Successfully treated C3 glomerulopathy in which protein and genetic analyses were useful for diagnosis.

C3 glomerulopathy is a rare disease that results in nephritis due to complement dysregulation and is characterized by C3 deposition in the glomerulus. Dysregulation of the alternative pathway underlies the pathogenesis, but activation of the terminal pathway is also common. The disease is often caused by acquired rather than genetic factors, i.e., autoantibodies against C3 or C5 converting enzyme (convertase) and other complement-related proteins. We report a case of C3 glomerulopathy diagnosed by renal biopsy that responded well to corticosteroids and went into complete remission within two months. Analysis of complements and complement-related proteins revealed a low level of C3 and a high level of soluble terminal pathway protein complex (sC5b-9). Under genetic analysis about complement-related genes, no pathogenic variant was observed. Based on these findings, we diagnosed this patient with C3 glomerulopathy with autoantibodies. Corticosteroids had a marked effect, which also supports this speculation. Analyses of complements and complement-related proteins, and genetic variants may be useful in understanding the pathogenesis of C3 glomerulopathy and in selecting treatment options.

The preliminary study of delta checks for immunoglobulins and complements in the clinical laboratory.

BACKGROUND: To determine delta check limits for immunoglobulins and complements in outpatients and inpatients based on patient data and biological variation due to the lack of relevant studies. METHODS: Patient data for IgA, IgG, IgM, IgE, C3, and C4 from 1 January 2022 to 31 December 2023 was collected from laboratory information system (LIS) in our clinical laboratory of Wuhan Union Hospital, which includes both outpatients and inpatients. The delta difference (DD), delta percent change (DPC), and reference change value (RCV) were calculated based on patient data and biological variation. RESULTS: For DDs, there are significant differences between outpatients and inpatients in C4, IgE, IgG, and IgM. For DPCs, the corresponding analytes which are significantly different are C3, C4, IgE, IgG, and IgM. Two sources of CVI to calculate the RCV of IgA, IgG, IgM, C3, and C4 were applied in this study, which revealed that two kinds of RCVs based on different biological variation databases are similar to each other, but both were smaller than delta check limits based on patient data, except for C4. CONCLUSIONS: The delta check is a useful tool to monitor potential errors which may occur in total testing process. We hope our findings could be helpful for future studies focused on delta checks in immunological analytes.

Membranoproliferative Glomerulonephritis Pattern of Injury.

Membranoproliferative glomerulonephritis (MPGN) is no longer a disease but a pattern of injury in various diseases. Characterized by electron-dense deposits, mesangial proliferation, and duplication of the glomerular basement membrane, MPGN was previously classified by findings seen by electron microscopy. However, recognizing complement dysfunction in relation to cases with the MPGN pattern of injury substantially changed our view of its pathogenesis. A new classification, including immune complex-mediated and complement-mediated MPGN, has become preferable and has been adopted by international guidelines. Despite these advancements, accurate diagnosis of MPGN remains a clinical challenge, given the pathological and clinical similarities between immune complex-mediated and complement-mediated MPGN. Additional testing, such as molecular and genetic testing, is often necessary. Here, we will summarize our current understanding of the MPGN pattern of injury from a pathology perspective as an introductory article in the following chapters.

[Nutritional management of patients during surgical prehabilitation and rehabilitation programs]. / Prise en charge nutritionnelle des patients pendant les programmes de préhabilitation et de réhabilitation en chirurgie.

Undernutrition (UD) increases perioperative morbidity and mortality. Its prevention and treatment are therefore essential in surgical prehabilitation and rehabilitation programs. Nutritional treatment is individualized according to the patient's nutritional status, ingesta and protein-energy requirements. Oral nutrition is optimized to increase intakes through personalized dietary advice and oral nutritional supplements. Artificial nutrition support is indicated in cases of UD or high risk of UD before major surgery. Enteral nutrition is preferred to parenteral nutrition when the digestive tract is functional.

Boundedness of Complements for Log Calabi-Yau Threefolds.

In this paper, we study the theory of complements, introduced by Shokurov, for Calabi-Yau type varieties with the coefficient set [0, 1]. We show that there exists a finite set of positive integers N, such that if a threefold pair (X/Z∋z,B) has an R-complement which is klt over a neighborhood of z, then it has an n-complement for some n∈N. We also show the boundedness of complements for R-complementary surface pairs.

To interpret and analyze the changing patterns of histology and direct immunofluorescence findings in membranoproliferative glomerulonephritis.

Background: Membranoproliferative glomerulonephritis has in the recent past been regrouped into immune complex-mediated (ICM MPGN) disease (driven by the classical complement pathway) and complement-mediated (C3GN) disease (driven by the alternative complement pathway) based on pathogenetic role of alternative complement pathway and immunofluorescence deposits. The proposed regrouping lent therapeutic and prognostic support in managing the disease of MPGN. Aims and Objectives: The present study is undertaken to study the patterns of MPGN based on histopathological and DIF examination and sub-categorize the cases into mainly complement dominant and immune complex-mediated diseases for better prognostic and therapeutic utility. Materials and Methods: This is a prospective observational study carried out in a tertiary care center over a period of 2 yrs. The clinically suspected cases of MPGN were subjected to histopathologic and direct immunofluorescence examination (DIF), and the findings were interpreted in light of complement-mediated and immune complex-mediated MPGN. Results: Out of 620 renal biopsies, diagnosis of MPGN was confirmed both on histopathology and DIF in 36 cases accounting for 5.8% of all biopsies. Based on DIF findings, the various groups comprised 20 cases (55.6%) of immune complex deposits, 11 (30.5%) of C3 dominant picture, and 5 (13.9%) of Nil immune deposits. On analysis of the patterns on DIF, 16 cases (80%) of C3 + Ig group and 6 (54.5%) of C3GN group showed predominantly MPGN pattern. Crescentic glomerulonephritis, global glomerulosclerosis, and interstitial fibrosis were markedly observed in C3GN group. Conclusion: DIF is of immense prognostic and therapeutic value in managing cases of MPGN.

Direct immunofluorescence on formalin-fixed, paraffin-embedded versus fresh frozen human renal biopsies: a comparative study.

BACKGROUND: The data referring to the value of direct immunofluorescence on formalin-fixed, paraffin-embedded tissue (IF-Paraffin) in the diagnosis of renal diseases is controversial. The aim of this study was to investigate whether renal biopsies evaluated by routine immunofluorescence on frozen tissue (IF-Frozen) would yield adequate findings to confirm diagnoses when the IF-Paraffin technique was applied. METHODS: To show immunoglobulins, complement components, and light chains, 55 native renal biopsies were subjected to IF-Paraffin and IF-Frozen staining techniques. The intensity of the staining was compared, and the sensitivity and specificity were calculated. RESULTS: The IF-Paraffin technique showed a sensitivity of 89%, 81%, 86%, 30%, 71%, 60%, and 77% for IgG, IgM, IgA, C1q, C3, κ, and λ, respectively, whereas specificity was 91%, 100%, 100%, 96%, 94%, 98%, and 100%. It showed diagnostic findings in 87% of cases. Compared to cases that had both IF-Paraffin and IF-Frozen staining techniques, 43 of 55 showed either equal intensity for the diagnostic immunoglobulin/complement or a little difference. CONCLUSIONS: Direct immunofluorescence on formalin-fixed, paraffin-embedded sections cannot replace immunofluorescence on frozen sections in the assessment of renal biopsies, but may be a "salvage technique" when frozen tissue is insufficient or unavailable and must be interpreted with great caution.

Paroxysmal nocturnal hemoglobinuria in a patient post COVID-19 virus infection: A case report with literature review.

COVID 19 is a serious infection that originated in Wuhan, China and has resulted in worldwide morbidity and mortality. It continues to be a major health concern in 2022, being associated with multiorgan failure. Although the pathophysiology of the disease and its complications are not well understood, it is believed that a cytokine storm, triggered by complement activation may be responsible for the severity and complications of the disease. As of now, there is no definitive treatment available. Hematological changes associated with COVID-19 include lymphopenia, anemia, thrombocytopenia, disseminated intravascular coagulopathy, and thrombosis. Paroxysmal nocturnal hemoglobinuria (PNH), on the other hand, is an acquired clonal hematopoietic stem cell disorder that occurs due to an acquired PIG-A mutation affecting the hematopoietic stem cells. Interestingly, PNH exhibits some clinical and laboratory manifestations like those seen in COVID-19. In this report, we present a rare case of PNH that developed following a COVID-19 infection.

Management of Idiopathic Granulomatous Mastitis: A Single Institution Experience.

Introduction: There are multiple management modalities for idiopathic granulomatous mastitis, but the treatment of choice is still under debate. This study aims to evaluate the diagnosis and outcomes of different management modalities in patients with idiopathic granulomatous mastitis and to identify the risk factors associated with recurrence. Method: This is a single-group cohort study that included those patients who had idiopathic granulomatous mastitis. Ultrasonography was conducted for all of the cases using LOGIQ E9 with an ML6-15 transducer (5-15 MHz). A core needle biopsy was conducted to take samples from the cases for histopathological examination. The patients were put on steroid therapy. Whenever the cases did not respond to the steroid therapy, treatment with a combination of low-dose steroids and methotrexate was started. In the lack of response to conservative treatments, surgical interventions were started. Results: Sixty-three cases with a confirmed histopathological diagnosis of granulomatous mastitis were included. The mean age of patients was 35.7 years. The history of more than one childbirth was positive in a large portion of the cases (82.5%). The lesion side was unilateral in 58.7% of the cases. A large proportion of the lesions were classified as BIRADS category 2. The best treatment outcome was yielded by a combination of low-dose steroids and incision and drainage. The factors of age, lesion area (cm2), skin thickening, and white blood cell count enhanced the chance of recurrence. Conclusion: Incision and drainage in combination with a low dose of steroids can give an acceptable outcome with a low rate of recurrence.

Inflammation balance in skeletal muscle damage and repair.

Responding to tissue injury, skeletal muscles undergo the tissue destruction and reconstruction accompanied with inflammation. The immune system recognizes the molecules released from or exposed on the damaged tissue. In the local minor tissue damage, tissue-resident macrophages sequester pro-inflammatory debris to prevent initiation of inflammation. In most cases of the skeletal muscle injury, however, a cascade of inflammation will be initiated through activation of local macrophages and mast cells and recruitment of immune cells from blood circulation to the injured site by recongnization of damage-associated molecular patterns (DAMPs) and activated complement system. During the inflammation, macrophages and neutrophils scavenge the tissue debris to release inflammatory cytokines and the latter stimulates myoblast fusion and vascularization to promote injured muscle repair. On the other hand, an abundance of released inflammatory cytokines and chemokines causes the profound hyper-inflammation and mobilization of immune cells to trigger a vicious cycle and lead to the cytokine storm. The cytokine storm results in the elevation of cytolytic and cytotoxic molecules and reactive oxygen species (ROS) in the damaged muscle to aggravates the tissue injury, including the healthy bystander tissue. Severe inflammation in the skeletal muscle can lead to rhabdomyolysis and cause sepsis-like systemic inflammation response syndrome (SIRS) and remote organ damage. Therefore, understanding more details on the involvement of inflammatory factors and immune cells in the skeletal muscle damage and repair can provide the new precise therapeutic strategies, including attenuation of the muscle damage and promotion of the muscle repair.

Disruption in the meat industry: new technologies in nonmeat substitutes.

After World War II, consumer patterns of food consumption changed dramatically. Initially, it was mobility, economic evolution, and home appliance technologies that induced a shift toward meals eaten outside of the home and to ready-to-eat foods at home. More recently, health concerns and sustainability issues shifted consumer tastes among meat products and gave rise to a change in attitudes about raising animals for human consumption. On the supply side, new technologies in nonmeat production enabled new producers, most notably Impossible Foods and Beyond Meat, to enter as fringe competitors to vertically integrated, oligopolistic meat processors. Today, these nonmeat products represent a small, but growing, share of consumer expenditures at grocery stores, restaurants, and direct-to-consumer delivery channels. In this paper, we evaluate the disruption of the traditional meat industry through the lens of consumer spending trends and substitution among meat products and find that the development of alternative meat products is market-driven rather than policy-driven. Given these findings, we identify implications for product development and industrial organization.

Darkness hormone or daylight hormone in women with systemic lupus erythematosus?

INTRODUCTION: In this study, it was aimed to compare the effects of both melatonin and 25-hydroxyvitamin D3, defined as an immune modulator, on laboratory diagnostic criteria parameters and disease activity in patients with systemic lupus erythematosus (SLE). METHODS: The study included 56 women with SLE and 40 healthy women (control group). Melatonin and 25-hydroxyvitamin D3 levels of patients and healthy individuals included in the study were examined. In addition, leukocytes, lymphocytes, platelets, C3, C4, anti-double-stranded DNA (Anti-dsDNA), antinuclear antibody, and SLE disease activity index (SLEDAI) were analyzed in women with SLE. Patients were divided into four subgroups according to SLEDAI. RESULTS: Melatonin and 25-hydroxyvitamin D3 levels of women with SLE were lower than healthy women (p < 0.001). Both melatonin and 25-hydroxyvitamin D3 levels were not correlated with laboratory diagnostic criteria parameters. Only 25-hydroxyvitamin D3 levels were correlated with leukocyte levels (p < 0.01). There was no significant difference between the melatonin levels of the subgroups. The 25-hydroxyvitamin D3 levels of the subgroup without disease activity were higher than levels of the subgroups with disease activity (p < 0.05). There was a negative correlation between SLEDAI score and 25-hydroxyvitamin D3 levels (p < 0.05). CONCLUSION: Women with SLE had lower melatonin and 25-hydroxyvitamin D3 levels than healthy women. On the other hand, parameters of laboratory diagnostic criteria of SLE disease were not related. Only 25-hydroxyvitamin D3 levels were inversely related leukocyte levels. SLE disease activity was not correlated with melatonin levels but negatively correlated with 25-hydroxyvitamin D3 levels. Key Points • Women with SLE have low levels of melatonin and 25-hydroxyvitamin D3. • Melatonin and 25-hydroxyvitamin D3 levels are not related to the laboratory diagnostic criteria parameters for SLE disease. • Low levels of melatonin and 25-hydroxyvitamin D3 may be a factor in the unbalanced immune system of SLE. • Supplementation of melatonin and 25-hydroxyvitamin D3 may be recommended for women patients with SLE.

Antibody-Dependent Enhancement (ADE) and the role of complement system in disease pathogenesis.

Antibody-dependent enhancement (ADE) has been associated with severe disease outcomes in several viral infections, including respiratory infections. In vitro and in vivo studies showed that antibody-response to SARS-CoV and MERS-CoV could exacerbate infection via ADE. Recently in SARS CoV-2, the in vitro studies and structural analysis shows a risk of disease severity via ADE. This phenomenon is partially attributed to non-neutralizing antibodies or antibodies at sub-neutralizing levels. These antibodies result in antigen-antibody complexes' deposition and propagation of a chronic inflammatory process that destroys affected tissues. Further, antigen-antibody complexes may enhance the internalization of the virus into cells through the Fc gamma receptor (FcγR) and lead to further virus replication. Thus, ADE occur via two mechanisms; 1. Antibody mediated replication and 2. Enhanced immune activation. Antibody-mediated effector functions are mainly driven by complement activation, and the first complement in the cascade is complement 1q (C1q) which binds to the virus-antibody complex. Reports say that deficiency in circulating plasma levels of C1q, an independent predictor of mortality in high-risk patients, including diabetes, is associated with severe viral infections. Complement mediated ADE is reported in several viral infections such as dengue, West Nile virus, measles, RSV, Human immunodeficiency virus (HIV), and Ebola virus. This review discusses ADE in viral infections and the in vitro evidence of ADE in coronaviruses. We outline the mechanisms of ADE, emphasizing the role of complements, especially C1q in the outcome of the enhanced disease.

On polyhedral graphs and their complements.

We find all polyhedral graphs such that their complements are still polyhedral. These turn out to be all self-complementary.

Trade and Resource Sustainability with Asset Markets.

Trade changes incentives to protect an open-access natural resource independently of its effect on the resource price. General equilibrium linkages cause resource policy to affect the price of privately owned assets regardless of whether they are used in the resource sector. In the closed economy, the asset market in our overlapping generations setting creates incentives for currently living agents to protect the natural resource. The interplay of the asset market and general equilibrium effects causes trade to reverse these incentives. Trade liberalization and the establishment of formal property rights are policy complements: the former makes the latter more important. Supplementary Information: The online version contains supplementary material available at 10.1007/s13235-021-00400-4.

Immuno-pathogenesis of neuromyelitis optica and emerging therapies.

Neuromyelitis optica (NMO) is an inflammatory disease that resembles MS in the relapsing clinical course of optic neuritis and myelitis. Two decades of studies have revealed that autoantibodies, reactive to the water channel protein aquaporin 4 (AQP4) are detected in the core group of patients. These autoantibodies play a crucial role in the inflammatory pathology of NMO, involving proinflammatory cytokines, chemokines, and various inflammatory cells such as Th17 cells. Anti-AQP4 antibody-positive NMO differs fundamentally from MS, particularly in the responsiveness to therapies and the neuropathology accompanying destruction of astrocytes. Research into the immunological mechanism has led to the identification of possible targets of therapy, including complement pathway and interleukin-6 (IL-6) receptor signaling. Recent randomized controlled clinical trials have shown the remarkable efficacy of antibodies specific for complement C5, IL-6 receptor, and CD19+ B cells in prevention of NMO spectrum disorder relapses, although no such effects were found in anti-AQP4 antibody-negative patients. These results imply that anti-AQP4 antibody is a biomarker predicting the efficacy of therapies, and indicate the future direction towards "precision medicine."

Elevated Cytokine Levels in Plasma of Patients with SARS-CoV-2 Do Not Contribute to Pulmonary Microvascular Endothelial Permeability.

The vascular endothelial injury occurs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, but the mechanisms are poorly understood. We sought to determine the frequency and type of cytokine elevations and their relationship to endothelial injury induced by plasma from patients with SARS-CoV-2 versus controls. Plasma from eight consecutively enrolled patients hospitalized with acute SARS-CoV-2 infection was compared to controls. Endothelial cell (EC) barrier integrity was evaluated using ECIS (electric cell-substrate impedance sensing) on human lung microvascular EC. Plasma from all SARS-CoV-2 but none from controls decreased transendothelial resistance to a greater degree than that produced by tumor necrosis factor-alpha (TNF-α), the positive control for the assay. Thrombin, angiopoietin 2 (Ang2), and vascular endothelial growth factor (VEGF), complement factor C3a and C5a, and spike protein increased endothelial permeability, but to a lesser extent and a shorter duration when compared to SARS-CoV-2 plasma. Analysis of Ang2, VEGF, and 15 cytokines measured in plasma revealed striking patient-to-patient variability within the SARS-CoV-2 patients. Pretreatment with thrombin inhibitors, single, or combinations of neutralizing antibodies against cytokines, Ca3 and C5a receptor antagonists, or with ACE2 antibody failed to lessen the SARS-CoV-2 plasma-induced EC permeability. The EC barrier destructive effects of plasma from patients with SARS-CoV-2 were susceptible to heat inactivation. Plasma from patients hospitalized with acute SARS-CoV-2 infection uniformly disrupts lung microvascular integrity. No predicted single, or set of, cytokine(s) accounted for the enhanced vascular permeability, although the factor(s) were heat-labile. A still unidentified but potent circulating factor(s) appears to cause the EC disruption in SARS-CoV-2 infected patients. IMPORTANCE Lung vascular endothelial injury in SARS-CoV-2 patients is one of the most important causes of morbidity and mortality and has been linked to more severe complications including acute respiratory distress syndrome (ARDS) and subsequent death due to multiorgan failure. We have demonstrated that in eight consecutive patients with SARS-CoV-2, who were not selected for evidence of endothelial injury, the diluted plasma-induced intense lung microvascular damage, in vitro. Known endothelial barrier-disruptive agents and proposed mediators of increased endothelial permeability in SARS-CoV-2, induced changes in permeability that were smaller in magnitude and shorter in duration than plasma from patients with SARS-CoV-2. The effect on endothelial cell permeability of plasma from patients with SARS-CoV-2 was heat-labile. The main plasma factor that causes the increased endothelial permeability remains to be identified. Our study provides a possible approach for future studies to understand the underlying mechanisms leading to vascular injury in SARS-CoV-2 infections.

Mechanism for the attenuation of neutrophil and complement hyperactivity by MSC exosomes.

Complements and neutrophils are two key players of the innate immune system that are widely implicated as drivers of severe COVID-19 pathogenesis, as evident by the direct correlation of respiratory failure and mortality with elevated levels of terminal complement complex C5b-9 and neutrophils. In this study, we identified a feed-forward loop between complements and neutrophils that could amplify and perpetuate the cytokine storm seen in severe SARS-CoV-2-infected patients. We observed for the first time that the terminal complement activation complex C5b-9 directly triggered neutrophil extracellular trap (NET) release and interleukin (IL)-17 production by neutrophils. This is also the first report that the production of NETs and IL-17 induced by C5b-9 assembly on neutrophils could be abrogated by mesenchymal stem cell (MSC) exosomes. Neutralizing anti-CD59 antibodies abolished this abrogation. Based on our findings, we hypothesize that MSC exosomes could alleviate the immune dysregulation in acute respiratory failure, such as that observed in severe COVID-19 patients, by inhibiting complement activation through exosomal CD59, thereby disrupting the feed-forward loop between complements and neutrophils to inhibit the amplification and perpetuation of inflammation during SARS-CoV-2 infection.

Surface Modification of Erythrocytes with Lipid Anchors: Structure-Activity Relationship for Optimal Membrane Incorporation, in vivo Retention, and Immunocompatibility.

Red blood cells (RBCs) are natural carriers for sustained drug delivery, imaging, and in vivo sensing. One of the popular approaches to functionalize RBCs is through lipophilic anchors, but the structural requirements for anchor stability and in vivo longevity remain to be investigated. Using fluorescent lipids with the same cyanine 3 (Cy3) headgroup but different lipid chain and linker, the labeling efficiency of RBCs and in vivo stability are investigated. Short-chain derivatives exhibited better insertion efficiency, and mouse RBCs are better labeled than human RBCs. Short-chain derivatives demonstrate low retention in vivo. Derivatives with ester bonds are especially unstable, due to removal and degradation. On the other hand, long-chain, covalently linked derivatives show remarkably long retention and stability (over 80 days half life in the membrane). The clearance organs are liver and spleen with evidence of lipid transfer to the liver sinusoidal endothelium. Notably, RBCs modified with PEGylated lipid show decreased macrophage uptake. Some of the derivatives promote binding of antibodies in human plasma and mouse sera and modest increase in complement deposition and hemolysis, but these do not correlate with in vivo stability of RBCs. Ultra-stable anchors can enable functionalization of RBCs for drug delivery, imaging, and sensing.

Association of immunological features with clinical manifestations in primary Sjogren's syndrome: a single-center cross-sectional study.

The objectives of this study were to describe the clinical features and evaluate the utility of immunological features as predictors of organ involvement and disease severity in patients with primary Sjogren's syndrome (pSS). In this single-center observational cross-sectional study, subjects fulfilling the 2012 AECG criteria or 2016 ACR/EULAR criteria for pSS were included. Details of glandular, extra-glandular manifestations, ESSDAI, ESSPRI, ANA, anti-Ro/La antibodies, rheumatoid factor (RF), complement (C3 and C4) levels and hyperglobulinemia were noted. Chi-square and Mann-Whitney U tests were performed for determining associations and relative risk (RR) was calculated. Sixty-four subjects with pSS were included in the study. Females constituted 92% and median age at onset was 37.5 (15-74) years. Ocular or oral sicca was noted in 61 (95.3%) subjects and parotidomegaly was noted in 17 (26.5%) subjects. Extra-glandular manifestations noted were: constitutional (85.9%), articular (65.6%), renal (29.6%), hematological (26.6%), cutaneous (12.5%), peripheral nerves (9.3%) and pulmonary (4.7%). Immunological features noted were: ANA (85.9%), anti-Ro (81.3%), anti-La (60.9%), RF (84.4%), hypocomplementemia (39.1%) and hyperglobulinemia (62.5%). Median ESSDAI was 6 (0-23) and ESSPRI was 7 (0-10). ANA was associated with younger age and renal involvement (RR 1.25). Anti-Ro was associated with younger age, renal involvement (RR 1.36) and high ESSDAI. Anti-La was associated with high renal (RR 3.4) and low articular involvement (RR 2.75). RF was associated with hematological involvement and hyperglobulinemia was associated with younger age. Certain immunological features can help predict the organ involvement in patients with pSS. Larger, prospective follow-up studies are needed to clearly understand these associations.