The presence of emerging pollutants in the environment is of major concern not only because of the potential negative impact in human health, but also due to the potential toxicity to non-target ...organisms. Within the personal and care products (PCPs), the disinfectant Triclosan (TCS) is one of the most concerning compounds. Once in the wastewater treatment plants (WWTPs), a small part of TCS can be biotransformed into a more persistent by-product: methyl-triclosan (M-TCS). Although several studies have focused on the occurrence of this compound in the water systems, the information on its toxicity to aquatic organisms is very limited. Here, we used embryo bioassays with two aquatic model animals to improve risk assessment of M-TCS; zebrafish (
Danio rerio
) embryo bioassays run up to 144 h post fertilization (hpf) and sea urchin (
Paracentrotus lividus
) up to 48 hpf, following established protocols. M-TCS and TCS exhibited similar toxicity to zebrafish with a NOEC of 160 µg/L. In contrast, M-TCS induced a delay in the development of the sea urchin larvae at all tested concentrations (1–1000 µg/L), whereas NOEC of TCS for
P. lividus
embryos was 40 µg/L. Overall, given the reported effects of M-TCS in the close range of environmentally relevant concentrations, and considering the low degradation rate and tendency to bioaccumulation (logKow: 5.2), further studies are warrant to better characterize the risk of this TCS metabolite to aquatic organisms.
DGCR8 emerged recently as miRNAs biogenesis pathway protein with a highlighted role in thyroid disease. This study aimed to characterize this miRNA biogenesis component, in particular the p.(E518K) ...mutation and DGCR8 expression in a series of thyroid lesions. The series of thyroid lesions was genotyped for the c.1552G>A p.(E518K) mutation. When frozen tissue was available, DGCR8 mRNA expression was analysed by qPCR. Formalin-fixed paraffin-embedded tissues were studied for DGCR8 immunoexpression. We present for the first time the p.(E518K) mutation in a case of poorly differentiated thyroid carcinoma and present the deregulation of DGCR8 expression at mRNA level in follicular-patterned tumours. The obtained data solidify DGCR8 as another important player of miRNA-related gene mutations in thyroid tumorigenesis, particularly in follicular-patterned thyroid tumours.
Introduction/objectives
Acute kidney injury (AKI) with the requirement of kidney replacement therapy (KRT) portends a poor prognosis for kidney function in lupus nephritis (LN). This study evaluated ...the kidney function recovery rates, the rates of reinitiation of KRT, and factors associated with these outcomes in LN.
Method
All consecutive patients hospitalized for LN with KRT requirement between 2000 and 2020 were included. Their clinical and histopathologic characteristics were retrospectively registered. The outcomes and associated factors were evaluated by multivariable Cox regression analysis.
Results
Among 140 patients, 75 (54%) recovered kidney function, with recovery rates of 50.9% and 54.2% by 6 and 12 months of therapy. The factors associated with a lower probability of recovery included a previous history of LN flares, worse eGFR and higher proteinuria at presentation, immunosuppression with azathioprine, and hospitalizations within 6 months of therapy initiation. There was no difference in the kidney function recovery rates between mycophenolate and cyclophosphamide treatment schemes. Out of 75 patients who recovered kidney function, 37 (49%) reinitiated KRT, with KRT reinitiation rates of 27.2% and 46.5% by 3 and 5 years. Seventy-three (52%) patients had at least one hospitalization within 6 months of initial therapy, 52 (72%) of them secondary to infectious events.
Conclusions
Approximately 50% of patients with LN and KRT requirement recover kidney function within 6 months. The risk-to-benefit ratio decisions may be aided by clinical and histological factors. These patients require close follow-up as ≈50% of those who recover kidney function will reinitiate dialysis in the long term.
Key Points
•
Approximately 50% of patients with severe acute lupus nephritis with the need for kidney replacement therapy requirement recover their kidney function.
•
The factors associated with a lower probability of recovery of kidney function include a previous history of LN flares, worse eGFR and higher proteinuria at presentation, immunosuppression with azathioprine, and hospitalizations within 6 months of therapy initiation.
•
Patients who recover kidney function will require close follow-up as around 50% of them will eventually reinitiate kidney replacement therapy.
COVID-19 is currently considered a systemic infection involving multiple systems and causing chronic complications. Compared to other post-viral fatigue syndromes, these complications are wider and ...more intense. The most frequent symptoms are profound fatigue, dyspnea, sleep difficulties, anxiety or depression, reduced lung capacity, memory/cognitive impairment, and hyposmia/anosmia. Risk factors for this condition are severity of illness, more than five symptoms in the first week of the disease, female sex, older age, the presence of comorbidities, and a weak anti-SARS-CoV-2 antibody response. Different lines of research have attempted to explain these protracted symptoms; chronic persistent inflammation, autonomic nervous system disruption, hypometabolism, and autoimmunity may play a role. Due to thyroid high ACE expression, the key molecular complex SARS-CoV-2 uses to infect the host cells, thyroid may be a target for the coronavirus infection. Thyroid dysfunction after SARS-CoV-2 infection may be a combination of numerous mechanisms, and its role in long-COVID manifestations is not yet established. The proposed mechanisms are a direct effect of SARS-CoV-2 on target cells, an indirect effect of systemic inflammatory immune response, and a dysfunction of the hypothalamic-pituitary-thyroid (HPT) axis leading to decreased serum TSH. Only a few studies have reported the thyroid gland status in the post-COVID-19 condition. The presence of post-COVID symptoms deserves recognition of COVID-19 as a cause of post-viral fatigue syndrome. It is important to recognize the affected individuals at an early stage so we can offer them the most adequate treatments, helping them thrive through the uncertainty of their condition.
Introduction/Objectives
The heterodimer exostosin-1/exostosin-2 (EXO-1/2) is a novel antigen observed in membranous nephropathy associated with systemic lupus erythematosus. This study aimed to ...evaluate the association between EXO-1/2 positivity in kidney biopsy and kidney outcomes.
Methods
The kidney biopsy tissue from 50 class 5 lupus nephritis (LN) and 55 mixed class 3/4 + 5 LN patients was stained for EXO-1/2. Baseline clinical and histological characteristics were compared between EXO-1/2 positive and EXO-1/2 negative patients. Time-to-event analyses were performed to compare rates of response to therapy, kidney flares, and progression to a 40% decline of the glomerular filtration rate (eGFR), doubling of serum creatinine, and kidney failure.
Results
Fourteen out of 50 (28%) of class 5 and 5 out of 55 (9%) of mixed class 3/4 + 5 LN stained positive for EXO-1/2. Patients with class 5 LN and EXO-1/2 positive stain were younger, with better kidney function at presentation, and lower scarring in the kidney biopsy analysis. Over a median follow-up of 100 months, patients with positive EXO-1/2 staining had significantly lower rates of progression in the full cohort. When analyzed separately in class 5 and mixed class LN subgroups, there were significantly lower rates of progression to a 40% decline of the eGFR and non-statistically significant trends for doubling of serum creatinine and kidney failure.
Conclusion
EXO-1/2 is a novel antigen detected in class 5 LN and associated with a good prognosis of kidney function. The incorporation of EXO-1/2 staining in clinical practice can potentially modify the management of LN due to its prognostic implications.
Key Points
•
Exostosin-1/exostosin-2 antigen has been found in cases of membranous nephropathy associated with autoimmune diseases such as systemic lupus erythematosus.
•
Exostosin-1/exostosin-2 staining in the kidney biopsy of class 5 or mixed class 3/4
+
5 lupus nephritis is associated with a good long-term prognosis of kidney function.
•
The incorporation of exostosin-1/exostosin-2 staining into clinical practice can potentially modify management due to its prognostic implications.
Cutaneous basal cell carcinoma (cBCC) is an economic burden to health services, due to its great morbidity and increasing incidence in old people. Infiltrative cBCCs and cBCCs with micronodular ...pattern are considered as more aggressive. The role of p53 expression and TERTp mutation on cBCC behavior remains to be clarified. We aimed to assess TERTp mutations and p53 expression in relation to the cBCC histological subtype in a cohort of patients referred to an ENT Department of a tertiary Hospital of Northern Portugal. We performed a retrospective clinicopathological and histological review of the head and neck cBCCs followed-up at the otorhinolaryngology department of Trás-os-Montes e Alto Douro hospital (January 2007-June 2018). We assessed TERTp mutations in 142 cBCCs and p53 protein expression, through immunohistochemistry, in 157 cBCCs. We detected TERTp mutations in 43.7% of cBCCs and p53 overexpression in 60.5% of cBCCs. We spotted association of p53 overexpression and TERTp mutation with necrosis. In the infitrative-growth pattern cBCCs, there was no significant association with the clinical and histological features evaluated, except for necrosis. In the indolent-growth cBCCs, we identified a significant association of TERTp mutation status with female sex, necrosis, multiple cBCCs, and p53 positive expression. Our results suggest that TERTp mutation may be useful to identify more aggressive features in the indolent-growth pattern cBCCs (nodular and superficial subtypes). Further studies with larger cohorts are warranted to clarify the relevance of TERTp mutation in cBCCs.
6-Hydroxynicotinic acid 3-monooxygenase (NicC) is a bacterial enzyme involved in the degradation of nicotinic acid. This enzyme is a Class A flavin-dependent monooxygenase that catalyzes a unique ...decarboxylative hydroxylation. The unliganded structure of this enzyme has previously been reported and studied using steady- and transient-state kinetics to support a comprehensive kinetic mechanism. Here we report the crystal structure of the H47Q NicC variant in both a ligand-bound (solved to 2.17 Å resolution) and unliganded (1.51 Å resolution) form. Interestingly, in the liganded form, H47Q NicC is bound to 2-mercaptopyridine (2-MP), a contaminant present in the commercial stock of 6-mercaptopyridine-3-carboxylic acid(6-MNA), a substrate analogue. 2-MP binds weakly to H47Q NicC and is not a substrate for the enzyme. Based on kinetic and thermodynamic characterization, we have fortuitously captured a catalytically inactive H47Q NicC•2-MP complex in our crystal structure. This complex reveals interesting mechanistic details about the reaction catalyzed by 6-hydroxynicotinic acid 3-monooxygenase.
Objectives
The present study aims to assess the course of uMCP-1 and its association with response to therapy and long-term kidney function in a prospective cohort of adults who received a kidney ...biopsy for suspicion of active lupus nephritis (LN).
Methods
Subjects were segregated into a histologically active LN group and a histologically chronic LN group. Both groups were followed for > = 36 months and urine were collected at flare, 3, 6, and 12 months of follow-up. The association between the course of uMCP-1, response to treatment, and progression to 30% loss of the eGFR was evaluated by linear mixed models for repeated measures.
Results
A kidney biopsy was performed on 125 subjects. In 114, the report was consistent with histologically active LN; in 11, with histologically chronic LN. Urine MCP-1 levels were significantly higher in the active LN than in the chronic LN group. Urine MCP-1 levels correlated with the histological findings of cellular crescents, endocapillary hypercellularity, interstitial inflammation, glomerular sclerosis, interstitial fibrosis, and tubular atrophy. The mean estimates of uMCP-1 at flare were higher in the non-response group than in the complete response group, and decreased in the complete/partial response groups by the third month, while they remained elevated in the non-response group. The mean estimates for uMCP-1 were higher at LN flare and remained elevated in patients who progressed to loss of 30% of the eGFR, while they decreased in patients with stable kidney function.
Conclusion
The first-year course of uMCP-1 is associated with response to therapy and kidney survival in LN.
Key Points
•
Urine MCP-1 levels differentiate histologically-active lupus nephritis from histologically-chronic lupus nephritis
•
Urine MCP-1 levels decrease by 3 months of therapy in subjects with a favorable response whose kidney function remains stable long-term
•
Urine MCP-1 levels remain elevated during the first year of therapy in subjects the will later lose kidney function
Abstract Objectives To evaluate the effect of antimalarial drugs in response to therapy, incidence of LN flares, and progression of kidney disease in a large LN cohort. Methods We retrospectively ...studied 424 biopsy-proven LN patients followed for >3 years. We obtained demographic, clinical, laboratory, histopathological and treatment variables. Antimalarial use was approached as (i) users vs no users, (ii) according to prevalent vs incident use regarding the LN flare and (iii) according to the type of antimalarial. All outcomes were evaluated by time-to-event analyses. Adjusted hazard ratios were obtained by Cox regression. Results The cohort included 424 patients, median age of 29 years (IQR 23–37), 96% female, with a median eGFR of 81 ml/min/1.73 m2 (IQR 48–118) and proteinuria of 3.4 g/g (IQR 1.9–5.5). Antimalarial use was associated with higher complete response (aHR 1.57, 1.08–2.27), lower incidence of kidney flares (aHR 0.63, 0.43–0.92) and lower progression to kidney failure (aHR 0.37, 0.23–0.53). The effect of antimalarials on these outcomes was modified by the presentation eGFR, histological class and/or concomitant initial immunosuppressor. These protective effects were observed in patients with prevalent or incident use regarding the LN flare and patients using hydroxychloroquine. The incidence of toxic retinopathy was 1.7%, 5.7% and 8.8% by 3, 5 and 7 years of continued antimalarial use, respectively. Conclusion The use of antimalarial drugs is associated with increased response to therapy, lower incidence of kidney flares, and lower progression to kidney failure in LN patients. Conversely, this population is at high risk of toxic maculopathy, and yearly ophthalmologic examination is recommended.
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