Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with Lymphoma.

The transcription factor STAT6 (Signal Transducer and Activator of Transcription 6) is a key regulator of Th2 (T-helper 2) mediated allergic inflammation via the IL-4 (interleukin-4) JAK (Janus kinase)/STAT signalling pathway. We identified a novel heterozygous germline mutation STAT6 c.1255G > C, p.D419H leading to overactivity of IL-4 JAK/STAT signalling pathway, in a kindred affected by early-onset atopic dermatitis, food allergy, eosinophilic asthma, anaphylaxis and follicular lymphoma. STAT6 D419H expression and functional activity were compared with wild type STAT6 in transduced HEK293T cells and to healthy control primary skin fibroblasts and peripheral blood mononuclear cells (PBMC). We observed consistently higher STAT6 levels at baseline and higher STAT6 and phosphorylated STAT6 following IL-4 stimulation in D419H cell lines and primary cells compared to wild type controls. The pSTAT6/STAT6 ratios were unchanged between D419H and control cells suggesting that elevated pSTAT6 levels resulted from higher total basal STAT6 expression. The selective JAK1/JAK2 inhibitor ruxolitinib reduced pSTAT6 levels in D419H HEK293T cells and patient PBMC. Nuclear staining demonstrated increased STAT6 in patient fibroblasts at baseline and both STAT6 and pSTAT6 after IL-4 stimulation. We also observed higher transcriptional upregulation of downstream genes (XBP1 and EPAS1) in patient PBMC. Our study confirms STAT6 gain of function (GOF) as a novel monogenetic cause of early onset atopic disease. The clinical association of lymphoma in our kindred, along with previous data linking somatic STAT6 D419H mutations to follicular lymphoma suggest that patients with STAT6 GOF disease may be at higher risk of lymphomagenesis.245 words.

Emerging Contaminants and New POPs (PFAS and HBCDD) in Endangered Southern Resident and Bigg's (Transient) Killer Whales (Orcinus orca): In Utero Maternal Transfer and Pollution Management Implications.

Killer whales (Orcinus orca) have been deemed one of the most contaminated cetacean species in the world. However, concentrations and potential health implications of selected 'contaminants of emerging concern' (CECs) and new persistent organic pollutants (POPs) in endangered Southern Resident and threatened Bigg's (Transient) killer whales in the Northeastern Pacific (NEP) have not yet been documented. Here, we quantify CECs [alkylphenols (APs), triclosan, methyl triclosan, and per- and polyfluoroalkyl substances (PFAS)] and new POPs [hexabromocyclododecane (HBCCD), PFOS, PFOA, and PFHxS] in skeletal muscle and liver samples of these sentinel species and investigate in utero transfer of these contaminants. Samples were collected from necropsied individuals from 2006 to 2018 and analyzed by LC-MS/MS or HRBC/HRMS. AP and PFAS contaminants were the most prevalent compounds; 4-nonylphenol (4NP) was the predominant AP (median 40.84 ng/g ww), and interestingly, 7:3-fluorotelomer carboxylic acid (7:3 FTCA) was the primary PFAS (median 66.35 ng/g ww). Maternal transfer ratios indicated 4NP as the most transferred contaminant from the dam to the fetus, with maternal transfer rates as high as 95.1%. Although too few killer whales have been screened for CECs and new POPs to infer the magnitude of contamination impact, these results raise concerns regarding pathological implications and potential impacts on fetal development and production of a viable neonate. This study outlines CEC and new POP concentrations in killer whales of the NEP and provides scientifically derived evidence to support and inform regulation to mitigate pollutant sources and contamination of Southern Resident killer whale critical habitat and other marine ecosystems.

Rare case of plasmablastic myeloma diagnosed on lung biopsy.

Plasmablastic myeloma is a rare variant of multiple myeloma characterised by neoplastic proliferation of single clone of plasma cells producing monoclonal immunoglobulins. A 60-year-old man presented to hospital with a 6-week history of chest pain, back pain, leg weakness and numbness. Imaging revealed a 75 mm left lobular lung mass with chest wall invasion, metastatic bony and soft-tissue deposits and spinal cord compression at T5 level. Lung biopsy, for suspected metastatic lung cancer, surprisingly showed features of plasmablastic myeloma. Protein electrophoresis demonstrated 2 g/L of IgG lambda paraproteinaemia and an increase in lambda light chains with reduced kappa/lambda ratio of 0.01. Bone marrow biopsy did not show evidence of infiltration by disease. The patient received radiotherapy to the spine; responded to third-line chemotherapy and received autologous stem cell transplant. This case adds to the rare causes of lung mass and is the first reported case of plasmablastic myeloma diagnosed on lung biopsy.

Effect of Sample Storage on the Quantitative Determination of 29 PFAS: Observation of Analyte Interconversions during Storage.

In this study, we measured the effects of sample type and storage temperature on the stability of 29 per- and polyfluorinated alkyl substances (PFAS) in water. Spiked bottled water, surface water, and two types of effluent samples were stored in HDPE containers at +20, 4, and -20 °C over a period of up to 180 days. The analytes studied included C4 through C14 perfluorinated carboxylates (PFCAs); C4 through C10 and C12 perfluorinated sulfonates (PFSAs); 4:2, 6:2, and 8:2 fluorotelomer sulfonates (FTS); three perfluorooctane sulfonamides (PFOSA, N-MeFOSA, and N-EtFOSA); two perfluorooctane sulfonamide ethanols (N-MeFOSE and N-EtFOSE); and two perfluorooctane sulfonamide acetic acids (N-MeFOSAA and EtFOSAA). Overall, 10 analytes, PFOA, PFNA, 8:2 FTS, PFOSA, N-MeFOSA, NEtFOSA, N-MeFOSAA, N-EtFOSAA, N-MeFOSE, and N-EtFOSE, showed increasing or decreasing concentration trends under at least one of the experimental conditions investigated. Increases in concentrations of N-MeFOSAA and N-EtFOSAA in surface water and effluent samples at +20 and 4 °C correlated with the decreases in the concentrations of N-MeFOSE and N-EtFOSE, respectively, suggesting analyte interconversion during sample storage. This is the first time such analyte conversion is reported in samples under storage, and this work demonstrates the importance of assessing stability of PFAS in environmentally relevant matrices. The significance of this study extends beyond sample storage for analysis, as toxicological and exposure studies conducted at room temperature also need to consider the significance of analyte degradation through the exposure process.

Long-term variation in concentrations and mass loads in a semi-arid watershed influenced by historic mercury mining and urban pollutant sources.

Urban watersheds are significantly anthropogenically-altered landscapes. Most previous studies cover relatively short periods, without addressing concentrations, loads, and yields in relation to annual climate fluctuations, and datasets on Ag, Se, PBDEs, and PCDD/Fs are rare. Intensive storm-focused sampling and continuous turbidity monitoring were employed to quantify pollution at two locations in the Guadalupe River (California, USA). At a downstream location, we determined loads of suspended sediment (SS) for 14yrs., mercury (HgT), PCBs, and total organic carbon (TOC) (8yrs), total methylmercury (MeHgT) (6yrs), nutrients, and trace elements including Ag and Se (3yrs), DDTs, chlordanes, dieldrin, and PBDEs (2yrs), and PCDD/Fs (1yr). At an upstream location, we determined loads of SS for 4yrs. and HgT, MeHgT, PCBs and PCDD/Fs for 1yr. These data were compared to previous studies, climatically adjusted, and used to critically assess the use of small datasets for estimating annual average conditions. Concentrations and yields in the Guadalupe River appear to be atypical for total phosphorus, DDTs, dieldrin, HgT, MeHgT, Cr, Ni, and possibly Se due to local conditions. Other pollutants appear to be similar to other urban systems. On average, wet season flow varied by 6.5-fold and flow-weighted mean (FWM) concentrations varied 4.4-fold, with an average 7.1-fold difference between minimum and maximum annual loads. Loads for an average runoff year for each pollutant were usually less than the best estimate of long-term average. The arithmetic average of multiple years of load data or a FWM concentration combined with mean annual flow was also usually below the best estimate of long-term average load. Mean annual loads using sampled years were also less than the best estimate of long-term average by a mean of 2.2-fold. Climatic adjustment techniques are needed for computing estimates of long-term average annual loads.

Per- and polyfluoroalkyl substances (PFASs) in San Francisco Bay wildlife: Temporal trends, exposure pathways, and notable presence of precursor compounds.

Concentrations of perfluorooctane sulfonate (PFOS) in San Francisco Bay (SF Bay) wildlife have historically been among the highest reported globally. To track continuing exposures to PFASs and assess the impact of the 2002 phase-out of production of PFOS and related chemicals in the US, nine perfluoroalkyl carboxylic acids (PFCAs; C4-C12), three perfluoroalkyl sulfonic acids (PFSAs; C4, C6, C8) and perfluorooctane sulfonamide (PFOSA, a PFOS precursor) were measured in SF Bay cormorant eggs in 2012 and harbor seal serum sampled between 2009 and 2014. PFOS remained the dominant perfluoroalkyl acid (PFAA) in both cormorant eggs (36.1-466 ng/g) and seals (12.6-796 ng/g) from 2012 and 2014, respectively. Concentrations in seal and bird eggs from the South Bay have declined approximately 70% in both matrices. To elucidate potential pathways of exposure, prey fish, sediments and wastewater effluent were analyzed for PFASs, and in the case of sediment and effluent, a suite of PFAA precursors. PFOS was the dominant PFAA in prey fish and sediment. In effluent, different mixtures of PFAAs were measured, with PFOS, PFHxA, and PFOA detected in the highest concentrations. Polyfluoroalkyl phosphate diesters (PFCA-precursors) were observed at concentrations over an order of magnitude higher than PFCAs in sediment, highlighting their importance as a potential, on-going source of PFCAs to SF Bay wildlife. These findings suggest that the PFOS phase-out has resulted in reduced burdens to wildlife in SF Bay, but that exposure to diverse and incompletely characterized PFASs continues.

Quantitative determination of hydroxy polycylic aromatic hydrocarbons as a biomarker of exposure to carcinogenic polycyclic aromatic hydrocarbons.

A high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS) method was developed for quantitative analysis of hydroxy polycyclic aromatic hydrocarbons (OH-PAHs). Four hydroxy metabolites of known and suspected carcinogenic PAHs (benzo[a]pyrene (B[a]P), benz[a]anthracene (B[a]A), and chrysene (CRY)) were selected as suitable biomarkers of PAH exposure and associated risks to human health. The analytical method included enzymatic deconjugation, liquid - liquid extraction, followed by derivatization with methyl-N-(trimethylsilyl) trifluoroacetamide and instrumental analysis. Photo-induced oxidation of target analytes - which has plagued previously published methods - was controlled by a combination of minimizing exposure to light, employing an antioxidant (2-mercaptoethanol) and utilizing a nitrogen atmosphere. Stability investigations also indicated that conjugated forms of the analytes are more stable than the non-conjugated forms. Accuracy and precision of the method were 77.4-101% (<4.9% RSD) in synthetic urine and 92.3-117% (<15% RSD) in human urine, respectively. Method detection limits, determined using eight replicates of low-level spiked human urine, ranged from 13 to 24pg/mL. The method was successfully applied for analysis of a pooled human urine sample and 78 mouse urine samples collected from mice fed with PAH-contaminated diets. In mouse urine, greater than 94% of each analyte was present in its conjugated form.

Pharmaceuticals and other anthropogenic tracers in surface water: a randomized survey of 50 Minnesota lakes.

Water from 50 randomly selected lakes across Minnesota, USA, was analyzed for pharmaceuticals, personal care products, hormones, and other commercial or industrial chemicals in conjunction with the US Environmental Protection Agency's 2012 National Lakes Assessment. Thirty-eight of the 125 chemicals analyzed were detected at least once, all at parts per trillion concentrations. The most widely detected was N,N-diethyl-m-toluamide, present in 48% of the lakes sampled. Amitriptyline, a widely used antidepressant, was found in 28% of the lakes. The endocrine active chemicals bisphenol A, androstenedione, and nonylphenol were found in 42%, 30%, and 10% of the lakes, respectively. Cocaine was found in 32% of the lakes, and its degradation product, benzoylecgonine, was detected at 28% of the locations. Carbadox, an antibiotic used solely in the production of swine, was also present in 28% of the lakes sampled. The means by which these and other chemicals were transported to several of the remote lakes is unclear but may involve atmospheric transport.

Quantitative determination of 13 organophosphorous flame retardants and plasticizers in a wastewater treatment system by high performance liquid chromatography tandem mass spectrometry.

A method for quantitative determination of 13 organophosphorous compounds (OPs) was developed and applied to influent, primary sludge, activated sludge, biosolids, primary effluent and final effluent from a wastewater treatment plant (WWTP). The method involved solvent extraction followed by solid phase clean-up and analysis by high performance liquid chromatography positive electrospray ionization-tandem mass spectrometry (HPLC(+ESI)MS/MS). Replicate spike/recovery experiments revealed the method to have good accuracy (70-132%) and precision (<19% RSD) in all matrices. Detection limits of 0.1-5 ng/L for aqueous samples and 0.01-0.5 ng/g for solid samples were achieved. In the liquid waste stream ∑OP concentrations were highest in influent (5764 ng/L) followed by primary effluent (4642 ng/L), and final effluent (2328 ng/L). In the solid waste stream, the highest ∑OP concentrations were observed in biosolids (3167 ng/g dw), followed by waste activated sludge (2294 ng/g dw), and primary sludge (2128 ng/g dw). These concentrations are nearly 30-fold higher than ∑polybrominated diphenyl ether (BDE) concentrations in influents and nearly 200-fold higher than ∑BDE concentrations in effluents from other sites in Canada. Tetrekis(2-chlorethyl)dichloroisopentyldiphosphate (V6), tripropylphosphate (TnPrP), and Tris(2,3-dibromopropyl)phosphate (TDBPP) are investigated for the first time in a WWTP. While TnPrP and TDBB were not detected, V6 was observed at concentrations up to 7.9 ng/g in solid waste streams and up to 40.7 ng/L in liquid waste streams. The lack of removal of OPs during wastewater treatment is a concern due to their release into the aquatic environment.

Declines in polybrominated diphenyl ether contamination of San Francisco Bay following production phase-outs and bans.

California has implemented unique consumer product flammability standards. Polybrominated diphenyl ether (PBDE) flame retardants were once widely incorporated into products to meet these standards, but concerns regarding toxicity and accumulation in humans and biota led to nationwide phase-outs and state bans. A decade of PBDE monitoring in San Francisco Bay has resulted in a data set that covers periods during and after PBDE use and consists of hundreds of measurements of water, sediment, and biota. While PBDEs remain widely detected in biota, levels have declined by nearly half in sport fish and 74-95% in bivalves and bird eggs. Concentrations of BDE-47 in sediment have dropped by over one-third from 2002 to 2012; in water, a decline is not yet evident. The dominant congener in sediment, DecaBDE component BDE-209, showed no temporal trend. U.S. production of DecaBDE ended in 2013; future monitoring may reveal declines. Overall, the data indicate that reduced production can result in relatively rapid reductions in the concentrations of some hydrophobic contaminants in biota and sediment, particularly when implemented after only a few decades of heavy use. Recent changes to California's flammability standards may lessen the use of other flame retardants and similarly reduce Bay contamination.

Occurrence of contaminants of emerging concern in mussels (Mytilus spp.) along the California coast and the influence of land use, storm water discharge, and treated wastewater effluent.

Contaminants of emerging concern were measured in mussels collected along the California coast in 2009-2010. The seven classes were alkylphenols, pharmaceuticals and personal care products, polybrominated diphenyl ethers (PBDE), other flame retardants, current use pesticides, perfluorinated compounds (PFC), and single walled carbon nanotubes. At least one contaminant was detected at 67 of the 68 stations (98%), and 67 of the 167 analytes had at least one detect (40%). Alkylphenol, PBDE, and PFC concentrations increased with urbanization and proximity to storm water discharge; pesticides had higher concentrations at agricultural stations. These results suggest that certain compounds; for example, alkylphenols, lomefloxacin and PBDE, are appropriate for inclusion in future coastal bivalve monitoring efforts based on maximum concentrations >50 ng/g dry weight and detection frequencies >50%. Other compounds, for example PFC and hexabromocyclododecane (HBCD), may also be suggested for inclusion due to their >25% detection frequency and potential for biomagnification.

Pure white cell aplasia: report of first case associated with autoimmune hepatitis.

Pure white cell aplasia (PWCA) is a rare, immune-mediated condition that causes a profound inhibition of myelopoiesis. It has been seen in association with other autoimmune conditions, thymomas, chronic lymphocytic leukaemia and as an adverse drug reaction. We report what we believe to be the first case of PWCA associated with autoimmune hepatitis. An 18-year-old woman presented with jaundice and was found to be suffering from acute hepatitis. Later she became neutropenic and lymphopenic. Liver biopsy was indicative of autoimmune hepatitis. This was later confirmed by autoantibody results. Bone marrow aspirate found an absence of all myeloid progenitor cells, highly suggestive of PWCA. The low white cell count only improved after immunosuppression with corticosteroids. Her condition remains stable 1 year later with azathioprine therapy.

Method validation and reconnaissance of pharmaceuticals, personal care products, and alkylphenols in surface waters, sediments, and mussels in an urban estuary.

Novel methods utilizing liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry were validated for low-level detection of 104 pharmaceuticals and personal care products ingredients (PPCPs) and four alkylphenols (APs) in environmental samples. The methods were applied to surface water, sediment, and mussel tissue samples collected from San Francisco Bay, CA, USA, an urban estuary that receives direct discharge from over forty municipal and industrial wastewater outfalls. Among the target PPCPs, 35% were detected in at least one sample, with 31, 10, and 17 compounds detected in water, sediment, and mussels, respectively. Maximum concentrations were 92 ng/L in water (valsartan), 33 ng/g dry weight (dw) in sediments (triclocarban), and 14 ng/g wet weight (ww) in mussels (N,N-diethyl-m-toluamide). Nonylphenol was detected in water (<2-73 ng/L), sediments (22-86 ng/g dw), and mussels (<0.04-95 ng/g ww), and nonylphenol mono- and diethoxylates were detected in sediments (<1-40 ng/g dw) and mussels (<5-192 ng/g ww). The concentrations of PPCPs and APs detected in the San Francisco Bay samples were generally at least an order of magnitude below concentrations expected to elicit toxic effects in aquatic organisms. This study represents the first reconnaissance of PPCPs in mussels living in an urban estuary and provides the first field-derived bioaccumulation factors (BAFs) for select compounds in aquatic organisms.

Perfluoroalkyl contaminants in an Arctic marine food web: trophic magnification and wildlife exposure.

To better understand the bioaccumulation behavior of perfluoroalkyl contaminants (PFCs), we conducted a comparative analysis of PFCs and lipophilic organohalogens in a Canadian Arctic marine food web. Concentrations of perfluorooctane sulfonic acid (PFOS), perfluorooctansulfoamide (PFOSA), and C7-C14 perfluorocarboxylic acids (PFCAs) ranged between 0.01 and 0.1 ng x g(-1) dry wt in sediments and 0.1 and 40 ng x g(-1) wet wt in biota, which was equivalent to or higher than levels of PCBs, PBDEs, and organochlorine pesticides. In beluga whales, PFOS and PFCA concentrations were higher (P < 0.05) in protein-rich compartments (liver and blood), compared to other tissues/fluids (milk, blubber, muscle, and fetus). In the marine mammalian food web, concentrations of PFOSA and lipophilic organochlorines (ng x g(-1) lipid equivalent) and proteinophilic substances (i.e., PFOS and C8-C14 PFCAs, ng x g(-1) protein) increased significantly (P < 0.05) with trophic level. Trophic magnification factors (TMFs) of organochlorines ranged between 5 and 14 and exhibited significant curvilinear relationships (P < 0.05) with octanol-water and octanol-air partition coefficients (KOW, KOA). TMFs of perfluorinated acids (PFAs) ranged between 2 and 11 and exhibited similar correlation (P < 0.05) with protein-water and protein-air partition coefficients (KPW, KPA). PFAs did not biomagnify in the aquatic piscivorous food web (TMF range: 0.3-2). This food web specific biomagnification behavior was attributed to the high aqueous solubility and low volatility of PFAs. Specifically, the anticipated phase-partitioning of these proteinophilic substances, represented by their protein-water (KPW) and protein-air (KPA) partition coefficients, likely results in efficient respiratory elimination in water-respiring organisms but very slow elimination and biomagnification in air-breathing animals. Lastly, the results indicate that PFOS exposure in nursing Hudson Bay beluga whale calves (CI95 range = 2.7 x 10(-5) to 1.8 x 10(-4) mg x kg bw(-1) x d(-1)), exceedsthe oral reference dose for PFOS (7.5 x 10(-5) mg x kg bw(-1) x d(-1)), which raises concern for potential biological effects in these and other sensitive Arctic marine wildlife species.

A mass budget of polybrominated diphenyl ethers in San Francisco Bay, CA.

A mass budget of polybrominated diphenyl ethers (PBDEs) in San Francisco Bay is developed as a first step towards understanding the local sources and transport processes controlling PBDE fate in a highly urbanized estuary. Extensive monitoring of PBDEs in estuarine water and sediment, freshwater tributaries, air, and wastewater effluents and sludges were integrated with a mass budget model to provide a synthetic view of these emerging contaminants. The Bay inventories of BDE 47 and BDE 209 in 2006 were estimated to be 33+/-3 kg and 153+/-45 kg, respectively. Empirically derived estimates of annual inputs of BDE 47 and BDE 209 from all quantifiable external sources ranged from 11 to 28 kg/y and 22 to 24 kg/y, respectively. BDE 47 loads were dominated by wastewater while runoff from local tributaries represented the largest contributor to BDE 209 loads. Model results suggest the Bay PBDE inventory is highly sensitive to changes in external loads, with degradation and outflow being the major processes governing PBDE fate. The mass budget presented provides a framework for integrating future monitoring and modeling efforts.

Extramedullary plasmacytomas of the larynx and parapharyngeal space: imaging and pathologic features.

Extramedullary plasmacytoma is a rare plasma cell neoplasm that can occur in the head and neck. In this article we describe a case of multiple synchronous extramedullary plasmacytomas involving the upper airway, pharynx, and larynx. The clinical, imaging, and pathologic features of this neoplasm are discussed, together with potential treatment options.

Salivary gland mucosa-associated lymphoid tissue lymphoma in 2 patients with Sjögren's syndrome: clinical and sonographic features with pathological correlation.

We report 2 cases of mucosa-associated lymphoid tissue lymphoma of the salivary glands, complicating Sjögren's syndrome. The sonographic and histological features are described in depth. The use of sonography as a diagnostic aid in such patients is discussed.