Innately expressed estrogen-related receptors in the skeletal muscle are indispensable for exercise fitness.

Transcriptional determinants in the skeletal muscle that govern exercise capacity, while poorly defined, could provide molecular insights into how exercise improves fitness. Here, we have elucidated the role of nuclear receptors, estrogen-related receptor alpha and gamma (ERRα/γ) in regulating myofibrillar composition, contractility, and exercise capacity in skeletal muscle. We used muscle-specific single or double (DKO) ERRα/γ knockout mice to investigate the effect of ERRα/γ deletion on muscle and exercise parameters. Individual knockout of ERRα/γ did not have a significant impact on the skeletal muscle. On the other hand, DKO mice exhibit pale muscles compared to wild-type (WT) littermates. RNA-seq analysis revealed a predominant decrease in expression of genes linked to mitochondrial and oxidative metabolism in DKO versus WT muscles. DKO muscles exhibit marked repression of oxidative enzymatic capacity, as well as mitochondrial number and size compared to WT muscles. Mitochondrial function is also impaired in single myofibers isolated from DKO versus WT muscles. In addition, mutant muscles exhibit reduced angiogenic gene expression and decreased capillarity. Consequently, DKO mice have a significantly reduced exercise capacity, further reflected in poor fatigue resistance of DKO mice in in vivo contraction assays. These results show that ERRα and ERRγ together are a critical link between muscle aerobic capacity and exercise tolerance. The ERRα/γ mutant mice could be valuable for understanding the long-term impact of impaired mitochondria and vascular supply on the pathogenesis of muscle-linked disorders.

Banff Human Organ Transplant Transcripts Correlate with Renal Allograft Pathology and Outcome: Importance of Capillaritis and Subpathologic Rejection.

BACKGROUND: To seek insights into the pathogenesis of chronic active antibody-mediated rejection (CAMR), we performed mRNA analysis and correlated transcripts with pathologic component scores and graft outcomes. METHODS: We utilized the NanoString nCounter platform and the Banff Human Organ Transplant gene panel to quantify transcripts on 326 archived renal allograft biopsy samples. This system allowed correlation of transcripts with Banff pathology scores from the same tissue block and correlation with long-term outcomes. RESULTS: The only pathology score that correlated with AMR pathways in CAMR was peritubular capillaritis (ptc). C4d, cg, g, v, i, t, or ci scores did not correlate. DSA-negative CAMR had lower AMR pathway scores than DSA-positive CAMR. Transcript analysis in non-CAMR biopsies yielded evidence of increased risk of later CAMR. Among 108 patients without histologic CAMR, 23 developed overt biopsy-documented CAMR within 5 years and as a group had higher AMR pathway scores (P=3.4 × 10-5). Random forest analysis correlated 3-year graft loss with elevated damage, innate immunity, and macrophage pathway scores in CAMR and TCMR. Graft failure in CAMR was associated with TCMR transcripts but not with AMR transcripts, and graft failure in TCMR was associated with AMR transcripts but not with TCMR transcripts. CONCLUSIONS: Peritubular capillary inflammation and DSA are the primary drivers of AMR transcript elevation. Transcripts revealed subpathological evidence of AMR, which often preceded histologic CAMR and subpathological evidence of TCMR that predicted graft loss in CAMR.

Mercury Speciation in Whole Blood and Dried Blood Spots from Capillary and Venous Sources.

There is interest in measuring total mercury (THg) and methylmercury (MeHg) in dried blood spots (DBS) though more research is required to evaluate mercury (Hg) speciation in DBS and to validate the agreement between blood sources (venous vs capillary) and matrices (whole blood vs DBS). Therefore, the present study aimed to develop, evaluate, and validate a DBS-based method to assess MeHg and inorganic mercury (InHg) exposure in human population studies. First, we used volume-controlled (40 µL) paired DBS-whole blood samples to develop an analytical method that involved the extraction and quantification of MeHg and InHg with gas chromatography-cold vapor atomic fluorescence spectrometry (GC-CVAFS). Next, we carried out a validation study using paired DBS-whole blood samples from venous and capillary sources from 49 volunteers with Hg exposures similar to background populations (i.e., MeHg in venous whole blood ranged from 0.2 to 3 µg/L with a median value of 0.8). The limits of detection were higher for InHg (1.9 and 1.1 µg/L in DBS and whole blood, respectively) than MeHg (0.3 and 0.2 µg/L in DBS and whole blood, respectively). The MeHg concentrations among blood sources and matrices were highly correlated (r ranged from 0.85 to 0.95), with no constant bias (intercept ranged from -0.05 to 0.13 µg/L) and small proportional bias (slopes ranged from 0.92 to 1.08). Bland-Altman plots indicated little bias between MeHg measurements with 82-98% of the cases meeting the analytical acceptance criterion of 35% maximum allowed difference. Our results indicate that measures of MeHg in capillary DBS reflect concentrations in the gold standard (i.e., venous whole blood) and that DBS is a suitable tool for assessing MeHg exposure in human population studies, but that more work is required to assess InHg exposures.

Acid suppression therapy, gastrointestinal bleeding and infection in acute pancreatitis - An international cohort study.

BACKGROUND: Acid suppressing drugs (ASD) are generally used in acute pancreatitis (AP); however, large cohorts are not available to understand their efficiency and safety. Therefore, our aims were to evaluate the association between the administration of ASDs, the outcome of AP, the frequency of gastrointestinal (GI) bleeding and GI infection in patients with AP. METHODS: We initiated an international survey and performed retrospective data analysis on AP patients hospitalized between January 2013 and December 2018. RESULTS: Data of 17,422 adult patients with AP were collected from 59 centers of 23 countries. We found that 23.3% of patients received ASDs before and 86.6% during the course of AP. ASDs were prescribed to 57.6% of patients at discharge. ASD administration was associated with more severe AP and higher mortality. GI bleeding was reported in 4.7% of patients, and it was associated with pancreatitis severity, mortality and ASD therapy. Stool culture test was performed in 6.3% of the patients with 28.4% positive results. Clostridium difficile was the cause of GI infection in 60.5% of cases. Among the patients with GI infections, 28.9% received ASDs, whereas 24.1% were without any acid suppression treatment. GI infection was associated with more severe pancreatitis and higher mortality. CONCLUSIONS: Although ASD therapy is widely used, it is unlikely to have beneficial effects either on the outcome of AP or on the prevention of GI bleeding during AP. Therefore, ASD therapy should be substantially decreased in the therapeutic management of AP.

Information and Communication Technology, Mobile Devices, and Medical Education.

Information and communication technologies (ICT) are practical and highly available tools. In medical education, ICTs allow physicians to update their knowledge and remember the necessary information within reach of current mobile devices. ICTs as preparation tools for medical education have not been reported for medical students in Mexico. To assess the use of mobile devices as ICTs with medical education purposes, we distributed a questionnaire through an online survey management system to all the medical students (n = 180) from a private university in Mexico City, 100% agreed to participate. We developed a questionnaire based on previous surveys and adapted it to our university. All participants reported possession of an electronic mobile device, and 95% used it regularly for learning purposes. Regardless of the school year, the most frequent usage given to these devices was the search and reading of medical articles, the use of medical calculators, and taking notes. As the levels in career advances, there was a reduction in the use of electronic devices. According to the students, the main barriers towards using mobile devices for learning purposes were both the lack of access to the Internet and permission from the professor to use them. Most medical students use mobile devices for learning purposes, but usage changes during their education. It is convenient to encourage the use of mobile devices and the development of ICT skills as tools for educational purposes rather than banning their use in schools and hospitals.

Development and application of a novel method to characterize methylmercury exposure in newborns using dried blood spots.

BACKGROUND: Methylmercury (MeHg) is a pollutant of global concern. While there is a need to gauge early-life exposures, there remain outstanding ethical, financial, and practical challenges with using the preferred biomarker, whole blood, notably in pregnant women, infants, toddlers, and children. Dried bloodspots (DBS) may help overcome some of these challenges. Notably DBS are collected from newborns in many jurisdictions offering an institutionalized platform to efficiently characterize exposures. OBJECTIVE: To develop, validate, and apply a new method to measure MeHg levels in DBS with a specific aim to use this method to increase understanding of newborn exposures. METHODS: Method development and validation was pursued by consulting U.S. EPA Method 1630 and other resources. The method was applied to measure MeHg levels in DBS from newborns (n = 675) from the Michigan BioTrust for Health program. RESULTS: The assay's detection limit (0.3µg/L), accuracy (96-115% of expected), precision, linearity, and range met performance criteria guidelines. In the newborn DBS samples, the mean (SD) and geometric mean values of MeHg were 1.46 (0.90) and 1.25µg/L respectively, and ranged from 0.09 to 9.97µg/L. The values we report here are similar to cord blood mercury values reported elsewhere. CONCLUSIONS: This is the first characterization of MeHg exposure in newborns, and thus fills an important data gap as prior studies have focused on pregnant women, cord blood, or toddlers. This method helps overcome technical challenges associated with other proposed approaches, and moving ahead there is great promise for applying this DBS-based method for population-level surveillance, particularly in resource-limited settings and for children's health.

Estrogen-Related Receptor Gamma Gene Therapy Promotes Therapeutic Angiogenesis and Muscle Recovery in Preclinical Model of PAD.

Background Peripheral arterial disease and critical limb ischemia are cardiovascular complications associated with vascular insufficiency, oxidative metabolic dysfunction, and myopathy in the limbs. Estrogen-related receptor gamma (ERRγ) has emerged as a dual regulator of paracrine angiogenesis and oxidative metabolism through transgenic mouse studies. Here our objective was to investigate whether postischemic intramuscular targeting of ERRγ via gene therapy promotes ischemic recovery in a preclinical model of peripheral arterial disease/critical limb ischemia. Methods and Results Adeno-associated virus 9 (AAV9) Esrrg gene delivery vector was developed and first tested via intramuscular injection in murine skeletal muscle. AAV9-Esrrg robustly increased ERRγ protein expression, induced angiogenic and oxidative genes, and boosted capillary density and succinate dehydrogenase oxidative metabolic activity in skeletal muscles of C57Bl/6J mice. Next, hindlimb ischemia was induced via unilateral femoral vessel ligation in mice, followed by intramuscular AAV9-Esrrg (or AAV9-green fluorescent protein) gene delivery 24 hours after injury. ERRγ overexpression increased ischemic neoangiogenesis and markers of endothelial activation, and significantly improved ischemic revascularization measured using laser Doppler flowmetry. Moreover, ERRγ overexpression restored succinate dehydrogenase oxidative metabolic capacity in ischemic muscle, which correlated with increased mitochondrial respiratory complex protein expression. Most importantly, myofiber size to number quantification revealed that AAV9-Esrrg restores myofibrillar size and mitigates ischemia-induced myopathy. Conclusions These results demonstrate that intramuscular AAV9-Esrrg delivery rescues ischemic pathology after hindlimb ischemia, underscoring that Esrrg gene therapy or pharmacological activation could be a promising strategy for the management of peripheral arterial disease/critical limb ischemia.

Utility of Banff Human Organ Transplant Gene Panel in Human Kidney Transplant Biopsies.

BACKGROUND: Microarray transcript analysis of human renal transplantation biopsies has successfully identified the many patterns of graft rejection. To evaluate an alternative, this report tests whether gene expression from the Banff Human Organ Transplant (B-HOT) probe set panel, derived from validated microarrays, can identify the relevant allograft diagnoses directly from archival human renal transplant formalin-fixed paraffin-embedded biopsies. To test this hypothesis, principal components (PCs) of gene expressions were used to identify allograft diagnoses, to classify diagnoses, and to determine whether the PC data were rich enough to identify diagnostic subtypes by clustering, which are all needed if the B-HOT panel can substitute for microarrays. METHODS: RNA was isolated from routine, archival formalin-fixed paraffin-embedded tissue renal biopsy cores with both rejection and nonrejection diagnoses. The B-HOT panel expression of 770 genes was analyzed by PCs, which were then tested to determine their ability to identify diagnoses. RESULTS: PCs of microarray gene sets identified the Banff categories of renal allograft diagnoses, modeled well the aggregate diagnoses, showing a similar correspondence with the pathologic diagnoses as microarrays. Clustering of the PCs identified diagnostic subtypes including non-chronic antibody-mediated rejection with high endothelial expression. PCs of cell types and pathways identified new mechanistic patterns including differential expression of B and plasma cells. CONCLUSIONS: Using PCs of gene expression from the B-Hot panel confirms the utility of the B-HOT panel to identify allograft diagnoses and is similar to microarrays. The B-HOT panel will accelerate and expand transcript analysis and will be useful for longitudinal and outcome studies.

Pharmaceuticals as emerging pollutants: Case naproxen an overview.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including naproxen (NP), diclofenac, ibuprofen, etc., are widely used for fever and pain relief. NP is one of the most widely consumed drugs in the world, because it is available over the counter in many countries. Many studies have proven that NP is not eliminated in conventional water treatment processes and its biodegradation in the environment is also difficult compared to other drugs. Along these lines, we are aware that both the original compound and its metabolites can be found in different destinations in the environment. To assess the environmental exposure and the risks associated with NP, it is important to understand better the environment where they finally reach, the behavior of its original compounds, its metabolites, and its transformation products. In this sense, the purpose of this review is to summarize the current state of knowledge about the introduction and behavior of NP in the environments they reach and highlight research needs and gaps. Likewise, we present the sources, environmental destinations, toxicology, environmental effects, and quantification methodologies.

Estrogen-related receptor alpha is an AMPK-regulated factor that promotes ischemic muscle revascularization and recovery in diet-induced obese mice.

Obesity and type II diabetes are leading causes of peripheral arterial disease (PAD), which is characterized by vascular insufficiency and ischemic damage in the limb skeletal muscle. Glycemic control is not sufficient to prevent progression of PAD, and molecular targets that can promote muscle neo-angiogenesis in obesity and diabetes remain poorly defined. Here, we have investigated whether nuclear receptor estrogen-related receptor alpha (ERRα) can promote ischemic revascularization in the skeletal muscles of diet-induced obese (DIO) mice. Using muscle-specific ERRα transgenic mice, we found that ERRα overexpression promotes revascularization, marked by increased capillary staining and muscle perfusion in DIO mice after hindlimb ischemic injury. Furthermore, ERRα facilitates repair and restoration of skeletal muscle myofiber size after limb ischemia in DIO mice. The ameliorative effects of ERRα overexpression did not involve the prevention of weight gain, hyperglycemia or glucose/insulin intolerance, suggesting a direct role for ERRα in promoting angiogenesis. Interestingly, levels of endogenous ERRα protein are suppressed in the skeletal muscles of DIO mice compared to lean controls, coinciding with the suppression of angiogenic gene expression, and reduced AMPK signaling in the DIO skeletal muscles. Upon further investigating the link between AMPK and ERRα, we found that AMPK activation increases the expression and recruitment of ERRα protein to specific angiogenic gene promoters in muscle cells. Further, the induction of angiogenic factors by AMPK activators in muscle cells is blocked by repressing ERRα. In summary, our results identify an AMPK/ERRα-dependent angiogenic gene program in the skeletal muscle, which is repressed by DIO, and demonstrate that forced ERRα activation can promote ischemic revascularization and muscle recovery in obesity.

A Systematic Review of Mercury Exposures from Skin-Lightening Products.

BACKGROUND: The Minamata Convention on Mercury (Article 4) prohibits the manufacture, import, or export of skin-lightening products containing mercury concentrations above 1 ppm. However, there is a lack of knowledge surrounding the global prevalence of mercury-added skin-lightening products. OBJECTIVE: The objective of this study was to increase our understanding of worldwide human mercury exposure from skin-lightening products. METHODS: A systematic search of peer-reviewed scientific literature was performed for relevant articles in four databases (PubMed, Web of Science Core Collection, Scopus, and TOXLINE). The search strategy, eligibility criteria, and data-extraction methods were established a priori. The search identified 2,303 unique scientific articles, of which 41 were ultimately deemed eligible for inclusion after iterative screens at the title, abstract, and whole-text levels. To facilitate data extraction and synthesis, all papers were organized according to four data groups a) "Mercury in products," b) "Usage of products," c) "Human biomarkers of exposure," and d) "Health impacts." RESULTS: This review was based on data contained in 41 peer-reviewed scientific papers from 22 countries worldwide published between 2000 and 2022. In total, we captured mercury concentration values from 787 skin-lightening product samples [overall pooled central median mercury level was 0.49µg/g; interquartile range (IQR): 0.02-5.9] and 1,042 human biomarker measurements from 863 individuals. We also synthesized usage information from 3,898 individuals and self-reported health impacts associated with using mercury-added products from 832 individuals. DISCUSSION: This review suggests that mercury widely exists as an active ingredient in many skin-lightening products worldwide and that users are at risk of variable and often high exposures. These synthesized findings identify data gaps and help increase our understanding of the health risks associated with the use of these products. https://doi.org/10.1289/EHP10808.

Methylmercury Measurements in Dried Blood Spots from Electronic Waste Workers Sampled from Agbogbloshie, Ghana.

Biomonitoring methylmercury (MeHg) exposure is problematic in resource-limited settings and with difficult-to-access populations where traditional biomarker approaches present logistical, economic, and ethical issues. The present study aimed to validate the use of dried blood spots (DBS) to assess MeHg exposure in a real-world contaminated field setting. Whole-blood and DBS samples were collected from electronic waste workers (n = 20) from Agbogbloshie (Ghana) in 2017, and DBS were also artificially created in the laboratory using the field-collected blood. Whole-blood MeHg concentrations averaged 0.84 µg/L, which was not different from levels measured in the corresponding DBS samples (field-collected or artificially created). Whole-blood MeHg comprised 61% of the blood total Hg concentrations. Linear regression analysis revealed no differences in MeHg concentrations between whole-blood samples and field-collected DBS (slope 0.89, R2 = 0.94) and between field and laboratory DBS (slope 0.89, R2 = 0.96). The MeHg content in DBS punch blanks averaged 0.86 pg and thus was not of concern. These findings indicate that DBS are a suitable tool for assessing MeHg exposure in real-world environmental settings that may be heavily contaminated.  Environ Toxicol Chem 2021;40:2183-2188. © 2021 SETAC.

The Use of Vaginal Lubricants and Ultrasound Gels Can have Deleterious Effects on Sperm Function.

CONTEXT: Some vaginal lubricants and ultrasound gels are known to be detrimental to sperm function and therefore could negatively affect fertility. AIMS: The aim of the current study was to develop a sperm motility index (SMI) to test the sperm toxicity of ultrasound gels and vaginal lubricants used in reproductive medicine. SETTINGS AND DESIGN: Two ultrasound gels (Aquasonic® and Kefus®) and five vaginal lubricants (Vaginesil™, Velastisa®, K-Y Jelly®, Control®, and Durex®) were studied. Three different concentrations (1%, 5%, and 10%) of each lubricant were tested. SUBJECTS AND METHODS: SMI was calculated dividing the percentage of progressively motile sperm in each tested gel by that in the control at 0.5, 1, 2, and 24 h of incubation at 5% of CO2 and 37°C. SMI values <0.75 indicate sperm toxicity. STATISTICAL ANALYSIS USED: The main outcome measured was SMI for each concentration and time of incubation. RESULTS: Only Durex® did not show any deleterious effect on sperm quality. The rest of lubricants presented different degrees of toxicity. Vaginesil™ resulted in toxic for all concentrations and incubation periods (SMI < 0.12). Control® and Velastisa® presented toxicity at 10% after 2 h, while K-Y Jelly® showed toxicity at 10% from 1 h of incubation. Regarding ultrasound gels, Aquasonic® showed toxic effects after only 0.5 h (SMI = 0.70 ± 0.15), while Kefus® showed slightly toxic effects after 2 h (SMI 0.69 ± 0.07). CONCLUSIONS: SMI is an accurate tool to evaluate sperm toxicity. One of the main strengths of the article is the inclusion of representative semen samples and known products used worldwide. This study has a relevant clinical translation since it highlights the importance of evaluating the possible sperm toxicity of simple products used in reproductive medicine.

Dried blood spots to characterize mercury speciation and exposure in a Colombian artisanal and small-scale gold mining community.

The artisanal and small-scale gold mining (ASGM) sector uses the most mercury (Hg) worldwide. Despite health concerns associated with high Hg exposures in these communities, ASGM sites are often situated in resource limited and remote regions which challenge traditional human biomonitoring approaches. To help overcome such challenges, here we report on the development of a high-quality method to characterize chemical speciation of Hg in dried blood spots (DBS), and then apply this method to assess Hg exposures in people sampled from an ASGM community (Pueblito Mejia) and a nearby town (Barranco de Loba) in Colombia. We collected DBS and urine samples from 35 individuals in 2018, and used these to assess occupational (DBS inorganic Hg (InHg) and urine total Hg (THg) measures) and environmental (DBS methylmercury (MeHg) measures) exposure of participants to different forms of Hg. The accuracy and precision of the DBS-based measures generally met assay performance guideline. In study participants, the mean concentrations of DBS MeHg, InHg, and THg, and urine THg were 1.9, 4.1, 6.0, and 3.1 µg/L, respectively. For 37% of the participants, DBS THg values exceeded the 5 µg/L 'alert level' proposed by the German HBM Commission. About 60% of the blood Hg was in the InHg form thus exemplifying a need to speciate Hg in blood sampled from ASGM sites to better understand the contributions of environmental and occupational exposure sources. This study demonstrates the feasibility of using DBS for Hg speciation exposure assessments in remote and resource-limited areas such as ASGM communities.

Pancreatogenic Diabetes, 2 Onset Forms and Lack of Metabolic Syndrome Components Differentiate It From Type 2 Diabetes.

OBJECTIVES: We compared pancreatogenic (DM3c) and type 2 diabetes mellitus. METHODS: We compared age-, sex-, and diabetes mellitus duration-matched DM3c cases (n = 142) and type 2 diabetes mellitus (n = 142). Pancreatogenic diabetes was considered when it appeared after the diagnosis of pancreatitis or after pancreatic surgery. RESULTS: Pancreatogenic diabetes presented lower body mass index (BMI) [odds ratio (OR), 1.2; 95% confidence interval (CI), 1.13-1.28; P < 0.001], worse glycemic control (OR, 1.196; 95% CI, 1.058-1.35; P = 0.004), required insulin more frequently (OR, 4.21; 95% CI, 2.57-6.93; P = 0.0001), had more hypoglycemic episodes (OR, 3.65; 95% CI, 1.64-8.16; P = 0.001) but lower frequency of dyslipidemia (OR, 0.42; 95% CI, 0.26-0.68; P = 0.001) and arterial hypertension (OR, 0.52; 95% CI, 0.32-0.86; P = 0.01). Pancreatogenic diabetes cases on pancreatic enzyme replacement therapy had lower glycosylated hemoglobin (8.52% vs 9.44%; P = 0.026), serum carotenes (79.1 vs 116.1; P = 0.03), and BMI (23.4 vs 26.1; P = 0.0005) than those not on pancreatic enzyme replacement therapy. Pancreatogenic diabetes onset occurred earlier in necrotizing pancreatitis and after pancreatic surgery. CONCLUSIONS: Pancreatogenic diabetes presents with low BMI and lacks metabolic syndrome components. The type of pancreatic disease or surgery defines its onset time.

Biophysical matter in a marine estuary identified by the Sentinel-3B OLCI satellite and the presence of terrestrial iron (Fe) nanoparticles.

The analysis of marine matter using the Sentinel-3B OLCI (Ocean Land Color Instrument) satellite is the most advanced technique for evaluating: the absorption of colored detrital and dissolved material (ADG_443_NN), total suspended matter concentration (TSM_NN) and of chlorophyll-a (CHL_NN) on a global scale. The objective is to analyze ADG_443_NN, TSM_NN and CHL_NN using the Sentinel-3B OLCI satellite and the presence of Fe-nanoparticles (NPs) + hazardous elements (HEs) in suspended sediments (SSs) in the maritime estuary of the Colombian city of Barranquilla. The study used the unpublished image of the Sentinel-3B OLCI satellite in the evaluation of ADG_443_NN, TSM_NN and CHL_NN in 72 sampled points. Subsequently, 36 samples of SSs were carried out in the Magdalena River, in the identification of Fe-NPs by advanced electron microscopies. The Sentinel-3B satellite revealed particulate accumulations in OCE1 through the intensity of OLCI in ocean. There was also a high Fe-NPs intensity of SSs in the Magdalena channel, spreading contamination to large regions.

Steroid-responsive pancreatitides.

Autoimmune pancreatitis has received considerable attention, especially due to the marked effect of corticosteroid therapy on its clinical course. Knowledge, especially regarding type 1 autoimmune pancreatitis, has significantly increased over the last decades, and despite significant differences in pathophysiology and outcomes, both type 1 and 2 autoimmune pancreatitis are still considered different types of the same disease. Some have proposed a different nomenclature reflecting these differences. Although the term steroid-responsive pancreatitides may be interpreted as synonymous to type 1 and 2 autoimmune pancreatitis, these are not the only pancreatic conditions that show a response to steroid therapy. Acute pancreatitis caused by vasculitis and connective tissue diseases and acute pancreatitis secondary to checkpoint inhibitors or programmed cell death receptor antibody-mediated blockage cancer therapy may also benefit from steroid treatment. This review presents current concepts on these disorders, aiming to increase awareness, analyze similarities and differences, and propose a new nomenclature that reflects their specific particularities, clustering them under the term "steroid-responsive pancreatitides".

Effects of Non-native Fish on Lacustrine Food Web Structure and Mercury Biomagnification along a Dissolved Organic Carbon Gradient.

Although the introduction of non-native fish species has been shown to alter trophic ecology in aquatic ecosystems, there has been limited research on how invasive species alter methylmercury (MeHg) biomagnification in lacustrine food webs. We sampled surface water and biota from 8 lakes in Quebec, Canada, spanning a range of dissolved organic carbon (DOC) concentrations (2.9-8.4 mg/L); 4 lakes were inhabited by native brook trout (Salvelinus fontinalis), and the remaining lakes contained brook trout and a non-native fish, Allegheny pearl dace (Margariscus margarita). Periphyton, zooplankton, macroinvertebrates, and fish were analyzed for: 1) stable carbon (δ13 C) and nitrogen (δ15 N) isotope ratios to delineate food webs, and 2) total Hg (THg) or MeHg. Compared with the brook trout from reference lakes, fish from invaded lakes had higher length-standardized THg concentrations as well as a narrower dietary range and elevated trophic level, inferred from unadjusted δ13 C and δ15 N values, respectively. The rate of Hg biomagnification was similar across invaded and reference lakes, implying little effect of the invasive fish on the trophic transfer of MeHg. Despite differences in food web structure due to pearl dace invasion, DOC was the strongest predictor of brook trout THg levels for all lakes, suggesting that underlying environmental factors exerted a stronger influence on brook trout THg concentrations than the presence of a non-native forage fish. Environ Toxicol Chem 2020;39:2196-2207. © 2020 SETAC.

Dried Blood Spot Sampling of Landlocked Arctic Char (Salvelinus alpinus) for Estimating Mercury Exposure and Stable Carbon Isotope Fingerprinting of Essential Amino Acids.

Dried blood spots (DBS), created by applying and drying a whole blood sample onto filter paper, provide a simple and minimally invasive procedure for collecting, transporting, and storing blood. Because DBS are ideal for use in field and resource-limited settings, we aimed to develop a simple and accurate DBS-based approach for assessing mercury (Hg) exposure and dietary carbon sources for landlocked Arctic char, a sentinel fish species in the Arctic. We collected liquid whole blood (from the caudal vein), muscle, liver, and brains of Arctic char (n = 36) from 8 lakes spanning a Hg gradient in the Canadian High Arctic. We measured total Hg concentrations ([THg]) of field-prepared DBS and Arctic char tissues. Across a considerable range, [THg] of DBS (0.04-3.38 µg/g wet wt) were highly correlated with [THg] of all tissues (r2 range = 0.928-0.996). We also analyzed the compound-specific carbon isotope ratios (expressed as δ13 C values) of essential amino acids (EAAs) isolated from DBS, liquid whole blood, and muscle. The δ13 C values of 5 EAAs (δ13 CEAAs ; isoleucine [Ile], leucine [Leu], phenylalanine [Phe], valine [Val], and threonine [Thr]) from DBS were highly correlated with δ13 CEAAs of liquid whole blood (r2 range = 0.693-0.895) and muscle (r2 range = 0.642-0.881). The patterns of δ13 CEAAs of landlocked Arctic char were remarkably consistent across sample types and indicate that EAAs are most likely of algal origin. Because a small volume of blood (~50 µL) dried on filter paper can be used to determine Hg exposure levels of various tissues and to fingerprint carbon sources, DBS sampling may decrease the burdens of research and may be developed as a nonlethal sampling technique. Environ Toxicol Chem 2020;39:893-903. © 2020 SETAC.

Retroperitoneal fibrosis. Steroid treatment response seems to depend on its association to IgG4 related disease.

Retroperitoneal fibrosis (RF) is part of a rare fibrosclerotic disorder. Oral steroids are the initial treatment. Steroid combination with other immunosupressants is used in refractory cases. Steroids refractoriness has been observed in chronic cases. Some cases of RF represent a manifestation of the IgG4 related disease (IgG4-RD) that is associated to a dramatic response to steroid therapy. It is uncertain if RF́s treatment response differs according to its association with IgG4-RD. We hypothesize that RF́s treatment response to steroids depends on the association with IgG4-RD, thus, we collected and compared clinical data from 10 RF cases; 6 male, mean age 50.6 (±16.15 SD) years. Mean FU was 28 (±25.7 SD) months. According to IgG4 levels, patients were categorized as idiopathic RF (IRF n = 5) or RF-IgG4-RD (n = 5). Therapy response was categorized as complete, partial, stable disease, recurrence or non-response. Nine cases received initial therapy with prednisone; complete response was achieved in 4 RF-IgG4 RD. The remaining 5 cases (1 RF-IgG4RD and 4 IRF) underwent a 2nd line therapy; 4 prednisone + tamoxifen and 1 prednisone + azathioprine. Prednisone + tamoxifen combination achieved complete response in 1 case (RF-IgG4RD), partial response in 1 IRF; in 1 IRF case, disease remained stable and 1 did not respond. The prednisone + azathioprine treatment achieved complete response. At follow-up all patients remained stable and no recurrence was registered. These observations suggest and support the hypothesis that response to steroid monotherapy depends on the association of RF with IgG4, suggesting that IRF cases might benefit from initial combination therapies instead of steroid monotherapy.