Prehydrated Electrons Activated by Continuous Electron Transfer Stemmed from Peracetic Acid Homolysis Mediated by Diamond Surface Defects for Enhanced PFOA Destruction.

Research on the use of peracetic acid (PAA) activated by nonmetal solid catalysts for the removal of dissolved refractory organic compounds has gained attention recently due to its improved efficiency and suitability for advanced water treatment (AWT). Among these catalysts, nanocarbon (NC) stands out as an exceptional example. In the NC-based peroxide AWT studies, the focus on the mechanism involving multimedia coordination on the NC surface (reactive species (RS) path, electron reduction non-RS pathway, and singlet oxygen non-RS path) has been confined to the one-step electron reaction, leaving the mechanisms of multichannel or continuous electron transfer paths unexplored. Moreover, there are very few studies that have identified the nonfree radical pathway initiated by electron transfer within PAA AWT. In this study, the complete decomposition (kobs = 0.1995) and significant defluorination of perfluorooctanoic acid (PFOA, deF% = 72%) through PAA/NC has been confirmed. Through the use of multiple electrochemical monitors and the exploration of current diffusion effects, the process of electron reception and conduction stimulated by PAA activation was examined, leading to the discovery of the dynamic process from the PAA molecule → NC solid surface → target object. The vital role of prehydrated electrons (epre-) before the entry of resolvable electrons into the aqueous phase was also detailed. To the best of our knowledge, this is the first instance of identifying the nonradical mechanism of continuous electron transfer in PAA-based AWT, which deviates from the previously identified mechanisms of singlet oxygen, single-electron, or double-electron single-path transfer. The pathway, along with the strong reducibility of epre- initiated by this pathway, has been proven to be essential in reducing the need for catalysts and chemicals in AWT.

Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis.

SIGNIFICANCE STATEMENT: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. BACKGROUND: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. METHODS: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234). RESULTS: We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. CONCLUSIONS: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.

Update on the role of genetic factors, environmental factors and allergens in canine atopic dermatitis.

BACKGROUND: Canine atopic dermatitis (cAD) is a common, complex and multifactorial disease involving, among others, genetic predisposition, environmental factors and allergic sensitisation. OBJECTIVE: This review summarises the current evidence on the role of genetic and environmental factors and allergic sensitisation in the pathogenesis of cAD since the last review by ICADA in 2015. MATERIALS AND METHODS: Online citation databases and proceedings from international meetings on genetic factors, environmental factors and allergens relevant to cAD that had been published between 2015 and 2022 were reviewed. RESULTS: Despite intensive research efforts, the detailed genetic background predisposing to cAD and the effect of a wide range of environmental factors still need more clarification. Genome-wide association studies and investigations on genetic biomarkers, such as microRNAs, have provided some new information. Environmental factors appear to play a major role. Lifestyle, especially during puppyhood, appears to have an important impact on the developing immune system. Factors such as growing up in a rural environment, large size of family, contact with other animals, and a nonprocessed meat-based diet may reduce the risk for subsequent development of cAD. It appears that Toxocara canis infection may have a protective effect against Dermatophagoides farinae-induced cAD. House dust mites (D. farinae and D. pteronyssinus) remain the most common allergen group to which atopic dogs react. Currently, the major allergens related to D. farinae in dogs include Der f 2, Der f 15, Der f 18 and Zen 1. CONCLUSIONS AND CLINICAL RELEVANCE: Canine atopic dermatitis remains a complex, genetically heterogeneous disease that is influenced by multiple environmental factors. Further, well-designed studies are necessary to shed more light on the role of genetics, environmental factors and major allergens in the pathogenesis of cAD.

Update on the skin barrier, cutaneous microbiome and host defence peptides in canine atopic dermatitis.

BACKGROUND: Canine atopic dermatitis (AD) is a complex inflammatory skin disease associated with cutaneous microbiome, immunological and skin barrier alterations. This review summarises the current evidence on skin barrier defects and on cutaneous microbiome dysfunction in canine AD. OBJECTIVE: To this aim, online citation databases, abstracts and proceedings from international meetings on skin barrier and cutaneous microbiome published between 2015 and 2023 were reviewed. RESULTS: Since the last update on the pathogenesis of canine AD, published by the International Committee on Allergic Diseases of Animals in 2015, 49 articles have been published on skin barrier function, cutaneous/aural innate immunity and the cutaneous/aural microbiome in atopic dogs. Skin barrier dysfunction and cutaneous microbial dysbiosis are essential players in the pathogenesis of canine AD. It is still unclear if such alterations are primary or secondary to cutaneous inflammation, although some evidence supports their primary involvement in the pathogenesis of canine AD. CONCLUSION AND CLINICAL RELEVANCE: Although many studies have been published since 2015, the understanding of the cutaneous host-microbe interaction is still unclear, as is the role that cutaneous dysbiosis plays in the development and/or worsening of canine AD. More studies are needed aiming to design new therapeutic approaches to restore the skin barrier, to increase and optimise the cutaneous natural defences, and to rebalance the cutaneous microbiome.

Treatment of moderate-to-severe canine atopic dermatitis with modified-release mycophenolate (OKV-1001): A pilot open-label, single-arm multicentric clinical trial.

BACKGROUND: Mycophenolate is an immunomodulating agent successfully used for the treatment of moderate-to-severe atopic dermatitis (AD) in people. Mycophenolate is an effective steroid-sparing treatment option for use in dogs with inflammatory skin diseases. OBJECTIVE: To evaluate whether once-daily modified-release mycophenolate (OKV-1001) is safe and effective for treating moderate-to-severe canine AD. ANIMALS: Client-owned atopic dogs (n = 9) were enrolled. MATERIALS AND METHODS: In an open-label multicentre pilot study, OKV-1001 (30 mg/kg every 24 h) was given orally for ≤84 days. Concomitant tapering doses of glucocorticoids were administered up to Day (D)28. Clinicians assessed Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04) on D0, D14, D28, D56 and D84. Body weight and clinical pathological parameters were measured at baseline and at the end of the study. RESULTS: Treatment with OKV-1001 combined with glucocorticoids significantly reduced the severity of AD within two weeks in seven of nine (77.8%) dogs. The mean percentage change from baseline in the CADESI-04 score was 29% (p = 0.009) at D14 (n = 9), 39% (p = 0.008) at D28 (n = 9) and 49% (p = 0.03) at D56 (n = 7) at which point glucocorticoids had been withdrawn. In two dogs the improvement in CADESI-04 was 62% and 23% (respectively) on D84. No significant adverse events including clinical pathological findings were reported. CONCLUSIONS AND CLINICAL RELEVANCE: Modified-release mycophenolate (OKV-1001) may represent a promising alternative treatment option for dogs with moderate-to-severe AD. The safety and efficacy profile of OKV-1001 will need to be established in larger, placebo-controlled clinical trials.

Update on the role of cytokines and chemokines in canine atopic dermatitis.

BACKGROUND: Cytokines and chemokines play central roles in the pathogenesis of canine atopic dermatitis (cAD). Numerous studies have been published and provide new insights into their roles in cAD. OBJECTIVES: To summarise the research updates on the role of cytokines and chemokines in the pathogenesis of cAD since the last review by the International Committee on Allergic Diseases of Animals in 2015. MATERIAL AND METHODS: Online citation databases, abstracts and proceedings from international meetings on cytokines and chemokines relevant to cAD that had been published between 2015 and 2022 were reviewed. RESULTS: Advances in technologies have allowed the simultaneous analysis of a broader range of cytokines and chemokines, which revealed an upregulation of a multipolar immunological axis (Th1, Th2, Th17 and Th22) in cAD. Most studies focused on specific cytokines, which were proposed as potential novel biomarkers and/or therapeutic targets for cAD, such as interleukin-31. Most other cytokines and chemokines had inconsistent results, perhaps as a consequence of their varied involvement in the pathogenesis of different endotypes of cAD. CONCLUSIONS AND CLINICAL RELEVANCE: Inconsistent results for many cytokines and chemokines illustrate the difficulty of studying the complex cytokine and chemokine networks in cAD, and highlight the need for more comprehensive and structured studies in the future.

Successful definitive radiation treatment of refractory canine oral papillomatosis.

This case report describes a three-year-old male intact border collie diagnosed with canine papillomavirus type 1 (CPV-1+) oral papillomas resistant to standard-of-care. With time, he developed lesions consistent with squamous cell carcinoma. Malignant tumors were incompletely excised and treated with definitive external beam radiation therapy (45 Gy, 3 Gy × 15 daily). The remaining oral cavity received 27 Gy (1.8 Gy x 15 daily) to treat the disseminated oral papillomatosis. A temporary treatment delay of 2 weeks was instituted due to grade 3 mucositis. The patient remained in complete remission after 10 months from radiotherapy. No tumor recurrences were noted by the owners after >1 year from treatment.

Prevalence of multidrug-resistant coagulase-positive staphylococci in canine and feline dermatological patients over a 10-year period: a retrospective study.

Coagulase-positive staphylococci (CPS) are common cutaneous pathogens often requiring multiple courses of antibiotics, which may facilitate selection for methicillin-resistant (MR) and/or multidrug-resistant (MDR) strains. To determine the prevalence of canine and feline MR/MDR CPS associated with skin diseases, medical records were retrospectively searched from April 2010 to April 2020. Pets with at least one positive culture for CPS were selected. Age, sex, antimicrobial sensitivity, previous history of antimicrobial/immunomodulatory medications and methicillin resistance/multidrug resistance status were recorded. Staphylococcus pseudintermedius (SP) (575/748) and Staphylococcus schleiferi (SS) (159/748) in dogs, and Staphylococcus aureus (12/22) in cats, were the most common CPS isolated. Three hundred and twenty-three out of 575 isolates were MR-SP (56.2 %), 304/575 were MDR-SP (52.8 %), 100/159 were MR-SS (62.9 %) and 71/159 were MDR-SS (44.6 %). A trend analysis showed a significant increase of resistance to oxacillin and chloramphenicol for S. pseudintermedius (r=0.86, 0.8; P=0.0007, 0.0034, respectively). Major risk factors for MDR-SP included oxacillin resistance (OR: 3; 95 % CI: 1.4-6.5; P=0.0044), positivity for PBP2a (OR: 2.3; 95 % CI: 1-5; P=0.031) and use of antibiotics in the previous year (OR: 2.8; 95 % CI: 1.3-5.8; P=0.0071). Oxacillin resistance was identified as a major risk factor for MDR-SS (OR: 8.8; 95 % CI: 3.6-21.1; P<0.0001). These results confirmed the widespread presence of MR/MDR CPS in referred dermatological patients. Judicious antibiotic use, surveillance for MR/MDR infections and consideration of alternative therapies are crucial in mitigating the development of resistant strains.

Modeling Antibiotic Concentrations in the Vicinity of Antibiotic-Producing Bacteria at the Micron Scale.

It is generally thought that antibiotics confer upon the producing bacteria the ability to inhibit or kill neighboring microorganisms, thereby providing the producer with a significant competitive advantage. Were this to be the case, the concentrations of emitted antibiotics in the vicinity of producing bacteria might be expected to fall within the ranges of MICs that are documented for a number of bacteria. Furthermore, antibiotic concentrations that bacteria are punctually or chronically exposed to in environments harboring antibiotic-producing bacteria might fall within the range of minimum selective concentrations (MSCs) that confer a fitness advantage to bacteria carrying acquired antibiotic resistance genes. There are, to our knowledge, no available in situ measured antibiotic concentrations in the biofilm environments that bacteria typically live in. The objective of the present study was to use a modeling approach to estimate the antibiotic concentrations that might accumulate in the vicinity of bacteria that are producing an antibiotic. Fick's law was used to model antibiotic diffusion using a series of key assumptions. The concentrations of antibiotics within a few microns of single producing cells could not reach MSC (8 to 16 µg/L) or MIC (500 µg/L) values, whereas the concentrations around aggregates of a thousand cells could reach these concentrations. The model outputs suggest that single cells could not produce an antibiotic at a rate sufficient to achieve a bioactive concentration in the vicinity, whereas a group of cells, each producing the antibiotic, could do so. IMPORTANCE It is generally assumed that a natural function of antibiotics is to provide their producers with a competitive advantage. If this were the case, sensitive organisms in proximity to producers would be exposed to inhibitory concentrations. The widespread detection of antibiotic resistance genes in pristine environments suggests that bacteria are indeed exposed to inhibitory antibiotic concentrations in the natural world. Here, a model using Fick's law was used to estimate potential antibiotic concentrations in the space surrounding producing cells at the micron scale. Key assumptions were that per-cell production rates drawn from the pharmaceutical manufacturing industry are applicable in situ, that production rates were constant, and that produced antibiotics are stable. The model outputs indicate that antibiotic concentrations in proximity to aggregates of a thousand cells can indeed be in the minimum inhibitory or minimum selective concentration range.

The risks associated with percutaneous native kidney biopsies: a prospective study.

BACKGROUND: The known risks and benefits of native kidney biopsies are mainly based on the findings of retrospective studies. The aim of this multicentre prospective study was to evaluate the safety of percutaneous renal biopsies and quantify biopsy-related complication rates in Italy. METHODS: The study examined the results of native kidney biopsies performed in 54 Italian nephrology centres between 2012 and 2020. The primary outcome was the rate of major complications 1 day after the procedure, or for longer if it was necessary to evaluate the evolution of a complication. Centre and patient risk predictors were analysed using multivariate logistic regression. RESULTS: Analysis of 5304 biopsies of patients with a median age of 53.2 years revealed 400 major complication events in 273 patients (5.1%): the most frequent was a ≥2 g/dL decrease in haemoglobin levels (2.2%), followed by macrohaematuria (1.2%), blood transfusion (1.1%), gross haematoma (0.9%), artero-venous fistula (0.7%), invasive intervention (0.5%), pain (0.5%), symptomatic hypotension (0.3%), a rapid increase in serum creatinine levels (0.1%) and death (0.02%). The risk factors for major complications were higher plasma creatinine levels [odds ratio (OR) 1.12 for each mg/dL increase, 95% confidence interval (95% CI) 1.08-1.17], liver disease (OR 2.27, 95% CI 1.21-4.25) and a higher number of needle passes (OR for each pass 1.22, 95% CI 1.07-1.39), whereas higher proteinuria levels (OR for each g/day increase 0.95, 95% CI 0.92-0.99) were protective. CONCLUSIONS: This is the first multicentre prospective study showing that percutaneous native kidney biopsies are associated with a 5% risk of a major post-biopsy complication. Predictors of increased risk include higher plasma creatinine levels, liver disease and a higher number of needle passes.

Dose-Response Behavior of Pathogens and Surrogate Microorganisms across the Ultraviolet-C Spectrum: Inactivation Efficiencies, Action Spectra, and Mechanisms.

The dose-response behavior of pathogens and inactivation mechanisms by UV-LEDs and excimer lamps remains unclear. This study used low-pressure (LP) UV lamps, UV-LEDs with different peak wavelengths, and a 222 nm krypton chlorine (KrCl) excimer lamp to inactivate six microorganisms and to investigate their UV sensitivities and electrical energy efficiencies. The 265 nm UV-LED had the highest inactivation rates (0.47-0.61 cm2/mJ) for all tested bacteria. The bacterial sensitivity strongly fitted the absorption curve of nucleic acids at wavelengths of 200-300 nm; however, indirect damage induced by reactive oxygen species (ROS) was the leading cause of bacterial inactivation under 222 nm UV irradiation. In addition, the guanine and cytosine (GC) content and cell wall constituents of bacteria affect inactivation efficiency. The inactivation rate constant of Phi6 (0.13 ± 0.002 cm2/mJ) at 222 nm due to lipid envelope damage was significantly higher than other UVC (0.006-0.035 cm2/mJ). To achieve 2log reduction, the LP UV lamp had the best electrical energy efficiency (required less energy, average 0.02 kWh/m3) followed by 222 nm KrCl excimer lamp (0.14 kWh/m3) and 285 nm UV-LED (0.49 kWh/m3).

Common superficial and deep cutaneous bacterial infections in domestic animals: A review.

The skin covers the external surface of animals, and it is constantly exposed to and inhabited by different microorganisms, including bacteria. Alterations in the skin barrier allow commensal and/or pathogenic bacteria to proliferate and penetrate deep into the lower layers of the skin. Being the first barrier to the external environment, the skin is prone to injuries, allowing the penetration of microorganisms that may lead to severe deep infections. Companion animals, especially dogs, are prone to bacterial infections, often secondary to allergic dermatitis. When environmental conditions are unfavorable, horses, cattle, sheep, and goats can develop superficial infections, such as those caused by Dermatophilus congolensis. Deep inflammation is commonly caused by Mycobacterium spp., which results in granulomatous to pyogranulomatous dermatitis and panniculitis. Likewise, bacteria such as Nocardia spp. and Actinomyces spp. can cause deep pyogranulomatous inflammation. Bacteria that lead to deep necrotizing lesions (eg, necrotizing fasciitis/flesh-eating bacteria) can be severe and even result in death. This review includes an overview of the most common cutaneous bacterial infections of domestic animals, highlighting the main features and histologic morphology of the bacteria, cutaneous structures involved, and the type of inflammatory infiltrates.

Comparison of the quantity and antimicrobial activity of host defence peptides in ear canals between healthy and atopic dogs: A preliminary study.

BACKGROUND: Host defence peptides (HDPs) are involved in cutaneous immune defence. The secretion of HDPs in the ears of healthy normal and noninfected atopic dogs has not been measured. HYPOTHESES/OBJECTIVES: The aim of this study was to quantify the concentrations of ß-defensins (cBD3)-like and cathelicidin (cCath) HDPs in ears of healthy and atopic dogs without infectious otitis, additionally to evaluate the antimicrobial effect of the HDPs obtained. ANIMALS: Ten healthy and 20 atopic dogs with mild inflammatory, noninfectious otitis were included. MATERIALS AND METHODS: Absence of infection was determined by cytological evaluation, and the severity of clinical signs, if present, was assessed by a previously validated score (Otitis Externa Scoring System for Clinical Study, OTIS-3). The left ear canal of each dog was rinsed with 2 mL of sodium phosphate buffer. The solution obtained was analysed by enzyme-linked immunosorbent assay to quantify HDPs. Additionally, aural secretions were incubated with two concentrations (5 × 105 and 5 × 104 colony-forming units/mL) of Staphylococcus pseudintermedius and the bacterial density measured after 24 h of incubation. Data were statistically analysed. Significance was set as p ≤ 0.05. RESULTS: There was a significantly lower concentration of HDPs from atopic ears when compared with those from normal healthy dogs (cBD3-like: p = 0.0007; cCath: p = 0.049). There was minimal to variable antimicrobial activity in the aural secretions of both groups. CONCLUSIONS AND CLINICAL RELEVANCE: This study showed, for the first time, that the ear canals of atopic dogs with mild noninfectious otitis contain a lower concentration of cBD3-like and cCath HDPs than those of healthy dogs with normal ears. A consistent antimicrobial activity was not present in the aural secretions from either group.

Efficacy of a spot-on combination of fluralaner plus moxidectin against naturally acquired Sarcoptes scabiei infestation in 10 pet rabbits: Retrospective case series.

BACKGROUND: Current treatments for sarcoptic mange in rabbits mainly include administration of avermectines every 10-30 days. Recently, a single oral dose of fluralaner has been shown to be effective to treat sarcoptic mange in 12 pet rabbits over a three-month period. OBJECTIVES: To retrospectively assess the efficacy of a spot-on combination of fluralaner plus moxidectin (Bravecto Plus) for the treatment of sarcoptic mange in rabbits. ANIMALS: Ten client-owned rabbits diagnosed with sarcoptic mange. MATERIALS AND METHODS: An application of fluralaner plus moxidectin at an average dose of 25 mg/kg and 1.24 mg/kg, respectively, was administered topically once. Parasitological and dermatological examination was carried out weekly for one month and monthly for three months. RESULTS: The median age at diagnosis was 15 (range 3-48) months. Based on the age of onset, there were three juvenile (<6-month-old) and seven adult-onset cases. Of those, four were generalized (head, feet and/or genital area) and six were localized form (head only). The combination of fluralaner plus moxidectin resulted in 100% eradication of mites and complete resolution of all skin lesions within 21 days. Recurrence was not observed 90 days post-treatment. Relapse was not observed in one case followed up for a further four months and two rabbits followed up for a further six months. The other pets were lost to follow-up. CONCLUSIONS AND CLINICAL RELEVANCE: These results indicated that a single dose of a formulation containing fluralaner plus moxidectin, at 25 mg/kg and 1.24 mg/kg, respectively, was effective for the treatment of naturally occurring sarcoptic mange in rabbits.

How to Choose the Right Treatment for Membranous Nephropathy.

Membranous nephropathy is an autoimmune disease affecting the glomeruli and is one of the most common causes of nephrotic syndrome. In the absence of any therapy, 35% of patients develop end-stage renal disease. The discovery of autoantibodies such as phospholipase A2 receptor 1, antithrombospondin and neural epidermal growth factor-like 1 protein has greatly helped us to understand the pathogenesis and enable the diagnosis of this disease and to guide its treatment. Depending on the complications of nephrotic syndrome, patients with this disease receive supportive treatment with diuretics, ACE inhibitors or angiotensin-receptor blockers, lipid-lowering agents and anticoagulants. After assessing the risk of progression of end-stage renal disease, patients receive immunosuppressive therapy with various drugs such as cyclophosphamide, steroids, calcineurin inhibitors or rituximab. Since immunosuppressive drugs can cause life-threatening side effects and up to 30% of patients do not respond to therapy, new therapeutic approaches with drugs such as adrenocorticotropic hormone, belimumab, anti-plasma cell antibodies or complement-guided drugs are currently being tested. However, special attention needs to be paid to the choice of therapy in secondary forms or in specific clinical contexts such as membranous disease in children, pregnant women and patients undergoing kidney transplantation.

Evidence for charge-based mimicry in anti dsDNA antibody generation.

Mechanisms for the generation of anti-dsDNA autoantibodies are still not completely elucidated. One theory states that dsDNA interacts for mimicry with antibodies raised versus other antigens but molecular features for mimicry are unknown. Here we show that, at physiological acid-base balance, anti-Annexin A1 binds IgG2 dsDNA in a competitive and dose-dependent way with Annexin A1 and that the competition between the two molecules is null at pH 9. On the other hand, these findings also show that dsDNA and Annexin A1 interact with their respective antibodies on a strictly pH-dependent basis: in both cases, the binding was minimal at pH 4 and maximal at pH9-10. The anionic charge of dsDNA is mainly conferred by the numerous phosphatidic residues. The epitope binding site of Annexin A1 for anti-Annexin A1 IgG2 was here characterized as a string of 34 amino acids at the NH2 terminus, 10 of which are anionic. Circulating levels of anti-dsDNA and anti-Annexin A1 IgG2 antibodies were strongly correlated in patients with systemic lupus erythematosus (n 496) and lupus nephritis (n 425) stratified for age, sex, etc. These results show that dsDNA competes with Annexin A1 for the binding with anti-Annexin A1 IgG2 on a dose and charged mediated base, being able to display an inhibition up to 75%. This study provides the first demonstration that dsDNA may interact with antibodies raised versus other anionic molecules (anti-Annexin A1 IgG2) because of charge mimicry and this interaction may contribute to anti-dsDNA antibodies generation.

Contactin 1, a Potential New Antigen Target in Membranous Nephropathy: A Case Report.

Several novel antigens have recently been characterized in membranous nephropathy (MN), but those involved in the rare cases of MN associated with inflammatory neuropathies remain elusive. Although several antibodies have been identified in the serum, there is no evidence so far for their deposition in glomeruli. We report the case of a 73-year-old woman who was referred because of subacute onset of proximal asymmetric lower limb weakness together with ataxic gait. She was diagnosed with inflammatory neuropathy. Testing showed an estimated glomerular filtration rate of 73mL/min/1.73m2, hypoalbuminemia (2.89g/dL), and proteinuria (3.6g/d). Autoantibodies (antinuclear antibody, anti-extractable nuclear antigen antibody, anti-double stranded DNA antibody, lupus anticoagulant, anticardiolipin antibody, antineutrophil cytoplasmic antibody) were undetectable. Serum immunoglobulin and complement levels were normal. A kidney biopsy with electron microscopy examination showed a classical picture of MN. Testing for antibodies to phospholipase A2 receptor (PLA2R) gave negative results in the serum, and PLA2R and THSD7A antigens were not detected in kidney tissue. Anti-contactin 1 (CNTN1) antibody was detected by enzyme-linked immunosorbent assay at a 1:100 dilution of serum and shown to be mostly of IgG4 subclass by Western blot. CNTN1 antigen was colocalized with IgG4 within immune deposits by confocal microscopy. This observation suggests a pathophysiological link between inflammatory neuropathies and MN. CNTN1 should be considered as a potential candidate antigen involved in MN and tested in PLA2R-negative forms associated with inflammatory neuropathies.

The DiaCoVAb Study in South Italy: Immune Response to SARS-CoV-2 Vaccination in Dialysis Patients.

INTRODUCTION: Since the pandemic of COVID-19 started from December 2019, remarkable numbers of infections and deaths associated with COVID-19 have been recorded worldwide. End-stage kidney disease patients on dialysis are particularly at high risk of infections due to impairments in the innate and adaptive immune systems. Vaccination on dialysis patients (DP) still remains challenging because of the variable response and a low seroconversion rate compared with healthy participants (HP). Therefore, it is urgently necessary to establish a different vaccination strategy for DP, in terms of the dose and administration time. METHODS: Here, we report an observational prospective cohort study in which the immunogenic efficacies of SARS-CoV-2 vaccine BNT162b2 on DP and HP were evaluated by absolute quantification of IgG levels in the blood. RESULTS: DP showed a delayed seroconversion after two vaccine doses, with a low absolute IgG levels compared to HP. While HP reached complete seroconversion within 10 days from the administration of a second dose, only 76% of DP were seropositive. After the booster dose, DP had a strongly improved seroconversion rate as well as antibody levels, reaching 97% seropositivity and 50 times enhancement on antibody levels. DISCUSSION/CONCLUSION: These results prompt to suggest an additional vaccine dose in DP, reducing the interval of time from the second dose. Since limited data are available on immune response in DP overtime after three vaccine doses currently, our study is among the first reports demonstrating the improved seropositivity and IgG levels in DP after the booster vaccine dose.

Effect of Nanosulfur Against Multidrug-Resistant Staphylococcus pseudintermedius and Pseudomonas aeruginosa.

Multidrug resistance (MDR) has significantly increased in the past decades and the use of nanotechnology has opened new venues for novel treatments. Nanosulfur is a potent antimicrobial agent and a cheaper alternative to other nanomaterials. However, very few studies have been published on its activity against MDR organisms. Therefore, the goal of this in vitro study was to assess cytotoxicity, antimicrobial, and anti-biofilm activity of nanosulfur (47 nm, orthorhombic) against clinical isolates of MDR Staphylococcus pseudintermedius (SP) and Pseudomonas aeruginosa (PA) in planktonic and biofilm state using canine skin explants. Nanosilver (50 nm, spherical) was tested as a comparative control. Concentrations between 1866.7 and 0.11 µg/mL of both nanoparticles were tested. The ultrastructure of nanosulfur was assessed via electron microscopy. Both types of nanoparticles showed no direct cytotoxicity on a canine keratinocyte cell line. In the planktonic phase, nanosulfur was able to inhibit or kill (6-log10 reduction of CFU) 7 of 10 MDR-SP isolates at 233.3 µg/mL, whereas, when in biofilm state, 6 of 10 isolates were killed at different concentrations (233.33 to 1866.7 µg/mL). Nanosilver did not show any antimicrobial or anti-biofilm activity at any concentrations tested. Both types of nanoparticles were ineffective against MDR-PA in either state. Ultrastructurally, nanosulfur was present in individual nanoparticles as well as forming larger nanoclusters. This is the first study showing an antimicrobial and anti-biofilm activity of nanosulfur for MDR-SP in absence of cytotoxicity. Nanosulfur has the potential to be used in veterinary and human medicine as effective, safe, and cheap alternative to antimicrobials and anti-biofilm agents currently available. KEY POINTS: • Nanosulfur is a better alternative than nanosilver to treat MDR-Staphylococci. • Nanosulfur is an effective agent against MDR-Staphyloccocal biofilm. • Canine skin explant model is reliable for testing anti-biofilm agents.

Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial.

BACKGROUND: A cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a head-to-head comparison is lacking. METHODS: We randomly assigned 74 adults with membranous nephropathy and proteinuria >3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events. RESULTS: At 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio [OR], 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen. CONCLUSIONS: This pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-to-head, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), NCT03018535.