficacy of iptacopan are currently recruiting.
Subject(s)
Hemoglobinuria, Paroxysmal , Hemoglobinuria, Paroxysmal/drug therapy , Humans , Complement Factor B/antagonists & inhibitors , Treatment Outcome , Complement Inactivating Agents/therapeutic use , Complement Inactivating Agents/adverse effectsABSTRACT
BACKGROUND: Numerous studies indicate a potential protective role of helminths in diabetes mellitus (DM) progression. The complement system, vital for host defense, plays a crucial role in tissue homeostasis and immune surveillance. Dysregulated complement activation is implicated in diabetic complications. We aimed to investigate the influence of the helminth, Strongyloides stercoralis (Ss) on complement activation in individuals with type 2 DM (T2D). METHODOLOGY: We assessed circulating levels of complement proteins (C1q, C2, C3, C4, C4b, C5, C5a, and MBL (Lectin)) and their regulatory components (Factor B, Factor D, Factor H, and Factor I) in individuals with T2D with (n = 60) or without concomitant Ss infection (n = 58). Additionally, we evaluated the impact of anthelmintic therapy on these parameters after 6 months in Ss-infected individuals (n = 60). RESULTS: Ss+DM+ individuals demonstrated reduced levels of complement proteins (C1q, C4b, MBL (Lectin), C3, C5a, and C3b/iC3b) and complement regulatory proteins (Factor B and Factor D) compared to Ss-DM+ individuals. Following anthelmintic therapy, there was a partial reversal of these levels in Ss+DM+ individuals. CONCLUSION: Our findings indicate that Ss infection reduces complement activation, potentially mitigating inflammatory processes in individuals with T2D. The study underscores the complex interplay between helminth infections, complement regulation, and diabetes mellitus, offering insights into potential therapeutic avenues.
Subject(s)
Anthelmintics , Diabetes Mellitus, Type 2 , Helminths , Strongyloides stercoralis , Strongyloidiasis , Animals , Humans , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Complement Factor B , Complement Factor D/therapeutic use , Complement C1q , Strongyloidiasis/complications , Strongyloidiasis/drug therapy , Complement Activation , Anthelmintics/therapeutic use , LectinsABSTRACT
BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).
Subject(s)
Anemia, Hemolytic , Complement Factor B , Complement Inactivating Agents , Hemoglobins , Hemoglobinuria, Paroxysmal , Humans , Administration, Oral , Anemia, Hemolytic/complications , Complement C5/antagonists & inhibitors , Complement Factor B/antagonists & inhibitors , Complement Inactivating Agents/administration & dosage , Complement Inactivating Agents/adverse effects , Complement Inactivating Agents/therapeutic use , Erythrocyte Transfusion , Headache/chemically induced , Hemoglobins/analysis , Hemoglobinuria, Paroxysmal/drug therapy , Hemoglobinuria, Paroxysmal/etiology , Clinical Trials, Phase III as Topic , Randomized Controlled Trials as TopicABSTRACT
This study aims to elucidate the cellular mechanisms behind the secretion of complement factor B (CFB), known for its dual roles as an early biomarker for pancreatic ductal adenocarcinoma (PDAC) and as the initial substrate for the alternative complement pathway (ACP). Using parallel reaction monitoring analysis, we confirmed a consistent â¼2-fold increase in CFB expression in PDAC patients compared with that in both healthy donors (HD) and chronic pancreatitis (CP) patients. Elevated ACP activity was observed in CP and other benign conditions compared with that in HD and PDAC patients, suggesting a functional link between ACP and PDAC. Protein-protein interaction analyses involving key complement proteins and their regulatory factors were conducted using blood samples from PDAC patients and cultured cell lines. Our findings revealed a complex control system governing the ACP and its regulatory factors, including Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, adrenomedullin (AM), and complement factor H (CFH). Particularly, AM emerged as a crucial player in CFB secretion, activating CFH and promoting its predominant binding to C3b over CFB. Mechanistically, our data suggest that the KRAS mutation stimulates AM expression, enhancing CFH activity in the fluid phase through binding. This heightened AM-CFH interaction conferred greater affinity for C3b over CFB, potentially suppressing the ACP cascade. This sequence of events likely culminated in the preferential release of ductal CFB into plasma during the early stages of PDAC. (Data set ID PXD047043.).
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Complement Factor B/genetics , Complement Factor B/metabolism , Complement Pathway, Alternative , Proto-Oncogene Proteins p21(ras) , Early Detection of Cancer , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/geneticsABSTRACT
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss among the elderly in the developed world. Whilst AMD is a multifactorial disease, the involvement of the complement system in its pathology is well documented, with single-nucleotide polymorphisms (SNPs) in different complement genes representing an increased risk factor. With several complement inhibitors explored in clinical trials showing limited success, patients with AMD are still without a reliable treatment option. This indicates that there is still a gap of knowledge in the functional implications and manipulation of the complement system in AMD, hindering the progress towards translational treatments. Since the discovery of the CRISPR/Cas system and its development into a powerful genome engineering tool, the field of molecular biology has been revolutionised. Genetic variants in the complement system have long been associated with an increased risk of AMD, and a variety of haplotypes have been identified to be predisposing/protective, with variation in complement genes believed to be the trigger for dysregulation of the cascade leading to inflammation. AMD-haplotypes (SNPs) alter specific aspects of the activation and regulation of the complement cascade, providing valuable insights into the pathogenic mechanisms of AMD with important diagnostic and therapeutic implications. The effect of targeting these AMD-related SNPs on the regulation of the complement cascade has been poorly explored, and the CRISPR/Cas system provides an ideal tool with which to explore this avenue. Current research concentrates on the association events of specific AMD-related SNPs in complement genes without looking into the effect of targeting these SNPs and therefore influencing the complement system in AMD pathogenesis. This review will explore the current understanding of manipulating the complement system in AMD pathogenesis utilising the genomic manipulation powers of the CRISPR/Cas systems. A number of AMD-related SNPs in different complement factor genes will be explored, with a particular emphasis on factor H (CFH), factor B (CFB), and complement C3 (C3).
Subject(s)
Complement Factor B , Macular Degeneration , Humans , Aged , Haplotypes , Macular Degeneration/genetics , Macular Degeneration/therapy , Macular Degeneration/pathology , Complement Activation/genetics , Risk Factors , Polymorphism, Single NucleotideABSTRACT
Mesangial complement C3 deposits, reflecting alternative and possibly lectin pathway activation, are characteristic in biopsies of patients with IgA nephropathy (IgAN). A recent randomized controlled trial tested the efficacy and safety of iptacopan, a factor B inhibitor, in patients with IgAN. Iptacopan dose-dependently reduced proteinuria, and there was a pronounced decrease of urinary C5b-9. This offers the perspective of "personalizing" therapy, which would be a unique feature of this novel approach to IgAN. A phase III clinical trial (APPLAUSE-IgAN) is ongoing.
Subject(s)
Glomerulonephritis, IGA , Humans , Glomerulonephritis, IGA/drug therapy , Complement Activation , Glomerular Mesangium , Biopsy , Complement Factor BABSTRACT
OBJECTIVE@#To explore the effects of (resolving stasis, promoting collateral circulation) moxibustion on learning and memory ability and the expressions of brain derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) in the rats of vascular dementia (VD) in the microenvironment of neurovascular niche.@*METHODS@#Using 2-vessel occlusion (2-VO), the VD rat models were duplicated. The neural stem cells (NSCs) labeled with lentiviral vector-mediated enhanced green fluorescent protein (EGFP) were co-cultured with endothelial progenitor cells (EPCs) to structure the NSCs + EPCs implant. The implant was transplanted into the lateral ventricle of VD rats and the VD rat models with neurovascular niche were established. In No.1 experiment, the successful-modeled rats were divided into 3 groups, i.e. a NSCs + EPCs moxibustion group, a NSCs + EPCs blank group and a model group, 12 rats in each one. No any treatment was provided in the model group and the NSCs + EPCs blank group. The moxibustion therapy was adopted in the NSCs + EPCs moxibustion group, in which, the suspending moxibustion technique was applied to "Baihui" (GV 20), "Dazhui" (GV 14) and "Shenting" (GV 24), 20 min at each acupoint. The treatment was given once every day and a 14-day treatment was as one course. Totally, 3 courses of treatment were required. At the end of treatment, Morris water maze experiment was adopted to determine the learning and memory ability of the rats in each group. In the No.2 experiment, the model rats were divided into 3 groups, a NSCs + EPCs moxibustion group, a NSCs + EPCs blank group and a model group, 18 rats in each one. In each group, according to the durations of treatment, 3 subgroups were divided and 6 rats in each one. The intervention method was same as the No.1 experiment. Additionally, after corresponding treatment course, using perfusion, the brains were collected in each subgroup and the slices were frozen. BDNF/TrkB expressions were observed in the immunofluorescence test.@*RESULTS@#After treatment, in the NSCs + EPCs moxibustion group, the escape incubation was reduced, the time of the first running-cross platform was shortened and the frequency of running-cross platform increased as compared with the model group and the NSCs + EPCs blank group (<0.01, <0.05). The protein expressions were increased in tendency among the 3 courses of treatment in the NSCs + EPCs moxibustion group, indicating the significant differences (all <0.05), in which, the increase of the protein expressions in the NSCs + EPCs moxibustion group was better than the NSCs + EPCs blank group (<0.05, <0.01).@*CONCLUSION@#The moxibustion therapy is the effective approach to VD in clinical treatment. This therapy up-regulates the BDNF/TrkB protein expressions in the microenvironment of neurovascular niche, co-modulates NSCs-EPCs coupling mechanism, promotes nerve neogenesis and repairs the injured nerve.
Subject(s)
Animals , Rats , Brain-Derived Neurotrophic Factor , Metabolism , Complement Factor B , Dementia, Vascular , Metabolism , Drugs, Chinese Herbal , Hippocampus , Moxibustion , Protein-Tyrosine Kinases , Metabolism , Rats, Sprague-DawleyABSTRACT
PURPOSE: T cell-mediated immune responses, and particularly activation of polyfunctional T cells that simultaneously produce multiple cytokines, are necessary for the control of Mycobacterium tuberculosis. In the present study, we examined if DNA immunization of Mycobacterium tuberculosis resuscitation-promoting factor B (RpfB) elicits polyfunctional T cell responses in mice. MATERIALS AND METHODS: C57BL/6 mice were immunized intramuscularly three times, at 3-week intervals, with RpfB-expressing plasmid DNA. For comparison, protein immunization was performed with recombinant RpfB in control mice. After immunization, RpfB-specific T cell responses were assessed by interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot assay and intracellular cytokine staining (ICS), and T cell polyfunctionality was assessed from the ICS data. RESULTS: RpfB DNA immunization induced not only humoral immune responses, but also CD8+ and CD4+ T cell responses. Immunodominant T-cell epitopes were identified within RpfB by assays with overlapping peptides. RpfB DNA immunization elicited a polyfunctional CD8+ T cell response that was dominated by a functional phenotype of IFN-gamma+/TNF-alpha+/IL-2-/CD107a+. CONCLUSION: RpfB DNA immunization elicits polyfunctional CD8+ T cell responses, suggesting that RpfB DNA immunization might induce protective immunity against tuberculosis.
Subject(s)
Animals , Mice , Complement Factor B , Cytokines , DNA , Epitopes, T-Lymphocyte , Immunity, Humoral , Immunization , Interferon-gamma , Mycobacterium tuberculosis , Peptides , Phenotype , Plasmids , T-Lymphocytes , Tuberculosis , Vaccines, DNAABSTRACT
OBJECTIVE: We have carried out a bibliometric study on the scientific publications in relation to atypical or second-generation antipsychotic drugs (SGAs) in South Korea. METHODS: With the EMBASE and MEDLINE databases, we selected those publications made in South Korea whose title included the descriptors atypic* (atypical*) antipsychotic*, second-generation antipsychotic*, clozapine, risperidone, olanzapine, ziprasidone, quetiapine, sertindole, aripiprazole, paliperidone, amisulpride, zotepine, asenapine, iloperidone, lurasidone, perospirone and blonanserin. We applied some bibliometric indicators of paper production and dispersion with Price's law and Bradford's law, respectively. We also calculated the participation index (PI) of the different countries, and correlated the bibliometric data with some social and health data from Korea (such as total per capita expenditure on health and gross domestic expenditure on research and development). RESULTS: We collected 326 original papers published between 1993 and 2011. Our results state fulfilment of fulfilled Price's law, with scientific production on SGAs showing exponential growth (correlation coefficient r=0.8978, as against an r=0.8149 after linear adjustment). The most widely studied drugs were risperidone (91 papers), aripiprazole (77), olanzapine (53), and clozapine (43). Division into Bradford zones yielded a nucleus occupied by the Progress in Neuro-Psychopharmacology and Biological Psychiatry (36 articles). A total of 86 different journals were published, with 4 of the first 10 used journals having an impact factor being greater than 4. CONCLUSION: The publications on SGAs in South Korea have undergone exponential growth over the studied period, without evidence of reaching a saturation point.
Subject(s)
Antipsychotic Agents , Benzodiazepines , Biological Psychiatry , Bipolar Disorder , Clozapine , Complement Factor B , Dibenzothiazepines , Dibenzothiepins , Health Expenditures , Heterocyclic Compounds, 4 or More Rings , Imidazoles , Indoles , Isoindoles , Isoxazoles , Jurisprudence , Korea , Piperazines , Piperidines , Pyrimidines , Quinolones , Republic of Korea , Risperidone , Schizophrenia , Subject Headings , Sulpiride , Thiazoles , Quetiapine Fumarate , Aripiprazole , Lurasidone HydrochlorideABSTRACT
Evaluating the activity of the complement system under conditions of altered thyroid hormone levels might help elucidate the role of complement in triggering autoimmune processes. Here, we investigated alternative pathway (AP) activity in male Wistar rats (180 ± 10 g) after altering their thyroid hormone levels by treatment with triiodothyronine (T3), propylthiouracil (PTU) or thyroidectomy. T3 and thyroxine (T4) levels were determined by chemiluminescence assays. Hemolytic assays were performed to evaluate the lytic activity of the AP. Factor B activity was evaluated using factor B-deficient serum. An anti-human factor B antibody was used to measure factor B levels in serum by radial immunodiffusion. T3 measurements in thyroidectomized animals or animals treated with PTU demonstrated a significant reduction in hormone levels compared to control. The results showed a reduction in AP lytic activity in rats treated with increasing amounts of T3 (1, 10, or 50 µg). Factor B activity was also decreased in the sera of hyperthyroid rats treated with 1 to 50 µg T3. Additionally, treating rats with 25 µg T3 significantly increased factor B levels in their sera (P < 0.01). In contrast, increased factor B concentration and activity (32 percent) were observed in hypothyroid rats. We conclude that alterations in thyroid hormone levels affect the activity of the AP and factor B, which may in turn affect the roles of AP and factor B in antibody production.
Subject(s)
Animals , Male , Rats , Antithyroid Agents/pharmacology , Complement Factor B/metabolism , Complement Pathway, Alternative/drug effects , Propylthiouracil/pharmacology , Thyroxine/blood , Triiodothyronine/blood , Complement Pathway, Alternative/physiology , Hyperthyroidism/blood , Hyperthyroidism/chemically induced , Hyperthyroidism/immunology , Hypothyroidism/blood , Hypothyroidism/chemically induced , Hypothyroidism/immunology , Luminescent Measurements , Rats, Wistar , ThyroidectomyABSTRACT
Patients should be treated with dignity and respect toward the end of their lives, being freed from unnecessary and painful life-sustaining therapy in hospitals. In Korea, the quality of endof-life (EOL) care has been variable, a major factor being the physicians' perception to the care. A firm consensus of EOL care decision-making has not yet explicitly stated in Korean law and ethics until recently. However, movements to make a law of so-called "the death with dignity act" are presently making its way to the National Assembly, initiated by a law case that allowed the hospital to withdraw mechanical ventilator support per request by the patients' family of a permanently vegetative patient. Socially agreed guidelines for EOL care can facilitate clinical decision process and communication between health service provider and the patient or his/her family. At the same time, EOL care should be individualized also in the same line of guideline to meet patient' and patient' family wish regarding the withdrawal of life-sustaining therapy. The painful EOL care experience of the loved one remains in the memory of the relatives who live on. Physicians should identify, document, respect, and act on behalf of the hospitalized patients' needs, priorities, and preference for EOL care. It has been advocated that competent patients can express their right of self-determination on EOL care through advance directives in Western countries. Advance directives are considered as a tool to facilitate EOL decision making. However, there are barriers to adopt the advance directives as a legitimate tool for an EOL decision making in Korea. For one thing, the reality of death and dying is rarely discussed in our society. In addition, the discussion about EOL care with chronically and critically ill patients has been considered as a taboo in the hospitals. In spite of these difficulties, physicians could do better EOL care by the open communication with patients or with their surrogates. Through the communication, physician should set a goal how to manage the EOL patient. The set goal should be shared among the caregivers to achieve the maximum benefit of the patient. The lack of open discussion with patient prior to EOL care results in inappropriate protraction of a patient's dying process. In summary, physicians, who know the clinical significance of delivering treatments to EOL patients, should play a central role in assisting patients' and their families' to make the best decision on EOL care. Moreover, the concerted actions to improve EOL care in our society among general public, professionals, stakeholders for EOL care, and governmental organizations are required to address ongoing social requests, although a policy or a guideline is made in this time.
Subject(s)
Humans , Advance Directives , Caregivers , Complement Factor B , Consensus , Critical Illness , Decision Making , Ethics, Medical , Health Services , Jurisprudence , Korea , Love , Memory , Physician's Role , Right to Die , Taboo , Ventilators, MechanicalABSTRACT
<p><b>BACKGROUND</b>The present study was undertaken to replicate the associations of representative polymorphisms in three genes (complement factor H (CFH), complement factor B (BF) and HtrA serine peptidase 1 (HTRA1)) with exudative age-related macular degeneration (AMD) in a Han Chinese population, and to test if the modifiable environmental factors affect AMD susceptibility associated with different type of genotype in these genes.</p><p><b>METHODS</b>An age, gender and ethnicity matched case-control study was conducted to genotype the representative single neucleotide polymorphisms (SNPs) loci including rs1061170 and rs1410996 in CFH, rs641153 and rs4151667 in BF and rs11200638 in HTRA1 gene in 144 exudative AMD patients and 126 normal controls using PCR-RFLP and direct resequencing. The demographic characteristics and behavioral risk factors were also recorded. Allelic and genotypic associations for individual SNP and joint associations with two loci were performed. The gene-gene and gene-environment interactions were analyzed using multivariate non-conditional Logistic regression analysis.</p><p><b>RESULTS</b>The C risk allele frequencies for CFH Y402H (rs1061170) in cases and controls were 12.5% and 5.4% respectively, which were much lower than those in Caucasians (P < 0.001). Compared with TT homozygous genotype, the CT heterozygous genotype was positively associated with AMD with odds ratio (OR) of 3.23 (1.36 - 5.07). However, the population attributable risk (PAR) of C allele was only 3.3% (1.4% - 4.3%). rs1410996 was also associated with AMD independent of Y402H. The ORs of exudative AMD for individuals carrying one copy risk allele and two copy risk alleles were 2.57 (1.21 - 5.45) and 4.76 (2.15 - 10.55) respectively, with correspondent PARs of 28.3% (2.0% - 40.5%) and 38.2% (21.8% - 45.4%). rs11200638 in HTRA1 was another susceptible locus for AMD and the risk homozygotes were significantly susceptible for exudutive AMD (OR = 3.98, 1.88 - 8.43) with PAR of 38.9% (24.3% - 45.8%). Education status and cigarette smoking were also related to exudative AMD. After controlling for environmental risk factors, CFH and HTRA1 SNPs were independently associated with exudative AMD, with OR of 3.50 (1.45 - 8.45) for CT genotype in Y402H, 3.34 (1.33 - 8.36) for GG genotype in rs1410996 and 3.85 (1.58 - 9.42) for AA genotype in rs11200638 respectively. The interaction analysis between gene and environmental factors showed that smoking synergistically increased susceptibility of AMD for heterozygotes of rs1410996, with OR(interaction) of 7.33 (P(interaction) = 0.029).</p><p><b>CONCLUSIONS</b>In a Han Chinese population, CFH and HTRA1 polymorphisms appear to be independently and possibly additively hereditary contributors to exudative AMD. Y402H polymorphism conferred a significant but relatively lower contribution in Chinese than in Caucasians with a low frequency of risk allele. The gene-environment interaction may be a best way to encourage those with a high genetic risk to prevent AMD by avoiding modifiable factors until there is effective treatment for AMD.</p>
Subject(s)
Aged , Female , Humans , Male , Middle Aged , Asian People , Complement Factor B , Genetics , Complement Factor H , Genetics , Gene Frequency , Genetics , Genetic Predisposition to Disease , Genetics , Genotype , High-Temperature Requirement A Serine Peptidase 1 , Macular Degeneration , Genetics , Polymerase Chain Reaction , Polymorphism, Single Nucleotide , Genetics , Risk Factors , Serine Endopeptidases , Genetics , SmokingABSTRACT
OBJETIVO: Avaliar a atividade funcional das vias clássica e alternativa do sistema complemento e os níveis de C3, C4 e fator B durante o primeiro episódio de infecção meningocócica e durante a convalescença. PACIENTES E MÉTODOS: Dez crianças brasileiras com idades entre 8 meses e 8 anos, admitidas de 1991 a 1993, com diagnóstico clínico-laboratorial de meningite meningocócica, foram estudadas durante infecção aguda (até 7 dias do diagnóstico) e no período de convalescença (entre 1 e 6 meses após). C3, C4 e fator B foram quantificados por nefelometria e a atividade lítica das vias clássica e alternativa foi avaliada por método cinético e expressa como tempo necessário para lisar 50% de uma suspensão de eritrócitos (T1/2, expresso em segundos). Baixos valores de T1/2 das vias clássica e alternativa se correlacionam com elevadas atividades de via clássica e via alternativa, respectivamente. RESULTADOS: Observaram-se diferenças significativas entre a atividade lítica da via alternativa durante a infecção e no período de convalescença (282 e 238 segundos, respectivamente, P= .01). Nenhuma diferença foi detectada nos outros parâmetros analisados. CONCLUSÕES: Na presença de meningite meningocócica a via alternativa é preferencialmente ativada, provavelmente devido à maior capacidade da endotoxina meningocócica para ativar esta via, in vivo.
Subject(s)
Humans , Infant , Child, Preschool , Child , Complement C3 , Complement C4 , Complement Factor B/analysis , Complement Pathway, Alternative/immunology , Complement Pathway, Classical/immunology , Meningitis, Meningococcal/immunology , Acute Disease , Brazil , Complement Hemolytic Activity Assay , Convalescence , Meningitis, Meningococcal/blood , Nephelometry and Turbidimetry , Reference ValuesABSTRACT
Objetivos - Analisar a variabilidade genética dos componentes C3 e BF do sistema complemento em pacientes brasileiros portadores de lúpus eritematoso sistêmico (LES) e as possíveis associações entre suas formas alotípicas e determinadas manifestações clínicas e laboratoriais da doença. Pacientes e métodos - O estudo foi realizado em 95 pacientes portadores de LES (88 mulheres e 7 homens, com variação etária de 14 a 57 anos, média de 30,18 anos), segundo os critérios de classificação do Colégio Americano de Reumatologia, e em 89 controles sadios. Os alótipos de C3 e de BF foram detectados no soro dos pacientes e controles através de eletroforese de alta voltagem em gel agarose, seguido de imunofixação com anticorpo específico. Resultados - Os alótipos de C3 e BF observados no presente estudo foram: C3S, C3F, C3SF, C3SS05 e BFS, BFF, BFSSF, BFSF1, BFSF075, BFSS07, BFF1. Os resultados obtidos demonstrarem aumento do alótipo BFF nos pacientes, quando comparados com os controles normais (p= 0,055; RR = 2,87); para os demais alótipos, não houve diferença signifiante quanto à sua distribuição. Menor frequência do alótipo BFS foi observada nos pacientes que apresentaram manifestações neurológicas, em relação aos que não as tiveram (p=0,059); RR = 0,28). Também nos pacientes que apresentaram serosites, observou-se frequência diminuída dos alótipos C3S e BFS, quando comparados com os que naõ apresentaram esta manifestação durante o curso da doença (p=0,036 para C3 e p=0,021 para BF; RR = 0,38 para ambos). Conclusões - A frequência diminuída de BFS nos pacientes com manifestações neurológicas e de C3S e BFS nos que apresentaram serosites no curso da doença sugere associação negativa e possível papel protetor desses alótipos no desenvolvimento dessas manifestações clínicas no LES. Os achados aqui descritos sugerem que a variabilidade genetica das proteínas C3 e BF do sistema complemento pode estar relacionada com o mecanismo etiopatogênico e com a expressão clínica do LES em pacientes brasileiros