Contamination and source apportionment of metals in urban road dust (Jinan, China) integrating the enrichment factor, receptor models (FA-NNC and PMF), local Moran's index, Pb isotopes and source-oriented health risk.

Contamination and source identifications of metals in urban road dust are critical for remediation and health protection. Receptor models are commonly used for metal source identification, whereas the results are usually subjective and not verified by other indicators. Here we present and discuss a comprehensive approach to study metal contamination and sources in urban road dust (Jinan) in spring and winter by integrating the enrichment factor (EF), receptor models (positive matrix factorization (PMF) and factor analysis with nonnegative constraints (FA-NNC)), local Moran's index, traffic factors and Pb isotopes. Cadmium, Cr, Cu, Pb, Sb, Sn and Zn were the main contaminants, with mean EFs of 2.0-7.1. The EFs were 1.0-1.6 times higher in winter than in spring but exhibited similar spatial trends. Chromium contamination hotspots occurred in the northern area, with other metal contamination hotspots in the central, southeastern and eastern areas. The FA-NNC results indicated Cr contamination primarily resulting from industrial sources and other metal contamination primarily originating from traffic emissions during the two seasons. Coal burning emissions also contributed to Cd, Pb and Zn contamination in winter. FA-NNC model-identified metal sources were verified via traffic factors, atmospheric monitoring and Pb isotopes. The PMF model failed to differentiate Cr contamination from other detrital metals and the above anthropogenic sources, largely due to the model grouping metals by emphasizing hotspots. Considering the FA-NNC results, industrial and traffic sources accounted for 28.5 % (23.3 %) and 44.7 % (28.4 %), respectively, of the metal concentrations in spring (winter), and coal burning emissions contributed 34.3 % in winter. Industrial emissions primarily contributed to the health risks of metals due to the high Cr loading factor, but traffic emissions dominated metal contamination. Through Monte Carlo simulations, Cr had 4.8 % and 0.4 % possibilities posing noncarcinogenic and 18.8 % and 8.2 % possibilities posing carcinogenic risks for children in spring and winter, respectively.

Mesenchymal stromal cells alleviate acute respiratory distress syndrome through the cholinergic anti-inflammatory pathway.

Mesenchymal stromal cells (MSCs) have been considered a promising alternative for treatment of acute respiratory distress syndrome (ARDS). However, there is significant heterogeneity in their therapeutic efficacy, largely owing to the incomplete understanding of the mechanisms underlying the therapeutic activities of MSCs. Here, we hypothesize that the cholinergic anti-inflammatory pathway (CAP), which is recognized as a neuroimmunological pathway, may be involved in the therapeutic mechanisms by which MSCs mitigate ARDS. Using lipopolysaccharide (LPS) and bacterial lung inflammation models, we found that inflammatory cell infiltration and Evans blue leakage were reduced and that the expression levels of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) in lung tissue were significantly increased 6 hours after MSC infusion. When the vagus nerve was blocked or α7 nicotinic acetylcholine (ACh) receptor (α7nAChR)-knockout mice were used, the therapeutic effects of MSCs were significantly reduced, suggesting that the CAP may play an important role in the effects of MSCs in ARDS treatment. Our results further showed that MSC-derived prostaglandin E2 (PGE2) likely promoted ACh synthesis and release. Additionally, based on the efficacy of nAChR and α7nAChR agonists, we found that lobeline, the nicotinic cholinergic receptor excitation stimulant, may attenuate pulmonary inflammation and alleviate respiratory symptoms of ARDS patients in a clinical study (ChiCTR2100047403). In summary, we reveal a previously unrecognized MSC-mediated mechanism of CAP activation as the means by which MSCs alleviate ARDS-like syndrome, providing insight into the clinical translation of MSCs or CAP-related strategies for the treatment of patients with ARDS.

Autologous transplantation of thecal stem cells restores ovarian function in nonhuman primates.

Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity under the age of 40. Theca cells (TCs) play a vital role during folliculogenesis and TCs dysfunction participate in the pathogenesis of POI. Therefore, transplantation of thecal stem cells (TSCs), which are capable of self-renewal and differentiation into mature TCs, may provide a new strategy for treating POI. To investigate the feasibility, safety, and efficacy of TSCs transplantation in clinically relevant non-human primate (NHP) models, we isolate TSCs from cynomolgus monkeys, and these cells are confirmed to expand continuously and show potential to differentiate into mature TCs. In addition, engraftment of autologous TSCs into POI monkeys significantly improves hormone levels, rescues the follicle development, promotes the quality of oocytes and boosts oocyte maturation/fertilization rate. Taken together, these results for the first time suggest that autologous TSCs can ameliorate POI symptoms in primate models and shed new light on developing stem cell therapy for POI.

Mesenchymal Stromal Cells Rapidly Suppress TCR Signaling-Mediated Cytokine Transcription in Activated T Cells Through the ICAM-1/CD43 Interaction.

Cell-cell contact participates in the process of mesenchymal stromal cell (MSC)-mediated T cell modulation and thus contributes to MSC-based therapies for various inflammatory diseases, especially T cell-mediated diseases. However, the mechanisms underlying the adhesion interactions between MSCs and T cells are still poorly understood. In this study, we explored the interaction between MSCs and T cells and found that activated T cells could rapidly adhere to MSCs, leading to significant reduction of TNF-α and IFN-γ mRNA expression. Furthermore, TCR-proximal signaling in activated T cells was also dramatically suppressed in the MSC co-culture, resulting in weakened Ca2+ signaling. MSCs rapidly suppressed TCR signaling and its downstream signaling in a cell-cell contact-dependent manner, partially through the ICAM-1/CD43 adhesion interaction. Blockade of either ICAM-1 on MSCs or CD43 on T cells significantly reversed this rapid suppression of proinflammatory cytokine expression in T cells. Mechanistically, MSC-derived ICAM-1 likely disrupts CD43-mediated TCR microcluster formation to limit T cell activation. Taken together, our results reveal a fast mechanism of activated T cell inhibition by MSCs, which provides new clues to unravel the MSC-mediated immunoregulatory mechanism for aGVHD and other severe acute T cell-related diseases.

Transplantation of hPSC-derived pericyte-like cells promotes functional recovery in ischemic stroke mice.

Pericytes play essential roles in blood-brain barrier (BBB) integrity and dysfunction or degeneration of pericytes is implicated in a set of neurological disorders although the underlying mechanism remains largely unknown. However, the scarcity of material sources hinders the application of BBB models in vitro for pathophysiological studies. Additionally, whether pericytes can be used to treat neurological disorders remains to be elucidated. Here, we generate pericyte-like cells (PCs) from human pluripotent stem cells (hPSCs) through the intermediate stage of the cranial neural crest (CNC) and reveal that the cranial neural crest-derived pericyte-like cells (hPSC-CNC PCs) express typical pericyte markers including PDGFRß, CD146, NG2, CD13, Caldesmon, and Vimentin, and display distinct contractile properties, vasculogenic potential and endothelial barrier function. More importantly, when transplanted into a murine model of transient middle cerebral artery occlusion (tMCAO) with BBB disruption, hPSC-CNC PCs efficiently promote neurological functional recovery in tMCAO mice by reconstructing the BBB integrity and preventing of neuronal apoptosis. Our results indicate that hPSC-CNC PCs may represent an ideal cell source for the treatment of BBB dysfunction-related disorders and help to model the human BBB in vitro for the study of the pathogenesis of such neurological diseases.

Human Mesenchymal Stem Cell-Treated Regulatory CD23+CD43+ B Cells Alleviate Intestinal Inflammation.

Rationale: Mesenchymal stem cells (MSCs) have been demonstrated to ameliorate inflammatory bowel disease by their actions on multiple immune cells, especially on regulatory B cells (Breg cells). However, the phenotypes and functions of human MSCs (hMSCs)-treated Breg cell subsets are not yet clear. Methods: Purified B cells were cocultured with MSCs and the phenotypes and immunomodulatory functions of the B cells were analyzed by FACS and proliferation assays in vitro. Also, a trinitrobenzenesulfonic acid-induced mouse colitis model was employed to detect the function of MSC-treated Breg cells in vivo. Results: We demonstrated that coculturing with hMSCs significantly enhanced the immunomodulatory activity of B cells by up-regulating IL-10 expression. We then identified that a novel regulatory B cell population characterized by CD23 and CD43 phenotypic markers could be induced by hMSCs. The CD23+CD43+ Breg cells substantially inhibited the inflammatory cytokine secretion and proliferation of T cells through an IL-10-dependent pathway. More significantly, intraperitoneal injection of hMSCs ameliorated the clinical and histopathological severity in the mouse experimental colitis model, accompanied by an increase in the number of CD23+CD43+ Breg cells. The adoptive transfer of CD23+CD43+ B cells effectively alleviated murine colitis, as compared with the CD23-CD43- B cells. Treatment with CD23+CD43+ B cells, and not hMSCs, substantially improved the symptoms of colitis in B cell-depleted mice. Conclusion: the novel CD23+CD43+ Breg cell subset appears to be involved in the immunomodulatory function of hMSCs and sheds new light on elucidating the therapeutic mechanism of hMSCs for the treatment of inflammation-related diseases.

Quadruple valve infective endocarditis presenting with suspected Austrian syndrome: a case report and a case series of quadruple valve infective endocarditis.

OBJECTIVES: Austrian syndrome comprises the triad of pneumonia, meningitis, and endocarditis secondary to Streptococcus pneumonia. We present what we believe to be the first reported case of Austrian syndrome with quadruple heart valve involvement and review the literature detailing cases of quadruple valve infective endocarditis. CASE PRESENTATION AND RESULTS: A case is presented of a patient with radiographic evidence of a left lower lobe pneumonia. Sequential transthoracic followed by transesophageal echocardiogram done to evaluate the presence of a cardiac murmur revealed the presence of quadruple valve vegetations. Multiple blood cultures were persistently negative. The patient went on to develop seizures secondary to proven meningitis. Microbiological diagnosis was eventually established through positive Streptococcus pneumoniae antigen (Alere BinaxNOW®) from cerebrospinal fluid, establishing a presumptive clinical diagnosis of Austrian syndrome. A computerized PubMed search for reports of quadruple valve infective endocarditis and their references was collated. A total of 22 patients were found, including our patient. The median age of presentation was 47.5 years. Five patients had a history of intravenous drug abuse, another 5 had underlying congenital heart disease, and 1 had both. Two patients (9.1%) had 2 microorganisms isolated. Staphylococcus aureus and Streptococcus viridans (3 cases, 13.6% each) were the most commonly implicated microorganism. Heart failure was the commonest complication, afflicting 11 patients (50.0%). Ten patients (45.5%) underwent surgery. Overall case fatality rate was 50.0%. Cardiac surgery was of statistical significance in predicting survival (P = 0.009). CONCLUSION: Quadruple valve endocarditis is associated with a high mortality rate, and cardiac surgery may be protective.

IgG4-Related Disease of the Thyroid Gland Requiring Emergent Total Thyroidectomy: A Case Report.

IgG4-related disease of the thyroid gland is a recently recognized subtype of thyroiditis, often with rapid progression requiring surgical treatment. It is considered as a spectrum of disease varying from early IgG4-related Hashimoto's thyroiditis (HT) pattern to late fibrosing HT or Riedel's thyroiditis patterns. Here, we report a 47-year-old Malay woman presenting with progressively painless neck swelling over 3 years and subclinical hypothyroidism. Computed tomography (CT) scan revealed diffuse thyroid enlargement (up to 13 cm) with retrosternal extension and without regional lymphadenopathy. Fine needle aspiration of the thyroid showed a limited number of follicular epithelial cell groups with widespread Hurthle cell change and scanty background colloid, but no evidence of lymphocytosis. The cytologic features fell into the category of 'atypia of undetermined significance'. Subsequently, the patient developed hypercapnic respiratory failure secondary to extrinsic upper airway compression by the thyroid mass and underwent emergent total thyroidectomy. Histology of the thyroid showed diffuse dense lymphoplasmacytic infiltrate and fibrosis. Follicular cells exhibited reactive nuclear features and some Hurthle cell change. IgG4+ plasma cells were over 40/high power field while overall IgG4/IgG ratio was above 50%. The overall features suggest the diagnosis of IgG4-related disease of the thyroid gland in the form of IgG4-related HT. Post-surgery, the patient was found to have markedly elevated serum IgG4 concentration but PET/CT did not show significant increased fludeoxyglucose uptake in other areas. Her recovery was complicated by a ventilator-associated pneumonia with empyema, limiting early use of corticosteroids for treatment of IgG4-related disease.

The paradoxical evolution in an unusual case of disseminated tuberculosis: Spontaneous resolution with disease progression.

Mycobacterium tuberculosis can cause a myriad of clinical manifestations. We describe a case of a patient with end-stage renal failure, who presented with disseminated tuberculosis over the course of five months, manifesting with a self-resolving mediastinal mass, progressive lymphadenopathy, genitourinary, and musculoskeletal tuberculosis.

Stanniocalcin-2 contributes to mesenchymal stromal cells attenuating murine contact hypersensitivity mainly via reducing CD8+ Tc1 cells.

Mesenchymal stromal cells (MSCs) have been demonstrated to ameliorate allergic contact dermatitis (ACD), a typical T-cell-mediated disorder. However, the underlying mechanisms behind the MSC-based treatment for ACD have not yet been fully elucidated. The stanniocalcins (STCs) comprise a family of secreted glycoprotein hormones that act as important anti-inflammatory proteins. Here, we investigated the roles of STCs in MSC-mediated T-cell suppression and their potential role in the MSC-based treatment for ACD. Gene expression profiling revealed that STC2, but not STC1, was highly expressed in MSCs. STC2 knockdown in MSCs significantly impaired their effects in reducing TNF-α- and IFN-γ-producing CD8+ T cells. Importantly, silencing the STC2 expression in MSCs abated their therapeutic effect on contact hypersensitivity (CHS) in mice, mainly restoring the generation and infiltration of IFN-γ-producing CD8+ T cells (Tc1 cells). Mechanistically, STC2 co-localized with heme oxygenase 1 (HO-1) in MSCs, and contributed to MSC-mediated reduction of CD8+ Tc1 cells via regulating HO-1 activity. Together, these findings newly identify STC2 as the first stanniocalcin responsible for mediating the immunomodulatory effects of MSCs on allogeneic T cells and STC2 contribute to MSC-based treatment for ACD mainly via reducing the CD8+ Tc1 cells.

An Unusual Case of Mycotic Popliteal Aneurysm Presenting as Recurrent Salmonella enteritidis Bacteraemia.

We describe a patient with a Salmonella enteritidis mycotic aneurysm. A 91-year-old man presented with recurrent episodes of S. enteritidis bacteraemia 2 months apart. During the second presentation, he underwent magnetic resonance imaging of the left lower limb that revealed rupture of the popliteal artery with a popliteal fossa collection. This was aspirated and cultures grew S. enteritidis. He underwent endovascular stenting and received a prolonged course of antibiotics. Popliteal artery mycotic aneurysm should be considered as a differential in patients presenting with unilateral painful leg swelling and bacteraemia from microorganisms with a propensity for endovascular infections. LEARNING POINTS: Our case illustrates a rare and unusual entity of ruptured popliteal mycotic aneurysm in an otherwise common scenario of recurrent nontyphoidal salmonellosis.In patients with recurrent Salmonella bacteraemia, clinicians often perform computed tomography scans to look for extraintestinal sites of involvement; however, this frequently misses any peripherally sited aneurysms, which often do not manifest with any early clinical symptoms.

Cryptococcus gattii Infection Presenting as an Aggressive Lung Mass.

Cryptococcus gattii is an endemic fungus predominantly isolated in the tropical and subtropical regions, causing predominantly pulmonary disease with a predilection for the central nervous system. Herein, we report a case of rapidly progressing C. gattii pneumonia in an immune-deficient but virologically suppressed host with underlying human immunodeficiency viral (HIV) infection, exhibiting various fungal morphologies from bronchoalveolar lavage (BAL) cytological specimens. A 51-year-old Chinese male with known HIV disease was admitted to the Singapore General Hospital for evaluation of functional decline, febrile episodes, and a left hilar mass on chest radiograph. Computed tomography (CT) showed consolidation in the apical segment of the left lower lobe. He underwent bronchoscopy and BAL. Positron emission tomography-computed tomography done 10 days after the initial CT showed approximate doubling of the pulmonary lesion. Cytological examination of the fluid revealed yeasts of varying sizes. Subsequent fungal culture from BAL fluid grew C. gattii 10 days later.